U.S. patent application number 14/298571 was filed with the patent office on 2014-09-25 for pharmaceutical compositions comprising dextromethorphan and quinidine for the treatment of neurological disorders.
The applicant listed for this patent is Avanir Pharmaceuticals, Inc.. Invention is credited to James Berg, Laura E. Pope, Richard A. Smith, Gerald Yakatan.
Application Number | 20140288114 14/298571 |
Document ID | / |
Family ID | 30116047 |
Filed Date | 2014-09-25 |
United States Patent
Application |
20140288114 |
Kind Code |
A1 |
Yakatan; Gerald ; et
al. |
September 25, 2014 |
PHARMACEUTICAL COMPOSITIONS COMPRISING DEXTROMETHORPHAN AND
QUINIDINE FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
Abstract
Pharmaceutical compositions and methods for treating
neurological disorders by administering same are provided. The
compositions comprise dextromethorphan in combination with
quinidine.
Inventors: |
Yakatan; Gerald; (Del Mar,
CA) ; Berg; James; (San Diego, CA) ; Pope;
Laura E.; (Cartsbad, CA) ; Smith; Richard A.;
(La Jolla, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Avanir Pharmaceuticals, Inc. |
Aliso Viejo |
CA |
US |
|
|
Family ID: |
30116047 |
Appl. No.: |
14/298571 |
Filed: |
June 6, 2014 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14059058 |
Oct 21, 2013 |
|
|
|
14298571 |
|
|
|
|
13679256 |
Nov 16, 2012 |
|
|
|
14059058 |
|
|
|
|
12699408 |
Feb 3, 2010 |
|
|
|
13679256 |
|
|
|
|
11035213 |
Jan 12, 2005 |
7659282 |
|
|
12699408 |
|
|
|
|
PCT/US03/22303 |
Jul 17, 2003 |
|
|
|
11035213 |
|
|
|
|
60396661 |
Jul 17, 2002 |
|
|
|
Current U.S.
Class: |
514/289 |
Current CPC
Class: |
A61K 31/485 20130101;
A61K 31/4709 20130101; A61K 45/06 20130101; A61K 31/4748 20130101;
A61P 25/02 20180101; A61K 31/49 20130101; A61K 31/485 20130101;
A61K 2300/00 20130101; A61K 31/49 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/289 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 31/4709 20060101 A61K031/4709 |
Claims
1. A method for treating traumatic brain injury, the method
comprising administering to a patient in need thereof
dextromethorphan in combination with quinidine, wherein the amount
of dextromethorphan administered comprises from about 20 mg/day to
about 60 mg/day and wherein the amount of quinidine administered
comprises from about 10 mg/day to about 30 mg/day with the proviso
that the weight-to-weight ratio of dextromethorphan to quinidine is
1:0.75 or less of quinidine.
2. The method of claim 1, wherein the dextromethorphan and the
quinidine are administered as one combined dose per day.
3. The method of claim 1, wherein the dextromethorphan and the
quinidine are administered as at least two combined doses per
day.
4. The method of claim 1, wherein the amount of quinidine
administered comprises from about 20 mg/day to 30 mg/day.
5. The method of claim 1, wherein the amount of dextromethorphan
administered comprises from about 40 mg/day to 60 mg/day.
6. The method of claim 1, wherein at least one of the quinidine and
the dextromethorphan is in a form of a pharmaceutically acceptable
salt.
7. The method of claim 1, wherein at least one of the quinidine and
the dextromethorphan is in a form of a pharmaceutically acceptable
salt selected from the group consisting of salts of free acids,
inorganic salts, salts of sulfate, salts of hydrochloride, and
salts of hydrobromide.
8. The method of claim 1, wherein about 20 mg quinidine sulfate is
administered per day.
9. The method of claim 1, wherein about 60 mg dextromethorphan
hydrobromide is administered per day.
10. The method of claim 1 wherein the dextromethorphan and
quinidine are administered in separate doses.
11. The method of claim 1 wherein the weight-to-weight ratio of
dextromethorphan to quinidine is 1:0.65 or less of quinidine.
12. The method of claim 1, wherein about 40 mg dextromethorphan
hydrobromide is administered per day.
13. The method of claim 1, wherein about 60 mg of dextromethorphan
and about 20 mg of quinidine is administered per day.
14. The method of claim 1, wherein about 40 mg of dextromethorphan
and about 20 mg of quinidine is administered per day.
15. The method of claim 1, wherein about 60 mg of dextromethorphan
hydrobromide and about 20 mg of quinidine sulfate is administered
per day.
16. The method of claim 1, wherein about 40 mg of dextromethorphan
hydrobromide and about 20 mg of quinidine sulfate is administered
per day.
Description
RELATED APPLICATION
[0001] This application is a continuation, under 35 U.S.C.
.sctn.120, of International Patent Application No.
PCT/US2003/022303, filed on Jul. 17, 2003 under the Patent
Cooperation Treaty (PCT), which was published by the International
Bureau in English on Jan. 22, 2004, which designates the United
States and claims the benefit of U.S. Provisional Application No.
60/396,661, filed Jul. 17, 2002.
FIELD OF THE INVENTION
[0002] Pharmaceutical compositions and methods for treating
neurological disorders are provided. The compositions comprise
dextromethorphan in combination with quinidine.
BACKGROUND OF THE INVENTION
[0003] Patients suffering from neurodegenerative diseases or brain
damage such as is caused by stroke or head injury often are
afflicted with emotional problems associated with the disease or
injury. The terms emotional lability and pseudobulbar affect are
used by psychiatrists and neurologists to refer to a set of
symptoms that are often observed in patients who have suffered a
brain insult such as a head injury, stroke, brain tumor, or
encephalitis, or who are suffering from a progressive
neurodegenerative disease such as Amyotrophic Lateral Sclerosis
(ALS, also called motor neuron disease or Lou Gehrig's disease),
Parkinson's disease, Alzheimer's disease, or multiple sclerosis. In
the great majority of such cases, emotional lability occurs in
patients who have bilateral damage (damage which affects both
hemispheres of the brain) involving subcortical forebrain
structures.
[0004] Emotional lability, which is distinct from clinical forms of
reactive or endogenous depression, is characterized by intermittent
spasmodic outbursts of emotion (usually manifested as intense or
even explosive crying or laughing) at inappropriate times or in the
absence of any particular provocation. Emotional lability or
pseudobulbar affect is also referred to by the terms emotionalism,
emotional incontinence, emotional discontrol, excessive
emotionalism, and pathological laughing and crying. The feelings
that accompany emotional lability are often described in words such
as "disconnectedness," since patients are fully aware that an
outburst is not appropriate in a particular situation, but they do
not have control over their emotional displays.
[0005] Emotional lability or pseudobulbar affect becomes a clinical
problem when the inability to control emotional outbursts
interferes in a substantial way with the ability to engage in
family, personal, or business affairs. For example, a businessman
suffering from early-stage ALS or Parkinson's disease might become
unable to sit through business meetings, or a patient might become
unable to go out in public, such as to a restaurant or movie, due
to transient but intense inability to keep from crying or laughing
at inappropriate times in front of other people. These symptoms can
occur even though the patient still has more than enough energy and
stamina to do the physical tasks necessary to interact with other
people. Such outbursts, along with the feelings of annoyance,
inadequacy, and confusion that they usually generate and the
visible effects they have on other people, can severely aggravate
the other symptoms of the disease; they lead to feelings of
ostracism, alienation, and isolation, and they can render it very
difficult for friends and family members to provide tolerant and
caring emotional support for the patient.
SUMMARY OF THE INVENTION
[0006] There remains a need for additional or improved forms of
treatment for emotional lability and other chronic disorders, such
as chronic pain. Such a treatment preferably provides at least some
degree of improvement compared to other known drugs, in at least
some patients. A method for treating emotional lability in at least
some patients suffering from neurologic impairment, such as a
progressive neurologic disease, is desirable.
[0007] A method of treating emotional lability, pseudobulbar
affect, and other chronic conditions in human patients who are in
need of such treatment, without oversedation or otherwise
significantly interfering with consciousness or alertness is
provided. The treatment involves administering dextromethorphan in
combination with a minimum dosage of quinidine.
[0008] In a first embodiment, a method for treating pseudobulbar
affect or emotional lability is provided, the method including
administering to a patient in need thereof dextromethorphan in
combination with quinidine, wherein an amount of dextromethorphan
administered includes from about 20 mg/day to about 200 mg/day, and
wherein an amount of quinidine administered includes from about 10
mg/day to less than about 50 mg/day.
[0009] In an aspect of the first embodiment, the pseudobulbar
affect or emotional lability is caused by a neurodegenerative
disease or condition or a brain injury.
[0010] In a second embodiment, a method for treating neuropathic
pain is provided, the method including administering to a patient
in need thereof dextromethorphan in combination with quinidine,
wherein an amount of dextromethorphan administered includes from
about 20 mg/day to about 200 mg/day, and wherein an amount of
quinidine administered includes from about 10 mg/day to less than
about 50 mg/day.
[0011] In a third embodiment, a method for treating a
neurodegenerative disease or condition is provided, the method
including administering to a patient in need thereof
dextromethorphan in combination with quinidine, wherein an amount
of dextromethorphan administered includes from about 20 mg/day to
about 200 mg/day, and wherein an amount of quinidine administered
includes from about 10 mg/day to less than about 50 mg/day.
[0012] In an aspect of the third embodiment, the neurodegenerative
disease or condition is selected from the group consisting of
amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's
disease, and Alzheimer's disease.
[0013] In a fourth embodiment, a method for treating a brain injury
is provided, the method including administering to a patient in
need thereof dextromethorphan in combination with quinidine,
wherein an amount of dextromethorphan administered includes from
about 20 mg/day to about 200 mg/day, and wherein an amount of
quinidine administered includes from about 10 mg/day to less than
about 50 mg/day.
[0014] In an aspect of the fourth embodiment, the brain injury is
selected from the group consisting of stroke, traumatic brain
injury, ischemic event, hypoxic event, and neuronal death.
[0015] In aspects of the first through fourth embodiments, the
dextromethorphan and the quinidine are administered as one combined
dose per day.
[0016] In aspects of the first through fourth embodiments, the
dextromethorphan and the quinidine are administered as at least two
combined doses per day.
[0017] In aspects of the first through fourth embodiments, the
amount of quinidine administered includes from about 20 mg/day to
about 45 mg/day.
[0018] In aspects of the first through fourth embodiments, the
amount of dextromethorphan administered includes from about 20
mg/day to about 60 mg/day.
[0019] In aspects of the first through fourth embodiments, at least
one of the quinidine and the dextromethorphan is in a form of a
pharmaceutically acceptable salt.
[0020] In aspects of the first through fourth embodiments, the
pharmaceutically acceptable salt is selected from the group
consisting of salts of alkali metals, salts of lithium, salts of
sodium, salts of potassium, salts of alkaline earth metals, salts
of calcium, salts of magnesium, salts of lysine, salts of
N,N'-dibenzylethylenediamine, salts of chloroprocaine, salts of
choline, salts of diethanolamine, salts of ethylenediamine, salts
of meglumine, salts of procaine, salts of tris, salts of free
acids, salts of free bases, inorganic salts, salts of sulfate,
salts of hydrochloride, and salts of hydrobromide.
[0021] In aspects of the first through fourth embodiments, the
quinidine includes quinidine sulfate and the dextromethorphan
includes dextromethorphan hydrobromide, and wherein an amount of
quinidine sulfate administered includes from about 30 mg/day to 60
mg/day and wherein an amount of dextromethorphan hydrobromide
administered includes from about 30 mg/day to about 60 mg/day.
[0022] In a fifth embodiment, a method for treating pseudobulbar
affect or emotional lability is provided, the method including
administering to a patient in need thereof dextromethorphan in
combination with quinidine, wherein the dextromethorphan and the
quinidine are administered in a combined dose, and wherein a weight
ratio of dextromethorphan to quinidine in the combined dose is
about 1:1.25 or less.
[0023] In an aspect of the fifth embodiment, the pseudobulbar
affect or emotional lability is caused by a neurodegenerative
disease or condition or a brain injury.
[0024] In a sixth embodiment, a method for treating neuropathic
pain is provided, the method including administering to a patient
in need thereof dextromethorphan in combination with quinidine,
wherein the dextromethorphan and the quinidine are administered in
a combined dose, and wherein a weight ratio of dextromethorphan to
quinidine in the combined dose is about 1:1.25 or less.
[0025] In a seventh embodiment, a method for treating a
neurodegenerative disease or condition is provided, the method
including administering to a patient in need thereof
dextromethorphan in combination with quinidine, wherein the
dextromethorphan and the quinidine are administered in a combined
dose, and wherein a weight ratio of dextromethorphan to quinidine
in the combined dose is about 1:1.25 or less.
[0026] In an aspect of the seventh embodiment, the
neurodegenerative disease or condition is selected from the group
consisting of amyotrophic lateral sclerosis, multiple sclerosis,
Parkinson's disease, and Alzheimer's disease.
[0027] In an eighth embodiment, a method for treating a brain
injury is provided, the method including administering to a patient
in need thereof dextromethorphan in combination with quinidine,
wherein the dextromethorphan and the quinidine are administered in
a combined dose, and wherein a weight ratio of dextromethorphan to
quinidine in the combined dose is about 1:1.25 or less.
[0028] In an aspect of the eighth embodiment, the brain injury is
selected from the group consisting of stroke, traumatic brain
injury, ischemic event, hypoxic event, and neuronal death.
[0029] In aspects of the fifth through eighth embodiments, the
weight ratio of dextromethorphan to quinidine in the combined dose
is about 1:0.75 or less.
[0030] In aspects of the fifth through eighth embodiments, the
amount of quinidine administered includes from about 20 mg/day to
about 45 mg/day, and wherein the amount of dextromethorphan
administered includes from about 20 mg/day to about 60 mg/day.
[0031] In aspects of the fifth through eighth embodiments, at least
one of the quinidine and the dextromethorphan is in a form of a
pharmaceutically acceptable salt.
[0032] In aspects of the fifth through eighth embodiments, the
pharmaceutically acceptable salt is selected from the group
consisting of salts of alkali metals, salts of lithium, salts of
sodium, salts of potassium, salts of alkaline earth metals, salts
of calcium, salts of magnesium, salts of lysine, salts of
N,N'-dibenzylethylenediamine, salts of chloroprocaine, salts of
choline, salts of diethanolamine, salts of ethylenediamine, salts
of meglumine, salts of procaine, salts of tris, salts of free
acids, salts of free bases, inorganic salts, salts of sulfate,
salts of hydrochloride, and salts of hydrobromide.
[0033] In aspects of the fifth through eighth embodiments, the
quinidine includes quinidine sulfate and the dextromethorphan
includes dextromethorphan hydrobromide, and wherein an amount of
quinidine sulfate administered includes from about 30 mg/day to
about 60 mg/day and wherein an amount of dextromethorphan
hydrobromide administered includes from about 30 mg/day to about 60
mg/day.
[0034] In aspects of the fifth through eighth embodiments, one
combined dose is administered per day.
[0035] In aspects of the fifth through eighth embodiments, two or
more combined doses are administered per day.
[0036] In a ninth embodiment, a pharmaceutical composition suitable
for use in treating pseudobulbar affect or emotional lability is
provided, the composition including a tablet or a capsule, the
tablet or capsule including dextromethorphan and quinidine, wherein
a weight ratio of dextromethorphan to quinidine is about 1:1.25 or
less.
[0037] In an aspect of the ninth embodiment, the pseudobulbar
affect or emotional lability is caused by a neurodegenerative
disease or condition or a brain injury.
[0038] In a tenth embodiment, a pharmaceutical composition suitable
for use in treating neuropathic pain is provided, the composition
including a tablet or a capsule, the tablet or capsule including
dextromethorphan and quinidine, wherein a weight ratio of
dextromethorphan to quinidine is about 1:1.25 or less.
[0039] In an eleventh embodiment, a pharmaceutical composition
suitable for use in treating a neurodegenerative disease or
condition is provided, the composition including a tablet or a
capsule, the tablet or capsule including dextromethorphan and
quinidine, wherein a weight ratio of dextromethorphan to quinidine
is about 1:1.25 or less.
[0040] In an aspect of the eleventh embodiment, the
neurodegenerative disease or condition is selected from the group
consisting of amyotrophic lateral sclerosis, multiple sclerosis,
Parkinson's disease, and Alzheimer's disease.
[0041] In a twelfth embodiment, a pharmaceutical composition
suitable for use in a brain injury is provided, the composition
including a tablet or a capsule, the tablet or capsule including
dextromethorphan and quinidine, wherein a weight ratio of
dextromethorphan to quinidine is about 1:1.25 or less.
[0042] In an aspect of the twelfth embodiment, the brain injury is
selected from the group consisting of stroke, traumatic brain
injury, ischemic event, hypoxic event, and neuronal death.
[0043] In aspects of the ninth through twelfth embodiments, the
weight ratio of dextromethorphan to quinidine is about 1:0.75 or
less.
[0044] In aspects of the ninth through twelfth embodiments, the
quinidine is present in an amount of from about 20 mg to about 45
mg, and wherein the dextromethorphan is present in an amount of
from about 20 mg to about 60 mg.
[0045] In aspects of the ninth through twelfth embodiments, at
least one of the quinidine and the dextromethorphan is in a form of
a pharmaceutically acceptable salt.
[0046] In aspects of the ninth through twelfth embodiments, the
pharmaceutically acceptable salt is selected from the group
consisting of salts of alkali metals, salts of lithium, salts of
sodium, salts of potassium, salts of alkaline earth metals, salts
of calcium, salts of magnesium, salts of lysine, salts of
N,N'-dibenzylethylenediamine, salts of chloroprocaine, salts of
choline, salts of diethanolamine, salts of ethylenediamine, salts
of meglumine, salts of procaine, salts of his, salts of free acids,
salts of free bases, inorganic salts, salts of sulfate, salts of
hydrochloride, and salts of hydrobromide.
[0047] In aspects of the ninth through twelfth embodiments, the
quinidine includes quinidine sulfate and the dextromethorphan
includes dextromethorphan hydrobromide, wherein the quinidine
sulfate is present in an amount of from about 30 mg to about 60 mg,
and wherein the dextromethorphan hydrobromide is present in an
amount of from about 30 mg to about 60 mg.
[0048] In a thirteenth embodiment, use of dextromethorphan and
quinidine in the preparation of a medicament for treating
pseudobulbar affect or emotional lability is provided, wherein the
medicament includes a capsule or a tablet, and wherein
dextromethorphan and quinidine are present in the capsule or tablet
at a weight ratio of dextromethorphan to quinidine of 1:1.25 or
less.
[0049] In an aspect of the thirteenth embodiment, the pseudobulbar
affect or emotional lability is caused by a neurodegenerative
disease or condition or a brain injury.
[0050] In a fourteenth embodiment, use of dextromethorphan and
quinidine in the preparation of a medicament for treating
neuropathic pain is provided, wherein the medicament includes a
capsule or a tablet, and wherein dextromethorphan and quinidine are
present in the capsule or tablet at a weight ratio of
dextromethorphan to quinidine of 1:1.25 or less.
[0051] In a fifteenth embodiment, use of dextromethorphan and
quinidine in the preparation of a medicament for treating a
neurodegenerative disease or condition is provided, wherein the
medicament includes a capsule or a tablet, and wherein
dextromethorphan and quinidine are present in the capsule or tablet
at a weight ratio of dextromethorphan to quinidine of 1:1.25 or
less.
[0052] In an aspect of the fifteenth embodiment, the
neurodegenerative disease or condition is selected from the group
consisting of amyotrophic lateral sclerosis, multiple sclerosis,
Parkinson's disease, and Alzheimer's disease.
[0053] In a sixteenth embodiment, use of dextromethorphan and
quinidine in the preparation of a medicament for treating a brain
injury is provided, wherein the medicament includes a capsule or a
tablet, and wherein dextromethorphan and quinidine are present in
the capsule or tablet at a weight ratio of dextromethorphan to
quinidine of 1:1.25 or less.
[0054] In an aspect of the sixteenth embodiment, the brain injury
is selected from the group consisting of stroke, traumatic brain
injury, ischemic event, hypoxic event, and neuronal death.
[0055] In aspects of the thirteenth through sixteenth embodiments,
dextromethorphan and quinidine are present in the capsule or tablet
at a weight ratio of dextromethorphan to quinidine of 1:0.75 or
less.
[0056] In aspects of the thirteenth through sixteenth embodiments,
at least one of the quinidine and the dextromethorphan is in a form
of a pharmaceutically acceptable salt.
[0057] In aspects of the thirteenth through sixteenth embodiments,
the pharmaceutically acceptable salt is selected from the group
consisting of salts of alkali metals, salts of lithium, salts of
sodium, salts of potassium, salts of alkaline earth metals, salts
of calcium, salts of magnesium, salts of lysine, salts of
N,N'-dibenzylethylenediamine, salts of chloroprocaine, salts of
choline, salts of diethanolamine, salts of ethylenediamine, salts
of meglumine, salts of procaine, salts of tris, salts of free
acids, salts of free bases, inorganic salts, salts of sulfate,
salts of hydrochloride, and salts of hydrobromide.
[0058] In aspects of the thirteenth through sixteenth embodiments,
the quinidine includes quinidine sulfate and the dextromethorphan
includes dextromethorphan hydrobromide, wherein the quinidine
sulfate is present in an amount of from about 30 mg to about 60 mg,
and wherein the dextromethorphan hydrobromide is present in an
amount of from about 30 mg to about 60 mg.
[0059] In aspects of the thirteenth through sixteenth embodiments,
the quinidine is present in an amount of from about 20 mg to about
45 mg, and wherein the dextromethorphan is present in an amount of
from about 20 mg to about 60 mg.
BRIEF DESCRIPTION OF THE DRAWINGS
[0060] FIG. 1 provides a box plot of CNS-LS scores for Clinical
Study #4. The distributions of CNS-LS scores are symmetrical and
contain only one outlier. These distributions support the use of
ANCOVA for the analysis of the CNS-LS scores. As prospectively
specified in the study protocol, the differences in mean
improvement in CNS-LS cores, adjusted for center and baseline
CNS-LS scores, were analyzed by using linear regression according
to the ANCOVA method of Frison and Pocock. The results of this
analysis are in Table 30. The results of the additional analyses
without any adjustments or with an adjustment for baseline CNS-LS
score alone are also in this table.
[0061] FIG. 2 provides a plot depicting adjusted mean reductions in
CNS-LS scores for the three treatment groups from the primary
efficacy analysis of the ITT population of Clinical Study #4.
Reductions in CNS-LS scores below the horizontal lines are
statistically significantly different from 30DM/30Q at the
significance levels indicated.
[0062] FIG. 3 provides the disposition of subjects by MTD group
participating in Clinical Study #5.
[0063] FIG. 4 depicts Mean Sleep Ratings from the Subject Diaries
of subjects participating in Clinical Study #5.
[0064] FIG. 5. Mean Present Pain Intensity Ratings from the Subject
Diaries of subjects participating in Clinical Study #5.
[0065] FIG. 6. Mean Activity Ratings from the Subject Diaries of
subjects participating in Clinical Study #5.
[0066] FIG. 7. Mean Pain Ratings from the Subject Diaries of
subjects participating in Clinical Study #5.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0067] The following description and examples illustrate a
preferred embodiment of the present invention in detail. Those of
skill in the art will recognize that there are numerous variations
and modifications of this invention that are encompassed by its
scope. Accordingly, the description of a preferred embodiment
should not be deemed to limit the scope of the present
invention.
[0068] Emotional lability or pseudobulbar affect is associated with
a number of neurological diseases, such as stroke (House et al.,
BMJ, 1989; 298:991-4), multiple sclerosis (MS) (Cotrell et al., J.
Neurol. Psychopathol., 1926; 7:1-30; Feinstein et al., Arch.
Neurol., 1997; 54:1116-21), amyotrophic lateral sclerosis (ALS)
(Miller et al., Neurol., 1999; 52:1311-23; Jackson et al., Semin.
Neurol. 1998; 18:27-39; Poeck, K., Pathophysiology of emotional
disorders associated with brain damage. In: P. J. Vinken, G. W.
Bruyn, editors. Handbook of Clinical Neurology. Amsterdam:
North-Holland Publishing Company 1969; pp. 343-67), Alzheimer's
disease (Starkstein et al., J. Neurol. Neurosurg. Psychiatry, 1995;
59:55-64), and traumatic brain injury (Brooks, N., Acta
Neurochirurgica Suppl., 44 1988; 59-64). Studies have suggested
that pseudobulbar affect occurs in up to 50% of patients with ALS
(Gallagher, J. P., Acta Neurol. Scand. 1989; 80:114-7).
[0069] Emotional lability or pseudobulbar affect in the context of
neurological injury can be considered a disconnection syndrome
resulting from loss of cortical communication with the brainstem or
cerebellum Wilson S A K, J. Neurol. Psychopathol., 1924;
IV:299-333; Parvivzi et al., Brain, 2001; 124:1708-19). At the
neurotransmitter level, disruptions of ascending and descending
serotonergic pathways arising in the brainstem, and dysregulation
of dopaminergic projections to the striatum and cortex have been
implicated (Andersen et al., Stroke, 1994; 25:1050-2; Ross et al.,
J. Nerv. Ment. Dis., 1987; 175:165-72; Shaw et al., Brain Sciences
in Psychiatry, London: Butterworth, 1982; Udaka et al., Arch.
Neurol. 1984; 41:1095-6).
[0070] A body of evidence suggests that pseudobulbar affect can be
modulated through pharmacologic intervention. In 1979, Wolf
reported that levodopa was effective in subjects with pathological
laughing (Wolf et al., Neurol., 1979; 29:1435-6.). However, in a
follow-up study, only 10 of 25 subjects responded satisfactorily to
treatment (Udaka et al., Arch. Neurol., 1984; 41:1095-6). There
have been reports of symptomatic benefit with other drugs,
including amantadine, imipramine, desipramine, nortriptyline,
amitriptyline, sertraline, fluoxetine, levodopa, methylphenidate,
and thyrotropin-releasing hormone (Dark et al., Austr. N. Zeal. J.
