U.S. patent application number 13/928317 was filed with the patent office on 2014-01-02 for nalmefene for reduction of alcohol consumption in specific target populations.
The applicant listed for this patent is H. Lundbeck A/S. Invention is credited to Afsaneh Abbariki, Anna Bladstrom, Thomas Jon Jensen, Didier Meulien, Jette Buch Ostergaard, Christine Persson, Per Sorensen, Lars Torup.
Application Number | 20140005216 13/928317 |
Document ID | / |
Family ID | 48703496 |
Filed Date | 2014-01-02 |
United States Patent
Application |
20140005216 |
Kind Code |
A1 |
Torup; Lars ; et
al. |
January 2, 2014 |
Nalmefene for reduction of alcohol consumption in specific target
populations
Abstract
The present invention relates to nalmefene for use in the
reduction of alcohol consumption in a patient with alcohol
dependence who has a high drinking risk level. The present
invention also relates to nalmefene for use in the reduction of
alcohol consumption in a patient with alcohol dependence who
maintains at least medium DRL after an observation period following
initial assessment.
Inventors: |
Torup; Lars; (Vaerlose,
DK) ; Abbariki; Afsaneh; (Holte, DK) ;
Bladstrom; Anna; (Lund, SE) ; Persson; Christine;
(Lund, SE) ; Meulien; Didier; (Boulogne
Billancourt, FR) ; Sorensen; Per; (Kobenhavn O,
DK) ; Jensen; Thomas Jon; (Virum, DK) ;
Ostergaard; Jette Buch; (Kobenhavn N, DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
H. Lundbeck A/S |
Valby-Copenhagen |
|
DK |
|
|
Family ID: |
48703496 |
Appl. No.: |
13/928317 |
Filed: |
June 26, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61788810 |
Mar 15, 2013 |
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61736740 |
Dec 13, 2012 |
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61721539 |
Nov 2, 2012 |
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61664804 |
Jun 27, 2012 |
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Current U.S.
Class: |
514/282 |
Current CPC
Class: |
A61K 9/0053 20130101;
A61K 31/485 20130101; A61P 25/32 20180101; A61P 43/00 20180101;
A61P 25/00 20180101 |
Class at
Publication: |
514/282 |
International
Class: |
A61K 31/485 20060101
A61K031/485 |
Claims
1-27. (canceled)
28. A method for reducing alcohol consumption in a patient with
alcohol dependence who has a high DRL, which method comprises
administering a therapeutically effective amount of nalmefene to
said patient.
29. The method according to claim 28, wherein said patient has a
DRL corresponding to consumption .gtoreq.60 g/day of pure alcohol
for men and >40 g/day for women.
30. The method according to claim 29, wherein said maintained high
DRL is assessed by calculating mean daily alcohol consumption in
g/day over said observation period.
31. The method according to claim 28, wherein nalmefene is
administered in a dose of 10-20 mg.
32. The method according to claim 28, where in nalmefene is
administered for a treatment period of 6 -12 months.
33. The method according to claim 28, wherein said nalmefene is
administered to the patient as-needed.
34. A method for reducing alcohol consumption in a patient with
alcohol dependence who maintains at least medium DRL after an
observation period following initial assessment, which method
comprises the administration of a therapeutically effective amount
of nalmefene to said patient.
35. The method according to claim 34, wherein said maintained DRL
corresponds to consumption .gtoreq.40 g/day of pure alcohol for men
and >20 g/day for women.
36. The method according to claim 34, wherein the patient has a
high DRL prior to the observation period and maintained a medium
DRL after the observation period.
37. The method according to claim 34, wherein the patient has a
medium DRL prior to the observation period.
38. The method according to claim 34, wherein said patient has a
DRL prior to the observation period corresponding to consumption
.gtoreq.60 g/day of pure alcohol for men and .gtoreq.40 g/day for
women.
39. The method according to claim 34, wherein said DRL is assessed
by calculating mean daily alcohol consumption in g/day over a
period preceding assessment, wherein said period is 1 week or
longer.
40. The method according to claim 34, wherein said DRL is assessed
by calculating mean daily alcohol consumption in g/day over a
period preceding assessment, wherein said period is 2 weeks or
longer.
41. The method according to claim 34, wherein nalmefene is
administered in a dose of 10-20 mg.
42. The method according to claim 34, where in nalmefene is
administered for a treatment period of 6 -12 months.
43. The method according to claim 34, wherein said nalmefene is
administered to the patient as-needed.
44. A method of reducing alcohol consumption in a patient who
maintains at least medium DRL after an observation period in
accordance with clinical practice, which method comprises the
administration of a therapeutically effective amount of nalmefene
to said patient.
45. The method according to claim 44, wherein said maintained DRL
corresponds to consumption .gtoreq.40 g/day of pure alcohol for men
and .gtoreq.20 /day for women.
46. The method according to claim 44, wherein the patient has a
high DRL prior to the observation period and maintained a high DRL
after the observation period.
47. The method according to claim 44, wherein the patient has a
medium DRL prior to the observation period.
48. The method according to claim 44, wherein said patient has a
DRL prior to the observation period corresponding to consumption
>60 g/day of pure alcohol for men and .gtoreq.40 g/day for
women.
49. The method according to claim 44, wherein said DRL is assessed
by calculating mean daily alcohol consumption in g/day over a
period preceding assessment, wherein said period is 1 week or
longer.
50. The method according to claim 44, wherein said DRL is assessed
by calculating mean daily alcohol consumption in g/day over a
period preceding assessment, wherein said period is 2 weeks or
longer.
51. The method according to claim 44, wherein nalmefene is
administered in a dose of 10-20 mg.
52. The method according to claim 44, where in nalmefene is
administered for a treatment period of 6 -12 months.
53. The method according to claim 44, wherein said nalmefene is
administered to the patient as-needed.
54. A method for reducing of alcohol consumption in a patient with
alcohol dependence, wherein said method comprises the following
steps: a) identifying a patient with alcohol dependence i) who has
a high DRL, and ii) who maintains a high DRL after an observation
period following initial assessment, and b) administering a
therapeutically effective amount of nalmefene to the patient
identified in step a), wherein said nalmefene is administered
as-needed.
55. The method according to claim 54, wherein nalmefene is
administered on each day the patient perceives a risk of drinking
alcohol.
56. The method according to claim 54, wherein nalmefene is
administered 1-2 hours prior to the anticipated time of
drinking.
57. The method according to claim 54, wherein said DRL is assessed
by calculating mean daily alcohol consumption in g/day over a
period preceding assessment, wherein said period is 1 week or
longer.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to nalmefene for use in the
reduction of alcohol consumption in a patient with alcohol
dependence who has a high drinking risk level. The present
invention also relates to nalmefene for use in the reduction of
alcohol consumption in a patient with alcohol dependence who
maintains at least medium DRL after an observation period following
initial assessment.
BACKGROUND OF THE INVENTION
[0002] Nalmefene
[17-(cyclopropylmethyl)-4,5-alpha-epoxy-6-methylenemorphinan-3,14-dial]
has the following general formula:
##STR00001##
and can be prepared using methods that are well known in the art
e.g. starting by manufacturing of naltrexone from noroxymorphone as
described in WO 2012/059103 and subsequently manufacturing
nalmefene from naltrexone e.g. by the Wittig reaction as described
in WO 20101136039. The entire contents of each of WO 2012/059103
and WO 2010/136039 are incorporated herein by reference.
[0003] Nalmefene is a known opioid system modulator, with a
distinct .mu., .delta., and .kappa. receptor profile, which can
inhibit pharmacological effects of both administered opioid
agonists and endogenous agonists derived from the opioid system.
The clinical usefulness of nalmefene comes from its ability to
promptly and selectively reverse the effects of these opioid
agonists.
[0004] Nalmefene has primarily been developed for use in the
management of alcohol dependence. A double-blind,
placebo-controlled study has shown good effect of 20 to 80 mg daily
oral dosing of nalmefene (Mason et al., Arch Gen. Psychiatry,
(1999), Vol. 56: 719-724); while another study reported no evidence
of superiority of nalmefene over placebo in a study evaluating 5,
20 and 40 mg daily doses of nalmefene (Anton et al., J. Clin.
Psychopharmacol., (2004), Vol. 24(4): 421-428). A more recent
study, showed good effect of nalmefene over placebo when a dose of
20 mg nalmefene was taken when the patient experienced a craving
for alcohol (Karhuvaara et al., Alcohol. Dirt Exp. Res., (2007),
Vol. 31 (7): 1179-1187.
[0005] Based on independent evidence, high levels of alcohol
consumption are associated with an increased risk of health-related
harm, as well as adverse social consequences. The World Health
Organization (WHO) has defined drinking risk levels (DRLs) based on
alcohol consumption in International Guide for Monitoring Alcohol
Consumption and Related Harm. 2000. World Health Organization, the
entire contents of which are incorporated herein by reference. See
Table 1.
TABLE-US-00001 TABLE 1 WHO Drinking Risk Levels (DRLs) of Alcohol
Consumption Total Alcohol Consumption (g/day) DRL Men Women Very
high risk >100 >60 High risk >60 to 100 >40 to 60
Medium risk >40 to 60 >20 to 40 Low risk 1 to 40 1 to 20
[0006] Risk levels according to Table 1 can be assessed e.g. by
calculating mean daily alcohol consumption in g/day over a month
such as over 4 weeks. There is a need for a new treatment for use
in reduction of alcohol consumption. Reduction of alcohol
consumption is likely to provide benefits associated with decreased
risk of health-related harm and decreased number of adverse social
consequences.
SUMMARY OF THE INVENTION
[0007] The present invention relates to a method for reduction of
alcohol consumption in a patient with alcohol dependence who has a
high DRL, which method comprises the administration of a
therapeutically effective amount of nalmefene to said patient.
[0008] In another embodiment, the invention relates to a method for
reduction of alcohol consumption in a patient with alcohol
dependence who maintains at least medium DRL after an observation
period following initial assessment such as an observation period
of 1-2 weeks, such as an observation period of about 2 weeks, which
method comprises the administration of a therapeutically effective
amount of nalmefene to said patient.
[0009] In one embodiment, the invention relates to a method for
reduction of alcohol consumption in a patient with alcohol
dependence who has a DRL corresponding to consumption >60 g/day
of pure alcohol for men and >40 g/day for women assessed by
calculating mean daily alcohol consumption in g/day over a period
preceding assessment, wherein said patient maintains a DRL
corresponding to consumption >60 g/day of pure alcohol for men
and >40 g/day for women after an observation following initial
assessment, assessed by calculating mean daily alcohol consumption
in g/day over said observation period, which method comprises the
administration of a therapeutically effective amount of nalmefene
to said patient.
[0010] In one embodiment, the invention relates to a method for
reduction of alcohol consumption in a patient with alcohol
dependence, wherein said method comprises the following steps:
[0011] a) identifying a patient with alcohol dependence i) who has
a high DRL, and/or ii) who maintains the DRL of alcohol consumption
after an observation period following initial assessment, and
[0012] b) administering a therapeutically effective amount of
nalmefene to the patient identified in step a), wherein said
nalmefene is to be administered as-needed, such as on each day the
patient perceives a risk of drinking alcohol, preferably 1-2 hours
prior to the anticipated time of drinking.
BRIEF DESCRIPTION OF DRAWINGS
[0013] FIGS. 1-12 show the change from baseline in monthly Heavy
Drinking days (HDDs) and Total Alcohol Consumption (TAC) (g/day)
per study. Results are shown for the Total study population,
Patients with a high DRL at baseline. Total study population
excluding Early Reducers (ERs) and Patients with a high DRL at
baseline and randomization
[0014] FIGS. 1a-12a show the change from baseline in monthly HDDs.
X-axis: time (months); Y-axis: change in HDD.
[0015] FIGS. 1b-12b show the change from baseline in monthly TAC
(g/day). X-axis: time (months); Y-axis: change in TAC (g/day).
(=placebo, =nalmefene, *=P-value<0.05), "B" denotes baseline,
"R" denotes randomization.
[0016] FIG. 1a: Study 12014A, total study population, change in
monthly HDD.
[0017] FIG. 1b: Study 12014A, total study population, change in
monthly TAC.
[0018] FIG. 2a: Study 12014A, high DRL at baseline, change in
monthly HDD.
[0019] FIG. 2b: Study 12014A, high DRL at baseline, change in
monthly TAC.
[0020] FIG. 3a: Study 12014A, total study population excluding ERs,
change in monthly HDD.
[0021] FIG. 3b: Study 12014A, total study population excluding ERs,
change in monthly TAC.
[0022] FIG. 4a: Study 12014A, high DRL at baseline and
randomization, change in monthly HDD.
[0023] FIG. 4b: Study 12014A, high DRL at baseline and
randomization, change in monthly TAC.
[0024] FIG. 5a: Study 12023A, total study population, change in
monthly HDD.
[0025] FIG. 5b: Study 12023A. total study population, change in
monthly TAG.
[0026] FIG. 6a: Study 12023A, high DRL at baseline, change in
monthly HDD,
[0027] FIG. 6b: Study 12023A, high DRL at baseline, change in
monthly TAC.
[0028] FIG. 7a: Study 12023A, total study population excluding ERs,
change in monthly HDD.
[0029] FIG. 7b: Study 12023A, total study population excluding ERs,
change in monthly TAC.
[0030] FIG. 8a: Study 12023A, high DRL at baseline and
randomization, change in monthly HDD.
[0031] FIG. 8b: Study 12023A, high DRL at baseline and
randomization, change in monthly TAC.
[0032] FIG. 9a. Study 12013A, total study population, change in
monthly HDD.
[0033] FIG. 9b: Study 12013A, total study population, change in
monthly TAG.
[0034] FIG. 10a: Study 12013A, high DRL at baseline, change in
monthly HDD.
[0035] FIG. 10b: Study 12013A, high DRL at baseline, change in
monthly TAG.
[0036] FIG. 11a: Study 12013A, total study population excluding
ERs, change in monthly HDD.
[0037] FIG. 11b: Study 12013A, total study population excluding
ERs, change in monthly TAG.
[0038] FIG. 12a: Study 12013A, high DRL at baseline and
randomization, change in monthly HDD.
[0039] FIG. 12b. Study 12013A, high DRL at baseline and
randomization, change in monthly TAG.