Psychiatry, 1996; 30:472-9; Iannoccone et al., Clin. Neuropharm.,
1996; 19:532-5).
[0071] The best previously known therapies for treating emotional
lability involve the drugs amitriptyline, amantadine, and levodopa.
Although reports such as Udaka et al., Arch. Neurol. 1984, 41:
1095-1096, and Schiffer et al., N. Engl. J. Med. 1985, 312:
1480-1482 indicate that these compounds may be effective in helping
reduce pathological displays of emotion in some patients, they make
it clear that none of these prior art drugs are effective in all
patients, and even in patients who receive some benefit, the effect
usually stops far short of an effective cure. A common practice for
many clinical neurologists is to prescribe amitriptyline and
amantadine, one at a time, in the hope that one of them might be
able to provide any level of improvement in the patient's
condition. However, all both fall short of offering an effective
cure. In addition, levodopa is not satisfactory, since it has other
effects and is a relatively powerful drug.
[0072] ALS is a neurodegenerative disease produced by progressive
loss of upper and lower motor neurons. Up to 50 percent of patients
with ALS exhibit emotional lability, and it is more prevalent in
those with the bulbar form of ALS (Gallagher J P, Acta Neurol.
Scand., 1989; 80:114-7). Based on the notion that excitotoxicity
secondary to impaired recycling of glutamate may be a factor in the
etiology of ALS, riluzole, a glutamate release inhibitor, has been
used to treat ALS (Jerusalem et al., Neurology, 1996; 47:S218-20;
Doble A., Neurology, 1996; 47:S233-41). Riluzole modestly extends
life span but does not confer symptomatic benefit (Bensimon et al.,
N. Eng. J. Med., 1994; 330:585-91; Kwiecinski H, Neurol. Neurochir.
Pol., 2001; 35:51-9).
[0073] Because of the possibility that an excitotoxic process
involving glutamate is etiologically implicated in ALS, several
investigators have attempted to modify or arrest the course of ALS
by the administration of dextromethorphan (DM). DM is an
noncompetitive antagonist of the N-methyl-D-aspartate-sensitive
ionotropic glutamate receptor, and it acts by reducing the level of
excitatory activity. However, DM is extensively metabolized to
dextrorphan (DX) and a number of other metabolites. Cytochrome P450
2D6 (CYP2D6) is the key enzyme responsible for the formation of DX
from DM. A subset of the population, 5 to 10% of Caucasians, has
reduced activity of this enzyme (Hildebrand et al., Eur. J. Clin.
Pharmacol., 1989; 36:315-318). Such individuals are referred to as
"poor metabolizers" of DM in contrast to the majority of
individuals who are referred to as "extensive metabolizers" of DM
(Vetticaden et al., Pharm. Res., 1989; 6:13-9).
[0074] A number of in vitro studies have been undertaken to
determine the types of drugs that inhibit CYP2D6 activity.
Quinidine (O) is one of the most potent of those that have been
studied (Inaba et al., Br. J. Clin. Pharmacol., 1986; 22:199-200).
These observations led to the hypothesis that concomitant dosing
with Q could increase the concentration of DM in plasma.
[0075] A number of chronic disorders other than emotional lability
also have symptoms which are known to be very difficult to treat,
and often fail to respond to safe, non-addictive, and non-steroid
medications. Disorders such as intractable coughing fail to respond
to conventional medicines and are typically treated by such drugs
as codeine, morphine, or the anti-inflammatory steroid prednisone.
These drugs are unacceptable for long-term treatment due to
dangerous side effects, long-term risks to the patient's health, or
the danger of addiction. There has been no satisfactory treatment
for the severe itching and rash associated with dermatitis. Drugs
such as prednisone and even tricyclic antidepressants, as well as
topical applications have been employed, but do not appear to offer
substantial and consistent relief. Chronic pain due to conditions
such as stroke, cancer, and trauma, as well as neuropathic pain
resulting from conditions such as diabetes and shingles (herpes
zoster), for example, is also a problem which resists treatment.
Neuropathic pain includes, for example, diabetic neuropathy,
postherpetic neuralgia, phantom limb pain, trigeminal neuralgia,
and sciatica. Postherpetic neuralgia (PHN) is a complication of
shingles and occurs in approximately ten percent of patients with
herpes zoster. The incidence of PHN increases with age. Diabetic
neuropathy is a common complication of diabetes which increases
with the duration of the disease. The pain for these types of
neuropathies has been described as a burning steady pain often
punctuated with stabbing pains, pins and needles pain, and
toothache-like pain. The skin can be sensitive with dysesthetic
sensations to even light touch and clothing. The pain can be
exacerbated by activity, temperature change, and emotional upset.
The pain can be so severe as to preclude daily activities or result
in sleep disturbance or anorexia. The mechanisms involved in
producing pain of these types are not well understood, but may
involve degeneration of myelinated nerve fibers. It is known that
in diabetic neuropathy, both small and large nerve fibers
deteriorate resulting in reduced thresholds for tolerance of
thermal sensitivity, pain, and vibration. Dysfunction of both large
and small fiber functions is more severe in the lower limbs when
pain develops. Most of the physiological measurements of nerves
that can be routinely done in patients experiencing neuropathic
pain demonstrate a slowing of nerve conduction over time. To date,
treatment for neuropathic pain has been less than universally
successful. Chronic pain is estimated to affect millions of
people.
[0076] Dextromethorphan is widely used as a cough syrup, and it has
been shown to be sufficiently safe in humans to allow its use as an
over-the-counter medicine. It is well tolerated in oral dosage
form, either alone or with quinidine, at up to 120 milligrams (mg)
per day, and a beneficial effect may be observed when receiving a
substantially smaller dose (e.g., 30 mg/day) (U.S. Pat. No.
5,206,248 to Smith).
[0077] The chemistry of dextromethorphan and its analogs is
described in various references such as Rodd, E. H., Ed., Chemistry
of Carbon Compounds, Elsevier Publ., N.Y., 1960; Goodman and
Gilman's Pharmacological Basis of Therapeutics; Choi, Brain Res.,
1987, 403: 333-336; and U.S. Pat. No. 4,806,543. Its chemical
structure is as follows:
##STR00001##
[0078] Dextromethorphan is the common name for
(+)-3-methoxy-N-methylmorphinan. It is one of a class of molecules
that are dextrorotatory analogs of morphine-like opioids. The term
"opiate" refers to drugs that are derived from opium, such as
morphine and codeine. The term "opioid" is broader. It includes
opiates, as well as other drugs, natural or synthetic, which act as
analgesics and sedatives in mammals.
[0079] Most of the addictive analgesic opiates, such as morphine,
codeine, and heroin, are levorotatory stereoisomers (they rotate
polarized light in the so-called left-handed direction). They have
four molecular rings in a configuration known as a "morphinan"
structure, which is depicted as follows:
##STR00002##
[0080] In this depiction, the carbon atoms are conventionally
numbered as shown, and the wedge-shaped bonds coupled to carbon
atoms 9 and 13 indicate that those bonds rise out of the plane of
the three other rings in the morphinan structure. Many analogs of
this basic structure (including morphine) are pentacyclic compounds
that have an additional ring formed by a bridging atom (such as
oxygen) between the number 4 and 5 carbon atoms.
[0081] Many dextrorotatory analogs of morphine are much less
addictive than the levorotatory compounds. Some of these
dextrorotatory analogs, including dextromethorphan and dextrorphan,
are enantiomers of the morphinan structure. In these enantiomers,
the ring that extends out from carbon atoms 9 and 13 is oriented in
the opposite direction from that depicted in the above
structure.
[0082] While not wishing to be limited to any particular mechanism
of action, dextromethorphan is known to have at least three
distinct receptor activities which affect central nervous system
(CNS) neurons. First, it acts as an antagonist at
N-methyl-D-aspartate (NMDA) receptors. NMDA receptors are one of
three major types of excitatory amino acid (EAA) receptors in CNS
neurons. Since activation of NMDA receptors causes neurons to
release excitatory neurotransmitter molecules (primarily glutamate,
an amino acid), the blocking activity of dextromethorphan at these
receptors reduces the level of excitatory activity in neurons
having these receptors. Dextromethorphan is believed to act at the
phencyclidine (PCP) binding site, which is part of the NMDA
receptor complex. Dextromethorphan is relatively weak in its NMDA
antagonist activity, particularly compared to drugs such as MK-801
(dizocilpine) and phencyclidine. Accordingly, when administered at
approved dosages, dextromethorphan is not believed to cause the
toxic side effects (discussed in U.S. Pat. No. 5,034,400 to Olney)
that are caused by powerful NMDA antagonists such as MK-801 or
PCP.
[0083] Dextromethorphan also functions as an agonist at certain
types of inhibitory receptors; unlike EAA receptors, activation of
inhibitory receptors suppresses the release of excitatory
neurotransmitters by affected cells. Initially, these inhibitory
receptors were called sigma opiate receptors. However, questions
have been raised as to whether they are actually opiate receptors,
so they are now generally referred to as sigma (a) receptors.
Subsequent experiments showed that dextromethorphan also binds to
another class of inhibitory receptors that are closely related to,
but distinct from, sigma receptors. The evidence, which indicates
that non-sigma inhibitory receptors exist and are bound by
dextromethorphan, is that certain molecules which bind to sigma
receptors are not able to completely block the binding of
dextromethorphan to certain types of neurons that are known to have
inhibitory receptors (Musacchio et al., Cell Mol. Neurobiol., 1988
June, 8(2):149-56; Musacchio et al., J. Pharmacol. Exp. Ther., 1988
November, 247(2):424-31; Craviso et al., Mol. Pharmacol., 1983 May,
23(3):629-40; Craviso et al., Mol. Pharmacol., 1983 May,
23(3):619-28; and Klein et al., Neurosci. Lett., 1989 Feb. 13,
97(1-2):175-80). These receptors are generally called
"high-affinity dextromethorphan receptors" or simply "DM receptors"
in the scientific literature. As used herein, the phrase
"dextromethorphan-binding inhibitory receptors" includes both sigma
and non-sigma receptors which undergo affinity-binding reactions
with dextromethorphan and which, when activated by
dextromethorphan, suppress the release of excitatory
neurotransmitters by the affected cells (Largent et al., Mol.
Pharmacol., 1987 December, 32(6):772-84).
[0084] Dextromethorphan also decreases the uptake of calcium ions
(Ca.sup.++) by neurons. Calcium uptake, which occurs during
transmission of nerve impulses, involves at least two different
types of channels, known as N-channels and L-channels.
Dextromethorphan suppressed calcium uptake fairly strongly in
certain types of cultured neurons (synaptosomes) which contain
N-channels; it also suppressed calcium uptake, although less
strongly, in other cultured neurons (PC12 cells) which contain
L-channels (Carpenter et al., Brain Res., 1988 Jan. 26,
439(1-2):372-5).
[0085] An increasing body of evidence indicates dextromethorphan
has therapeutic potential for treating several neuronal disorders
(Zhang et al., Clin. Pharmacol. Ther. 1992; 51: 647-655; Palmer G
C, Curr. Drug Targets, 2001; 2: 241-271; and Liu et al., J.
Pharmacol. Exp. Ther. 2003; 21: 21; Kim et al., Life Sci., 2003;
72: 769-783). Pharmacological studies demonstrate that DM is a
noncompetitive NMDA antagonist that has neuroprotective,
anticonvulsant and antinociceptive activities in a number of
experimental models (Desmeules et al., J. Pharmacol. Exp. Ther.,
1999; 288: 607-612). In addition to acting as an NMDA antagonist,
both DM and its primary metabolite, dextrorphan, bind to sigma-1
sites, inhibit calcium flux channels and interact with high
voltage-gated sodium channels (Dickenson et al., Neuropharmacology,
1987; 26: 1235-1238; Carpenter et al., Brain Res., 1988; 439:
372-375; Netzer et al., Eur. J. Pharmacol., 1993; 238: 209-216).
Recent reports indicate that an additional neuroprotective
mechanism of DM may include interference with the inflammatory
responses associated with some neurodegenerative disorders that
include Parkinson's disease and Alzheimer's disease (Liu et al., J.
Pharmacol. Exp. Ther., 2003; 21: 21). The potential efficacy of DM
as a neuroprotectant was explored in limited clinical trials in
patients with amyotrophic lateral sclerosis (Gredal et al., Acta
Neurol. Scand. 1997; 96: 8-13; Blin et al., Clin. Neuropharmacol.,
1996; 19: 189-192) Huntington's disease (Walker et al., Clin.
Neuropharmacol., 1989; 12: 322-330) and Parkinson's Disease (Chase
et al., J. Neurol., 2000; 247 Suppl 2: 1136-42). DM was also
examined in patients with various types of neuropathic pain (Mcquay
et al., Pain, 1994; 59: 127-133; Vinik A I, Am. J. Med., 1999; 107:
17S-26S; Weinbroum et al., Can. J. Anaesth., 2000; 47: 585-596;
Sang et al., Anesthesiology, 2002; 96: 1053-1061; Heiskanen et al.,
Pain, 2002; 96: 261-267; Ben Abraham et al., Clin. J. Pain, 2002;
18: 282-285; Sang C N, J. Pain Symptom Manage., 2000; 19: S21-25).
Although the pharmacological profile of DM points to clinical
efficacy, most clinical trials have been disappointing with
equivocal efficacy for DM compared to placebo treatment.
[0086] Several investigators suggested that the limited benefit
seen with DM in clinical trials is associated with rapid hepatic
metabolism that limits systemic drug concentrations. In one trial
in patients with Huntington's disease, plasma concentrations were
undetectable in some patients after DM doses that were eight times
the maximum antitussive dose (Walker et al., Clin. Neuropharmacol.,
1989; 12: 322-330).
[0087] As discussed above, DM undergoes extensive hepatic
O-demethylation to dextrorphan that is catalyzed by CYP2D6. This is
the same enzyme that is responsible for polymorphic debrisoquine
hydroxylation in humans (Schmid et al., Clin. Pharmacol. Ther.,
1985; 38: 618-624). An alternate pathway is mediated primarily by
CYP3A4 and N-demethylation to form 3-methoxymorphinan (Von Moltke
et al., J. Pharm. Pharmacol., 1998; 50: 997-1004). Both DX and
3-methoxymorphinan can be further demethylated to
3-hydroxymorphinan that is then subject to glucuronidation. The
metabolic pathway that converts DM to DX is dominant in the
majority of the population and is the principle for using DM as a
probe to phenotype individuals as CYP2D6 extensive and poor
metabolizers (Kupfer et al., Lancet 1984; 2: 517-518; Guttendorf et
al., Ther. Drug Monit., 1988; 10: 490-498). Approximately 7% of the
Caucasian population shows the poor metabolizer phenotype, while
the incidence of poor metabolizer phenotype in Chinese and Black
African populations is lower (Droll et al., Pharmacogenetics, 1998;
8: 325-333). A study examining the ability of DM to increase pain
threshold in extensive and poor metabolizers found antinociceptive
effects of DM were significant in poor metabolizers but not in
extensive metabolizers (Desmeules et al., J. Pharmacol. Exp. Ther.,
1999; 288: 607-612). The results are consistent with direct effects
of parent DM rather than the DX metabolite on neuromodulation.
[0088] One approach for increasing systemically available DM is to
coadminister the CYP2D6 inhibitor, quinidine, to protect DM from
metabolism (Zhang et al., Clin. Pharmacol. Ther. 1992; 51:
647-655). Quinidine administration can convert subjects with
extensive metabolizer phenotype to poor metabolizer phenotype
(Inaba et al., Br. J. Clin. Pharmacol., 1986; 22: 199-200). When
this combination therapy was tried in amyotrophic lateral sclerosis
patients it appeared to exert a palliative effect on symptoms of
pseudobulbar affect (Smith et al., Neurol., 1995; 54: 604P).
Combination treatment with DM and quinidine also appeared effective
for patients with chronic pain that could not be adequately
controlled with other medications. This observation is consistent
with a report that showed DM was effective in increasing pain
threshold in poor metabolizers and in extensive metabolizers given
quinidine, but not in extensive metabolizers (Desmeules et al., J.
Pharmacol. Exp. Ther., 1999; 288: 607-612). To date, most studies
have used quinidine doses ranging from 50 to 200 mg to inhibit
CYP2D6 mediated drug metabolism, but no studies have identified a
minimal dose of quinidine for enzyme inhibition.
[0089] The highly complex interactions between different types of
neurons having varying populations of different receptors, and the
cross-affinity of different receptor types for dextromethorphan as
well as other types of molecules which can interact with some or
all of those same types of receptors, render it very difficult to
attribute the overall effects of dextromethorphan to binding
activity at any particular receptor type. Nevertheless, it is
believed that dextromethorphan suppresses neuronal activity by
means of at least three molecular functions: it reduces activity at
(excitatory) NMDA receptors; it inhibits neuronal activity by
binding to certain types of inhibitory receptors; and it suppresses
calcium uptake through N-channels and L-channels.
[0090] Unlike some analogs of morphine, dextromethorphan has little
or no agonist or antagonist activity at various other opiate
receptors, including the mu (.mu.) and kappa (.kappa.) classes of
opiate receptors. This is highly desirable, since agonist or
antagonist activity at those opiate receptors can cause undesired
side effects such as respiratory depression (which interferes with
breathing) and blockade of analgesia (which reduces the
effectiveness of pain-killers).
[0091] Accordingly, emotional lability or pseudobulbar affect can
be treated in at least some patients by means of administering a
drug which functions as an antagonist at NMDA receptors and as an
agonist at dextromethorphan-binding inhibitory receptors, and
wherein the drug is also characterized by a lack of agonist or
antagonist activity at mu or kappa opiate receptors, namely,
dextromethorphan.
[0092] It has long been known that in most people (estimated to
include about 90% of the general population in the United States),
dextromethorphan is rapidly metabolized and eliminated by the body
(Ramachander et al., J. Pharm. Sci., 1977 July, 66(7):1047-8; and
Vetticaden et al., Pharm. Res., 1989 January, 6(1):13-9). This
elimination is largely due to an enzyme known as the P450 2D6 (or
11D6) enzyme, which is one member of a class of oxidative enzymes
that exist in high concentrations in the liver, known as cytochrome
P450 enzymes (Kronbach et al., Anal. Biochem., 1987 April,
162(1):24-32; and Dayer et al., Clin. Pharmacol. Ther., 1989
January, 45(1):34-40). In addition to metabolizing
dextromethorphan, the P450 2D6 isozyme also oxidizes sparteine and
debrisoquine. It is known that the P450 2D6 enzyme can be inhibited
by a number of drugs, particularly quinidine (Brinn et al., Br. J.
Clin. Pharmacol., 1986 August, 22(2):194-7; Inaba et al., Br. J.
Clin. Pharmacol., 1986 August, 22(2):199-200; Brosen et al.,
Pharmacol. Toxicol., 1987 April, 60(4):312-4; Otton et al., Drug
Metab. Dispos., 1988 January-February, 16(1):15-7; Otton et al., J.
Pharmacol. Exp. Ther., 1988 October, 247(1):242-7; Funck-Brentano
et al., Br. J. Clin. Pharmacol., 1989 April, 27(4):435-44;
Funck-Brentano et al., J. Pharmacol. Exp. Ther., 1989 April,
249(1):134-42; Nielsen et al., Br. J. Clin. Pharmacol., 1990 March,
29(3):299-304; Broly et al., Br. J. Clin. Pharmacol., 1989 July,
28(1):29-36).
[0093] Patients who lack the normal levels of P450 2D6 activity are
classified in the medical literature as "poor metabolizers," and
doctors are generally warned to be cautious about administering
various drugs to such patients. "The diminished oxidative
biotransformation of these compounds in the poor metabolizer (PM)
population can lead to excessive drug accumulation, increased peak
drug levels, or in some cases, decreased generation of active
metabolites . . . Patients with the PM phenotype are at increased
risk of potentially serious untoward effects . . . " (Guttendorf et
al., Ther. Drug Monit., 1988, 10(4):490-8, page 490). Accordingly,
doctors are cautious about administering quinidine to patients, and
rather than using drugs such as quinidine to inhibit the rapid
elimination of dextromethorphan, researchers working in this field
have administered very large quantities (such as 750 mg/day) of
dextromethorphan to their patients, even though this is known to
introduce various problems (Walker et al., Clin Neuropharmacol.,
1989 August, 12(4):322-30; and Albers et al., Stroke, 1991 August,
22(8):1075-7).
[0094] Dextromethorphan is a weak, noncompetitive NMDA receptor
antagonist that binds with moderate-to-high affinity to the
phencyclidine site of the receptor complex. However, DM has
additional, unique pharmacological properties. Binding studies
suggest it is a ligand at the high affinity sigma 1 site, where it
initially was proposed to act as an antagonist (Tortella et al.,
TiPS, 1989; 10:501-7) but more recently as an agonist (Maurice et
al., Brain Res. Brain Res. Rev., 2001; 37:116-32). Sigma ligands
also modulate NMDA responses (Debonnel et al., Life Sci., 1996;
58:721-34). Due to its inhibitory actions on glutamate, a number of
investigators have treated ALS patients with DM in the hope of
modifying or arresting the disease (Askmark et al., J. Neurol.
Neurosurg. Psychiatry, 1993; 56:197-200; Hollander et al., Ann.
Neurol., 1994; 36:920-4; and Blin et al., Clin. Neuropharmacol.,
1996; 19:189-92). These trials have failed to demonstrate any
benefit, possibly due to the rapid and extensive metabolism of DM
that occurs in approximately 90 percent of the Caucasian population
(referred to as extensive metabolizers) (see Hildebrand et al.,
Eur. J. Clin. Pharmacol., 1989; 36:315-8).
[0095] DM metabolism is primarily mediated by CYP2D6 in extensive
metabolizers. This can be circumvented by co-administration of
quinidine, a selective CYP2D6 inhibitor, at Q doses 1 to 1.5 logs
below those employed for the treatment of cardiac arrhythmias
(Schadel et al., J. Clin. Psychopharmacol., 1995; 15:263-9). Blood
levels of DM increase linearly with DM dose following
co-administration with Q but are undetectable in most subjects
given DM alone, even at high doses (Zhang et al., Clin. Pharmac.
& Therap., 1992; 51:647-55). The observed plasma levels in
these individuals thus mimic the plasma levels observed in
individuals expressing the minority phenotype where polymorphisms
in the gene result in reduced levels of P450 2D6 (poor
metabolizers). Unexpectedly, during a study of DM and Q in ALS
patients, patients reported that their emotional lability improved
during treatment. Subsequently, in a placebo controlled crossover
study (N=12) conducted to investigate this, the concomitant
administration of DM and Q administered to ALS patients was found
to suppress emotional lability (P<0.001 compared to placebo)
(Smith et al., Neurology, 1995; 45:A330).
[0096] Rapid dextromethorphan elimination may be overcome by
co-administration of quinidine along with dextromethorphan (U.S.
Pat. No. 5,206,248 to Smith). The chemical structure of quinidine
is as follows:
##STR00003##
[0097] Quinidine co-administration has at least two distinct
beneficial effects. First, it greatly increases the quantity of
dextromethorphan circulating in the blood. In addition, it also
yields more consistent and predictable dextromethorphan
concentrations. Research involving dextromethorphan or
co-administration of quinidine and dextromethorphan, and the
effects of quinidine on blood plasma concentrations, are described
in the patent literature (U.S. Pat. No. 5,166,207, U.S. Pat. No.
5,863,927, U.S. Pat. No. 5,366,980, U.S. Pat. No. 5,206,248, and
U.S. Pat. No. 5,350,756 to Smith).
[0098] The discovery that dextromethorphan can reduce the internal
feelings and external symptoms of emotional lability or
pseudobulbar affect in some patients suffering from progressive
neurological disease suggests that dextromethorphan is also likely
to be useful for helping some patients suffering from emotional
lability due to other causes, such as stroke or other ischemic (low
blood flow) or hypoxic (low oxygen supply) events which led to
neuronal death or damage in limited regions of the brain, or head
injury or trauma as might occur during an automobile, motorcycle,
or bicycling accident or due to a gunshot wound.
[0099] In addition, the results obtained to date also suggest that
dextromethorphan is likely to be useful for treating some cases of
emotional lability which are due to administration of other drugs.
For example, various steroids, such as prednisone, are widely used
to treat autoimmune diseases such as lupus. However, prednisone has
adverse events on the emotional state of many patients, ranging
from mild but noticeably increased levels of moodiness and
depression, up to severely aggravated levels of emotional lability
that can impair the business, family, or personal affairs of the
patient.
[0100] In addition, dextromethorphan in combination with quinidine
can reduce the external displays or the internal feelings that are
caused by or which accompany various other problems such as
"premenstrual syndrome" (PMS), Tourette's syndrome, and the
outburst displays that occur in people suffering from certain types
of mental illness. Although such problems may not be clinically
regarded as emotional lability, they involve manifestations that
appear to be sufficiently similar to emotional lability to suggest
that dextromethorphan can offer an effective treatment for at least
some patients suffering from such problems.
[0101] One of the significant characteristics of the treatments of
preferred embodiments is that the treatments function to reduce
emotional lability without tranquilizing or otherwise significantly
interfering with consciousness or alertness in the patient. As used
herein, "significant interference" refers to adverse events that
would be significant either on a clinical level (they would provoke
a specific concern in a doctor or psychologist) or on a personal or
social level (such as by causing drowsiness sufficiently severe
that it would impair someone's ability to drive an automobile). In
contrast, the types of very minor side effects that can be caused
by an over-the-counter drug such as a dextromethorphan-containing
cough syrup when used at recommended dosages are not regarded as
significant interference.