DEFINITIONS
[0040] Throughout the description, the term "nalmefene" is intended
to include any forms of the compound, such as the free base and
pharmaceutically acceptable salts. The free base and
pharmaceutically acceptable salts include anhydrous forms and
solvated forms such as hydrates. The anhydrous forms and the
solvates include amorphous and crystalline forms. In a particular
embodiment, nalmefene is in the form of the hydrochloride. In a
more particular embodiment, nalmefene is in the form of the
hydrochloride dihydrate. Throughout the application, when a dose is
specified for nalmefene, said dose is calculated as the free base.
i.e. when the nalmefene dose is 18 mg this corresponds to 18 mg of
nalmefene free base.
[0041] As used herein, the term "total alcohol consumption"
abbreviated TAG indicates mean daily total alcohol consumption
measured in g/day over a month =28 days).
[0042] As used herein, the term "heavy drinking day" abbreviated
HDD indicates a day with a total alcohol consumption .gtoreq.60 g
of pure alcohol for men and .gtoreq.40 g for women.
[0043] As used herein, "as-needed dosing" indicates that on each
day a patient perceives a risk of drinking alcohol, one dose of
nalmefene should be taken, preferably 1-2 hours prior to the
anticipated time of drinking. If the patient has started drinking
alcohol without taking nalmefene, the patient should take one dose
as soon as possible after that.
[0044] As used herein, the term "drinking risk level" abbreviated
DRL is defined according to WHOs criteria according to Table 1
below.
TABLE-US-00002 TABLE 1 WHO Drinking Risk Levels (DRLs) of Alcohol
Consumption Total Alcohol Consumption (g/day) DRL Men Women Very
high risk >100 >60 High risk >60 to 100 >40 to 60
Medium risk >40 to 60 >20 to 40 Low risk 1 to 40 1 to 20
[0045] Drinking Risk Levels according to Table 1 can be assessed
e.g. by calculating mean daily alcohol consumption in g/day over a
period such as 1 week or longer, such as 2 weeks or longer, such as
3 weeks or longer, such as 4 weeks or longer, such as 1 month or
longer such as 2 months or longer, such as 3 months or longer, such
as 4 months or longer, such as 5 months or longer, such as 6 months
or longer, such as about 1 year. Assessment of DRL can be performed
by specialists and/or physicians such as general practitioners
and/or other health care providers based on patients estimates of
their alcohol consumption. In the three Lundbeck phase III studies
described in the examples (12014A, 12023A and 12013A) DRL was
measured by assessment of mean daily alcohol consumption in g/day
over a 4 week period up to the initial visit. After a 1-2 week
observation period the drinking risk level was re-assessed by
assessment of mean daily alcohol consumption in g/day over said 1-2
week observation period.
[0046] Throughout the application, the term "high risk" or "at
least high risk" is intended to include the two groups defined as
"high risk" and "very high risk" according to WHOs drinking risk
levels listed in Table 1, i.e. patients having drinking risk level
corresponding to a total alcohol consumption of >60 g/day of
pure alcohol for men and >40 g/day for women. The present
invention does not distinguish between patients with high and very
high drinking risk levels, and when the terms "high drinking risk
level" or "high DRL" are used in a claim or in an embodiment of the
invention it is intended to include both the group defined as "high
risk" and the group defined as "very high risk" according to WHOs
drinking risk levels listed in Table 1.
[0047] As used herein, the term `early reducer` abbreviated ER
indicates a patient included in the three Lundbeck phase III
studies (12014A, 12023A and 12013A) who had considerably reduced
the alcohol consumption in the period between screening and
randomisation. More specifically, patients defined as ERs have
reduced their alcohol consumption from high or medium DRL to a
level below medium drinking risk level i.e. said patients had an
alcohol consumption of 0-40 g/day for men and 0-20 g/day for women
estimated as the mean daily alcohol consumption in a 1-2 week
period between screening and randomization.
[0048] As used herein, an "observation period in accordance with
clinical practice" is an observation following initial assessment
of the DRL. Said period is preferably 1-2 weeks most preferably
about 2 weeks.
[0049] As used herein, the term "adult" indicates a person who is
at least 16 years old such as at least 18 years old.
[0050] As used herein, the term "adolescent" indicates a person who
is 12-18 years old such as 12-16 years old.
[0051] As used herein, the terms "motivational support" and
"counseling focused on enhanced treatment adherence and reduced
alcohol consumption" indicate psychological motivation-enhancing
interventions and can be used interchangeably with the terms
"psychosocial support" or "psychosocial intervention focused on
treatment adherence and reducing alcohol consumption". Said
motivational support can be administered by a specialist and/or a
physician such as a general practitioner and/or other health care
providers. One example of such interventions is the BRENDA model,
which is a time-limited, patient-centered clinical motivational
intervention that complements the use of medication with focus on
changing behavior and increasing medication adherence. The BRENDA
model has been described by Starosta et al., J. Psychiatr. Pract.
(2006), Vol. 12(2): 80-89, the entire contents of which are
incorporated herein by reference. The term "initial motivational
support" indicates such motivation-enhancing interventions provided
to the patient prior to treatment with nalmefene. The term "ongoing
motivational support" indicates such motivation-enhancing
interventions provided to the patient concurrent to treatment with
nalmefene e.g. on a recurrent basis.
[0052] As used herein, "Pharmaceutical composition" refers to a
dose such as an oral dose form, such as a solid oral dose form,
typically tablets or capsules. In a preferred embodiment, said dose
form is suitable for as-needed dosing. Said pharmaceutical
composition typically comprises a therapeutically effective amount
of nalmefene and one or more pharmaceutically acceptable carrier.
"Pharmaceutical compositions of the present invention" refers to
all pharmaceutical compositions covered by the claims and
description.
[0053] As used herein, a "unit dosage form" refers to a formulation
unit of a pharmaceutical composition e.g. one tablet or
capsule.
[0054] As used herein, "therapeutically effective amount" of a
compound means the amount/dose of a compound or pharmaceutical
composition that is sufficient to produce an effective response
(i.e., a biological or medical response of a tissue, system, animal
or human sought by a researcher, veterinarian, medical doctor or
other clinician) upon administration to a patient. The
"therapeutically effective amount" will vary depending on, inter
alia, the disease and its severity, and on the age, weight,
physical condition and responsiveness of the patient to be treated.
Furthermore, the "therapeutically effective amount" may vary if the
compound of the invention is combined with one or more compounds:
In such a case the amount of a given compound might be lower, such
as a sub-effective amount. In one embodiment, a "therapeutically
effective amount" of nalmefene is 18 mg.
[0055] As used herein, "treatment" and "treating" refers to the
management and care of a patient for the purpose of combating a
condition, such as a disease or a disorder. The term is intended to
include the full spectrum of treatments for a given condition from
which the patient is suffering, such as administration of the
active compound to alleviate the symptoms or complications, to
delay the progression of the disease, disorder or condition, to
alleviate or relieve the symptoms and complications, and/or to cure
or eliminate the disease, disorder or condition as well as to
prevent the condition, wherein prevention is to be understood as
the management and care of a patient for the purpose of combating
the disease, condition, or disorder and includes the administration
of the active compounds to prevent the onset of the symptoms or
complications.