[0102] The magnitude of a prophylactic or therapeutic dose of
dextromethorphan in combination with quinidine in the acute or
chronic management of emotional lability or other chronic
conditions can vary with the particular cause of the condition, the
severity of the condition, and the route of administration. The
dose and/or the dose frequency can also vary according to the age,
body weight, and response of the individual patient.
[0103] In general, it is preferred to administer the
dextromethorphan and quinidine in a combined dose, or in separate
doses administered substantially simultaneously. The preferred
weight ratio of dextromethorphan to quinidine is about 1:1.5 or
less, preferably about 1:1.45, 1:1.4, 1:1.35, or 1:1.3 or less,
more preferably about 1:1.25, 1:1.2, 1:1.15, 1:1.1, 1:1.05, 1:1,
1:0.95, 1:0.9, 1:0.85, 1:0.8, 1:0.75, 1:0.7, 1:0.65, 1:0.6, 1:0.55
or 1:0.5 or less. In certain embodiments, however, dosages wherein
the weight ratio of dextromethorphan to quinidine is greater than
about 1:1.5 may be preferred, for example, dosages of about 1:1.6,
1:1.7, 1:1.8, 1:1.9, 1:2 or greater. Likewise, in certain
embodiments, dosages wherein the ratio of dextromethorphan to
quinidine is less than about 1:0.5 may be preferred, for example,
about 1:0.45, 1:0.4, 1:0.35, 1:0.3, 1:0.25, 1:0.2, 1:0.15, or 1:0.1
or less. When dextromethorphan and quinidine are administered at
the preferred ratio of 1:1.25 or less, it is generally preferred
that less than 50 mg quinidine is administered at any one time,
more preferably about 45, 40, or 35 mg or less, and most preferably
about 30, 25, or 20 mg or less. It may also be preferred to
administer the combined dose (or separate doses simultaneously
administered) at the preferred ratio of 1:1.25 or less twice daily,
three times daily, four times daily, or more frequently so as to
provide the patient with a preferred dosage level per day, for
example: 60 mg quinidine and 60 mg dextromethorphan per day
provided in two doses, each dose containing 30 mg quinidine and 30
mg dextromethorphan; 50 mg quinidine and 50 mg dextromethorphan per
day provided in two doses, each dose containing 25 mg quinidine and
25 mg dextromethorphan; 40 mg quinidine and 40 mg dextromethorphan
per day provided in two doses, each dose containing 20 mg quinidine
and 20 mg dextromethorphan; 30 mg quinidine and 30 mg
dextromethorphan per day provided in two doses, each dose
containing 15 mg quinidine and 15 mg dextromethorphan; or mg
quinidine and 20 mg dextromethorphan per day provided in two doses,
each dose containing 10 mg quinidine and 10 mg dextromethorphan.
The total amount of dextromethorphan and quinidine in a combined
dose may be adjusted, depending upon the number of doses to be
administered per day, so as to provide a suitable daily total
dosage to the patient, while maintaining the preferred ratio of
1:1.25 or less. These ratios are particularly preferred for the
treatment of emotional lability and neuropathic pain.
[0104] In general, the total daily dose for dextromethorphan in
combination with quinidine, for the conditions described herein, is
about 10 mg or less up to about 200 mg or more dextromethorphan in
combination with about 1 mg or less up to about 150 mg or more
quinidine; preferably from about 15 or 20 mg to about 65, 70, 75,
80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, or 190
mg dextromethorphan in combination with from about 2.5, 5, 7.5, 10,
15, or 20 mg to about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110,
120, 130, or 140 mg quinidine; more preferably from about 25, 30,
35, or 40 mg to about 55 or 60 mg dextromethorphan in combination
with from about 25, 30, or 35 mg to about 40, 45, or 50 mg
quinidine. In particularly preferred embodiments, the daily dose of
dextromethorphan (DM) to quinidine (O) is: 20 mg DM to 20 mg Q; 20
mg DM to 30 mg Q; 20 mg DM to 40 mg Q; 20 mg DM to 50 mg Q; 20 mg
DM to 60 mg Q; 30 mg DM to 20 mg Q; 30 mg DM to 30 mg Q; 30 mg DM
to 40 mg Q; 30 mg DM to 50 mg Q; 30 mg DM to 60 mg Q; 40 mg DM to
20 mg Q; 40 mg DM to 30 mg Q; 40 mg DM to 40 mg Q; 40 mg DM to 50
mg Q; 40 mg DM to 60 mg Q; 50 mg DM to 20 mg Q; 50 mg DM to 30 mg
Q; 50 mg DM to 40 mg Q; 50 mg DM to 50 mg Q; 50 mg DM to 50 mg Q;
60 mg DM to 20 mg Q; 60 mg DM to 30 mg Q; 60 mg DM to 40 mg Q; 60
mg DM to 50 mg Q; or 60 mg DM to 60 mg Q. A single dose per day or
divided doses (two, three, four or more doses per day) can be
administered.
[0105] Preferably, a daily dose for emotional lability is about 20
mg to about 60 mg dextromethorphan in combination with about 20 mg
to about 60 mg quinidine, in single or divided doses. Particularly
preferred daily dose for emotional lability is about 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, or 30 mg dextromethorphan in
combination with about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or
30 mg quinidine; about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or
40 mg dextromethorphan in combination with about 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, or 30 mg quinidine; about 40, 41, 42, 43,
44, 45, 46, 47, 48, 49, or 50 mg dextromethorphan in combination
with about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg
quinidine; or about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60
mg dextromethorphan in combination with about 20, 21, 22, 23, 24,
25, 26, 27, 28, 29, or 30 mg quinidine; in single or divided
doses.
[0106] In general, the total daily dose for dextromethorphan in
combination with quinidine, for chronic pain, such as neuropathic
pain, intractable coughing, dermatitis, tinnitus, and sexual
dysfunction is preferably about 10 mg or less up to about 200 mg or
more dextromethorphan in combination with about 1 mg or less up to
about 150 mg or more quinidine. Particularly preferred total daily
dosages for chronic pain, such as neuropathic pain, intractable
coughing, dermatitis, tinnitus, and sexual dysfunction are about
20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg dextromethorphan
in combination with about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
or 30 mg quinidine; about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
or 40 mg dextromethorphan in combination with about 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, or 30 mg quinidine; about 40, 41, 42, 43,
44, 45, 46, 47, 48, 49, or 50 mg dextromethorphan in combination
with about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg
quinidine; or about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60
mg dextromethorphan in combination with about 20, 21, 22, 23, 24,
25, 26, 27, 28, 29, or 30 mg quinidine; in single or divided doses.
Similar daily doses for other indications as mentioned herein are
generally preferred.
[0107] In managing treatment, the therapy is preferably initiated
at a lower daily dose, preferably about 20 or 30 mg
dextromethorphan in combination with about 2.5 mg quinidine per
day, and increased up to about 60 mg dextromethorphan in
combination with about 75 mg quinidine, or higher, depending on the
patient's global response. It is further preferred that infants,
children, patients over 65 years, and those with impaired renal or
hepatic function, initially receive low doses, and that they be
titrated based on individual response(s) and blood level(s).
Generally, a daily dosage of 20 to 30 mg dextromethorphan and 20 to
30 mg quinidine is well-tolerated by most patients.
[0108] It can be preferred to administer dosages outside of these
preferred ranges in some cases, as will be apparent to those
skilled in the art. Further, it is noted that the ordinary skilled
clinician or treating physician will know how and when to
interrupt, adjust, or terminate therapy in consideration of
individual patient response.
[0109] Any suitable route of administration can be employed for
providing the patient with an effective dosage of dextromethorphan
in combination with quinidine. For example, oral, rectal,
transdermal, parenteral (subcutaneous, intramuscular, intravenous),
intrathecal, topical, inhalable, and like forms of administration
can be employed. Suitable dosage forms include tablets, troches,
dispersions, suspensions, solutions, capsules, patches, and the
like. Administration of medicaments prepared from the compounds
described herein can be by any suitable method capable of
introducing the compounds into the bloodstream. Formulations of
preferred embodiments can contain a mixture of active compounds
with pharmaceutically acceptable carriers or diluents as are known
by those of skill in the art.
[0110] The present method of treatment of emotional lability can be
enhanced by the use of dextromethorphan in combination with
quinidine as an adjuvant to known therapeutic agents, such as
fluoxetine hydrochloride, marketed as PROZAC.RTM. by Eli Lilly and
Company, and the like. Preferred adjuvants include pharmaceutical
compositions conventionally employed in the treatment of the
disordered as discussed herein.
[0111] The pharmaceutical compositions of the present invention
comprise dextromethorphan in combination with quinidine, or
pharmaceutically acceptable salts of dextromethorphan and/or
quinidine, as the active ingredient and can also contain a
pharmaceutically acceptable carrier, and optionally, other
therapeutic ingredients.
[0112] The terms "pharmaceutically acceptable salts" or "a
pharmaceutically acceptable salt thereof" refer to salts prepared
from pharmaceutically acceptable, non-toxic acids or bases.
Suitable pharmaceutically acceptable salts include metallic salts,
e.g., salts of aluminum, zinc, alkali metal salts such as lithium,
sodium, and potassium salts, alkaline earth metal salts such as
calcium and magnesium salts; organic salts, e.g., salts of lysine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine),
procaine, and tris; salts of free acids and bases; inorganic salts,
e.g., sulfate, hydrochloride, and hydrobromide; and other salts
which are currently in widespread pharmaceutical use and are listed
in sources well known to those of skill in the art, such as The
Merck Index. Any suitable constituent can be selected to make a
salt of an active drug discussed herein, provided that it is
non-toxic and does not substantially interfere with the desired
activity. In addition to salts, pharmaceutically acceptable
precursors and derivatives of the compounds can be employed.
Pharmaceutically acceptable amides, lower alkyl esters, and
protected derivatives of dextromethorphan and/or quinidine can also
be suitable for use in compositions and methods of preferred
embodiments. In particularly preferred embodiments, the
dextromethorphan is administered in the form of dextromethorphan
hydrobromide, and the quinidine is administered in the form of
quinidine sulfate. For example, a dose of 30 mg dextromethorphan
hydrobromide (of molecular formula C.sub.18H.sub.25NO.HBr.H.sub.2O)
and 30 quinidine sulfate (of molecular formula
(C.sub.20H.sub.24N.sub.2O.sub.2).sub.2.H.sub.2SO.sub.4.2H.sub.2O)
may be administered (corresponding to an effective dosage of
approximately 22 mg dextromethorphan and 25 mg quinidine). Other
preferred dosages include, for example, 45 mg dextromethorphan
hydrobromide and 30 quinidine sulfate (corresponding to an
effective dosage of approximately 33 mg dextromethorphan and
approximately 25 mg quinidine); 60 mg dextromethorphan hydrobromide
and 30 quinidine sulfate (corresponding to an effective dosage of
approximately 44 mg dextromethorphan and approximately 25 mg
quinidine); 45 mg dextromethorphan hydrobromide and 45 quinidine
sulfate (corresponding to an effective dosage of approximately 33
mg dextromethorphan and 37.5 mg quinidine); 60 mg dextromethorphan
hydrobromide and 60 quinidine sulfate (corresponding to an
effective dosage of approximately 44 mg dextromethorphan and 50 mg
quinidine).
[0113] The compositions can be prepared in any desired form, for
example, tables, powders, capsules, suspensions, solutions,
elixirs, and aerosols. Carriers such as starches, sugars,
microcrystalline cellulose, diluents, granulating agents,
lubricants, binders, disintegrating agents, and the like can be
used in oral solid preparations. Oral solid preparations (such as
powders, capsules, and tablets) are generally preferred over oral
liquid preparations. However, in certain embodiments oral liquid
preparations can be preferred over oral solid preparations. The
most preferred oral solid preparations are tablets. If desired,
tablets can be coated by standard aqueous or nonaqueous
techniques.
[0114] In addition to the common dosage forms set out above, the
compounds can also be administered by sustained release, delayed
release, or controlled release compositions and/or delivery
devices, for example, such as those described in U.S. Pat. Nos.
3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719.
[0115] Pharmaceutical compositions suitable for oral administration
can be provided as discrete units such as capsules, cachets,
tablets, and aerosol sprays, each containing predetermined amounts
of the active ingredients, as powder or granules, or as a solution
or a suspension in an aqueous liquid, a non-aqueous liquid, an
oil-in-water emulsion, or a water-in-oil liquid emulsion. Such
compositions can be prepared by any of the conventional methods of
pharmacy, but the majority of the methods typically include the
step of bringing into association the active ingredients with a
carrier which constitutes one or more ingredients. In general, the
compositions are prepared by uniformly and intimately admixing the
active ingredients with liquid carriers, finely divided solid
carriers, or both, and then, optionally, shaping the product into
the desired presentation.
[0116] For example, a tablet can be prepared by compression or
molding, optionally, with one or more additional ingredients.
Compressed tablets can be prepared by compressing in a suitable
machine the active ingredient in a free-flowing form such as powder
or granules, optionally mixed with a binder, lubricant, inert
diluent, surface active or dispersing agent. Molded tablets can be
made by molding, in a suitable machine, a mixture of the powdered
compound moistened with an inert liquid diluent.
[0117] Preferably, each tablet contains from about 30 mg to about
60 mg of dextromethorphan and from about 30 mg to about 45 mg
quinidine, and each capsule contains from about 30 mg to about 60
mg of dextromethorphan and from about 30 mg to about 45 mg
quinidine. Most preferably, tablets or capsules are provided in a
range of dosages to permit divided dosages to be administered. For
example, tablets, cachets or capsules can be provided that contain
about 10 mg dextromethorphan and about 5, 10, or 15 mg quinidine;
about 20 mg dextromethorphan and about 10, 20 or 30 mg quinidine;
about 30 mg dextromethorphan and about 15, 30, or 45 mg quinidine;
and the like. A dosage appropriate to the patient, the condition to
be treated, and the number of doses to be administered daily can
thus be conveniently selected. While it is generally preferred to
incorporate both dextromethorphan and quinidine in a single tablet
or other dosage form, in certain embodiments it can be desirable to
provide the dextromethorphan and quinidine in separate dosage
forms.
[0118] It has been unexpectedly discovered that patients suffering
from emotional lability and other conditions as described herein
can treated with dextromethorphan in combination with an amount of
quinidine substantially lower than the minimum amount heretofore
believed to be necessary to provide a significant therapeutic
effect. As used herein, a "minimum effective therapeutic amount" is
that amount which provides a satisfactory degree of inhibition of
the rapid elimination of dextromethorphan from the body, while
producing no adverse effect or only adverse events of an acceptable
degree and nature. More specifically, a preferred effective
therapeutic amount is within the range of from about 20, 25 or 30
mg to about 60 mg of dextromethorphan and less than about 50 mg of
quinidine per day, preferably about 20 or 30 mg to about 60 mg of
dextromethorphan and about 30 mg to about 45 mg of quinidine per
day, the amount being preferably administered in a divided dose
based on the plasma half-life of dextromethorphan. For example, in
a preferred embodiment dextromethorphan and quinidine are
administered in specified mg increments to achieve a target
concentration of dextromethorphan of a specified level in .mu.g/mL
plasma, with a maximum preferred specified dosage of
dextromethorphan and quinidine based on body weight. The target
dose is then preferably administered every 12 hours. Since the
level of quinidine is minimized, the side effects observed at high
dosages for quinidine are minimized or eliminated, a significant
benefit over compositions containing dextromethorphan in
combination with higher levels of quinidine.
[0119] The combination of dextromethorphan and quinidine of
preferred embodiments can also be extremely effective in
formulations for the treatment for other chronic disorders which do
not respond well to other treatments. Dextromethorphan in
combination with quinidine can be used to effectively treat severe
or intractable coughing, which has not responded adequately to
non-addictive, non-steroid medications, with minimal side-effects.
Intractable coughing is a consequence of respiratory infections,
asthma, emphysema, and other conditions affecting the pulmonary
system.
[0120] Dextromethorphan in combination with quinidine as in the
preferred embodiments can also be used in pharmaceutical
compositions for treating dermatitis. As used herein, "dermatitis"
or "eczema" is a skin condition characterized by visible skin
lesions and/or an itching or burning sensation on the skin.
Dextromethorphan in combination with quinidine as in the preferred
embodiments can also be used in pharmaceutical compositions for the
treatment of chronic pain from conditions such as stroke, trauma,
cancer, and pain due to neuropathies such as herpes zoster
infections and diabetes. Other conditions that can be treated using
dextromethorphan in combination with quinidine according to the
preferred embodiments can include sexual dysfunctions, such as
priapism or premature ejaculation, as well as tinnitus.
Clinical Study #1
[0121] Clinical testing was conducted to determine the lowest dose
of quinidine which inhibits the conversion of dextromethorphan to
dextrorphan; and to chronicle the occurrence of side effects during
administration of dextromethorphan/quinidine.
[0122] Testing protocol specifications and a detailed time and
events schedule were prepared to assure consistent execution of the
protocol throughout the study conduct.
[0123] A phenotyping study directed to dextromethorphan was
conducted. The study was an open-label single dose study. Subjects
were screened to ensure they met the inclusion and exclusion
criteria. Subjects received a single oral dose of dextromethorphan
hydrobromide 30 mg capsule taken with 240 mL of tap water. A total
of fifty-eight subjects were screened and fifty subjects dosed. The
study determined each subject's ability to metabolize
dextromethorphan. Subjects who met the inclusion/exclusion criteria
remained in house for dosing. Each subject was administered one 30
mg capsule (P.M.) of dextromethorphan. Urine was collected predose
through 12 hours postdose and analyzed for dextromethorphan and
dextrorphan. A blood sample (5 mL) was collected for analysis of
plasma dextromethorphan, dextrorphan, and quinidine predose and at
2, 4 and 8 hours postdose. Following a wash-out period of at least
two days, forty-eight subjects determined to be extensive
metabolizers of dextromethorphan were asked to participate in the
quinidine dosing study. Forty-six of these subjects were determined
to be extensive metabolizers of dextromethorphan. One adverse
effect was reported during the study (a headache, classified as
mild, that resolved without intervention).
[0124] Thereafter, a quinidine dose determination study was
conducted. The study was an open-label, randomized, multiple dose
study. Subjects identified as extensive metabolizers received an
evening dose on Day 1, at 12-hour intervals for the next six days,
with a final morning dose on Day 8. All subjects were instructed to
dose themselves at home on eight occasions with medication
dispensed to them. Subjects maintained a diary during the study to
record adverse effects.
[0125] Subjects randomized to Treatment A received fourteen oral
doses of dextromethorphan hydrobromide 30 mg capsule taken with 240
mL of tap water. Subjects randomized to Treatment B received
fourteen oral doses of dextromethorphan hydrobromide 30
mg/quinidine 2.5 mg capsule taken with 240 mL of tap water.
Subjects randomized to Treatment C received fourteen oral doses of
dextromethorphan hydrobromide 30 mg/quinidine 10 mg capsule taken
with 240 mL of tap water. Subjects randomized to Treatment D
received fourteen oral doses of dextromethorphan Hydrobromide 30
mg/quinidine 25 mg capsule taken with 240 mL of tap water. Subjects
randomized to Treatment E received fourteen oral doses of
dextromethorphan hydrobromide 30 mg/quinidine 50 mg capsule taken
with 240 mL of tap water. Subjects randomized to Treatment F
received fourteen oral doses of dextromethorphan hydrobromide 30
mg/quinidine 75 mg capsule taken with 240 mL of tap water.
[0126] All subjects enrolled in the study except for one satisfied
the inclusion/exclusion criteria as listed in the protocol. Medical
histories, clinical laboratory evaluations, and performed physical
examinations were reviewed prior to subjects being enrolled in the
study. The subjects were instructed not to consume any grapefruit
products while participating in the study. Over-the-counter
medications were prohibited three days prior to dosing and during
the study, and prescription medications (with the exception of oral
contraceptives) were prohibited fourteen days prior to dosing and
during the study.
[0127] A total of forty-six subjects, twenty-two males and
twenty-four females, were enrolled in the study and forty-five
subjects, twenty-two males and twenty-three females, completed the
study. The subjects were screened within twenty-one days prior to
study enrollment. The screening procedure included medical history,
physical examination (height, weight, frame size, vital signs, and
ECG), and clinical laboratory tests (hematology, serum chemistry,
urinalysis, HIV antibody screen, serum pregnancy, and a screen for
THECA).
[0128] Subjects were dosed in the clinic on the following schedule:
Day 1 (P.M.), Day 2 (A.M.), Day 3 (P.M.), Day 4 (A.M.) and Day 7
(P.M.). The subjects reported to the clinic on Day 8 for the A.M.
dosing and remained in house for 8 hours postdose. Subjects self
medicated at home on Day 2 (P.M.), Day 3 (A.M.), Day 4 (P.M.), Day
5 (A.M. and P.M.), Day 6 (A.M. and P.M.), and Day 7 (A.M.).
Subjects were dosed twice daily except they received only a PM dose
on Day 1 and an AM dose on Day 8.
[0129] A clinical laboratory evaluation (hematology, chemistries,
urinalysis), vital signs, ECG, and a brief physical examination
were performed at the completion of the study. Subjects were
instructed to inform the study physician and/or safety nurses of
any adverse events that occurred during the study.
[0130] Blood samples (5 mL) were collected on Day 8 prior to dosing
and at 2, 4 and 8 hours postdose for analysis of dextromethorphan,
dextrorphan, and quinidine. A total of eight blood samples (40 mL)
were drawn during the study (including the dextromethorphan screen)
for drug analysis. Plasma samples were separated by centrifugation
and then frozen at -20.degree. C. and kept frozen until assayed.
Urine was collected predose through twelve hours post doses 1, 5,
and 13. Urine samples were pooled for the entire collection
interval. At the end of the interval, the total volume was recorded
and two aliquots were frozen at -20.degree. C. until assayed for
dextromethorphan and dextrorphan.
[0131] A total of forty-six subjects were dosed and forty-five
subjects completed the study. One subject was
discontinued/withdrawn from the study as not tolerating adverse
events experienced. The mean age of the subjects was 51 years
(range of 20 through 86), the mean height of the subjects was 67.6
inches (range of 61.5 through 74.5), and the mean weight of the
subjects was 162.9 pounds (range 101.0 through 229.0).
[0132] A total of eight subjects were enrolled in Treatment Groups
B, D, and E. Seven subjects were enrolled in Treatment Groups A and
C.
[0133] A total of 150 adverse events were experienced by
thirty-four subjects (74%). Other than one serious adverse effect,
all adverse events were classified as mild (96%) or moderate (4%).
The most frequently reported adverse events included headache,
loose stool, lightheadedness, dizziness, and nausea. The
relationship to study drug was classified as possibly, probably, or
almost certainly for 120 of the 150 adverse events (80%). There
were no clear differences between dose groups in the type or
frequency of adverse events observed. No clinically significant
trends regarding vital signs, physical examinations or clinical
laboratory tests were observed.
Clinical Study #2
[0134] The objectives of this study were to determine
pharmacokinetic parameters of dextromethorphan upon single-dose and
multiple-doses of a capsule formulation containing 30 mg
dextromethorphan hydrobromide and 25 mg quinidine sulfate capsules,
to determine the differences in these pharmacokinetic parameters
for extensive metabolizers and poor metabolizers, and to chronicle
the occurrence of side effects during administration of the
formulation. This study had an open-label, single, and multiple
dose design.
[0135] Ten subjects were enrolled in the study. A total of nine
subjects completed the study. Ten subjects were included in safety
analyses, and nine were included in pharmacokinetic analyses. All
subjects enrolled in this study were judged by the investigator to
be normal, healthy volunteers.
[0136] The test formulation was 30 mg dextromethorphan hydrobromide
and 25 mg quinidine sulfate capsules. All subjects received one 30
mg dextromethorphan hydrobromide and 25 mg quinidine sulfate
capsule taken orally with 240 mL of water every 12 hours for a
total of 15 doses.
[0137] The noncompartmental pharmacokinetic parameters Cmax, Tmax,
and AUC (0-12) were calculated from the plasma concentration-time
data for dextromethorphan, dextrorphan, and quinidine on Days 1, 4,
and 8. In addition, the parameters Kel and T 1/2el were calculated
for dextrorphan (Day 8), and quinidine (Days 1, 4, and 8).
[0138] The amount of dextromethorphan and dextrorphan excreted in
the urine was calculated from the 12-hour urine collections on Day
1 (postdose 1), Day 8 (postdose 15), and Days 9-14. The molar
metabolic ratio (dextromethorphan:dextrorphan) was calculated for
each urine-collection day.
[0139] Subjects were evaluated by physical examination, vital
signs, electrocardiogram (ECG), clinical laboratory (hematology,
serum chemistry, and urinalysis), and adverse event assessment.
[0140] Descriptive statistics for each parameter, including mean,
median, standard deviation, coefficient of variation, N, minimum,
and maximum were calculated for all of the subjects by Day. In
addition, descriptive statistics were presented by the subgroups:
extensive metabolizer (EM) and poor metabolizer (PM).
[0141] A normal theory, general linear model (GLM) was applied to
the log-transformed parameters Cmax and AUC (0-12), and
untransformed Tmax (dextromethorphan and dextrorphan), and to
untransformed parameters Cmax, AUC (0-12), and Tmax (quinidine).
The ANOVA model included the factors group (EM or PM), subject
within group, day, and the interaction term day by group. The group
effect was tested using the subject within group mean square, and
all other main effects were tested using the residual error (error
mean square). In addition, tests of the hypotheses Day 1=Day 4, Day
1=Day 8, and Day 4=Day 8 were performed.