[0056] The term "alcohol dependence" is a commonly known term for a
skilled person. In the revised 4.sup.th edition of the Diagnostic
and Statistical Manual of Mental Disorders (DSM-IV-TR) (Diagnostic
and Statistical Manual of Mental Disorders, 4.sup.th edition text
revision, American Psychiatric Publishing, 2000). As used herein,
the term "alcohol dependence" is defined as the presence of three
or more of the seven areas of life impairment related to alcohol in
the same 12-month period. These impairments include 1) tolerance,
2) withdrawal, 3) the alcohol is often taken in larger amounts or
over a longer period than was intended, 4) persistent desire or
unsuccessful efforts to cut down or control alcohol intake, 5) a
great deal of time is spent in activities necessary to obtain
alcohol, intake alcohol, or recover from its effects, 6) important
social, occupational, or recreational activities are given up or
reduced because of alcohol consumption, 7) alcohol use is continued
despite knowledge of having a persistent or recurrent physical or
psychological problem that is likely to have been caused or
exacerbated by alcohol consumption.
[0057] The term "Timeline Follow-back" (TLFB) is a method to obtain
estimates of daily drinking. Using memory aids, such as a calendar,
patients provide retrospective estimates of the number of standard
drinks for each day. In the three Lundbeck phase Hi studies
(12014A, 12023A and 12013A) TLFB was characterized by the following
approach. A day was defined as a 24-hour period starting at 6.00
a.m. and ending at 6.00 a.m. the following morning. At the
Screening Visit, each patient was to provide a retrospective
estimate of his/her daily drinking over the previous month (a month
was defined as a period of 28 consecutive days). At each subsequent
visit, the patient was to provide information on his/her drinking
since the previous visit. If a patient missed a visit, the TLFB
that was completed at the next visit was extended to cover the days
that should have been recorded at the missing visit. Patients could
use their personal calendars to help them recalling their drinking
or they could use a calendar provided by the site for their
personal use. Calendars were only to be used as a memory aid to
support the patients' input to TLFB. The patients were asked to
report their alcohol intake by standard units according to the
national definition of a standard unit. The standard national units
were defined in standard drink conversion cards distributed to the
patients.
[0058] "Hepatic impairment" can be assessed by the Child-Pugh
scoring system, as defined in Child and Turcotte J G. Surgery and
portal hypertension. In: The liver and portal hypertension. Edited
by C G Child. Philadelphia: Saunders 1964:50-64, the entire
contents of which are incorporated herein by reference. Patients
can be classified according to this system with e.g. "moderate or
severe hepatic impairment".
[0059] "Renal impairment" can be assessed by measuring estimated
global filtration rate (eGFR) as described in Stevens at al., N.
Engl. J. Med. (2006) 354:2473-2483, the entire contents of which
are incorporated herein by reference. Patients with "severe renal
impairment" are classified by an eGFR<30 ml/min per. 1.73
m.sup.2.
DETAILED DESCRIPTION OF THE INVENTION
[0060] The efficacy of nalmefene in the reduction of alcohol
consumption in patients with alcohol dependence (DSM-IV) has been
evaluated in two efficacy studies (Study 12014A and Study 12023A)
and one safety study (Study 12013A) as described in the examples.
All three studies were randomized, double blind, parallel-group and
placebo-controlled.
[0061] The studies included outpatients, aged years, with a primary
diagnosis of alcohol dependence. A patient was eligible for
participation in the study if, in the 4 weeks preceding the
Screening Visit (Baseline period), he/she had >6 HDDs, at least
a medium DRL (calculated as mean daily alcohol consumption in g/day
i.e. >40 g/day for men and >20 g/day for women calculated as
mean daily alcohol consumption over the 4 week period preceding the
screening visit), and .ltoreq.14 consecutive abstinent days. The
timeline followback (TLFB) method was used to obtain estimates of
the patient's daily drinking.
[0062] At the initial visit (screening visit), the patients'
clinical status, social situation, and alcohol consumption pattern
were evaluated. After a 1- to 2-week observation period the
drinking risk level was re-assessed by calculating mean daily
alcohol consumption in g/day over the 1- to 2-week observation
period, and treatment with nalmefene was initiated together with
counseling with focus on motivating the patients to adhere to the
treatment and to change their drinking behavior.
[0063] The efficacy of nalmefene was measured using two co-primary
endpoints: the change in the monthly number of heavy drinking days
(HDDs) and the change in the mean daily total alcohol consumption
(TAC) per month (=28 days). In the two 6 month efficacy studies and
in the 12 month safety study, nalmefene was superior to placebo in
reducing the number of HDDs and TAC at month 6 (see Table 6 and
FIGS. 1, 5 and 9).
[0064] The inventors have found that in patients with a high DRL at
baseline, i.e. alcohol consumption >60 g/day in men and >40
g/day in women at baseline (based on mean daily alcohol consumption
in g/day over a 4 week period preceding the initial visit), the
effect of nalmefene on HDDs and TAG was more pronounced compared to
placebo than in the total population i.e. nalmefene has a better
effect in this patient group than in the total study population
(see Table 6 and FIGS. 2, 6 and 10). Therefore in one aspect, the
present invention relates to nalmefene for use in the reduction of
alcohol consumption in a patient with alcohol dependence who has a
high drinking risk level i.e. a drinking risk level corresponding
to >60 g/day of pure alcohol for men and >40 g/day for women.
In one embodiment, the present invention relates to nalmefene for
use in the reduction of alcohol consumption in a patient with
alcohol dependence who has at a least high drinking risk level
according to WHO criteria, such as a high or very high drinking
risk level according to WHO criteria.
[0065] Furthermore, the inventors have observed that a sizeable
proportion of the patients included in the three phase III studies
(18%, 33% and 39% in studies 12014A, 12023A and 12013A,
respectively) had considerably reduced their alcohol consumption in
the 1- to 2-week observation period between screening and
randomisation i.e. these patients had reduced their alcohol
consumption from high or medium DRL to below medium DRL in the 1-
to 2-week observation period between screening and randomisation.
These patients were characterized as Early Reducers (ERs). It was
found that in the group of patients that were not ERs, the effect
of nalmefene on HDDs and TAC was more pronounced compared to
placebo than in the total population i.e. nalmefene has a better
effect in this group of patients than in the total study population
(see Table 6 and FIGS. 3, 7 and 11). Accordingly in another aspect
the present invention relates to nalmefene for use in the reduction
of alcohol consumption in a patient with alcohol dependence who
maintains the level of alcohol consumption after an observation
period in accordance with clinical practice, such as an observation
period of 1-2 weeks. In one embodiment, the invention relates to
nalmefene for use in the reduction of alcohol consumption in a
patient with alcohol dependence who maintains at least medium DRL
after an observation period in accordance with clinical practice,
such as an observation period of 1-2 weeks.
[0066] It was found that in patients with a high DRL both at
baseline and at randomisation; i.e. patients who had a high DRL at
baseline based on mean daily alcohol consumption in g/day over a 4
week period preceding the initial visit and who maintained a high
DRL in the 1- to 2-week observation period between screening and
randomization; the effect of nalmefene on HDDs and TAC was even
further pronounced compared to placebo than in the total population
i.e. nalmefene has a particularly good effect in this group of
patients compared to its effect in the total study population (see
Table 6 and FIGS. 4, 8 and 12). Accordingly, in one embodiment the
present invention relates to nalmefene for use in the reduction of
alcohol consumption in a patient with alcohol dependence who have a
high drinking risk level. i.e. alcohol consumption >60 g/day of
pure alcohol for men and >40 g/day for women, and who continue
to have a high drinking risk level after an observation period in
accordance with clinical practice.