[0142] Safety and tolerability were assessed via data listings and
calculation of summary statistics as follows: hematology, serum
chemistry, and urinalysis test results from predose and postdose
were listed in by-subject data listings. Descriptive statistics
were reported by time point of collection, and changes from predose
to postdose were summarized and statistically tested using the
paired t-test (H.sub.o: change=0). Shift tables describing
out-of-range shifts from predose to postdose were created.
Out-of-normal range and clinically significant laboratory values
were listed by subject.
[0143] Descriptive statistics (mean, standard deviation, minimum,
maximum, and sample size) were reported by time point (screen and
Day 8 postdose) for vital sign measurements: systolic and diastolic
blood pressure, pulse rate, respiration and temperature. Summary
statistics were presented by metabolizer type. Differences between
screening and postdose measurements were presented and
statistically tested using a paired t-test (H.sub.o: difference=0).
Individual vital signs results were listed in by-subject data
listings. Changes in physical examination results that occurred
from predose to postdose were also identified.
[0144] Twelve-lead ECGs were recorded prior to dosing. Descriptive
statistics (mean, standard deviation, minimum, maximum, and sample
size) were reported by time point (predose and Day 8 postdose) for
ECG measurements: QRS, PR, QTc, and heart rate. Summary statistics
were presented by metabolizer type. Differences between predose and
Day 8 postdose measurements were presented and statistically
testing using a paired t-test (H.sub.o: difference=0). ECG results
were listed in by-subject data listings.
[0145] Adverse events were classified using the 5.sup.th Edition of
the COSTART dictionary. Summary tables include number of subjects
reporting the adverse event and as percent of number of subjects
dosed by metabolizer type. Summary tables were also presented by
adverse event frequency, severity, and relationship to study
medication. Adverse events were listed by subject, including
verbatim term, severity, frequency, and relationship to treatment
in data listings.
[0146] Mean pharmacokinetic parameters for dextromethorphan,
dextrorphan, and quinidine are summarized in Table 1 for extensive
metabolizers of dextromethorphan (EMs), poor metabolizers of
dextromethorphan (PMs), and all subjects.
TABLE-US-00001 TABLE 1 Pharmaco- Metabolizer Type kinetics EM PM
AllSubjects Compound Parameter Day Mean N S.D. Mean N S.D. Mean N
S.D. Dextrome- Cmax 1 15.89 7 8.22 22.30 2 0.14 17.31 9 7.66
thorphan (ng/mL) 4 76.69 7 15.28 105.70 2 9.48 83.13 9 18.71 8
95.50 7 19.92 136.20 2 3.25 104.54 9 24.92 Tmax (hr) 1 6.85 7 2.78
8.00 2 0.00 7.11 9 2.46 4 5.42 7 1.90 6.00 2 2.82 5.55 9 1.94 8
5.99 7 2.58 4.99 2 1.41 5.77 9 2.33 AUC (0-12) 1 133.27 7 59.86
198.33 2 6.97 147.73 9 59.30 (ng*hr./ml) 4 811.68 7 151.7 1146.4 2
84.43 886.07 9 199.8 8 1049.0 7 243.3 1533.5 2 80.97 1156.7 9 301.4
T 1/2el (hr) 8 13.13 6 3.41 41.96 2 4.47 20.33 8 13.76 Dextrorphan
Cmax 1 124.86 7 53.26 10.80 2 3.39 99.51 9 68.25 (ng/ml) 4 79.33 7
18.63 37.05 2 0.21 69.93 9 24.65 8 123.51 7 17.07 51.45 2 4.17
107.50 9 35.08 Tmax (hr) 1 4.00 7 0.00 3.00 2 1.42 3.78 9 0.67 4
2.21 7 1.40 2.00 2 0.00 2.17 9 1.22 8 41.18 7 11.57 2.99 2 1.41
32.70 9 19.61 AUC (0-12) 1 933.83 7 324.8 90.95 2 19.08 748.52 9
466.2 (ng*hr/mL) 4 849.22 7 181.9 365.27 2 30.37 741.68 9 265.4 8
1000.5 7 147.2 530.40 2 82.39 896.04 9 245.1 Quinidine Cmax 1 0.09
7 0.02 0.08 2 0.01 0.09 9 0.02 (.mu.g/ml) 4 0.15 7 0.03 0.14 2 0.01
0.15 9 0.03 8 0.16 7 0.04 0.16 2 0.02 0.16 9 0.03 Tmax (hr) 1 1.71
7 0.27 1.50 2 0.00 1.67 9 0.25 4 1.65 7 0.37 1.52 2 0.00 1.62 9
0.33 8 1.99 7 0.01 1.49 2 0.00 1.88 9 0.22 AUC (0-12) 1 0.48 7 0.18
0.51 2 0.13 0.49 9 0.17 (.mu.g*hr/mL) 4 1.20 7 0.21 0.97 2 0.05
1.15 9 0.21 8 1.31 7 0.19 1.07 2 0.02 1.26 9 0.19 T 1/2el (hr) 1
8.11 7 2.95 8.25 2 2.65 8.14 9 2.72 4 6.86 7 1.11 6.51 2 0.70 6.78
9 1.01 8 7.66 7 1.09 6.66 2 0.41 7.44 9 1.05
[0147] Mean urinary metabolic ratios (dextromethorphan:dextrorphan)
are summarized in Table for extensive metabolizers of
dextromethorphan (EMs), poor metabolizers of dextromethorphan
(PMs), and all subjects.
TABLE-US-00002 TABLE 2 Metabolizer Type EM PM All Subjects Day Mean
N S.D. Mean N S.D. Mean N S.D. 1 0.268 7 0.227 1.790 2 0.493 0.608
9 0.721 8 0.804 7 0.366 1.859 2 0.507 1.039 9 0.591 9 0.445 6 0.170
1.398 2 0.597 0.683 8 0.516 10 0.198 7 0.152 2.538 2 1.593 0.718 9
1.183 11 0.145 7 0.125 2.200 2 1.136 0.601 9 0.997 12 0.091 7 0.086
3.333 2 0.090 0.812 9 1.432 13 0.037 7 0.064 2.250 2 0.554 0.529 9
0.997 14 0.027 5 0.061 2.061 2 0.115 0.608 7 0.995
[0148] No serious adverse events occurred during this study. Drug
related adverse events included asthenia, diarrhea, anorexia,
nausea, vomiting, anxiety, depersonalization, insomnia, and
somnolence. The majority of the adverse events were mild in
severity and all were resolved without treatment. Prolonged QT
intervals and decreased ventricular rates were observed for the
extensive metabolizer group following dosing. No clinically
significant trends regarding vital signs, physical examinations, or
routine clinical laboratory tests were observed.
[0149] Over the course of this study, low dose quinidine inhibited
the metabolism of dextromethorphan, resulting in increased systemic
availability. This effect was most pronounced in extensive
metabolizers. The mean urinary metabolic ratio
(dextromethorphan:dextrorphan) increased at least 29-fold in
extensive metabolizers by Day 8. The plasma dextrorphan AUC (0-12)
increased approximately 8-fold between Day 1 and Day 8, whereas the
mean plasma dextrorphan AUC (0-12) remained the same between Day 1
and Day 8.
[0150] The effect of quinidine on dextromethorphan metabolism in
poor metabolizers was unclear. The urinary metabolic ratios did not
appear to change with quinidine treatment. The excretion of both
dextromethorphan and dextrorphan increased. However, dextrorphan
excretion increased proportionally to dextromethorphan. This
suggests that quinidine did not inhibit dextromethorphan metabolism
to dextrorphan in poor metabolizers. However, there was 6.1-fold
increase in dextromethorphan AUC (0-12) from Day 1 to Day 8,
compared to a 4.8-fold increase in dextrorphan AUC (0-12), which is
consistent with a small decrease in metabolic clearance.
[0151] Quinidine pharmacokinetics were similar between extensive
metabolizers and poor metabolizers. Mean quinidine elimination
half-life values (6.78 to 8.14 hours) were similar to previously
reported values.
[0152] Dextromethorphan hydrobromide and quinidine sulfate capsules
administered as a single-dose or multiple-doses product appeared to
be well tolerated in this healthy population.
Clinical Study #3
[0153] The objectives of this study were to determine the lowest
dose of quinidine sulfate that effectively inhibits the conversion
of 45 mg of dextromethorphan to dextrorphan and the lowest dose of
quinidine that effectively inhibits the conversion of 60 mg of
dextromethorphan to dextrorphan, and to chronicle the occurrence of
side effects during administration of dextromethorphan in
combination with quinidine.
[0154] This dose interaction study was a Phase 1, open-label,
parallel group, multiple-dose, single-center, safety, and
pharmacokinetic study. A total of sixty-four subjects were planned,
and sixty-five subjects were enrolled in the study. A total of
forty-seven subjects completed the study and were included in
pharmacokinetic analyses. All subjects were included in safety
analyses. Males and females between 18 and 60 years of age,
identified as extensive metabolizers of dextromethorphan, were
enrolled. All subjects were judged to be healthy volunteers.
Enrolled subjects met inclusion and exclusion criteria.
[0155] The test formulation was dextromethorphan hydrobromide and
quinidine sulfate capsules, administered orally with water.
Subjects receiving Treatment A received an oral dose of one
dextromethorphan hydrobromide of 60 mg/0 mg quinidine sulfate
capsule taken twice daily with 240 mL of water on Days 1 through 8.
Subjects receiving Treatment B received an oral dose of one
dextromethorphan hydrobromide of 60 mg/30 mg quinidine sulfate
capsule taken twice daily with 240 mL of water on Days 1 through 8.
Subjects receiving Treatment C received an oral dose of one
dextromethorphan hydrobromide of 60 mg/45 mg quinidine sulfate
capsule taken twice daily with 240 mL of water on Days 1 through 8.
Subjects receiving Treatment D received an oral dose of one
dextromethorphan hydrobromide of 60 mg/60 mg quinidine sulfate
capsule taken twice daily with 240 mL of water on Days 1 through 8.
Subjects receiving Treatment E received an oral dose of one
dextromethorphan hydrobromide of 45 mg/0 mg quinidine sulfate
capsule taken twice daily with 240 mL of water on Days 1 through 8.
Subjects receiving Treatment F received an oral dose of one
dextromethorphan hydrobromide of 45 mg/30 mg quinidine sulfate
capsule taken twice daily with 240 mL of water on Days 1 through 8.
Subjects receiving Treatment G received an oral dose of one
dextromethorphan hydrobromide of 45 mg/45 mg quinidine sulfate
capsule taken twice daily with 240 mL of water on Days 1 through 8.
Subjects receiving Treatment H received an oral dose of one
dextromethorphan hydrobromide of 45 mg/60 mg quinidine sulfate
capsule taken twice daily with 240 mL of water on Days 1 through 8.
For Treatments B, C, D, F, G, and H, subjects received a single
dose of dextromethorphan hydrobromide (either 60 mg for Treatments
B, C, and D or 45 mg for Treatments F, G, and H) without quinidine
for the first dose and then 14 does of the designated capsule,
i.e., all subjects received one dose of either Treatment A or E as
a baseline.
[0156] The first dose of Treatments A and E was considered as
reference. Dextromethorphan hydrobromide 30 mg capsules were used
for phenotyping. Subjects received a single oral dose of one
dextromethorphan hydrobromide 30 mg capsule taken with 240 mL of
water.
[0157] The plasma pharmacokinetic parameters, Cmax, Tmax, AUC
(0-5), and AUC (0-12) were calculated using noncompartmental
analysis. Pharmacokinetic parameters were summarized and
descriptive statistics for all groups were calculated. Changes in
these parameters from baseline were calculated and summarized.
Urine metabolic ratios (dextromethorphan/dextrorphan) were
calculated. Descriptive statistics for all groups were calculated,
and changes in metabolic ratio from baseline were calculated and
summarized.
[0158] Adverse events assessments, monitoring of hematology, blood
chemistry, and urine values, measurements of vital signs and
electrocardiogram (ECG) as well as the performance of physical
examinations were evaluated for safety.
[0159] The effect of quinidine on the pharmacokinetics of
dextromethorphan was assessed by measuring serial plasma
dextromethorphan and dextrorphan concentrations on Days 1 and 8,
quinidine concentrations on Day 8, and the amount of
dextromethorphan and dextrorphan excreted in the urine for 12-hour
urine collections on Day, 1, Day 3, and Day 7, following a multiple
dose administration of dextromethorphan and quinidine. The
noncompartmental pharmacokinetic parameters Cmax, Tmax, AUC (0-5),
and AUC (0-12) were calculated from the plasma concentration-time
data for dextromethorphan and dextrorphan on Days 1 and 8,
quinidine on Day 8. The amount of dextromethorphan and dextrorphan
excreted in the urine was calculated from the 12-hour urine
collections on Day 1, Day 3, and Day 7. The molar metabolic ratio
(dextromethorphan:dextrorphan) was calculated for each
urine-collection day. To assess the effect of quinidine on
dextromethorphan, analysis of variance was performed using SAS PROC
Mixed on the parameter AUC of dextromethorphan from the 4
dextromethorphan and quinidine treatments, respectively, for 60 mg
and 45 mg dextromethorphan doses. Least square means of doses, the
differences (pairwise comparisons) between doses, plus the P-values
for the significance of the differences were presented. To assess
the effect of dextromethorphan on quinidine, analysis of variance
was performed using SAS PROC Mixed on the parameter AUC of
quinidine. Least square means of doses, the differences (pairwise
comparisons) between doses, plus the P-values for the significance
of the differences were presented.
[0160] Safety and tolerability were assessed through calculation of
summary statistics and were displayed in data listings of
individual subjects. Adverse events were coded using the MedDRA
Adverse Event Dictionary (Version 3.0, 2000). The frequency, type,
severity, and relationship to study drug of treatment-emergent
adverse events were displayed and compared across treatments.
[0161] For laboratory tests, the study screening and poststudy
measurements, along with the change between these time points, were
summarized by descriptive statistics (median, mean, standard
deviation, minimum, maximum, and sample size) for serum chemistry
and hematology tests. Shift tables from screening to poststudy for
serum chemistry, hematology, and urinalysis laboratory tests were
constructed. Out-of-range clinical laboratory results and their
associated recheck values were listed.
[0162] Descriptive statistics (median, mean, standard deviation,
minimum, maximum, and sample size) were calculated for vital signs
and 12-lead electrocardiogram (ECG) measurements for baseline and
postdose, along with the change between these time points. The ECG
shift table from baseline to postdose was also presented.
[0163] The arithmetic means of pharmacokinetic parameters of plasma
dextromethorphan, dextrorphan, and quinidine following Treatments
A, B, C, D, E, F, G, and H, and results of statistical comparisons
between treatment groups are presented in the following tables.
Table 3 provides a summary of the plasma DM pharmacokinetic
parameters following a 60 mg dose of dextromethorphan.
TABLE-US-00003 TABLE 3 Pharmacokinetic Treatment A Treatment B
Treatment C Treatment D Parameters Day* Mean S.D. Mean S.D. Mean
S.D. Mean S.D. Cmax (ng/mL) 1 3.7 3.70 2.1 2.82 3.5 3.19 4.8 4.74 8
7.7 7.01 191.8 45.48 204.8 22.93 231.9 96.36 C 4.0 4.75 189.7 43.90
201.3 22.19 227.1 97.52 Tmax (hr) 1 2.6 0.96 2.5 0.57 2.4 0.56 3.5
1.05 8 2.1 0.38 3.5 1.73 3.7 1.17 5.2 1.94 C -0.5 1.12 1.0 1.42 1.3
1.51 1.7 1.97 AUC (0-t) 1 23.0 23.64 12.1 16.04 20.7 17.39 32.0
34.66 (ng*hr/mL) 8 52.3 46.72 1963.0 608.50 2121.0 278.50 2252.0
689.30 C 29.3 34.57 1951.0 600.30 2100.0 275.90 2220.0 697.70 AUC
(0-12) 1 23.2 23.50 12.3 15.93 20.7 17.39 32.2 34.45 (ng*hr/mL) 8
52.3 46.72 1963.0 608.50 2121.0 278.50 2252.0 689.30 C 29.2 34.79
1951.0 600.10 2100.0 275.90 2220.0 697.80 1n (Cmax) 1 0.9 1.07 0.1
1.21 0.9 1.05 1.2 0.88 8 1.6 1.03 5.2 0.24 5.3 0.11 5.4 0.40 C 2.3
1.03 219.5 132.00 108.8 92.40 85.0 54.87 In (AUC (0-12) 1 2.7 1.07
2.0 1.08 2.8 0.95 3.1 0.98 8 3.6 1.02 7.5 0.33 7.7 0.13 7.7 0.32 C
2.6 1.22 324.9 185.30 170.9 130.30 141.0 114.80 * = Code C
corresponds to the change from the baseline, calculated as follows:
for the untransformed parameters, it is the difference between Day
8 and Baseline values, for the In-transformed parameters, it is the
ratio of Day 8 over Baseline values.
[0164] Table 4 provides a summary of statistical comparisons of
plasma dextromethorphan AUC (0-12) relating to the effect of
quinidine doses on a 60 mg dose of dextromethorphan.
TABLE-US-00004 TABLE 4 Treatment Comparison Geometric Means Ratio
of GEOMEANS P A vs. D 35.11 2159.23 0.02 0.0001 B vs. D 1888.72
2159.23 0.87 0.7601 C vs. D 2108.96 2159.23 0.98 0.9608
[0165] Table 5 provides a summary of statistical comparisons of
plasma dextromethorphan AUC (0-t) relating to the effect of
quinidine doses on a 60 mg dose of dextromethorphan.
TABLE-US-00005 TABLE 5 Treatment Comparison Geometric Means Ratio
of GEOMEANS P A vs. D 35.11 2159.23 0.02 0.0001 B vs. D 1888.72
2159.23 0.87 0.7601 C vs. D 2108.96 2159.23 0.98 0.9608
[0166] Table 6 provides a summary of plasma dextromethorphan
pharmacokinetic parameters following a 45 mg dose of
dextromethorphan.
TABLE-US-00006 TABLE 6 Pharmacokinetic Treatment E Treatment F
Treatment G Treatment H Parameters Day* Mean S.D. Mean S.D. Mean
S.D. Mean S.D. Cmax (ng/mL) 1 2.3 1.60 9.6 13.91 3.6 5.04 1.7 1.08
8 4.2 3.01 141.5 74.68 138.9 25.97 136.1 50.59 C 1.9 2.03 131.9
62.92 135.3 23.87 134.4 50.80 Tmax (hr) 1 3.5 0.93 2.9 0.37 3.4
1.40 3.0 1.0 8 3.4 0.50 4.3 1.70 3.3 1.80 3.6 2.07 C -0.1 1.16 1.4
1.51 -0.1 1.21 0.6 2.20 AUC (0-t) 1 14.9 11.39 77.5 120.80 25.4
36.89 10.2 7.08 (ng*hr/mL) 8 31.3 23.85 1438.0 842.60 1403.0 283.10
1464.0 588.60 C 16.3 17.0 1360.0 736.20 1378.0 259.50 1453.0 589.30
AUC (0-12) 1 15.0 11.36 77.5 120.80 25.5 36.79 10.3 6.98 (ng*hr/mL)
8 31.5 23.64 1488.0 842.60 1403.0 283.10 1464.0 588.50 C 16.5 16.82
1360.0 736.20 1378.0 259.60 1453.0 589.50 1n (Cmax) 1 0.5 0.95 1.2
1.56 0.5 1.33 0.4 0.55 8 1.1 1.09 4.8 0.52 4.9 0.19 4.8 0.45 C 1.9
0.93 62.6 54.58 138.3 107.10 100.3 59.37 In (AUC (0-t) 1 2.2 1.45
3.2 1.64 2.3 1.45 2.1 0.65 8 3.0 1.23 7.1 0.54 7.2 0.19 7.2 0.50 C
2.6 1.60 89.6 78.74 241.2 206.30 188.5 112.20 In (AUC (0-12) 1 2.3
1.34 3.2 1.64 2.4 1.39 2.2 0.62 8 3.0 1.17 7.1 0.54 7.2 0.19 7.2
0.50 C 2.5 1.38 89.6 78.74 218.9 177.50 185.4 113.80 * = Code C
corresponds to the change from the baseline, calculated as follows:
for the untransformed parameters, it is the difference between Day
8 and Baseline values, for the In-transformed parameters, it is the
ratio of Day 8 over Baseline values.
[0167] Table 7 provides a summary of statistical comparisons of
plasma dextromethorphan AUC (0-12) relating to the effect of
quinidine doses on a 60 mg dose of dextromethorphan.
TABLE-US-00007 TABLE 7 Treatment Comparison Geometric Means Ratio
of GEOMEANS P E vs. H 20.89 1342.73 0.02 0.0001 F vs. H 1266.94
1342.73 0.94 0.8945 G vs. H 1380.84 1342.73 1.03 0.9490
[0168] Table 8 provides a summary of statistical comparisons of
plasma dextromethorphan AUC (0-t) relating to the effect of
quinidine doses on a 60 mg dose of dextromethorphan.
TABLE-US-00008 TABLE 8 Treatment Comparison Geometric Means Ratio
of GEOMEANS P E vs. H 20.18 1342.73 0.02 0.0001 F vs. H 1266.94
1342.73 0.94 0.8980 G vs. H 1380.84 1342.73 1.03 0.9490
[0169] Table 9 provides a summary of plasma dextromethorphan
pharmacokinetic parameters following a 60 mg dose of
dextromethorphan.
TABLE-US-00009 TABLE 9 Pharmacokinetic Treatment A Treatment B
Treatment C Treatment D Parameters Day* Mean S.D. Mean S.D. Mean
S.D. Mean S.D. Cmax (ng/mL) 1 663.6 111.69 858.1 75.95 885 .4 33.23
655.5 145.57 8 709.6 88.82 176.7 41.40 90.1 24.55 110.8 27.68 C
46.0 142.71 -681.4 75.24 -795.3 57.72 -544.8 126.32 Tmax (hr) 1 2.2
0.37 2.0 0.01 2.0 0.03 2.0 0.01 8 2.1 0.38 1.6 1.60 5.3 5.77 4.3
4.13 C -0.0 0.58 -0.4 1.59 3.3 5.78 2.3 4.13 AUC (0-t) 1 3240.0
494.10 3953.0 516.80 3669.0 468.10 3237.0 515.10 (ng*hr/mL) 8
3608.0 386.80 1830.0 443.10 958.0 248.80 1157.0 281.30 C 367.9
581.60 -2123.0 322.70 -2711.0 467.40 -2080.0 369.40 AUC (0-12) 1
3240.0 494.10 3953.0 516.80 3669.0 468.10 3237.0 515.10 (ng*hr/mL)
8 3608.0 386.80 1830.0 443.10 958.0 248.80 1157.0 281.30 C 367.9
581.60 -2123.0 322.70 -2711.0 467.40 -2080.0 369.40 1n (Cmax) 1 6.5
0.16 6.8 0.09 6.8 0.04 6.5 0.23 8 6.6 0.12 5.2 0.24 4.5 0.27 4.7
0.27 C 1.1 0.22 0.2 0.05 0.1 0.03 0.2 0.04 In (AUC (0-t) 1 8.1 0.15
8.3 0.13 8.2 0.13 8.1 0.16 8 8.2 0.11 7.5 0.26 6.8 0.25 7.0 0.27 C
1.1 0.19 0.5 0.08 0.3 0.07 0.4 0.06 In (AUC (0-12) 1 8.1 0.15 8.3
0.13 8.2 0.13 8.1 0.16 8 8.2 0.11 7.5 0.26 6.8 0.25 7.0 0.27 C 1.1
0.19 0.5 0.08 0.3 0.07 0.4 0.06 * = Code C corresponds to the
Change from the baseline, calculated as follows: for the
untransformed parameters, it is the difference between Day 8 and
Baseline values, for the In-transformed parameters, it is the ratio
of Day 8 over Baseline values.
[0170] Table 10 provides a summary of statistical comparisons of
plasma dextromethorphan AUC (0-12) as relates to the effect of
quinidine doses on 60 mg of Dextromethorphan.
TABLE-US-00010 TABLE 10 Treatment Comparison Geometric Means Ratio
of GEOMEANS P A vs. D 3589.57 1125.35 3.19 0.0001 B vs. D 1786.16
1125.35 1.59 0.0046 C vs. D 937.28 1125.35 0.83 0.2521
[0171] Table 11 provides a summary of statistical comparisons of
plasma dextromethorphan AUC (0-t) as relates to the effect of
quinidine doses on 60 mg of Dextromethorphan.
TABLE-US-00011 TABLE 11 Treatment Ratio of Comparison Geometric
Means GEOMEANS P A vs. D 3589.57 1125.35 3.19 0.0001 B vs. D
1786.16 1125.35 1.59 0.0046 C vs. D 937.28 1125.35 0.83 0.2521
[0172] Table 12 provides a summary of plasma dextromethorphan
pharmacokinetic parameters following a 45 mg dose of
dextromethorphan.
TABLE-US-00012 TABLE 12 Pharmacokinetic Treatment E Treatment F
Treatment G Treatment H Parameters Day* Mean S.D. Mean S.D. Mean
S.D. Mean S.D. Cmax (ng/mL) 1 587.4 172.23 446.6 216.16 554.0
209.23 607.3 125.85 8 599.2 199.89 89.1 25.97 86.8 23.11 77.7 15.81
C 11.9 94.36 -357.5 215.39 -467.2 188.06 -529.6 126.09 Tmax (hr) 1
2.0 0.00 2.0 0.01 2.2 .038 2.0 0.01 8 2.0 0.01 2.3 1.38 1.0 1.12
1.3 1.20 C 0.0 0.01 0.3 1.38 -1.2 1.25 0.7 1.20 AUC (0-t) 1 2618.0
603.10 2260.0 751.50 2462.0 737.10 2860.0 580.40 (ng*hr/mL) 8
2898.0 900.50 920.7 275.90 874.1 283.80 782.6 129.9 C 280.7 430.70
-1340.0 751.40 -1588.0 537.30 -2078.0 535.00 AUC (0-12) 1 2618.0
603.10 2260.0 751.50 2481.0 732.00 2860.0 580.40 (ng*hr/mL) 8
2898.0 900.50 920.7 275.90 874.1 238.80 782.6 129.90 C 280.7 430.70
-1340.0 751.40 -1607.0 536.50 -2078.0 535.00 1n (Cmax) 1 6.3 0.30
6.0 0.62 6.3 0.37 6.4 0.20 8 6.3 0.35 4.5 0.29 4.4 0.27 4.3 0.20 C
1.0 0.19 0.3 0.24 0.2 0.03 0.1 0.04 In (AUC (0-t) 1 7.8 0.22 7.7
0.39 7.8 0.27 7.9 0.21 8 7.9 0.31 6.8 0.31 6.7 0.28 6.7 0.17 C 1.1
0.17 0.5 0.24 0.4 0.05 0.3 0.06 In (AUC (0-12) 1 7.8 0.22 7.7 0.39
7.8 0.27 7.9 0.21 8 7.9 0.31 6.8 0.31 6.7 0.28 6.7 0.17 C 1.1 0.17
0.5 0.24 0.4 0.05 0.3 0.06 * = Code C corresponds to the Change
from the baseline, calculated as follows: for the untransformed
parameters, it is the difference between Day 8 and Baseline values,
for the In-transformed parameters, it is the ratio of Day 8 over
Baseline values.
[0173] Table 13 provides a summary of statistical comparisons of
plasma dextromethorphan AUC (0-12) as relates to the effect of
quinidine doses on a 45 mg dose of dextromethorphan.
TABLE-US-00013 TABLE 13 Treatment Ratio of Comparison Geometric
Means GEOMEANS P E vs. H 2777.40 773.75 3.59 0.0001 F vs. H 884.33
773.75 1.14 0.4276 G vs. H 846.26 773.75 1.09 0.5933
[0174] Table 14 provides a summary of statistical comparisons of
plasma dextromethorphan AUC (0-t) as relates to the effect of
quinidine doses on a 45 mg dose of dextromethorphan.
TABLE-US-00014 TABLE 14 Treatment Ratio of Comparison Geometric
Means GEOMEANS P E vs. H 277.40 773.75 3.59 0.0001 F vs. H 884.33
773.75 1.14 0.4276 G vs. H 846.26 773.75 1.09 0.5933
[0175] Table 15 provides a summary of plasma dextromethorphan
pharmacokinetic parameters following a 60 mg dose of
dextromethorphan.
TABLE-US-00015 TABLE 15 Pharmacokinetic Treatment A Treatment B
Treatment C Treatment D Parameters Day* Mean S.D. Mean S.D. Mean
S.D. Mean S.D. Cmax (mcg/mL) 8 0.0 0.00 0.1 0.05 0.3 0.02 0.3 0.15
Tmax (mcr) 8 . . 2.3 1.26 1.3 0.58 1.8 0.40 AUC (0-Tt ) (mcg-hr/mL)
8 0.0 0.00 0.9 0.40 1.9 0.10 2.4 1.29 AUC (0-12) (mcg*hr/mL) 8 0.0
0.00 1.0 0.34 1.9 0.10 2.5 1.22 1n (Cmax) 8 . . -2.0 0.33 -1.3 0.07
-1.1 0.43 1n[AUC (0-t)] 8 . . -0.2 0.40 0.6 0.05 0.8 0.58 1n[AUC
(0-12)] 8 . . -0.1 0.33 0.6 0.05 0.8 0.51 * = For Quinidine only
Day 8 data were analyzed
[0176] Table 16 provides a summary of plasma dextromethorphan
pharmacokinetic parameters following a 45 mg dose of
dextromethorphan.
TABLE-US-00016 TABLE 16 Pharmacokinetic Treatment E Treatment F
Treatment G Treatment H Parameters Day* Mean S.D. Mean S.D. Mean
S.D. Mean S.D. Cmax (mcg/mL) 8 0.0 0.00 0.2 0.11 0.3 0.13 0.3 0.06
Tmax (mcr) 8 . . 1.6 0.79 1.2 0.57 1.8 1.3 AUC(0-Tt) (mcg- 8 0.0
0.00 1.0 0.77 2.0 0.91 2.3 0.71 hr/mL) AUC(0-12) 8 0.0 0.00 1.1
0.74 2.0 0.88 2.3 0.64 (mcg*hr/mL) 1n(Cmax) 8 . . -1.8 0.58 -1.3
0.44 -1.1 0.19 1n[AUC(0-t)] 8 . . -0.2 0.66 0.6 0.48 0.8 0.33
1n[AUC(0-12)] 8 . . -0.1 0.61 0.6 0.44 0.8 0.28 *= For Quinidine,
only Day 8 data were analyzed
[0177] Table 17 provides a summary of statistical comparisons of
plasma quinidine AUC (0-12) as relates to different
dextromethorphan/quinidine dose combinations.
TABLE-US-00017 TABLE 17 Treatment Ratio of Comparison Geometric
Means GEOMEANS P F vs. B 0.94 0.94 1.00 0.9925 G vs. C 1.88 1.89
1.00 0.9930 H vs. D 2.24 2.23 1.01 0.9765
[0178] Table 18 provides a summary of statistical comparisons of
plasma quinidine AUC (0-t) as relates to different
dextromethorphan/quinidine dose combinations.
TABLE-US-00018 TABLE 18 Treatment Ratio of Comparison Geometric
Means GEOMEANS P F vs. B 0.84 0.84 1.00 0.9987 G vs. C 1.84 1.89
0.97 0.9421 H vs. D 2.18 2.12 1.03 0.9294
[0179] A summary of the metabolic ratios for urinary
pharmacokinetic parameters following a 60 mg dose of
dextromethorphan are provided in Table 19.
TABLE-US-00019 TABLE 19 Treatment A Treatment B Treatment C
Treatment D Pharmacokinetic Arithmetic Arithmetic Arithmetic
Arithmetic Period Parameters Mean S.D. Mean S.D. Mean S.D. Mean
S.D. 0-12 hr Ae 0.0013 0.0023 0.0010 0.0015 0.0027 0.0048 0.0041
0.0070 CumAe 0.0013 0.0023 0.0010 0.0015 0.0027 0.0048 0.0041
0.0070 12-24 hr Ae 0.0058 0.0055 0.0865 0.0496 0.2748 0.2228 0.2934
0.2046 CumAe 0.0031 0.0039 0.0253 0.0116 0.0641 0.0504 0.0632
0.0362 60-72 hr Ae 0.0133 0.0122 0.8139 0.3464 1.3598 0.7454 2.0366
0.9219 CumAe 0.0058 0.0061 0.1248 0.0545 0.2374 0.1904 0.2966
0.1670 156-168 hr Ae 0.0179 0.0163 0.6513 0.4119 1.1785 0.1517
1.3023 0.7430 CumAe 0.0085 0.0092 0.2005 0.1129 0.3493 0.1676
0.4374 0.1767 0-12 hr collecting period corresponds to Baseline,
when only Dextromethorphan (no Quinidine) was administered at the
specific dose. Ae = Amount excreted (mcg) CumAe = Cumulative Amount
Excreted (mcg)
[0180] A summary of statistical comparisons of urinary metabolic
ratio for Ae (156-168 Hr) as relates to the effect of quinidine
doses on a 60 mg dose of dextromethorphan are provided Table
20.
TABLE-US-00020 TABLE 20 Treatment Ratio of Comparison Geometric
Means GEOMEANS P A vs. D 0.01 1.12 0.01 0.0001 B vs. D 0.54 1.12
0.49 0.1947 C vs. D 1.17 1.12 1.05 0.9347
[0181] A summary of statistical comparisons of urinary metabolic
ratio for CumAe (156-168 Hr) as relates to the effect of quinidine
doses on a 60 mg dose of dextromethorphan are provided Table
21.
TABLE-US-00021 TABLE 21 Treatment Ratio of Comparison Geometric
Means GEOMEANS P A vs. D 0.01 0.41 0.02 0.0001 B vs. D 0.18 0.41
0.45 0.0822 C vs. D 0.32 0.41 0.80 0.6485
[0182] A summary of the metabolic ratios for urinary
pharmacokinetic parameters following a 45 mg dose of
dextromethorphan are provided in Table 22.
TABLE-US-00022 TABLE 22 Treatment A Treatment B Treatment C
Treatment D Pharmacokinetic Arithmetic Arithmetic Arithmetic
Arithmetic Period Parameters Mean S.D. Mean S.D. Mean S.D. Mean
S.D. 0-12 hr Ae 0.0022 0.0043 0.0454 0.0768 0.0130 0.0271 0.0017
0.0025 CumAe 0.0022 0.0043 0.0454 0.0768 0.0130 0.0271 0.0017
0.0025 12-24 hr Ae 0.0044 0.0043 0.2338 0.1996 0.2647 0.1224 0.3252
0.1955 CumAe 0.0032 0.0043 0.1078 0.1130 0.0798 0.0393 0.0774
0.0554 60-72 hr Ae 0.0089 0.0096 1.2159 0.4110 1.2594 0.5056 0.8073
0.4256 CumAe 0.0052 0.0061 0.3673 0.1438 0.2837 0.1087 0.1889
0.0621 156-168 hr Ae 0.0087 0.0097 0.9387 0.2688 1.6276 0.7287
0.8770 0.4967 CumAe 0.0059 0.0054 0.4826 0.1201 0.4912 0.2480
0.3468 0.1477 0-12 hr collecting period corresponds to Baseline,
when only Dextromethorphan (no Quinidine) was administered at the
specific dose. Ae = Amount excreted (mcg) CumAe = Cumulative Amount
Excreted (mcg)
[0183] A summary of statistical comparisons of urinary metabolic
ratio for Ae (156-168 Hr) as relates to the effect of quinidine
doses on a 45 mg dose of dextromethorphan are provided Table
23.
TABLE-US-00023 TABLE 23 Ratio Treatment Comparison Geometric Means
of GEOMEANS P E vs. H 0.01 0.75 0.01 0.0001 F vs. H 0.90 0.75 1.20
0.5713 G vs. H 1.46 0.75 1.95 0.0469
[0184] A summary of statistical comparisons of urinary metabolic
ratio for CumAe (156-168 Hr) as relates to the effect of quinidine
doses on a 45 mg dose of dextromethorphan are provided Table
24.
TABLE-US-00024 TABLE 24 Ratio Treatment Comparison Geometric Means
of GEOMEANS P E vs. H 0.01 0.32 0.02 0.0001 F vs. H 0.47 0.32 1.48
0.2201 G vs. H 0.43 0.32 1.36 0.3345
[0185] The data suggest that co-administration of dextromethorphan
and quinidine sulfate is safe and moderately well tolerated up to
the highest dose level (60 mg dextromethorphan/60 mg
quinidine).
[0186] There were a total of 279 treatment-emergent adverse events
experienced by forty-eight of the sixty-five subjects dosed (74%)
during the trial. There were 206 adverse events reported by
twenty-seven of the thirty-two subjects dosed (84%) following the
60 mg dextromethorphan treatments and seventy-three adverse events
reported by twenty-one of the thirty-three subjects dosed (64%)
following the 45 mg dextromethorphan treatments. Twelve subjects
following the 60 mg dextromethorphan treatments and five subjects
following the 45 mg dextromethorphan treatments were discontinued
from the trial due to adverse events.
[0187] Dizziness, nausea, and headache were the most common adverse
events following both dextromethorphan groups, and fewer adverse
events were reported following the 45 mg dextromethorphan
treatments. All of the adverse events were mild or moderate in
severity and no serious adverse events occurred. No clinically
significant differences were observed between the treatment groups
regarding clinical laboratory results, vital signs, physical
examination, or ECG results.
[0188] Over the course of this study, quinidine inhibited the
metabolism of dextromethorphan dosed at 45 and 60 mg resulting in
increased systemic availability of dextromethorphan. The 60 mg
quinidine dose resulted in the largest dextromethorphan AUC at both
the 45 and 60 mg dextromethorphan doses, compared to the 30 and 45
mg quinidine doses. The statistical comparisons, however, showed
there were not only statistically significant differences in the
quinidine inhibition of dextromethorphan metabolism among the
different quinidine doses. Based on dextromethorphan AUC
statistical comparisons, the lowest effective dose of quinidine
that inhibits the metabolism of 45 and 60 mg dextromethorphan is 30
mg. Thus, a 30 mg quinidine dose is recommended for
dextromethorphan inhibition.
[0189] The occurrence of side effects during the co-administration
of dextromethorphan and quinidine sulfate indicated the treatments
were moderately well tolerated up to the highest dose level (60 mg
dextromethorphan/60 mg quinidine).
Clinical Study #4
[0190] The objectives of this study were to compare and evaluate
the efficacy, safety, and tolerance of a combination of 30DM/30Q
taken twice daily relative to 30 mg DM and 30 mg Q taken
individually in a population of ALS subjects with pseudobulbar
affect.
[0191] This was a multicenter, randomized, double-blind,
controlled, parallel-group study. All study drugs were
self-administered orally every twelve hours for twenty-eight days.
The study included a screening visit and three other clinic visits
on Days 1, 15, and 29. Day 29 was the last day the subject was on
study and could occur anywhere between the morning of Day 26 and
the morning of Day 32.
[0192] Subjects with clinically diagnosed pseudobulbar affect were
screened for general health within four weeks before entry into the
study. All eligible subjects had attained a score of 13 or above on
the Center for Neurologic Study-Lability Scale (CNS-LS) at the
clinic visit on Day 1.
[0193] Subjects were randomized to one of three treatment groups to
receive 30DM/30Q, or 30 mg DM, or 30 mg Q. They received a diary in
which they recorded the date and time each dose was taken, the
number of laughing/crying episodes experienced, and any adverse
events that had occurred since the last visit. Diary cards were
collected on Day 15 and at the time of study completion.
[0194] Subjects completed the CNS-LS questionnaire and visual
analog scales assessing quality of life (QOL) and quality of
relationships (QOR) every two weeks (Days 1, 15, and 29) during the
treatment period. A clinical psychologist, or other approved
clinician, administered the Hamilton Rating Scale for Depression
(HRSD) at the Screening Visit and on Day 29. Safety was evaluated
on Day 15 and Day 29 by examining adverse events, results of
physical examinations, vital signs, clinical laboratory values, and
resting electrocardiograms (ECGs). In addition to blood samples
taken to provide clinical laboratory data, blood was also taken for
pharmacokinetic analysis and CYP2D6 genotyping. Each subject
completed a diary in which the number of episodes experienced,
medications taken, and any adverse events were recorded daily.
[0195] DM and Q were chosen as control groups because they are the
components of the drug investigated in this study (30DM/30Q).
[0196] Subjects included in the study were 18 to 80 years of age,
inclusive. The subjects had a confirmed diagnosis of ALS or
probable ALS according to the World Federation of Neurology (WFN)
criteria, and a clinical history of pseudobulbar affect. Every
effort was made by the to continue a subject in the study; however,
if the subject decided to withdraw, all efforts were made to
complete all assessments listed on Day 29 in Table 25. An
explanation of why the subject withdrew from the study was
obtained. Subjects who withdrew from the study could not re-enter
it, and no subject who had been randomized was replaced.
[0197] The study drugs were randomized in blocks of four. Each
block contained two assignments to the 30DM/30Q, one to DM and one
to Q in random order. Specifically, each block was constructed by
selecting one of the four possibilities to be received first. From
the three remaining treatments, one was selected to be received
next, and so forth. Subject numbers were allocated to study sites
in one block of four assignments at a time.
[0198] There were three treatments administered in the study:
30DM/30Q, or 30 mg DM, or 30 mg Q. Study medications were provided
as hard, gelatin capsules. The contents of the capsules is listed
in Table 25. All medication used in the study was prepared
according to current Good Manufacturing Practice (cGMP).
TABLE-US-00025 TABLE 25 Amount (mg) Ingredient DM/Q DM Q
Dextromethorphan hydrobromide 31.50 31.50 0.00 monohydrate USP
Quinidine sulfate dihydrate USP 31.40 0.00 31.40 Croscarmellose
sodium NF 7.80 7.80 7.80 Microcrystalline cellulose NF 94.00 109.70
109.75 Colloidal silicone dioxide NF 0.65 0.65 0.65 Lactose
monohydrate NF 94.00 109.70 109.75 Magnesium stearate NF 0.65 0.65
0.65
[0199] Subjects took one capsule twice a day (every 12 hours) for
twenty-eight days. The first dose was taken in the evening of Day
1, and the final dose was taken in the morning on Day 29. The
investigators were supplied with capsules of 30DM/30Q, DM, and Q in
identical blister-packs, and all capsules were identical in
appearance and weight.
[0200] Subjects could not take any disallowed medications during
the study or for one week before the start of dosing on Day 1.
These medications included amantadine, amitriptyline, any
anti-depressant medication including St. John's Wort, any monoamine
oxidase inhibitor, aspirin (for pain or fever acetaminophen was
recommended), captopril, cimetidine, desipramine, dextromethorphan
(over-the-counter cough medicines), digoxin, diltiazem,
erythromycin, fluoxetine, imipramine, itraconazole, ketoconazole,
nortriptyline, paroxetine, quinidine, quinine, and verapamil. At
each visit, subjects were queried as to whether or not they had
taken any medications, and if they had, the medication was recorded
on the Case Report Form.
[0201] Subjects were instructed to bring unused study medication to
the visit on Day 15 visit and to return all unused study medication
to the clinic at the end of study participation. Percent of doses
taken was calculated as the total number of doses taken divided by
the total number of doses planned, and the result was multiplied by
100. Subjects were considered to be compliant if they had taken 80%
of their prescribed doses.
[0202] The primary efficacy variable was the CNS-LS score. All
efficacy variables involving a change were determined by the
baseline score being subtracted from the mean of the non-missing
scores on Days 15 and 29. The secondary efficacy variables were
laughing/crying episodes, QOL scores, and QOR scores. All efficacy
variables involving a change were determined by subtracting the
baseline score from the mean of the scores on Days 15 and 29.
[0203] The CNS-LS questionnaire used to assess primary efficacy is
a seven-item self-report measure that provides a score for total
pseudobulbar affect; it required approximately five minutes for the
subject to complete. The range of possible scores was 7 to 35. The
cut-off score of 13 was selected because it has been reported in
the literature to provide the highest incremental validity,
accurately predicting the neurologists' diagnoses for 82% of
participants with a sensitivity of 0.84 and a specificity of 0.81.
This questionnaire is the only instrument for the measurement of
pseudobulbar affect validated for use with ALS subjects.
[0204] Secondary efficacy was assessed by using two, 10-cm visual
analog scales (VAS). One scale asked subjects to rate how much
uncontrollable laughter, tearfulness, or anger had affected the
overall quality of their life during the past week, and one scale
asked subjects to rate how much uncontrollable laughter,
tearfulness, or anger had affected the quality of their
relationships with others during the past week. Each scale required
less than one minute to complete. The subjects recorded episodes of
pathological laughing and crying in a diary daily.
[0205] Safety was assessed by the following measurements: adverse
events; clinical laboratory values; vital signs; physical
examinations; and resting ECGs. An adverse event was defined any
untoward medical occurrence or unintended change from the subject's
baseline (pre-treatment) condition, including intercurrent illness,
that occurs during the course of a clinical trial after treatment
has started, whether considered related to treatment or not. An
adverse event was any unfavorable and unintended sign (including an
abnormal laboratory finding, for example), symptom, or disease
temporally associated with the use of a medicinal product, whether
or not considered related to the medicinal product. Changes
associated with normal growth and development not varying in
frequency or magnitude from that ordinarily anticipated clinically
are not adverse events (for example, onset of menstruation
occurring at a physiologically appropriate time). Clinical adverse
events were described by diagnosis and not by symptoms when
possible (for example, cold or seasonal allergies, instead of
"runny nose").
[0206] The severity of adverse events was graded on a 3-point scale
and reported in detail as indicated on the Case Report Form:
mild--easily tolerated, causing minimal discomfort, and not
interfering with normal everyday activities; moderate--sufficiently
discomforting to interfere with normal everyday activities; and
severe--incapacitating and/or preventing normal everyday
activities. The relationship of study medication to each adverse
event was determined by the investigator by using the following
definitions: not related--the event was clearly related to other
factors, such as the subject's clinical state, therapeutic
interventions, or concomitant medications administered to the
subject; unlikely--the event was most likely produced by other
factors, such as the subject's clinical state, therapeutic
interventions, or concomitant medications administered to the
subject, and did not follow a known response pattern to the study
drug; possible--the event followed a reasonable temporal sequence
from the time of drug administration, and/or followed a known
response pattern to the study drug, but could have been produced by
other factors, such as the subject's clinical state, therapeutic
interventions, or concomitant medications administered to the
subject; probable--the event followed a reasonable temporal
sequence from the time of drug administration, followed a known
response pattern to the trial drug, and could not be reasonably
explained by other factors, such as the subject's clinical state,
therapeutic interventions, or concomitant medications administered
to the subject; highly probable--the event followed a reasonable
temporal sequence from the time of drug administration, and
followed a known response pattern to the trial drug, and could not
be reasonably explained by other factors, such as the subject's
clinical state, therapeutic interventions, or concomitant
medications administered to the subject, and either occurs
immediately following study drug administration or improves on
stopping the drug or reappears on repeat exposure.
[0207] A serious adverse event was any adverse event occurring at
any dose that resulted in any of the following outcomes: death;
life-threatening experience (one that places the subject at
immediate risk of death from the adverse event as it occurred, for
example, it does not include an adverse event that, had it occurred
in a more severe form, might have caused death); persistent or
significant disability/incapacity (disability is a substantial
disruption of a person's ability to conduct normal life functions);
in-patient hospitalization or prolongation of hospitalization; and
congenital anomaly/birth defect.
[0208] Subjects were instructed to promptly report any adverse
event. The serious adverse event was assessed for the following
details: seriousness of event, start date, stop date, intensity,
frequency, relationship to test drug, action taken regarding test
drug, treatment required, and outcome to date. These details were
recorded on the Case Report Form. Such preliminary reports were
followed by detailed descriptions that included copies of hospital
case reports, autopsy reports, and other documents when requested
and applicable.
[0209] Blood and urine were collected at the screening visit and
Day 29 for clinical chemistry, hematology, urinalysis, and
pregnancy testing. In the event of an abnormal laboratory test
value, the test was repeated within one week, and the subject was
followed up until the value returned to the normal range and/or
until an adequate explanation of the abnormality was found.
[0210] Values were obtained for systolic and diastolic blood
pressure, heart rate, and respiration rate on the screening visit
and all other study visits. All values outside the pre-defined
ranges were flagged in the subject data listings.
Electrocardiography (twelve lead) was used to obtain ventricular
rate (VR), QT, Q-T, intervals, pulse rate (PR), and QRS duration. A
blood sample (10 mL whole blood) was taken from each subject at the
Screening Visit for CYP2D6 genotyping to determine which subjects
were poor metabolizers of DM and which were extensive metabolizers.
Blood samples were taken on Day 29 for the determination of
concentrations of DM, DX, and Q in plasma. The relationship between
the concentration of drug in plasma and changes in CNS-LS scores
was determined, and the effect of the CYP2D6 genotype on this
relationship was evaluated.
[0211] Sample sizes of forty-eight subjects in the 30DM/30Q group
and twenty-four subjects in each of the DM and Q groups were
sufficient to detect a difference in CNS-LS score of 5.5 between
the DM/Q group and each of the other groups. These calculations
were based on standard deviations of 7, 5, and 3 in the DM/Q, DM,
and Q groups, respectively. The power is approximately 85% based on
a 2-sided, 5% test, assuming baseline/Day 15 and baseline/Day 29
correlations are both 0.3, and the Day 15/Day 29 correlation is
0.7. The assumptions on which sample sizes were based were drawn
from a small, fourteen subject crossover study, in which DM/Q
subjects had a mean change from baseline of -6.6 points with
standard deviation of 7.5; and placebo-treated subjects had a mean
change of +0.83 with a standard deviation of 3.2.
[0212] A total of 140 subjects were randomized to treatment;
seventy were in the 30DM/30Q group, thirty-three were in the DM
group, and thirty-seven were in the Q group. The sample size
calculations required that there be only forty-eight subjects in
the 30DM/30Q group and twenty-four subjects in each of the other
treatment groups. Therefore, under the assumptions made in the
sample size calculations, the number of subjects in each group was
adequate to detect the defined difference in treatment effect. The
percent of subjects with compliance.gtoreq.80% was 73.5 in the
30DM/30Q group, 87.9 in the DM group, and 86.5 in the Q group.
[0213] Three data sets were analyzed in this study; the safety data
set consisting of data for 140 subjects, the intent-to-treat data
set consisting of data for 129 subjects, and the efficacy-evaluable
data set consisting of data for 101 subjects. The definitions of
these three populations are as follows: safety population--all
randomized subjects; intent-to-treat population--all randomized
subjects who are not "poor metabolizers" of cytochrome P450 2D6;
and efficacy evaluable population--all subjects in the ITT
population who were protocol adherent. Subjects were considered
adherent if they completed the visit on Day 29, completed all study
procedures, and took 80% of their scheduled doses.
[0214] The demographic characteristics of the ITT population are
provided in Table 26; the history of ALS is in Table 27, and the
scores at baseline for depression, pseudobulbar affect, QOL, and
QOR are in Table 28.