[0067] In one embodiment, patients according to the invention have
a diagnosis of alcohol dependence according to the DSM-IV-TR
criteria. In one embodiment, patients according to the invention
have a diagnosis of alcohol use disorder according to the DSM-V
criteria.
[0068] In a separate aspect, the present invention relates to a
method for conducting a clinical study for assessment of the
efficacy of a treatment on the reduction of alcohol consumption,
wherein the method comprises the following steps: [0069] a)
screening patients based on their drinking risk level, [0070] b)
re-assessing the drinking risk level after an observation period
such as a 1- to 2-week observation period, such as a 2-week
observation period, [0071] c) excluding patients from the study who
have considerably reduced their alcohol consumption in the
observation period of step b).
[0072] In a further embodiment said patients selected for screening
according to step a) have a primary diagnosis of DSM-IV alcohol
dependence or DSM-V alcohol use disorder. in another further
embodiment, said patients excluded in step c) have reduced their
alcohol consumption to a drinking risk level from high or medium
DRL to below medium DRL or from high DRL to below high DRL.
[0073] According to the present invention, nalmefene or a
pharmaceutically acceptable salt thereof may be administered in any
suitable way, e.g. orally or parenterally, and it may be presented
in any suitable form for such administration, e.g. in the form of
tablets, capsules, powders, syrups or solutions or dispersions for
injection. In another embodiment. and in accordance with the
purpose of the present invention, nalmefene is administered in the
form of a solid pharmaceutical entity, suitably as a tablet or a
capsule or in the form of a suspension, solution or dispersion for
injection. Additionally, nalmefene may be administered with a
pharmaceutically acceptable carrier, such as an adjuvant and/or
diluent.
[0074] Methods for the preparation of solid or liquid
pharmaceutical preparations are well known in the art. See e.g.
Remington: The Science and Practice of Pharmacy. 21.sup.st ed.,
Lippincott Williams & Wilkins (2005). Tablets may thus be
prepared by mixing the active ingredients with an ordinary carrier,
such as an adjuvant and/or diluent, and subsequently compressing
the mixture in a tabletting machine. Non-limiting examples of
adjuvants and/or diluents include: corn starch, lactose, talcum,
magnesium stearate, gelatine, lactose, gums, and the like. Any
other adjuvant or additive such as colorings, aroma, and
preservatives may also be used provided that they are compatible
with the active ingredients. The pharmaceutical compositions of the
invention thus typically comprise a therapeutically effective
amount of nalmefene and one or more pharmaceutically acceptable
carrier. A suitable oral formulation of nalmefene is described in
WO 2012/059103.
[0075] Without limiting the invention in any way, it is intended
that any one of the aspects or embodiments of this patent
application is suitable for the medicaments or pharmaceutical
compositions described herein.
[0076] Nalmefene may be administered as an oral dose form, such as
a solid oral dose form, typically tablets or capsules, or as a
liquid oral dose form. Nalmefene may be administered in an
immediate release dosage form or a controlled or sustained release
dosage form. Nalmefene may be conveniently administered orally in
unit dosage forms, such as tablets or capsules, containing the
active ingredient in an amount from about 1 to about 100 mg, such
as from 5 to 50 mg. Typically, the pharmaceutical composition
comprises from 10 mg to 20 mg, such as about 10 mg, about 11 mg,
about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 15 mg,
about 17 mg, about 18 mg, about 19 mg or about 20 mg of nalmefene.
In a preferred embodiment, the pharmaceutical composition comprises
about 18 mg of nalmefene. in one embodiment, the unit dosage form
comprises nalmefene in a therapeutically effective amount.
[0077] In one embodiment, nalmefene is taken as-needed, that is, on
each day a patient perceives a risk of drinking alcohol, one dose
of nalmefene should be taken, preferably 1-2 hours prior to
anticipated time of drinking. In one embodiment, if the patient has
started drinking alcohol without taking nalmefene, the patient
should take one dose of nalmefene as soon as possible after
that.
[0078] In one embodiment, nalmefene is in the form of the
hydrochloride dihydrate.
[0079] Nalmefene according to the present invention is intended to
be used for dosing in humans which are adults or adolescents. In
one embodiment, nalmefene is intended to be used for dosing in
humans 12 years or older, such as 14 years or older, such as 16
years or older, such as 18 years or older.
[0080] All references, including publications, patent applications,
and patents, cited herein are hereby incorporated by reference in
their entirety and to the same extent as if each reference were
individually and specifically indicated to be incorporated by
reference and were set forth in its entirety herein (to the maximum
extent permitted by law), regardless of any separately provided
incorporation of particular documents made elsewhere herein.
[0081] The use of the terms "a" and "an" and "the" and similar
referents in the context of describing the invention are to be
construed to cover both the singular and the plural, unless
otherwise indicated herein or clearly contradicted by context. For
example, the phrase "the compound" is to be understood as referring
to various "compounds" of the invention or particular described
aspect, unless otherwise indicated.
[0082] The description herein of any aspect or aspect of the
invention using terms such as "comprising", "having," "including,"
or "containing" with reference to an element or elements is
intended to provide support for a similar aspect or aspect of the
invention that "consists of", "consists essentially of", or
"substantially comprises" that particular element or elements,
unless otherwise stated or clearly contradicted by context (e.g., a
composition described herein as comprising a particular element
should be understood as also describing a composition consisting of
that element, unless otherwise stated or clearly contradicted by
context).
[0083] It should be understood that the various aspects,
embodiments, implementations and features of the invention
mentioned herein may be claimed separately, or in any
combination.
EMBODIMENTS ACCORDING TO THE INVENTION
[0084] In the following, embodiments of the invention are
disclosed. The first embodiment is denoted E1, the second
embodiment is denoted E2 and so forth. [0085] E1. Nalmefene for use
in the reduction of alcohol consumption in a patient with alcohol
dependence who has a high DRL. [0086] E2. Nalmefene according to
embodiment 1, wherein said patient has a DRL corresponding to
consumption >60 g/day of pure alcohol for men and >40 g/day
for women. [0087] E3. Nalmefene according to any of embodiments
1-2, wherein said DRL is assessed by calculating mean daily alcohol
consumption in g/day over a period preceding assessment, wherein
said period is 1 week or longer, such as 2 weeks or longer, such as
3 weeks or longer, such as 4 weeks or longer, such as 1 month or
longer such as 2 months or longer, such as 3 months or longer, such
as 4 months or longer, such as 5 months or longer, such as 6 months
or longer, such as about 1 year. [0088] E4. Nalmefene according to
any of embodiments 1-3, wherein said patient has been identified as
having a high DRL. [0089] E5. Nalmefene according to any of
embodiments 1-4, wherein said patient continues to have a high DRL
despite initial motivational support. [0090] E6. Nalmefene
according to any of embodiments 1-4, wherein said patient maintains
a high DRL after an observation period in accordance with clinical
practice such as an observation period of 1-2 weeks, such as an
observation period of about 2 weeks. [0091] E7. Nalmefene according
to any of embodiments 1-5, wherein said patient maintains a high
DRL after an observation period of 1-2 weeks following initial
assessment of the DRL such as after an observation period of about
2 weeks following initial assessment of the DRL. [0092] E8.
Nalmefene according to any of embodiments 5-7, wherein said
maintained high DRL is assessed by calculating mean daily alcohol
consumption in g/day over said observation period. [0093] E9.
Nalmefene according to any of embodiments 5-8, wherein said
maintained DRL corresponds to consumption >60 g/day of pure
alcohol for men and >40 g/day for women. [0094] E10. Nalmefene
for use in the reduction of alcohol consumption in a patient with
alcohol dependence who maintains the level of alcohol consumption
despite initial motivational support. [0095] E11. Nalmefene for use
in the reduction of alcohol consumption in a patient who maintains
the level of alcohol consumption after an observation period in
accordance with clinical practice such as an observation period of
1-2 weeks, such as an observation period of about 2 weeks. [0096]
E12. Nalmefene for use in the reduction of alcohol consumption in a
patient with alcohol dependence who maintains at least medium DRL
after an observation period following initial assessment such as an
observation period of 1-2 weeks, such as an observation period of
about 2 weeks. [0097] E13. Nalmefene according to embodiments
10-12, wherein said maintained DRL corresponds to consumption
>40 g/day of pure alcohol for men arid >20 g/day for women.
[0098] E14. Nalmefene according to any of embodiments 10-13,
wherein said patient has a high DRL at initial assessment. [0099]
E15. Nalmefene according to embodiment 14, wherein said patient has
a DRL corresponding to consumption >60 g/day of pure alcohol for
men and >40 g/day for women at initial assessment. [0100] E16.
Nalmefene according to any of embodiments 14-15, wherein said
patient maintains a high DRL after said observation period. [0101]
E17. Nalmefene according to any of embodiments 10-16, wherein said
maintained DRL is assessed by calculating mean daily alcohol
consumption in g/day over said observation period. [0102] E18.
Nalmefene according to any of embodiments 14-17, wherein said high
DRL at initial assessment is assessed by calculating mean daily
alcohol consumption in g/day over a period preceding assessment,
wherein said period is 1 week or longer, such as 2 weeks or longer,
such as 3 weeks or longer, such as 4 weeks or longer, such as 1
month or longer such as 2 months or longer, such as 3 months or
longer, such as 4 months or longer, such as 5 months or longer,
such as 6 months or longer, such as about 1 year. [0103] E19.
Nalmefene according to any of embodiments 14-18, wherein said
patient has been identified as having a high DRL. [0104] E20.
Nalmefene for use in reduction of alcohol consumption in a patient
with alcohol dependence who has a DRL corresponding to consumption
>60 g/day of pure alcohol for men and >40 g/day for women
assessed by calculating mean daily alcohol consumption in g/day
over a period preceding assessment; wherein said patient maintains
a DRL corresponding to consumption >60 g/day of pure alcohol for
men and >40 g/day for women after an observation period
following initial assessment. assessed by calculating mean daily
alcohol consumption in g/day over said observation period. [0105]
E21. Nalmefene according to embodiment 20, wherein said period
preceding assessment is 1 week or longer, such as 2 weeks or
longer, such as 3 weeks or longer, such as 4 weeks or longer, such
as 1 month or longer such as 2 months or longer, such as 3 months
or longer, such as 4 months or longer, such as 5 months or longer,
such as 6 months or longer, such as about 1 year. [0106] E22.
Nalmefene according to any of embodiments 20-21, wherein said
observation period following initial assessment is 1-2 weeks such
as about 2 weeks. [0107] E23. Nalmefene according to any of
embodiments 1-22, wherein said nalmefene is to be used as-needed,
such as on each day the patient perceives a risk of drinking
alcohol, preferably 1-2 hours prior to the anticipated time of
drinking. [0108] E24. Nalmefene for use in reduction of alcohol
consumption in a patient with alcohol dependence, wherein said use
comprises the following steps:
[0109] a) identifying a patient with alcohol dependence i) who has
a high DRL, and/or ii) who maintains the DRL of alcohol consumption
after an observation period following initial assessment, and
[0110] b) administering nalmefene to the patient identified in step
a), wherein said nalmefene is to be administered as-needed, such as
on each day the patient perceives a risk of drinking alcohol,
preferably 1-2 hours prior to the anticipated time of drinking.
[0111] E25. Nalmefene according to embodiment 24, wherein said
observation period following initial assessment is 1-2 weeks, such
as about 2 weeks. [0112] E26. Nalmefene according to any of
embodiments 21-25, wherein said patient identified in step a) has a
DRL corresponding to consumption >60 g/day of pure alcohol for
men and >40 g/day for women. [0113] E27. Nalmefene according to
any of embodiments 24-26, wherein said high DRL identified in step
a) i) has been assessed by calculating mean daily alcohol
consumption in g/day over a period preceding assessment, wherein
said period of 1 week or longer, such as 2 weeks or longer, such as
3 weeks or longer, such as 4 weeks or longer, such as 1 month or
longer such as 2 months or longer, such as 3 months or longer, such
as 4 months or longer, such as 5 months or longer, such as 6 months
or longer, such as about 1 year. [0114] E28. Nalmefene according to
any of embodiments 24-27, wherein said maintained DRL in step a)
ii) is assessed by calculating mean daily alcohol consumption in
g/day over said observation period. [0115] E29. Nalmefene according
to any of embodiments 1-28, wherein said patient does not require
immediate detoxification and/or wherein said patient does not have
physical withdrawal symptoms. [0116] E30. Nalmefene according to
any of embodiments 1-29, wherein said patient is subject to ongoing
motivational support. [0117] E31. Nalmefene according to any of
embodiments 1-30, wherein said patient is subject to counseling
focused on enhanced treatment adherence and reduced alcohol
consumption. [0118] E32. Nalmefene according to embodiment 31,
wherein said counseling is performed according to the BRENDA model.
[0119] E33. Nalmefene according to any of embodiments 1-32, wherein
said patient is a patient for whom immediate abstinence is not a
treatment goal. [0120] E34. Nalmefene according to any of
embodiments 1-33, wherein said nalmefene is to be used for a
treatment period of 6 -12 months, such as 6 months. [0121] E35.
Nalmefene according to any of embodiments 1-34, wherein said
patient is an adult or an adolescent. [0122] E36. Nalmefene
according to any of embodiments 1-35, wherein said patient is 12
years or older, such as 14 years or older, such as 16 years or
older, such as 18 years or older. [0123] E37. Nalmefene according
to any of embodiments 1-36, wherein said nalmefene is used in a
dose of 10-20 mg such as 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg,
16 mg, 17 mg, 18 mg, 19 mg or 20 mg. [0124] E38. Nalmefene
according to embodiment 37, wherein said nalmefene is used in a
dose of 18 mg. [0125] E39. Nalmefene according to any of
embodiments 1-38, wherein said nalmefene is used in the form of a
pharmaceutically acceptable acid addition salt. [0126] E40.