TABLE-US-00026 TABLE 26 P-values.sup.a 30DM/ 30DM/30Q DM Q 30Q
30DM/30Q Category (N = 65) (N = 30) (N = 34) vs DM vs Q Age (years)
n 65 30 34 Mean 54.82 53.77 55.32 0.7788 0.9976 Std Dev 12.79 11.25
9.47 Median 55 54 58 Min/Max 38/82 33/75 35/72 Gender, n (%) Female
23 (35.4) 14 (46.7) 12 (35.3) 0.1549 0.8105 Male 42 (64.6) 16
(53.3) 22 (64.7) Race, n (%) Asian 0 (0) 1 (3.3) 0 (0) 0.2100
0.5522 Black 2 (3.1) 0 (0) 0 (0) Caucasian 58 (89.2) 25 (83.3) 31
(91.2) Hispanic 5 (7.7) 3 (10.0) 3 (8.8) Other 0 (0.00) 1 (3.3) 0
(0.00) .sup.aP-values to compare means for continuous variables are
computed by using ANOVA with an adjustment for treatment and center
to obtain overall F-tests. P-values for categorical values were
computed by using Cochran-Mantel-Haenszel chi-square with an
adjustment for center.
TABLE-US-00027 TABLE 27 P-values.sup.a 30DM/ 30DM/30Q DM Q 30Q
30DM/30Q Category (N = 65) (N = 30) (N = 34) vs DM vs Q ALS Type, n
(%) Bulbar 29 (44.6) 14 (46.7) 21 (61.8) 0.8341 0.0793 Limb 36
(55.4) 16 (53.3) 13 (38.2) Weekly Episode of Laughing/Crying n 65
30 34 Mean 22.18 38.93 19.35 0.0897 0.7043 Std Dev 31.62 66.28
19.04 Median 11 17 13 Min/Max 2/210 1/350 2/70 .sup.aP-values to
compare means for continuous variables are computed by using ANOVA
with an adjustment for treatment and center to obtain overall
F-tests. P-values for categorical values were computed by using
Cochran-Mantel-Haenszel chi-square with an adjustment for
center.
TABLE-US-00028 TABLE 28 P-values.sup.b 30DM/ 30DM/ 30DM/ Baseline
30Q DM Q 30Q 30Q Characteristics.sup.a (N = 65) (N = 30) (N = 34)
vs DM vs Q HRSD N 65 30 34 Mean 5.37 4.27 5.79 0.1404 0.7066 Std
Dev 4.33 3.05 4.20 Median 4.0 3.5 5.0 Min/Max 0/16 0/14 0/15 CNS-LS
n 65 30 34 Mean 20.06 21.40 22.26 0.3202 0.0705 Std Dev 5.46 6.17
5.22 Median 19.0 20.0 21.0 Min/Max 11/33 13/35 13/33 VAS-QOL n 65
30 34 Mean 35.05 47.57 46.56 0.0209 0.0261 Std Dev 26.70 27.24
26.93 Median 33.0 48.5 42.0 Min/Max 0/96 5/95 2/100 VAS-QOR n 65 30
34 Mean 31.77 41.07 42.18 0.1435 0.0646 Std Dev 28.50 28.16 29.93
Median 28.0 41.5 34.5 Min/Max 0/99 0/95 0/100 .sup.aHRSD = Hamilton
Rating Scale for Depression; CNS-LS = Center for Neurologic Study
Lability Scale; VAS = Visual Analog Scale; QOL = Quality of Life;
QOR = Quality of Relationships. Baseline measurements for HRSD were
done at screening. Baseline measurements for CNS-LS, VAS-QOL, and
VAS-QOR were done on Day 1. .sup.bP-values to compare means were
computed by using ANOVA with an adjustment for treatment and center
to obtain overall F-tests.
[0215] There were no statistically significant differences between
the 30DM/30Q group and the DM and Q groups for any demographic
variable. The only statistically significant difference in the
baseline characteristics was in the QOL scores. Subjects in the
30DM/30Q group rated their QOL better at baseline than did the
subjects in either of the other two treatment groups. Similar
demographic results were obtained in the efficacy-evaluable
population, and the trend in the baseline characteristics was in
the same direction as that in the ITT population. The population of
interest in the primary and secondary analyses of efficacy was the
ITT population. Therefore, all results shown in the text are those
obtained from this population.
[0216] The primary efficacy analysis was the change from baseline
in CNS-LS scores, adjusted for center and baseline CNS-LS score.
The descriptive statistics for the ITT Population are in Table
29.
TABLE-US-00029 TABLE 29 Change in 30DM/30Q DM Q Score.sup.a (N =
65) (N = 30) (N = 34) n 61 30 34 Mean -7.39 -5.12 -4.91 Std Dev
5.37 5.56 5.56 Median -6.50 -4.50 -4.25 Min/Max -24.00/0.0
-25.00/2.0 -21.00/2.0 .sup.aChange in CNS-LS scores was defined as
the mean of scores on Day 15 and Day 29 minus the baseline (Day 1)
score.
[0217] The distributions of CNS-LS scores at baseline, Day 15, and
Day 29 for each of the three treatment groups are provided in FIG.
1. These distributions have not been adjusted for baseline scores
or for study site. As shown in FIG. 1, the distributions of CNS-LS
scores are symmetrical and contain only one outlier. These
distributions support the use of ANCOVA for the analysis of the
CNS-LS scores. As prospectively specified in the protocol, the
differences in mean improvement in CNS-LS scores, adjusted for
center and baseline CNS-LS scores, were analyzed by using linear
regression according to the ANCOVA method of Frison and Pocock. The
results of this analysis are in Table 30. The results of additional
analyses without any adjustments or with an adjustment for baseline
CNS-LS score alone are also in this table.
TABLE-US-00030 TABLE 30 30DM/30Q Statistics 30DM/30Q vs DM vs Q
Unadjusted difference in mean score -2.27 -2.47 Std Err 1.22 1.17
p-value 0.0652 0.0366 Difference in mean score adjusted for -2.97
-3.65 baseline CNS-LS score Std Err 1.03 1.00 p-value 0.0046 0.0004
Difference in mean score adjusted for -3.29 -3.71 baseline CNS-LS
score and center.sup.b Std Err 1.00 0.97 p-value 0.0013 0.0002
.sup.aChange in CNS-LS scores was defined as the mean of the scores
on Day 15 and Day 29 minus the baseline (Day 1) score.
.sup.bAnalysis in italics was pre-specified in the Statistical
Analysis Plan.
[0218] The mean score in the group treated with 30DM/30Q was
statistically significantly different from the mean scores of the
group treated with DM and from the mean scores of the group treated
with Q. Therefore, subjects treated with 30DM/30Q showed a
significant improvement in pseudobulbar affect.
[0219] The results for the analysis pre-specified in the protocol
are shown graphically in FIG. 2. Adjusted mean reductions in CNS-LS
scores for the three treatment groups from the primary efficacy
analysis of the ITT population. Reductions in CNS-LS scores below
the horizontal lines are statistically significantly different from
30DM/30Q at the significance levels indicated.
[0220] The primary efficacy analysis was also done for the
efficacy-evaluable and the safety populations. These results are in
Table 31. The results in these populations also showed that
30DM/30Q significantly improved pseudobulbar affect.
TABLE-US-00031 TABLE 31 P-values vs 30DM/30Q Statistics.sup.b DM Q
DM Q ITT Population (n = 125) Difference vs 30DM/ -3.29 -3.71
0.0013 0.0002 30Q Std Error 1.00 0.97 Efficacy Evaluable Population
(n = 101) Difference vs 30DM/ -3.78 -5.00 0.0009 <0.0001 30Q Std
Error 1.10 1.10 Safety Population (n = 136) Difference vs 30DM/
-3.09 -4.23 0.0016 <0.0001 30Q Std Error 0.96 0.93 .sup.aThe ITT
and EFF populations excluded poor metabolizers. .sup.bDifferences
are mean differences in the CNS-LS reduction, controlling for
baseline CNS-LS and study site, using the analysis pre-specified in
the Statistical Analysis Plan.
[0221] The results in these populations also showed that 30DM/30Q
significantly improved pseudobulbar affect.
[0222] The primary efficacy data were also analyzed by using linear
regression according to the ANCOVA method of Frison and Pocock with
an adjustment for center, baseline CNS-LS scores, and
treatment-by-center interaction. Because of small sample sizes at
some centers, this interaction could not be estimated.
[0223] An analysis of secondary efficacy data was conducted. Weekly
episode counts were analyzed by using the Poisson regression model
as specified in the statistical analysis plan, and the results are
in Table 32.
TABLE-US-00032 TABLE 32 Episode.sup.a 30DM/30Q DM Q Statistic (N =
65) (N = 30) (N = 34) Laughing n 62 30 34 Wtd. Mean.sup.b 4.70
35.29 6.79 Wtd. Std Dev 49.66 709.97 53.93 Median 0.66 2.50 2.23
Min/Max 0.00/116.67 0.00/726.55 0.00/45.00 Crying n 62 30 34 Wtd.
Mean.sup.b 2.04 4.30 5.64 Wtd. Std Dev 33.99 32.86 28.14 Median
0.44 0.70 4.00 Min/Max 0.00/66.00 0.00/21.00 0.00/19.83
Laughing/Crying n 62 30 34 Wtd. Mean.sup.b 6.74 39.58 12.45 Wtd.
Std Dev 69.23 707.62 69.91 Median 2.00 8.97 6.19 Min/Max
0.00/116.67 0.00/726.55 0.00/49.00 .sup.aThe number of episodes
were collected continuously by each subject in a diary. The diaries
were reviewed at the visits on Days 15 and 29. .sup.bThe mean
across all subjects was the weighted mean of each subject's mean
(total number of episodes divided by the total number of days). The
weight is the number of days in the study for each subject.
[0224] This analysis of episode rates, pre-specified in the
protocol, showed that total episodes were 6.4 times greater
(calculated by using the episode rates from the Poisson regression
model with an adjustment for center) in the DM group than in the
30DM/30Q group and were 1.9 times greater in the Q group than in
the 30DM/30Q group. A single outlier in the DM group was a subject
who reported 10 times more episodes than any other subject in the
study--an average of over 100 episodes per day. When this outlier
was omitted, the ratios were 2.3 and 1.8 for the DM and Q groups,
respectively. In each case, the calculated p-values were
<0.0001. Separate assessments for crying and laughing were also
highly statistically significant. This subject's extreme episodes
counts were primarily laughing episodes; as a result, the estimated
effects on crying were changed little by omitting this subject.
[0225] For the assessments for episode counts described above,
there is evidence of substantial overdispersion in the data,
signifying that the data did not meet the assumptions of the model.
A number of additional analyses were carried out to assess the
sensitivity of the conclusions to model specification; these
analyses are discussed below.
[0226] When the data were analyzed by using the quadratic-variance
(mean dispersion) negative binomial model (one model for
overdispersion), the results indicated that 30DM/30Q crying rates
were twice as large as those for DM (p=0.06) and 4.5 times as large
as those for Q (p<0.001). The corresponding factors for laughing
were 2.6 (p=0.10) and 0.9 (p=0.84) and for total are 2.6 (p=0.013)
and 1.5 (p=0.29). However, there is a continued lack of fit of the
data in this model also.
[0227] The data were also analyzed by using the
proportional-variance (constant dispersion) negative binomial model
(another model that takes overdispersion into account). The
results, indicated by an analysis of residuals, showed a better fit
to this overdispersed data. The estimated ratios from this model
for crying were 2.0 (p=0.007) and 3.3 (p<0.001) relative to DM
and Q, respectively. For laughing, the ratios were 1.4 and 1.5,
with p-values of 0.21 and 0.13 for DM and Q, respectively. (With
the outlier subject omitted, the laughing ratios were 1.5 (p=0.14)
and 1.6 (p=0.05). Total counts had ratios of 1.7 and 1.8, with
p-values 0.02 and 0.006 relative to DM and Q, respectively.
[0228] When center was omitted from the model as a sensitivity
analysis, the magnitude of response was similar to the analyses
with center. The p-values increased somewhat, as expected. The
normal probability plots of residuals from these models, however,
indicate that adjustment for center substantially improved the
normality of the residuals.
[0229] Additional studies to determine the sensitivity of the
results to model assumptions were also carried out. These analyses
explored nonparametric approaches, as well as an assessment
designed to examine "steady-state" differences between groups.
[0230] The assessment of statistical significance of the relative
effects of 30DM/30Q, DM, and Q is dependent on the model
assumptions used. However, statistical estimates of the relative
effects in all models consistently favored 30DM/30Q over DM and Q,
even when statistical significance was not reached. In the model
for which the assumptions best describe the observed data, these
differences were statistically significant.
[0231] To help quantify and understand how changes in the primary
efficacy variable, CNS-LS score, affect episode count, the effect
of a 1-point difference in CNS-LS score on the episode rate during
the previous two weeks was estimated. For each 1-point increase in
CNS-LS score, the average episode rate increased 12%. Thus, a
3.5-point decrease in CNS-LS score would correspond to a 50%
decrease in episode rate. This was true for both laughing and
crying episodes. Summary statistics of QOL and QOR scores are in
provided in Table 33.
TABLE-US-00033 TABLE 33 30DM/30Q DM Q Change in Score.sup.a (N =
65) (N = 30) (N = 34) All Days QOL n 51 27 32 Mean -23.34 -17.41
-18.97 Std Dev 24.38 27.61 28.30 Median -19.0 -11.0 -14.3 Min/Max
-84.0/29 -90.5/27 -98.0/19 QOR n 51 27 32 Mean -22.36 -9.98 -14.14
Std Dev 27.32 22.09 27.54 Median -12.00 -4.50 -10.50 Min/Max
-90.0/24.0 -71.0/23.5 -74.5/42.0 Day 15 QOL n 52 28 33 Mean -20.54
-17.14 -15.94 Std Dev 23.05 29.06 28.51 Median -18 -13 -6 Min/Max
-84/28 -90/55 -96/22 QOR n 52 28 33 Mean -20.77 -11.75 -12.15 Std
Dev 26.11 24.88 29.05 Median -10 -7 -2 Min/Max -89/25 -71/34 -84/41
Day 29 QOL n 60 29 33 Mean -24.13 -19.31 -21.15 Std Dev 25.77 29.29
30.97 Median -17 -7 -14 Min/Max -90/30 -91/27 -100/23 QOR n 59 29
33 Mean -22.42 -10.38 -15.67 Std Dev 27.92 23.62 27.85 Median -13.0
-3.0 -13.0 Min/Max -91/34 -71/26 -77/43 .sup.aThe change in VAS
scores for all days was defined as the mean of the scores on Days
15 and 29 minus the score on Day 1; the change in score for Day 15
was defined as the score on Day 15 minus the score on Day 1; and
the score on Day 29 was defined as the score on Day 29 minus the
score on Day 1.
[0232] The differences in the mean changes in QOL and QOR scores
between 30DM/30Q and DM and Q, adjusted for baseline and study
site, are in Table 34. The group treated with 30DM/30Q showed a
statistically significant improvement in these scores when compared
with the group treated with DM and compared with the group treated
with Q. These results were similar for all time periods.
TABLE-US-00034 TABLE 34 Variable Statistics.sup.a 30DM/30Q vs DM
30DM/30Q vs Q All Days QOL Difference -15.00 -14.67 Std Err 4.58
4.44 p-value.sup.b 0.0015 0.0013 QOR Difference -18.35 -16.08 Std
Err 4.27 4.16 p-value <0.0001 0.0002 Day 15 QOL Difference
-11.11 -12.60 Std Err 4.03 4.63 p-value 0.0235 0.0077 QOR
Difference -15.04 -15.25 Std Err 4.49 4.32 p-value 0.0012 0.0006
Day 29 QOL Difference -16.33 -13.57 Std Err 4.78 4.62 p-value
0.0009 0.0041 QOR Difference -19.14 -14.77 Std Err 4.33 4.24
p-value <0.0001 0.0007 .sup.aChange in VAS "all-day" scores was
defined as the mean of the scores on Day 15 and Day 29 minus the
baseline (Day 1) score. Change in the scores on Day 15 and Day 29
was defined as the score on that day minus the baseline score.
Differences in changed scores were adjusted for baseline levels and
center effects. .sup.bP-values were computed by using linear
regression according to the ANOVA method of Frison and Pocock with
an adjustment for center and baseline QOL and QOR scores.
[0233] To account for multiple comparisons, all the secondary
efficacy variables were combined and analyzed simultaneously by
using the O'Brien Rank Sum Method, as specified in the protocol.
The results showed that subjects treated with 30DM/30Q had a
statistically significant reduction in episodes of laughing and
crying and an improvement in QOL and QOR relative to the subjects
treated with DM (p=0.0041) or Q (p=0.0001) after adjustment for
multiple comparisons. 30DM/30Q was statistically significantly
better that either DM or Q in improving pseudobulbar affect, number
of episodes of laughing and crying, QOL, and QOR in subjects with
ALS.
[0234] The extent of exposure to study medication, in terms of
number of doses taken, is reported in Table 35. The mean days of
exposure were very similar across all treatment groups.
TABLE-US-00035 TABLE 35 30DM/30Q DM Q Exposure Statistics.sup.a (N
= 70) (N = 33) (N = 37) n 68 33 36 Mean 24.4 27.6 28.0 Std Dev 9.66
6.25 4.40 Median 29.0 29.0 29.0 Min/Max 3/32 7/33 5/32
.sup.aExposure was calculated by using the date of the last dose of
study drug minus the date of the first dose of study drug + 1.
[0235] Nausea was the most common adverse event experienced, and it
afflicted more subjects [twenty-three (32.9%)] in the 30DM/30Q
group than in either the DM [2 (6.1%)] or the Q [3 (8.1%)] groups.
However, in the 30DM/30Q group, nausea was judged to be mild or
moderate in twenty of the twenty-three subjects, but it was judged
to be at least possibly related to treatment with 30DM/30Q in
nineteen of the twenty-three subjects. All instances of nausea in
the DM and Q groups were mild or moderate, and all but one was
judged to be at least possibly related to treatment. Dizziness was
also reported by more subjects [fourteen (20%)] in the 30DM/30Q
group than in either the DM [five (15.2%)] or the Q [one (2.7%)]
groups. All instances of this adverse event in all treatment groups
were mild or moderate, and almost all were judged to be at least
possibly related to treatment. Somnolence was the third event that
was reported by more subjects [nine (12.9%)] in the 30DM/30Q group
than in either the DM [one (3.0%)] or the Q [zero (0%)] groups. All
instances of this adverse event in all treatment groups were mild
or moderate, and almost all were judged to be at least possibly
related to treatment. Three subjects experienced loose stools as an
adverse event, and all of them were in the DM group. All instances
of the event were mild, and all were judged to be related to
treatment.
[0236] A total of twenty-two subjects withdrew from the study
because of adverse events; seventeen (24.3%) were in the 30DM/30Q
group, two (6.1%) in the DM group, and three (8.1%) in the Q group.
The seventeen subjects in the 30DM/30Q group experienced fifty
adverse events, and most of these [seventeen (34%)] were related to
the nervous system. All of these fifty events except four were mild
or moderate, and all but one were judged to be at least possibly
related to treatment. One subject had a severe headache, one
subject had severe nausea and severe vomiting, and one subject had
severe respiratory failure. The subject died as a result of the
respiratory failure. This was judged not related to study
medication. The other two subjects recovered without sequelae.
[0237] In the DM group, there were seven adverse events experienced
by two subjects. All of these events except one were mild or
moderate, and all were judged to be related to treatment. One
subject, who had six of the seven adverse events, experienced
severe diarrhea; received appropriate drug treatment for this
condition; and recovered without sequelae.
[0238] Three subjects in the Q group experienced five adverse
events. One subject had a severe kidney infection that was judged
to be not related to treatment, and one subject had severe muscle
cramping that was judged to be related to treatment. Both of these
subjects recovered without sequelae. All other adverse events were
mild or moderate, and most were judged to be not related to
treatment.
[0239] Overall, there were four serious adverse events experienced
by subjects in this study. Three subjects in the 30DM/30Q group
reported serious adverse events, but only one of these discontinued
taking the drug. All three of these serious adverse events were
judged to be not related to the study drug. The only other serious
adverse event was experienced by a subject in the Q group. This
subject continued on the study drug, and the event was also judged
to be not related to the study drug. There was one death during the
study; one subject in the 30DM/30Q group died because of
respiratory failure unrelated to study treatment.
[0240] There was no statistically significant change in hematology,
clinical chemistry, or urinalysis values from Baseline to Day 29 in
any treatment group, nor any statistically significant change among
the treatment groups in any laboratory value except a significant
increase in CPK in the DM group relative to the 30DM/30Q group.
There were no clinically relevant changes from Baseline to Day 29
in systolic blood pressure, diastolic blood pressure, heart rate,
or respiration. There were no clinically relevant changes from
Baseline to Day 29 in the results of physical examinations. There
was a statistically significant difference in the change from
Baseline to Day 29 in VR and in the QT interval between the
30DM/30Q and Q groups. However, these changes were so small that
they were not clinically relevant. There was no statistically
significant difference among the treatment groups in QT.sub.c, PR,
and QRS duration.
[0241] Since the nature, frequency, and intensity of the adverse
events were within acceptable limits in this subject population,
and there were no clinically relevant findings for any other safety
variable, 30DM/30Q is safe in this subject population.
[0242] The CYP2D6 genotypes in each treatment group of the safety
population were determined and are provided in Table 36. As defined
in the Statistical Analysis Plan, the ITT population did not
include poor metabolizers. Extensive metabolizer was the most
prevalent genotype in all treatment groups in the ITT
population.
TABLE-US-00036 TABLE 36 30DM/ 30Q DM Q (N = 70) (N = 33) (N = 37)
Genotype n (%) n (%) n (%) Poor metabolizer 5 (7.2) 3 (9.1) 3 (8.1)
Extensive metabolizer 61 (88.4) 30 (90.9) 32 (86.5) Ultrarapid
metabolizer 3 (4.3) 0 (0.0) 2 (5.4)
[0243] Q in this combination product inhibits the rapid first-pass
metabolism of DM. Therefore, it was expected that the
concentrations of DM in plasma would be higher and the
concentration of its metabolite, DX, would be lower in subjects who
had received 30DM/30Q. The concentrations of DM and DX in the group
receiving 30DM/30Q and the group receiving DM are provided in Table
37.
TABLE-US-00037 TABLE 37 30DM/30Q DM N = 70 N = 33 P-values.sup.b
Statistics DM DX DM DX DM DX n 35 35 23 23 Mean 96.37 89.46 5.18
295.92 <0.0001 <0.0001 Std Dev 46.71 52.25 4.97 143.21 Median
96.26 78.24 4.55 262.35 Min/Max 1.07/212.40 8.17/235.27 0.35/15.81
101.07/526.65 .sup.aOnly those subjects whose time of blood
collection was within 8 hours of the time of their last dose of
study medication were included in this table. .sup.bP-value from
ANOVA with adjustment for treatment.
[0244] The mean DM concentration was 18.6-fold higher in the
30DM/30Q group than in the DM group, and the mean DX concentration
was 3.3-fold lower in the 30DM/30Q group than in the DM group.
These differences were both statistically significant. The data for
the levels in plasma of all subjects show the same results as in
those subjects whose blood was collected within eight hours of the
last dose of study medication.
[0245] The results of the study demonstrate that 30DM/30Q was
statistically significantly more effective than its components in
the treatment of pseudobulbar affect as indicated by the primary
and all secondary endpoints. Expected adverse events were reported,
and no unexpected safety issues emerged. More subjects in the
30DM/30Q group had adverse events than in either of the other
groups, and seventeen subjects in the 30DM/30Q group discontinued
the study because of adverse events; however, all adverse events
except four in the subjects who discontinued were mild or moderate.
Only two of the seventeen subjects had severe adverse events
(headache, nausea, vomiting), and these events, although
debilitating, resolved without sequelae. There were three subjects
treated with 30DM/30Q with serious events, and all of the events
were unrelated to this treatment. Furthermore, as the results of
the assessments of QOL and QOR were markedly and statistically
significantly better in the subjects treated with 30DM/30Q, the
benefits of the drug outweighed any discomfort caused by the
adverse events. Therefore, 30DM/30Q was very effective in treating
pseudobulbar affect in ALS subjects, and the drug was safe and well
tolerated.
Clinical Study #5
[0246] The primary objective of this study was to evaluate the
safety and tolerability of capsules containing dextromethorphan
hydrobromide and quinidine sulfate (DM/Q) during an open-label,
dose-escalation study to the subject's maximum tolerated dose
(MTD), not to exceed 120 mg DM/120 mg Q per day. The secondary
objective was to obtain a preliminary assessment of the efficacy of
DM/Q in the treatment of pain associated with diabetic
neuropathy.
[0247] This was an open-label, dose-escalation study in subjects
experiencing pain associated with diabetic neuropathy. After
screening for inclusion/exclusion criteria, subjects underwent a
washout period during which all analgesics were discontinued. This
was followed by twenty-nine days of treatment with capsules
containing 30 mg DM/30 mg Q, beginning with one capsule per day and
escalating approximately weekly to a maximum permitted dose of four
capsules per day. Subjects who could not tolerate a dose level
could return to the previous level; could substitute a capsule
containing 15 mg DM/30 mg Q; or, if they were unable to tolerate
the lowest dose level, could be discontinued from the study.
[0248] Subjects were screened for general health, including
electrocardiography, within four weeks before Day 1 of dosing. The
first dose of DM/Q was administered at the clinic, and a resting
electrocardiogram was obtained one hour after this dose and
interpreted on site. If the corrected QT interval (QT.sub.c)
determined in this preliminary interpretation was not .gtoreq.450
msec for males or .gtoreq.470 msec for females, and the QT.sub.c
did not change from the screening electrocardiogram by more than 30
msec, the subject was issued study medication to take as directed
by the physician. The subject was instructed on the use of a daily
diary to record study medication taken and scores from rating
scales for sleep, present and average pain intensity, and
activity.