Nalmefene according to embodiment 39, wherein said nalmefene is
used in the form of the hydrochloride salt. [0127] E41. Nalmefene
according to embodiment 40, wherein said nalmefene is used in the
form of the hydrochloride dihydrate. [0128] E42. Nalmefene
according to any of embodiments 1-41, wherein said nalmefene is
used in a crystalline form. [0129] E43. Nalmefene according to any
of embodiments 1-42, wherein said nalmefene is used in an oral dose
form such as tablets or capsules. [0130] E44. Nalmefene according
to any of embodiments 1-43, wherein said nalmefene is used in
combination with a further active ingredient. [0131] E45. Nalmefene
according to any of embodiments 1-44, wherein said patient does not
fall into one or more of the following categories: patients taking
opioid analgesics, opioid-addicted patients without successful
withdrawal, patients with acute symptoms of opioid withdrawal,
patients for whom recent use of opioids is suspected, patients with
moderate or severe hepatic impairment, patients with moderate or
severe renal impairment, patients with current or recent opioid
addiction, patients with a recent history of acute alcohol
withdrawal syndrome (including hallucinations, seizures, and
delirium tremens). [0132] E46. A method for reduction of alcohol
consumption in a patient with alcohol dependence who has a high
DRL, which method comprises the administration of a therapeutically
effective amount of nalmefene to said patient. [0133] E47. The
method according to embodiment 46, wherein said patient has a DRL
corresponding to consumption >60 g/day of pure alcohol for men
and >40 g/day for women. [0134] 48. The method according to any
of embodiments 46-47, wherein said DRL is assessed by calculating
mean daily alcohol consumption in g/day over a period preceding
assessment, wherein said period is 1 week or longer, such as 2
weeks or longer, such as 3 weeks or longer, such as 4 weeks or
longer, such as 1 month or longer such as 2 months or longer, such
as 3 months or longer, such as 4 months or longer, such as 5 months
or longer, such as 6 months or longer, such as about 1 year. [0135]
E49. The method according to any of embodiments 46-48, wherein said
patient has been identified as having a high DRL. [0136] E50. The
method according to any of embodiments 46-49, wherein said patient
continues to have a high DRL despite initial motivational support.
[0137] E51. The method according to any of embodiments 46-50,
wherein said patient maintains a high DRL after an observation
period in accordance with clinical practice such as an observation
period of 1-2 weeks such as an observation period of about 2 weeks.
[0138] E52. The method according to any of embodiments 46-50,
wherein said patient maintains a high DRL after an observation
period of least 1 week following initial assessment of the DRL such
as after an observation period of about 2 weeks following initial
assessment of the DRL. [0139] E53. The method according to any of
embodiments 50-52, wherein said maintained high DRL is assessed by
calculating mean daily alcohol consumption in g/day over said
observation period. [0140] E54. The method according to any of
embodiments 50-53, wherein said maintained DRL corresponds to
consumption >60 g/day of pure alcohol for men and >40 g/day
for women. [0141] E55. A method for reduction of alcohol
consumption in a patient with alcohol dependence who maintains the
level of alcohol consumption despite initial motivational support,
which method comprises the administration of a therapeutically
effective amount of nalmefene to said patient. [0142] E56. A method
for reduction of alcohol consumption in a patient with alcohol
dependence who maintains the level of alcohol consumption after an
observation period in accordance with clinical practice such as an
observation period of 1-2 weeks such as an observation period of
about 2 weeks, which method comprises the administration of a
therapeutically effective amount of nalmefene to said patient.
[0143] E57. A method for reduction of alcohol consumption in a
patient with alcohol dependence who maintains at least medium DRL
after an observation period following initial assessment such as an
observation period of 1-2 weeks, such as an observation period of
about 2 weeks, which method comprises the administration of a
therapeutically effective amount of nalmefene to said patient.
[0144] E58. The method according to embodiments 55-57, wherein said
maintained
[0145] DRL corresponds to consumption >40 g/day of pure alcohol
for men and >20 g/day for women. [0146] E59. The method to any
of embodiments 55-58, wherein said patient has a high DRL at
initial assessment. [0147] E60. The method according to embodiment
59, wherein said patient has a DRL corresponding to consumption
>60 g/day of pure alcohol for men and >40 g/day for women at
initial assessment. [0148] E61. The method according to any of
embodiments 55-60, wherein said patient maintains a high DRL after
said observation period.
[0149] E62. The method according to any of embodiments 55-61,
wherein said maintained DRL is assessed by calculating mean daily
alcohol consumption in g/day over said observation period. [0150]
63. The method according to any of embodiments 59-62, wherein said
high DRL at initial assessment is assessed by calculating mean
daily alcohol consumption in g/day over a period preceding
assessment, wherein said period is 1 week or longer, such as 2
weeks or longer, such as 3 weeks or longer, such as 4 weeks or
longer, such as 1 month or longer such as 2 months or longer, such
as 3 months or longer, such as 4 months or longer, such as 5 months
or longer, such as 6 months or longer, such as about 1 year. [0151]
E64. The method according to any of embodiments 59-63, where said
patient has been identified as having a high DRL. [0152] E65. A
method for reduction of alcohol consumption in a patient with
alcohol dependence who has a DRL corresponding to consumption
>60 g/day of pure alcohol for men and >40 g/day for women
assessed by calculating mean daily alcohol consumption in g/day
over a period preceding assessment, wherein said patient maintains
a DRL corresponding to consumption >60 g/day of pure alcohol for
men and >40 g/day for women after an observation following
initial assessment, assessed by calculating mean daily alcohol
consumption in g/day over said observation period, which method
comprises the administration of a therapeutically effective amount
of nalmefene to said patient. [0153] E66. The method according to
embodiment 65, wherein said period preceding assessment is 1 week
or longer, such as 2 weeks or longer, such as 3 weeks or longer,
such as 4 weeks or longer, such as 1 month or longer such as 2
months or longer, such as 3 months or longer, such as 4 months or
longer, such as 5 months or longer, such as 6 months or longer,
such as about 1 year. [0154] E67. The method according to any of
embodiments 65-66, wherein said observation period in following
initial assessment is 1-2 weeks such as about 2 weeks. [0155] E68.
The method according to any of embodiments 46-67, wherein said
nalmefene is administered as-needed, such as on each day the
patient perceives a risk of drinking alcohol, preferably 1-2 hours
prior to the anticipated time of drinking. [0156] E69. A method for
reduction of alcohol consumption in a patient with alcohol
dependence, wherein said method comprises the following steps:
[0157] a) identifying a patient with alcohol dependence i) who has
a high DRL, and/or ii) who maintains the DRL of alcohol consumption
after an observation period following initial assessment, and
[0158] b) administering a therapeutically effective amount of
nalmefene to the patient identified in step a), wherein said
nalmefene is to be administered as-needed, such as on each day the
patient perceives a risk of drinking alcohol, preferably 1-2 hours
prior to the anticipated time of drinking. [0159] E70. The method
according to embodiment 35 and 69, wherein said observation period
following initial assessment is 1-2 weeks, such as about 2 weeks.