[0249] Subjects visited the clinic every two weeks during the
four-week duration of the study and were contacted by telephone
during weeks without clinic visits. At each subsequent study visit
or weekly phone call, the subjects were given the Pain Intensity
Rating Scale and the Pain Relief Rating Scale and were queried
regarding any adverse events that might have occurred since their
previous visit. Subjects were administered the Peripheral
Neuropathy Quality of Life (QOL) Instrument on Days 1 and 29 (or
the final visit). Blood samples were taken at the visits on Day 15
and Day 29 to determine concentrations in plasma of DM, DX, and
Q.
[0250] Subjects selected were 18 to 80 years of age, inclusive, and
had a confirmed diagnosis of diabetes mellitus. Subject had
acceptable glycemic control, with total glycosylated hemoglobin
(HbA1c) <12%, had been on established diabetic therapy for at
least 3 months, had a clinical diagnosis of distal symmetrical
diabetic neuropathy, and had daily pain associated with diabetic
neuropathy for the previous 3 months. Subjects scored moderate or
greater 2) on the Pain Intensity Rating Scale before receiving DM/Q
on Day 1.
[0251] Every effort was made to continue each subject in the study.
However, if a subject decided to withdraw, all efforts were made to
complete all assessments and an explanation of why the subject
withdrew from the study was provided.
[0252] Subjects received capsules containing 30 mg DM/30 mg Q or 15
mg DM/30 mg Q in increasing dosages, to a maximum of 120 mg DM/120
mg Q. Study medications were provided as hard gelatin capsules;
Capsule A was opaque orange, and Capsule B was opaque white. The
contents of the capsules are listed in Table 38.
TABLE-US-00038 TABLE 38 Amount (mg) Capsule A Capsule B.sup.a
Ingredient 30 mg DM/30 mg Q 15 mg DM/30 mg Q Dextromethorphan
31.50.sup.b 15.75.sup.c hydrobromide monohydrate USP (DM) Quinidine
sulfate dihydrate 31.40.sup.d 31.40.sup.d USP (Q) Croscarmellose
sodium NF 7.80 7.80 Microcrystalline cellulose NF 94.00 101.87
Colloidal silicone dioxide NF 0.050 0.065 Lactose monohydrate NF
94.00 101.88 Magnesium stearate NF 0.05 0.05 .sup.aFor optional use
if Capsule A was not tolerated. .sup.bEquivalent to 30.0 mg
dextromethorphan hydrobromide. .sup.cEquivalent to 15.0 mg
dextromethorphan hydrobromide. .sup.dEquivalent to 30.0 mg
quinidine sulfate.
[0253] Subjects received capsules containing DM/Q in escalating
doses, as indicated in Table 39. Subjects who could not tolerate a
dose level were permitted to return to the previous level,
substitute a capsule containing 15 mg DM/30 mg Q, or be
discontinued from the study if they were unable to tolerate the
lowest dose level.
TABLE-US-00039 TABLE 39 AM Dose PM Dose Total Daily Dose Number of
DM Q Number of DM Q Number of DM Q Study Day Capsules (mg) (mg)
Capsules (mg) (mg) Capsules (mg) (mg) 1 (in clinic) 0 0 0 1 30 30 1
30 30 2 to 3 0 0 0 1 30 30 1 30 30 4 to 13 1 30 30 1 30 30 2 60 60
14 to 20 1 30 30 2 60 60 3 90 90 21 to 29 2 60 60 2 60 60 4 120
120
[0254] Subjects could not take any disallowed medications during
the study or for one week (or two weeks, where applicable) before
the start of dosing on Day 1. These medications included:
amantadine; amitriptyline; any antidepressant medication, including
St. John's Wort; any monoamine oxidase inhibitor; analgesics (only
acetaminophen could be used); captopril; cimetidine; carbonic
anhydrase inhibitors; desipramine; dextromethorphan (OTC cough
medicines); digoxin; diltiazem; erythromycin; fluoxetine;
haloperidol; imipramine; itraconazole; ketoconazole; nortriptyline;
paroxetine; quinidine or other antiarrhythmic drugs; sodium
bicarbonate; thiazide diuretics; and verapamil. If a subject was
unable to complete the washout period without analgesia, he/she was
permitted to begin the dose-escalation phase of the study, provided
that sufficient washout of other disallowed, non-pain medications
had occurred. Daily, low-dose aspirin was not considered an
analgesic and was permitted for cardiac prophylaxis.
[0255] Acetaminophen was the only analgesic permitted as a rescue
pain medication and was to be taken at the dosage specified on the
package label. Subjects were instructed to consult the study clinic
before taking any medication, including over-the-counter (OTC)
medications, and they were counseled that acetaminophen-containing
products that also contained other analgesics (e.g., codeine) or
dextromethorphan should be avoided.
[0256] Subjects were instructed to bring unused study medication to
the clinic on Day 15 and to return all unused study medication to
the clinic at the final visit. Diary cards were collected from
subjects at these visits. The percent of doses taken was calculated
as the total number of doses taken divided by the total number of
doses prescribed, multiplied by 100.
[0257] Safety was assessed by the following measurements: adverse
events; clinical laboratory values; vital signs; physical
examinations; electrocardiograms; and measurements of nerve
conduction velocity.
[0258] Subjects underwent nerve conduction studies at Screening and
on Day 29 (or the final visit). Nerve conduction velocity was
measured with surface stimulation and recording. Bilateral sural
nerve sensory studies and a unilateral peroneal nerve motor study
were performed or supervised by a clinical electromyographer
certified by the American Board of Electrodiagnostic Medicine.
Techniques were standardized to minimize variability among
electromyographers. Limb temperature was maintained above a
standard temperature in all studies. Results were interpreted at a
central reading laboratory.
[0259] Efficacy was assessed through the following instruments:
Pain Intensity Rating Scale; Diary Present Pain Intensity Scale;
Pain Relief Rating Scale; Diary Activity Rating Scale; Peripheral
Neuropathy QOL Instrument; Diary Average Pain Rating Scale; and
Diary Sleep Rating Scale.
[0260] Score on the Pain Intensity Rating Scale was determined on
Day 8, Day 15, Day 22, and Day 29 (or the final visit). Subjects
indicated the amount of pain experienced in the lower extremities
within the previous twenty-four hours by using a 5-point Likert
scale (0=None, 1=Mild, 2=Moderate, 3=Severe, 4=Extreme). Subjects
were required to complete the Pain Intensity Rating Scale at the
clinic on Day 1, before entry into the study and on Day 15 and Day
29 (or the final visit). The scale was also administered verbally
in telephone calls to the subject during weeks when no clinic visit
was scheduled (Day 8 and Day 22).
[0261] The Pain Relief Rating Scale was completed on Day 8, Day 15,
Day 22, and Day 29 (or the final visit). Subjects indicated the
amount of pain relief experienced in the lower extremities relative
to the end of the washout/screening phase by using a 6-point Likert
scale (-1=Worse, 0=None, 1=Slight, 2=Moderate, 3=A lot,
4=Complete). Subjects were required to complete the scale at the
clinic on Day 15 and Day 29 (or the final visit). The Pain Relief
Rating Scale was also administered verbally in telephone calls to
the subject during weeks when no clinic visit was scheduled (Day 8
and Day 22).
[0262] The QOL score was obtained at the clinic on Day 1 and Day 29
(or the final visit). QOL was assessed by using the Peripheral
Neuropathy QOL Instrument-97 as in Vickrey et al., Neurorehabi.
Neural. Repair, 2000; 14:93-104. This is a self-administered,
health-related, QOL measure for peripheral neuropathy. It
incorporates the Health Status Survey SF-36 scale in its entirety
and includes additional questions determined to be particularly
relevant to subjects with peripheral neuropathy.
[0263] The instrument comprises 21 subscales containing items about
general health issues, specific peripheral neuropathy issues,
health symptoms or problems, assessment of overall health, and
feelings in general and about health. All of the items use 3-, 4-,
5-, or 6-point categorical rating scales, except for number of
disability days, overall health rating (0 to 100), and a yes/no
question about sexual activity.
[0264] To analyze the QOL results, a scoring algorithm was used to
convert the categorical item ratings to appropriate percent
ratings. The most favorable rating was 100%, the least favorable
was 0%, and the intermediate percents were spaced at equal
intervals, depending on the number of points in the scale (e.g., 0,
25, 50, 75, 100 for a 5-point ascending scale; 100, 50, 0 for a
3-point descending scale). The converted ratings for each item in a
subscale were averaged to provide the subscale scores. All subscale
scores were constructed so that a higher value reflected a more
favorable result. The composite QOL score was obtained by averaging
all subscale scores, except for number of disability days.
[0265] The subject diary included a sleep rating scale and a
present pain intensity scale to be completed in the morning, and an
activity rating scale and an average pain rating scale to be
completed in the evening. In the Sleep Rating Scale, subjects were
instructed to circle the number on a scale of 0 to 10 that best
described the extent that pain had interfered with their sleep in
the past 24 hours (0=Does not interfere and 10=Completely
interferes). In the Present Pain Intensity Scale, subjects were
instructed to circle the statement that best described their
present pain intensity: O--No Pain; 1--Mild; 2--Discomforting;
3--Distressing; 4--Horrible; and 5--Excruciating. In the Activity
Rating Scale, subjects were instructed to circle the number on a
scale of 0 to 10 (the same as the Sleep Rating Scale) that best
described the extent that pain had interfered with their general
activity in the past 24 hours (0=Does not interfere and
10=Completely interferes). In the Average Pain in Past 12 Hours
Rating Scale, subjects were instructed to circle the number on a
scale of 0 to 10 (the same as the Sleep Rating Scale) that best
described their average pain intensity during the past 12 hours
(0=None and 10=Worst pain ever). The rating scales used as efficacy
measures are well-established instruments in pain research, and the
Peripheral Neuropathy QOL instrument, in particular, contains
material that is specific for subjects with peripheral
neuropathy.
[0266] Efficacy evaluations consisted of inferential analyses and
summary statistics, calculated on all subjects and on subjects
categorized by MTD, for the following variables (except where
noted): change from baseline in the Pain Intensity Rating Scale
score on Days 8, 15, 22, and 29 (or the final visit); the Pain
Relief Rating Scale score on Days 8, 15, 22, and 29 (or the final
visit); change from baseline in the composite score on the
Peripheral Neuropathy Quality of Life Instrument on Day 29 (or the
final visit); Sleep Interference score calculated from values
recorded in the diary for the Sleep Rating Scale (the score for Day
15 was the average of the Sleep Rating Scale scores from the
subject diary for Days 13, 14, and 15; the score for Day 29 was the
average of the Day 27, 28, and 29 scores; and the Final Visit score
was the average of scores from the final 3 consecutive days of
study treatment); Daily Present Pain Intensity, Activity, Pain, and
Sleep Rating scales, recorded in subject diaries; the percent of
subjects experiencing improved scores for each of the efficacy
variables.
[0267] The disposition of subjects is provided in FIG. 3. Subjects
are classified by MTD group in this figure and in subsequent
summary tables and figures. Except for a subject with an MTD of 45
mg, who was classified with the 60-mg group (see below), subjects
in the 30-, 60-, and 90-mg groups received the MTDs indicated.
Subjects in the 120-mg group tolerated this dose, which was the
highest dose permitted in the study but is technically not an MTD.
For brevity these groupings are all referred to as "MTDs."
[0268] Of the thirty-six subjects who were enrolled and received
study medication, thirty-three completed the study. One subject
completed the study with an MTD of 45 mg DM. Because there was only
one subject with this MTD, this subject is included with the 60-mg
MTD group in the data tables and in FIG. 3. The number of subjects
in each MTD group and overall in each study site is reported in
Table 40.
TABLE-US-00040 TABLE 40 MTD (mg) Site 30 45 60 90 120 Total 01 1 0
0 0 4 5 02 1 0 0 0 3 4 03 0 0 3 0 0 3 04 2 1 2 2 5 12 05 1 0 0 0 11
12 Total 5 1 5 2 23 36
[0269] Only one population was used in the data analyses. Analyses
and summaries were performed by using all 36 subjects who took
study medication. The demographic characteristics of the study
population are reported in Table 41.
TABLE-US-00041 TABLE 41 Maximum Tolerated Dose (mg).sup.a 30.sup.b
60.sup.c 90 120 Total Characteristic (N = 5) (N = 6) (N = 2) (N =
23) (N = 36) Age (years) n 5 6 2 23 36 Mean 62.2 57.7 57.0 57.1
57.9 SD.sup.d 10.99 8.14 9.90 11.99 10.94 Median 65.0 59.0 57.0
56.0 57.0 Min/Max 49/77 45/67 50/64 22/78 22/78 Gender, n (%) Male
4 (80.0) 3 (50.0) 1 (50.0) 11 (47.8) 19 (52.8) Female 1 (20.0) 3
(50.0) 1 (50.0) 12 (52.2) 17 (47.2) Race, n (%) Caucasian 3 (60.0)
5 (83.3) 2 (100.0) 15 (65.2) 25 (69.4) Black 1 (20.0) 0 (0.0) 0
(0.0) 2 (8.7) 3 (8.3) Asian 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Other.sup.e 1 (20.0) 1 (16.7) 0 (0.0) 6 (26.1) 8 (22.2)
.sup.aMaximum Tolerated Dose is the last dose taken when the
subject left or completed the study. .sup.bThis group included
subjects who took two 15-mg capsules/day as well as subjects who
took one 30-mg capsule/day. .sup.cThis group included one subject
whose MTD was 45 mg. .sup.dSD = Standard deviation. .sup.eAll of
the subjects in the category "Other" were described as
Hispanic.
[0270] The history of the subjects' diabetic neuropathy is
summarized in Table 42.
TABLE-US-00042 TABLE 42 Maximum Tolerated Dose (mg).sup.a 30.sup.b
60.sup.c 90 120 Total Characteristic (N = 5) (N = 6) (N = 2) (N =
23) (N = 36) Duration of Diabetic Neuropathy (years) n 5 6 2 23 36
Mean 3.9 3.8 3.2 5.3 4.7 SD 4.30 5.01 0.21 6.35 5.63 Median 2.5 0.9
3.2 2.4 2.5 Min/Max 0.6/11.4 0.2/10.4 3.0/3.3 0.5/24.3 0.2/24.3
Duration of Daily Pain (months) n 5 6 2 23 36 Mean 30.2 30.0 9.0
38.0 34.0 SD 30.99 17.47 4.24 46.32 39.42 Median 24.0 27.0 9.0 18.0
24.0 Min/Max 7/84 7/60 6/12 4/180 4/180 .sup.aMaximum Tolerated
Dose is the last dose taken when the subject left or completed the
study. .sup.bThis group included subjects who took two 15-mg
capsules/day as well as subjects who took one 30-mg capsule/day.
.sup.cThis group included one subject whose MTD was 45 mg.
[0271] Subjects enrolled in the study had received their diagnosis
of diabetic neuropathy a minimum of 0.2 years and a maximum of 24.3
years previously (median of 2.5 years). Subjects had experienced
daily pain from their diabetic neuropathy for a minimum of four
months and a maximum of 180 months/15.0 years (median of 24.0
months/2.0 years).
[0272] Concomitant medications were reported for up to 30 days
before the study and throughout the treatment period. Concomitant
medications reported by at least 10% of subjects overall are listed
in Table 43 by WHO term.
TABLE-US-00043 TABLE 43 Maximum Tolerated Dose (mg).sup.a 30.sup.b
60.sup.c 90 120 Total Drug Category (N = 5) (N = 6) (N = 2) (N =
23) (N = 36) WHO Preferred Term n (%) n (%) n (%) n (%) n (%)
Analgesics Paracetamol (acetaminophen) 0 (0.0) 1 (16.7) 1 (50.0) 2
(8.7) 4 (11.4) ACE inhibitors Lisinopril 0 (0.0) 1 (16.7) 0 (0.0) 4
(17.4) 5 (14.3) Diuretics Furosemide 0 (0.0) 1 (16.7) 0 (0.0) 4
(17.4) 5 (14.3) Hydrochlorothiazide 2 (40.0) 1 (16.7) 0 (0.0) 2
(8.7) 5 (14.3) Anticoagulants Acetylsalicylic acid.sup.d 1 (20.0) 2
(33.3) 1 (50.0) 6 (26.1) 10 (28.6) Lipid-lowering agents
Atorvastatin 1 (20.0) 0 (0.0) 0 (0.0) 5 (21.7) 6 (17.1)
Antidiabetic agents Glibenclamide 1 (20.0) 1 (16.7) 1 (50.0) 5
(21.7) 8 (22.9) Glipizide 0 (0.0) 2 (33.3) 0 (0.0) 2 (8.7) 4 (11.4)
Insulin 2 (40.0) 0 (0.0) 0 (0.0) 3 (13.0) 5 (14.3) Insulin human
injection, isophane 0 (0.0) 2 (33.3) 0 (0.0) 2 (8.7) 4 (11.4)
Metformin 1 (20.0) 1 (16.7) 1 (50.0) 6 (26.1) 9 (25.7) Metformin
hydrochloride 0 (0.0) 1 (16.7) 0 (0.0) 6 (26.1) 7 (20.0) Oral
antidiabetics 4 (80.0) 1 (16.7) 1 (50.0) 11 (47.8) 17 (48.6)
Nutritional supplements Ascorbic acid 1 (20.0) 0 (0.0) 1 (50.0) 2
(8.7) 4 (11.4) Calcium 1 (20.0) 1 (16.7) 1 (50.0) 3 (13.0) 6 (17.1)
Multivitamins 0 (0.0) 0 (0.0) 1 (50.0) 3 (13.0) 4 (11.4) Tocopherol
1 (20.0) 0 (0.0) 0 (0.0) 4 (17.4) 5 (14.3) Other Levothyroxine
sodium 0 (0.0) 0 (0.0) 1 (50.0) 3 (13.0) 4 (11.4) Sildenafil
citrate 1 (20.0) 3 (50.0) 0 (0.0) 0 (0.0) 4 (11.4) All other
therapeutic products 1 (20.0) 1 (16.7) 0 (0.0) 2 (8.7) 4 (11.4)
.sup.aMaximum Tolerated Dose is the last dose taken when the
subject left or completed the study. .sup.bThis group included
subjects who took two 15-mg capsules/day as well as subjects who
took one 30-mg capsule/day. .sup.cThis group included one subject
whose MTD was 45 mg. .sup.dAll subjects who took acetylsalicylic
acid concurrently with their study treatment did so for the
indication of cardiac prophylaxis and not analgesia.
[0273] Use of rescue medication (acetaminophen) was limited. Only
four subjects took rescue medication: one took acetaminophen on
twenty-eight out of twenty-nine study days, one on sixteen study
days, and two on only one study day. Overall, there was little use
of rescue medication for pain during this study; subjects took
rescue medication on an average of 1.3 days each (4.5% of study
days).
[0274] The extent of exposure to study medication is in Table
44.
TABLE-US-00044 TABLE 44 Maximum Tolerated Dose (mg).sup.a Exposure
30.sup.b 60.sup.c 90 120 Total Statistic (N = 5) (N = 6) (N = 2) (N
= 23) (N = 36) Amount of DM Taken (mg) n 4 6 2 23 35 Mean 960.0
1442.5 2160 2321.7 2006.1 SD 667.68 682.42 42.43 121.94 609.17
Median 1095 1530 2160 2310 2310 Min/Max 30/1620 270/2370 2130/2190
2010/2640 30/2640 Amount of Q Taken (mg) n 4 6 2 23 35 Mean 1200.0
1525.0 2160.0 2321.7 2047.7 SD 781.15 682.90 42.43 121.94 562.49
Median 1575 1620 2160 2310 2310 Min/Max 30/1620 270/2370 2130/2190
2010/2640 30/2640 Days on Study Medication.sup.d n 4 6 2 23 35 Mean
22.0 25.3 29.0 29.0 27.6 SD 14.00 9.48 0.00 1.22 6.13 Median 29 29
29 29 29 Min/Max 1/29 6/30 29/29 25/32 1/32 .sup.aMaximum Tolerated
Dose is the last dose taken when the subject left or completed the
study. .sup.bThis group included subjects who took two 15-mg
capsules/day as well as subjects who took one 30-mg capsule/day.
.sup.cThis group included one subject whose MTD was 45 mg.
.sup.dNumber of days on study medication was calculated by using
the date of the last dose of study drug minus the date of the first
dose of study drug, plus 1.
[0275] The number of subjects with adverse events is reported in
Table 45.
TABLE-US-00045 TABLE 45 Maximum Tolerated Dose (mg).sup.a 30.sup.b
60.sup.c 90 120 Total (N = 5) (N = 6) (N = 2) (N = 23) (N = 36)
Category n (%) n (%) n (%) n (%) n (%) Adverse Events 4 (80.0) 6
(100.0) 2 (100.0) 19 (82.6) 31 (86.1) Serious 1 (20.0) 2 (33.3) 0
(0.0) 0 (0.0) 3 (8.3) Adverse Events Discontinued 1 (20.0) 1 (16.7)
0 (0.0) 0 (0.0) 2 (5.6) Because of Adverse Events .sup.aMaximum
Tolerated Dose is the last dose taken when the subject left or
completed the study. .sup.bThis group included subjects who took
two 15-mg capsules/day as well as subjects who took one 30-mg
capsule/day. .sup.cThis group included one subject whose MTD was 45
mg.
[0276] The majority of subjects had at least one adverse event
during the study. Nearly all of the adverse events were mild or
moderate in intensity. Four subjects had a total of seven serious
adverse events. Two subjects had four severe adverse events. One
subject had severe insomnia and recovered with a reduced dose of
study drug; and one subject had severe fatigue and severe rigors,
and recovered without change in study drug. Adverse events
experienced by at least 5% of subjects overall are reported in
Table 46.
TABLE-US-00046 TABLE 46 Maximum Tolerated Dose (mg).sup.a 30.sup.b
60.sup.c 90 120 Total Adverse Event (N = 5) (N = 6) (N = 2) (N =
23) (N = 36) Preferred Term n (%) n (%) n (%) n (%) n (%) Alanine
aminotransferase 0 (0.0) 0 (0.0) 0 (0.0) 2 (8.7) 2 (5.6) increased
Appetite decreased NOS.sup.d 1 (20.0) 0 (0.0) 0 (0.0) 1 (4.3) 2
(5.6) Back pain 0 (0.0) 0 (0.0) 0 (0.0) 2 (8.7) 2 (5.6)
Constipation 0 (0.0) 0 (0.0) 0 (0.0) 3 (13.0) 3 (8.3) Diarrhea NOS
2 (40.0) 0 (0.0) 1 (50.0) 3 (13.0) 6 (16.7) Dizziness (exc.
vertigo) 1 (20.0) 2 (33.3) 1 (50.0) 5 (21.7) 9 (25.0) Dry mouth 2
(40.0) 1 (16.7) 0 (0.0) 1 (4.3) 4 (11.1) Fatigue 0 (0.0) 3 (50.0) 1
(50.0) 2 (8.7) 6 (16.7) Flatulence 2 (40.0) 0 (0.0) 0 (0.0) 0 (0.0)
2 (5.6) Gamma-glutamyl- 0 (0.0) 0 (0.0) 0 (0.0) 2 (8.7) 2 (5.6)
transferase increased Headache NOS 1 (20.0) 3 (50.0) 1 (50.0) 4
(17.4) 9 (25.0) Insomnia NEC.sup.e 1 (20.0) 0 (0.0) 1 (50.0) 1
(4.3) 3 (8.3) Libido decreased 1 (20.0) 0 (0.0) 0 (0.0) 1 (4.3) 2
(5.6) Nausea 2 (40.0) 2 (33.3) 1 (50.0) 5 (21.7) 10 (27.8)
Somnolence 2 (40.0) 0 (0.0) 1 (50.0) 3 (13.0) 6 (16.7) Syncope 0
(0.0) 0 (0.0) 0 (0.0) 2 (8.7) 2 (5.6) Tinnitus 0 (0.0) 0 (0.0) 1
(50.0) 1 (4.3) 2 (5.6) Upper respiratory 0 (0.0) 1 (16.7) 0 (0.0) 2
(8.7) 3 (8.3) tract infection NOS .sup.aMaximum Tolerated Dose is
the last dose taken when the subject left or completed the study.
.sup.bThis group included subjects who took two 15-mg capsules/day
as well as subjects who took one 30-mg capsule/day. .sup.cThis
group included one subject whose MTD was 45 mg. .sup.dNOS = Not
otherwise specified. .sup.eNEC = Not elsewhere classified.
[0277] Nausea was the most common adverse event experienced,
occurring in 10 (27.8%) subjects overall. Nausea was judged to be
mild in seven subjects (19.4%) and moderate in three subjects.
Nausea was judged to be at least possibly related to treatment in
all cases. There was no apparent relationship between the maximum
tolerated dose and the occurrence, severity, or relationship of
nausea to study drug. Dizziness was reported by nine subjects
(25.0%) overall. Dizziness was mild in six subjects (16.7%) and
moderate in three subjects (8.3%). For the majority of these
subjects (seven versus two), dizziness was judged to be at least
possibly related to treatment. Nine subjects (25.0%) reported
headache. All instances of this adverse event were mild or
moderate, and the majority (six out of nine) were judged to be
possibly related to treatment. Two subjects withdrew from the study
because of adverse events. One subject, with an MTD of 30 mg,
withdrew after one dose of study medication because of a
pre-existing colon polyp that required resection. The other
subject, with an MTD of 60 mg, withdrew on Day 6 because of
recurring, intermittent chest pain.
[0278] One subject had an exacerbation of Chronic Obstructive
Pulmonary Disease (COPD) at the time of his final visit on Day 29,
was counseled to contact his primary care physician, and was
hospitalized that day. On Day 33 the subject died suddenly while
still in the hospital; his primary care physician indicated
myocardial infarction and arrhythmia as the presumed causes of
death. The investigator indicated that this subject's COPD
exacerbation was not related to study drug and that his myocardial
infarction and arrhythmia were unlikely to be related to study
drug.
[0279] One subject, whose MTD was 60 mg, had a history of
hypertension (four years) and atypical chest pain (two years). She
developed recurring, intermittent chest pain on Day 6 and was
admitted to the hospital on Day 7. She discontinued study
medication. All tests for cardiac causes were negative. The subject
recovered on Day 8, was discharged on Day 9, and returned to work
on Day 10. The underlying cause of this subject's chest pain was
unclear and her chest pain was possibly related to study drug.
[0280] All of the clinical laboratory adverse events were mild or
moderate in intensity. Two subjects had elevated creatine kinase
values, two subjects had elevated liver enzyme values accompanied
by other abnormalities, and one subject had blood in the stool. Two
subjects recovered from all of their clinical laboratory adverse
events, one subject did not recover, and the outcome of the adverse
events was unknown for 2 subjects because they did not return to
the study clinic for follow-up testing. The majority of these
adverse events were judged to have a "possible" relationship to
study drug. None of the clinical laboratory adverse events were
serious adverse events, and none required a dosage reduction or
discontinuation of study drug.
[0281] There were no clinically relevant changes from Baseline to
Day 29 in systolic blood pressure, diastolic blood pressure, heart
rate, or respiration at any MTD. There were no clinically relevant
changes in the results of physical examinations during study
treatment. There was no clinically relevant difference among the
MTD groups in mean QT, QT.sub.c, PR, or QRS duration, or change in
any electrocardiogram values during the study.
[0282] There were no meaningful differences in motor conduction
velocities in the distal peroneal nerve segment, between the
fibular head and ankle, for each of the 4 MTD groups at Screening.
The mean baseline motor conduction velocity was 39.2 m/sec (range
of 26.6 to 49.0 m/sec). There were also no differences between the
change in motor nerve conduction from Screening to the final visit
for each of the MTDs. The mean change in motor conduction velocity
in the fibular head-to-ankle segment for the total study population
was 0.8 m/sec (range of -4.0 to +7.7 m/sec). There was a marked
slowing of conduction velocity in the proximal peroneal nerve
segment, between the fibular head and popliteal fossa, for the
120-mg MTD group (-6.7 m/sec) and for the total study population
(-5.5 m/sec). However, this can be explained by the unusually high
nerve conduction velocity measured in this segment at Screening
(mean of 47.6 m/sec and range of 21.7 to 66.7 m/sec in the 120-mg
MTD group). Twelve of the twenty-three subjects in this group had
baseline motor conduction velocities greater than 50 m/sec; these
unusually high values for this population could reflect the short
distance over which this segment of the nerve was stimulated, which
could have resulted in measurement errors.
[0283] Any significant slowing of nerve conduction velocity would
manifest more severely in distal segments of nerve, as is seen
electrophysiologically in diabetic neuropathy, because the
frequency of this condition increases with length of the nerve
pathway. For these reasons, the proximal conduction velocities
measured in this study were interpreted as an assessment of the
presence of focal peroneal neuropathy at the fibular head, and not
as a measure of safety or tolerance of the study medication. In
conclusion, there was no electrophysiologic evidence to suggest
that the analgesic property of DM/Q is due to a toxic effect on
peripheral nerves.
[0284] The combination of DM/Q, at daily doses from 30 mg DM/30 mg
Q to 120 mg DM/120 mg Q, was safe and well tolerated in this
subject population. The nature, frequency, and intensity of adverse
events were within acceptable limits. Although five subjects had at
least one laboratory adverse event, all were mild or moderate in
intensity and none required a change in study drug dosing. There
were no findings of clinical concern for vital signs, physical
examinations, or electrocardiographic results. No clinically
significant changes in nerve conduction velocity were detected.
Study treatment was well tolerated; and the majority of subjects
had an MTD of the highest permissible dose (120 mg DM/120 mg
Q).
[0285] The frequencies of subjects with each pain intensity score
at each time point are reported in Table 47.
TABLE-US-00047 TABLE 47 Pain Intensity Rating Scale Score 0 1 2 3 4
Study Visit (None) (Mild) (Moderate) (Severe) (Extreme) Total Day 1
0 (0.0) 0 (0.0) 20 (55.6) 15 (41.7) 1 (2.8) 36 (100.0) Day 8 3
(9.1) 14 (42.4) 14 (42.4) 2 (6.1) 0 (0.0) 33 (100.0) Day 15 5
(15.2) 18 (54.6) 10 (30.3) 0 (0.0) 0 (0.0) 33 (100.0) Day 22 10
(30.3) 15 (45.5) 6 (18.2) 2 (6.1) 0 (0.0) 33 (100.0) Final Visit 14
(40.0) 14 (40.0) 5 (14.3) 2 (5.7) 0 (0.0) 35 (100.0)
[0286] On Day 1 (baseline), all subjects had a pain intensity of 2
(moderate) or greater, as specified in the protocol inclusion
criteria. By the final visit, only a minority of subjects (20.0%)
had moderate or greater pain, and 40% reported no pain.
[0287] The changes from baseline in the Pain Intensity Rating Scale
scores are reported in Table 48.
TABLE-US-00048 TABLE 48 Maximum Tolerated Dose (mg).sup.a P-value
30.sup.b 60.sup.c 90 120 Total Baseline Visit Statistic (N = 5) (N
= 6) (N = 2) (N = 23) (N = 36) and MTD.sup.d Baseline.sup.e Day 8 n
3 5 2 23 33 0.9525 <0.0001 Mean -1.0 -1.0 -0.5 -1.1 -1.0 SD 1.00
1.00 0.71 0.90 0.88 Median -1.0 -1.0 -0.5 -1.0 -1.0 Min/Max -2/0
-2/0 -1/0 -3/0 -3/0 Day n 3 5 2 23 33 0.4858 <0.0001 15 Mean
-0.3 -1.8 -0.5 -1.4 -1.3 SD 0.58 0.45 0.71 0.84 0.85 Median 0.0
-2.0 -0.5 -1.0 -1.0 Min/Max -1/0 -2/-1 -1/0 -3/0 -3/0 Day n 3 5 2
23 33 0.2053 <0.0001 22 Mean -0.3 -1.6 -1.5 -1.6 -1.5 SD 0.58
0.55 0.71 1.08 1.00 Median 0.0 -2.0 -1.5 -2.0 -2.0 Min/Max -1/0
-2/-1 -2/-1 -3/1 -3/1 Day n 3 5 2 22 32 0.1628 <0.0001 29 Mean
-0.7 -1.6 -2.5 -1.8 -1.7 SD 0.58 0.55 0.71 0.96 0.92 Median -1.0
-2.0 -2.5 -2.0 -2.0 Min/Max -1/0 -2/-1 -3/-2 -3/0 -3/0 Final n 4 6
2 23 35 0.0348 <0.0001 Visit Mean -0.5 -1.5 -2.5 -1.8 -1.6 SD
0.58 0.55 0.71 0.95 0.94 Median -0.5 -1.5 -2.5 -2.0 -2.0 Min/Max
-1/0 -2/-1 -3/-2 -3/0 -3/0 .sup.aMaximum Tolerated Dose is the last
dose taken when the subject left or completed the study. .sup.bThis
group included subjects who took two 15-mg capsules/day as well as
subjects who took one 30-mg capsule/day. .sup.cThis group included
one subject whose MTD was 45 mg. .sup.dP-value for MTD from a
regression model that models the efficacy variable as a function of
both baseline score and MTD. .sup.eP-value for mean change in score
from a regression model that models the efficacy variable as a
function of baseline score.
[0288] Mean scores on the Pain Intensity Rating Scale decreased
between baseline and each subsequent visit for subjects overall.
This decrease was highly significant (all p-values<0.0001). For
the change from baseline to the final visit, the score decreases
were significantly related to MTD (p=0.0348), but there was no
significant effect of MTD on scores for any of the other visits
(all p-values.gtoreq.0.1628).
[0289] Frequencies of subjects with each pain relief score at each
study visit are reported in Table 49.
TABLE-US-00049 TABLE 49 Pain Relief -1 0 1 2 3 4 Study Visit
(Worse) (None) (Slight) (Moderate) (A Lot) (Complete) Total Day 8 0
(0.0) 3 (9.1) 6 (18.2) 13 (39.4) 8 (24.2) 3 (9.1) 33 (100.0) Day 15
0 (0.0) 1 (3.0) 5 (15.2) 6 (18.2) 18 (54.6) 3 (9.1) 33 (100.0) Day
22 0 (0.0) 1 (3.0) 5 (15.2) 4 (12.1) 17 (51.5) 6 (18.2) 33 (100.0)
Final Visit 0 (0.0) 1 (2.9) 6 (17.7) 5 (14.7) 13 (38.2) 9 (26.5) 34
(100.0)
[0290] In general, pain relief scores increased during the study.
At Day 8, only 33.3% of subjects reported "a lot" or "complete"
pain relief; by the final visit, the majority (64.7%) did so. No
subject reported "worse" pain compared to baseline at any visit,
and only 1 subject reported "None" at any visit after Day 8.
[0291] Summary statistics for Pain Relief Scale scores are reported
in Table 50.
TABLE-US-00050 TABLE 50 Maximum Tolerated Dose (mg).sup.a P-value
30.sup.b 60.sup.c 90 120 Total Difference Visit Statistic (N = 5)
(N = 6) (N = 2) (N = 23) (N = 36) MTD.sup.d from 0.sup.e Day 8 n 3
5 2 23 33 0.4880 <0.0001 Mean 2.7 2.0 2.0 2.0 2.1 SD 0.58 1.58
0.00 1.09 1.09 Median 3.0 2.0 2.0 2.0 2.0 Min/Max 2/3 0/4 2/2 0/4
0/4 Day n 3 5 2 23 33 0.7953 <0.0001 15 Mean 2.0 2.8 2.5 2.5 2.5
SD 1.00 1.10 0.71 0.99 0.97 Median 2.0 3.0 2.5 3.0 3.0 Min/Max 1/3
1/4 2/3 0/4 0/4 Day n 3 5 2 23 33 0.6110 <0.0001 22 Mean 2.3 2.6
3.0 2.7 2.7 SD 0.58 1.14 0.00 1.15 1.05 Median 2.0 3.0 3.0 3.0 3.0
Min/Max 2/3 1/4 3/3 0/4 0/4 Day n 3 5 2 22 32 0.6263 <0.0001 29
Mean 2.3 2.6 3.5 2.7 2.7 SD 1.15 1.14 0.71 1.20 1.14 Median 3.0 3.0
3.5 3.0 3.0 Min/Max 1/3 1/4 3/4 0/4 0/4 Final n 3 6 2 23 34 0.7958
<0.0001 Visit Mean 2.3 2.7 3.5 2.7 2.7 SD 1.15 1.03 0.71 1.23
1.15 Median 3.0 3.0 3.5 3.0 3.0 Min/Max 1/3 1/4 3/4 0/4 0/4
.sup.aMaximum Tolerated Dose is the last dose taken when the
subject left or completed the study. .sup.bThis group included
subjects who took two 15-mg capsules/day as well as subjects who
took one 30-mg capsule/day. .sup.cThis group included one subject
whose MTD was 45 mg. .sup.dP-value for MTD from a regression model
that models the efficacy variable as a function of MTD.
.sup.eP-value from a t-test testing that the mean of the total
column is significantly different from 0.
[0292] Mean scores on the Pain Relief Rating Scale increased
significantly from the first assessment on Day 8 to each subsequent
visit for subjects overall (all p-values<0.0001). There was no
significant effect of MTD on pain relief scores at any visit (all
p-values.gtoreq.0.4880).
[0293] The change from baseline in the composite score from the
Peripheral Neuropathy QOL Instrument is reported in Table 51.
TABLE-US-00051 TABLE 51 P-value Maximum Tolerated Dose (mg).sup.a
Baseline Visit/ 30.sup.b 60.sup.c 90 120 Total and Variable
Statistic N = 5) (N = 6) (N = 2) (N = 23) (N = 36) MTD.sup.d
Baseline.sup.e Day 1 n 4 6 2 23 35 N/A.sup.f N/A (Baseline)/ Mean
61.3 69.7 72.8 63.7 65.0 Score SD 15.26 13.68 0.18 13.48 13.26
Median 60.8 66.8 72.8 65.3 66.7 Min/Max 47.1/76.4 49.8/86.9
72.7/72.9 35.6/87.2 35.6/87.2 Day 29/ n 3 5 2 22 32 N/A N/A Score
Mean 68.3 75.7 79.0 75.5 75.0 SD 13.38 15.88 4.68 9.93 10.82 Median
66.3 79.9 79.0 75.4 76.5 Min/Max 56.0/82.6 49.1/91.8 75.7/82.3
51.4/88.5 49.1/91.8 Day 29/ n 3 5 2 22 32 0.1397 <0.0001 Change
Mean 2.4 8.8 6.2 12.1 10.3 from SD 10.87 13.35 4.85 10.77 10.95
Baseline Median 6.9 10.7 6.2 12.8 10.4 Min/Max -10.1/10.2 -6.8/27.7
2.7/9.6 -10.2/34.5 -10.2/34.5 Final Visit/ n 3 6 2 23 34 N/A N/A
Score Mean 68.3 77.6 79.0 75.4 75.4 SD 13.38 14.99 4.68 9.71 10.71
Median 66.3 80.0 79.0 75.1 76.5 Min/Max 56.0/82.6 49.1/91.8
75.7/82.3 51.4/88.5 49.1/91.8 Final Visit/ n 3 6 2 23 34 0.1828
<0.0001 Change Mean 2.4 7.9 6.2 11.6 9.8 from SD 10.87 12.11
4.85 10.76 10.78 Baseline Median 6.9 7.2 6.2 12.7 9.9 Min/Max
-10.1/10.2 -6.8/27.7 2.7/9.6 -10.2/34.5 -10.2/34.5 .sup.aMaximum
Tolerated Dose is the last dose taken when the subject left or
completed the study. .sup.bThis group included subjects who took
two 15-mg capsules/day as well as subjects who took one 30-mg
capsule/day. .sup.cThis group included one subject whose MTD was 45
mg. .sup.dP-value for MTD from a regression model that models the
efficacy variable as a function of both baseline score and MTD.
.sup.eP-value for mean change in score from a regression model that
models the efficacy variable as a function of baseline score.
.sup.fN/A = Not applicable.
[0294] Mean composite scores on the Peripheral Neuropathy QOL
Instrument increased (i.e., improved) significantly from Day 1
(baseline) to Day 29 and to the final visit for subjects overall
(both p-values<0.0001). Change from baseline to either Day 29 or
the final visit was not related to MTD (all
p-values.gtoreq.0.1837).
[0295] P-values for change from baseline to the final visit in
individual QOL scales are reported in Table 52.
TABLE-US-00052 TABLE 52 Scale P-value Scale P-value Physical
Functioning 0.0012 General Health Perceptions <0.0001 Role
Limitations 0.0003 Sleep <0.0001 Disease-Targeted Pain
<0.0001 Social Functioning <0.0001 Energy/Fatigue 0.0001
Sexual Function 0.7714 Upper Extremities 0.0007 Health Distress
<0.0001 Balance 0.0001 Severity 0.0129 Self Esteem 0.1258
Disability Days 0.1096 Emotional Well Being 0.0277 Health Change
0.0001 Stigma 0.7851 Overall Health Rating 0.0064 Cognitive
Function 0.0313 Satisfaction with Sexual 0.3413 Functioning
Emotional Role 0.2956 Limitations .sup.aP-value for the change from
baseline. A regression model was used to test whether the mean
baseline value was different from the mean value at the final
visit.
[0296] The majority of individual QOL scale items improved
significantly between baseline and the final visit (15/21,
74.1%).
[0297] Sleep interference scores, calculated for Day 15, Day 29,
and the final visit, are reported in Table 53.
TABLE-US-00053 TABLE 53 Maximum Tolerated Dose (mg).sup.b P-
30.sup.c 60.sup.d 90 120 Total value Visit Statistic (N = 5) (N =
6) (N = 2) (N = 23) (N = 36) MTD.sup.e Day n 3 5 2 23 33 0.8509 15
Mean 1.4 2.2 2.2 1.8 1.8 SD 1.35 1.66 0.71 1.64 1.54 Median 1.7 2.0
2.2 1.3 1.7 Min/Max 0/3 0/4 2/3 0/5 0/5 Day n 3 5 2 22 32 0.1405 29
Mean 1.6 2.5 0.2 1.2 1.4 SD 1.35 2.09 0.24 1.29 1.47 Median 1.3 2.0
0.2 0.7 0.8 Min/Max 0/3 0/5 0/0 0/4 0/5 Final n 3 5 2 23 33 0.1077
Visit Mean 1.6 2.5 0.2 1.1 1.3 SD 1.35 2.09 0.24 1.20 1.41 Median
1.3 2.0 0.2 0.7 1.0 Min/Max 0/3 0/5 0/0 0/4 0/5 .sup.aThe score for
Day 15 is the average of the Sleep Rating Scale scores from the
subject diary for Days 13, 14, and 15; the score for Day 29 is the
average of the Day 27, 28, and 29 scores; and the Final Visit score
is the average of the final 3 consecutive days of study treatment.
.sup.bMaximum Tolerated Dose is the last dose taken when the
subject left or completed the study. .sup.cThis group included
subjects who took two 15-mg capsules/day as well as subjects who
took one 30-mg capsule/day. .sup.dThis group included one subject
whose MTD was 45 mg. .sup.eP-value for MTD from a regression model
that models the efficacy variable as a function of MTD.
[0298] Mean sleep interference scores declined during the study,
indicating decreasing interference of the subjects' pain with their
sleep. There was no significant effect of MTD on sleep interference
scores at any visit (all p values.gtoreq.0.1077). Results from the
Sleep Rating Scale are plotted by study day in FIG. 4. Sleep scores
decreased significantly (regression p<0.001) from Day 2 to the
final study day (the lower the score, the less pain was judged to
interfere with sleep).
[0299] Results from the Present Pain Intensity Rating Scale are
plotted by study day in FIG. 5. Present Pain Intensity scores
decreased significantly (regression p<0.001) from Day 2 to the
final study day. Results from the Activity Rating Scale are plotted
by study day in FIG. 6. Activity scores decreased significantly
(regression p<0.001) from Day 1 to the final study day (the
lower the score, the less pain was judged to interfere with general
activity). Results from the Pain Rating Scale are plotted by study
day in FIG. 7. Scores for average pain over the previous twelve
hours decreased significantly (regression p<0.001) from Day 1 to
the final study day. An improvement in efficacy score was defined
as an improvement from the first recorded value to the last
recorded value, except for the Pain Relief Rating Scale, where an
improvement was defined as a value>0 for the last recorded
value. The frequencies of subjects whose score improved during the
study are presented for each efficacy measure in Table 54.
TABLE-US-00054 TABLE 54 Maximum Tolerated Dose (mg).sup.b 30.sup.c
60.sup.d 90 120 Total (N = 5) (N = 6) (N = 2) (N = 23) (N = 36)
P-value Efficacy Variable n (%) n (%) n (%) n (%) n (%) MTD.sup.e
50%.sup.f Pain Intensity Rating Scale 2 (50.0) 6 (100.0) 2 (100.0)
21 (91.3) 31 (88.6) 0.1698 <0.0001 Pain Relief Rating Scale 3
(100.0) 5 (100.0) 2 (100.0) 22 (95.7) 32 (97.0) 0.9419 <0.0001
QOL Composite Score 2 (66.7) 5 (83.3) 2 (100.0) 19 (82.6) 28 (82.4)
0.6877 0.0002 Sleep Rating Scale (Diary) 3 (100.0) 5 (83.3) 2
(100.0) 20 (87.0) 30 (88.2) 0.7222 <0.0001 Present Pain
Intensity Rating Scale 2 (66.7) 3 (50.0) 2 (100.0) 16 (69.6) 23
(67.6) 0.5877 0.0396 (Diary) Activity Rating Scale (Diary) 2 (50.0)
5 (83.3) 2 (100.0) 20 (87.0) 29 (82.9) 0.1668 0.0001 Pain Rating
Scale (Diary) 3 (75.0) 5 (83.3) 2 (100.0) 20 (87.0) 30 (85.7)
0.5772 <0.0001 .sup.aAn improvement in efficacy score is an
improvement from the first recorded value to the last recorded
value, except for the Pain Relief Rating Scale, where an
improvement is a value > 0 for the last recorded value.
.sup.bMaximum Tolerated Dose is the last dose taken when the
subject left or completed the study. .sup.cThis group included
subjects who took two 15-mg capsules/day as well as subjects who
took one 30-mg capsule/day. .sup.dThis group included one subject
whose MTD was 45 mg. .sup.eP-value for MTD from a regression model
that models improvement in the efficacy variable as a function of
MTD. .sup.fP-value from a test that the total percent of subjects
whose score improved = 50%.
[0300] A significant proportion of subjects improved during the
study in every efficacy measure (all p-values<0.0396).
Improvement was not related to MTD for any of the efficacy measures
(all p-values.gtoreq.0.1668).
[0301] Subjects treated with open-label DM/Q, in the dose range of
30 mg DM/30 mg Q to 120 mg DM/120 mg Q, reported a statistically
significant reduction in pain from diabetic peripheral neuropathy
and in the extent to which this pain interfered with general
activity and sleep. Subjects receiving this treatment also
experienced statistically significant improvement in their QOL.
[0302] The CYP2D6 phenotypes of subjects, based upon their genotype
results, are summarized in Table 55. There were no intermediate or
ultra-rapid metabolizers in this study population.
TABLE-US-00055 TABLE 55 Maximum Tolerated Dose (mg).sup.a 30.sup.b
60.sup.c 90 120 Total (N = 5) (N = 6) (N = 2) (N = 23) (N = 36)
Phenotype n (%) n (%) n (%) n (%) n (%) Extensive 5 (100.0) 5
(83.3) 2 (100.0) 23 (100.0) 35 (97.2) Metabolizer Poor 0 (0.0) 1
(16.7) 0 (0.0) 0 (0.0) 1 (2.8) Metabolizer .sup.aMaximum Tolerated
Dose is the last dose taken when the subject left or completed the
study. .sup.bThis group included subjects who took two 15-mg
capsules/day as well as subjects who took one 30-mg capsule/day.
.sup.cThis group included one subject whose MTD was 45 mg.
[0303] All except one subject were extensive metabolizers.
Concentrations in plasma of DM increased between the visit on Day
15 and the final visit for the 90-mg and 120-mg MTDs. A similar
increase in concentration was seen for the metabolite DX and for Q.
Concentrations of DM, DX, and Q in plasma of extensive metabolizers
at the final visit are summarized by MTD in Table 56.
TABLE-US-00056 TABLE 56 Drug MTD.sup.b (mg) or Metabolite 30.sup.c
60.sup.d 90 120 Total (ng/mL) Statistic N = 5 N = 5 N = 2 N = 23 N
= 35 DM n 3 5 2 23 33 Mean 59.0 46.2 117.0 192.6 153.7 SD 30.28
67.38 44.47 98.93 106.01 Median 67.4 1.5 117.0 178.0 144.5 Min/Max
25.4/84.2 0.0/150.2 85.5/148.4 48.7/388.5 0.0/388.5 DX n 3 5 2 23
33 Mean 70.7 65.4 88.4 146.6 123.9 SD 48.49 67.38 34.83 96.88 91.94
Median 94.6 58.2 88.4 122.6 102.6 Min/Max 14.9/102.6 0.0/135.6
63.8/113.0 53.2/417.9 0.0/417.9 Q n 3 5 2 23 33 Mean 114.0 41.8
114.5 269.0 211.1 SD 48.75 66.72 70.00 176.88 175.28 Median 137.0
0.0 114.5 211.0 164.0 Min/Max 58/147 0/153 65/164 74/681 0/681
.sup.aOne of the thirty-six subjects was a poor metabolizer.
.sup.bMaximum Tolerated Dose is the last dose taken when the
subject left or completed the study. .sup.cThis group included
subjects who took two 15-mg capsules/day as well as subjects who
took one 30-mg capsule/day. .sup.dThis group included one subject
whose MTD was 45 mg.
[0304] For comparison, the poor metabolizer (MTD of 60 mg) had the
following concentrations in plasma at the final visit: DM 126.4
ng/mL, DX 41.0 ng/mL, and Q 165.0 ng/mL. Correlations between the
concentration of DM in plasma with pain intensity ratings on Day
15, Day 29, and the final visit are summarized in Table 57
(extensive metabolizers only).
TABLE-US-00057 TABLE 57 Visit n.sup.b Correlation Coefficient
P-value Day 15 33 -0.3479 0.0473 Day 29 30 -0.1336 0.4817 Final
Visit 33 -0.1487 0.4088 .sup.aOne of the thirty-six subjects was a
poor metabolizer. .sup.bData were not available for all
subjects.
[0305] There was a weak, negative correlation between concentration
of DM in plasma and rating of pain intensity at Day 15 (coefficient
of -0.3572) and negligible correlations at the other time points
(.ltoreq.-0.1487). The Day 15 correlation was statistically
significant (p=0.0473), but the correlations at Day 29 and the
final visit were not (p.gtoreq.0.4088). However, a weak or
nonexistent correlation between concentrations of drug in plasma
and pain ratings is a typical result in pharmacodynamic studies of
analgesics.
[0306] The safety results demonstrate that the combination of DM/Q,
in the dose range from 30 mg DM/30 mg Q to 120 mg DM/120 mg Q, is
safe and well tolerated in the treatment of subjects with pain
associated with diabetic peripheral neuropathy, and provide
indications of efficacy in pain reduction.
[0307] The preferred embodiments have been described in connection
with specific embodiments thereof. It will be understood that it is
capable of further modification, and this application is intended
to cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure as come
within known or customary practices in the art to which the
invention pertains and as may be applied to the essential features
hereinbefore set forth, and as fall within the scope of the
invention and any equivalents thereof. All references cited herein,
including but not limited to technical literature references and
patents, are hereby incorporated herein by reference in their
entireties.
* * * * *