[0160] E71. The method according to any of embodiments 69-70,
wherein the patient identified in step a) has a DRL corresponding
to consumption >60 g/day of pure alcohol for men and >40
g/day for women. [0161] E72. The method according to any of
embodiments 69-71, wherein said high DRL identified in step a) i)
has been assessed by calculating mean daily alcohol consumption in
g/day over a period preceding assessment, wherein said period is 1
week or longer, such as 2 weeks or longer, such as 3 weeks or
longer, such as 4 weeks or longer, such as 1 month or longer such
as 2 months or longer, such as 3 months or longer, such as 4 months
or longer, such as 5 months or longer, such as 6 months or longer,
such as about 1 year. [0162] E73. The method according to any of
embodiments 69-72, wherein wherein said maintained DRL in step a)
ii) is assessed by calculating mean daily alcohol consumption in
g/day over said observation period. [0163] E74. The method
according to any of embodiments 46-73, wherein said patient does
not require immediate detoxification and/or wherein said patient
does not have physical withdrawal symptoms. [0164] E75. The method
according to any of embodiments 46-74, wherein said patient is
subject to ongoing motivational support. [0165] E76. The method
according to any of embodiments 46-76, wherein said patient is
subject to counseling focused on enhanced treatment adherence and
reduced alcohol consumption. [0166] E77. The method according to
embodiment 76, wherein said counseling is performed according to
the BRENDA model. [0167] E78. The method according to any of
embodiments 46-77, wherein said patient is a patient for whom
immediate abstinence is not a treatment goal. [0168] E79. The
method according to any of embodiments 46-78, wherein said
nalmefene is to be used for a treatment period of 6 -12 months,
such as 6 months. [0169] E80. The method according to any of
embodiments 46-79, wherein said patient is an adult or an
adolescent. [0170] E81. The method according to any of embodiments
46-80, wherein said patient is 12 years or older, such as 14 years
or older, such as 16 years or older, such as 18 years or older.
[0171] E82. The method according to any of embodiments 46-81,
wherein the amount of nalmefene is 10-20 mg such as 10 mg, 11 mg,
12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg.
[0172] E83. The method according to embodiment 82, wherein the
amount of nalmefene is 18 mg. [0173] E84. The method according to
any of embodiments 46-83, wherein said nalmefene is administered in
the form of a pharmaceutically acceptable acid addition salt.
[0174] E85. The method according to embodiment 84, wherein said
nalmefene is administered in the form of the hydrochloride salt.
[0175] E86. The method according to embodiment 85, wherein said
nalmefene is administered in the form of the hydrochloride
dihydrate. [0176] E87. The method according to any of embodiments
46-86, wherein said nalmefene is administered in a crystalline
form. [0177] E88. The method according to any of embodiments 46-87,
wherein said nalmefene is administered in an oral dose form such as
tablets or capsules. [0178] E89. The method according to any of
embodiments 46-88, wherein said nalmefene is administered in
combination with a further active ingredient. [0179] E90. The
method according to any of embodiments 46-89, wherein said patient
does not fall into one or more of the following categories:
patients taking opioid analgesics, opioid addicted patients without
successful withdrawal, patients with acute symptoms of opioid
withdrawal, patients for whom recent use of opioids is suspected,
patients with moderate or severe hepatic impairment, patients with
moderate or severe renal impairment, patients with current or
recent opioid addiction, patients with a recent history of acute
alcohol withdrawal syndrome (including hallucinations, seizures,
and delirium tremens). [0180] E91. Use of nalmefene for the
manufacture of a medicament for reduction of alcohol consumption in
a patient with alcohol dependence who has a high DRL. [0181] E92.
The use according to embodiment 91, wherein said patient has a DRL
corresponding to consumption >60 g/day of pure alcohol for men
and >40 g/day for women. [0182] E93. The use according to any of
embodiments 91-92, wherein said DRL is assessed by calculating mean
daily alcohol consumption in g/day over a period preceding
assessment, wherein said period is 1 week or longer, such as 2
weeks or longer, such as 3 weeks or longer, such as 4 weeks or
longer, such as 1 month or longer such as 2 months or longer, such
as 3 months or longer, such as 4 months or longer, such as 5 months
or longer, such as 6 months or longer, such as about 1 year. [0183]
E94. The use according to any of embodiments 91-93, wherein said
patient has been identified as having a high DRL. [0184] E95. The
use according to any of embodiments 91-94, wherein said patient
continues to have a high DRL despite initial motivational support.
[0185] E96. The use according to any of embodiments 91-95, wherein
said patient maintains a high DRL after an observation period in
accordance with clink cal practice such as an observation period of
1-2 weeks such as an observation period of about 2 weeks. [0186]
E97. The use according to any of embodiments 91-95, wherein said
patient maintains a high DRL after an observation period of 1-2
weeks following initial assessment of the DRL such as after an
observation period of about 2 weeks following initial assessment of
the DRL. [0187] E98. The use according to any of embodiments 95-97,
wherein said maintained high DRL is assessed by calculating mean
daily alcohol consumption in g/day over said observation period.
[0188] E99. The use according to any of embodiments 95-98, wherein
said maintained DRL corresponds to consumption >60 g/day of pure
alcohol for men and >40 g/day for women. [0189] E100. Use of
nalmefene for the manufacture of a medicament for reduction of
alcohol consumption in a patient with alcohol dependence who
maintains the level of alcohol consumption despite initial
motivational support. [0190] E101. Use of nalmefene for the
manufacture of a medicament for reduction of alcohol consumption in
a patient who maintains the level of alcohol consumption after an
observation period in accordance with clinical practice such as an
observation period of 1-2 weeks, such as an observation period of
about 2 weeks. [0191] E102. Use of nalmefene for the manufacture of
a medicament for reduction of alcohol consumption in a patient with
alcohol dependence who maintains at least medium DRL after an
observation period following initial assessment such as an
observation period of 1-2 weeks, such as an observation period of 2
weeks. [0192] E103. The use according to any of embodiments
100-102, wherein said maintained DRL corresponds to consumption
>40 g/day of pure alcohol for men and >20 g/day for women.
[0193] E104. The use according to any of embodiments 100-103,
wherein said patient has a high DRL at initial assessment. [0194]
E105. The use according to embodiment 104, wherein said patient has
a DRL corresponding to consumption >60 g/day of pure alcohol for
men and >40 g/day for women at initial assessment. [0195] E106.
He use according to any of embodiments 101-105, wherein said
patient maintains a high DRL after said observation period. [0196]
E107. The use according to any of embodiments 101-106, wherein said
maintained DRL is assessed by calculating mean daily alcohol
consumption in g/day over said observation period. [0197] E108. The
use according to any of embodiments 104-107, wherein said high DRL
at initial assessment is assessed by calculating mean daily alcohol
consumption in g/day over a period preceding assessment, wherein
said period is 1 week or longer, such as 2 weeks or longer, such as
3 weeks or longer, such as 4 weeks or longer, such as 1 month or
longer such as 2 months or longer, such as 3 months or longer, such
as 4 months or longer, such as 5 months or longer, such as 6 months
or longer, such as about 1 year. [0198] E109. The use according to
any of embodiments 104-108, wherein said patient has been
identified as having a high DRL. [0199] E110. Use of nalmefene for
the manufacture of a medicament for reduction of alcohol
consumption in a patient with alcohol dependence who has a DRL
corresponding to consumption >60 g/day of pure alcohol for men
and >40 g/day for women assessed by calculating mean daily
alcohol consumption in g/day over a preceding assessment, wherein
said patient maintains a DRL corresponding to consumption >60
g/day of pure alcohol for men and >40 g/day for women after an
observation period following initial assessment, assessed by
calculating mean daily alcohol consumption in g/day over said
observation period. [0200] E111. The use according to embodiment
110, wherein said period preceding assessment is 1 week or longer,
such as 2 weeks or longer, such as 3 weeks or longer, such as 4
weeks or longer, such as 1 month or longer such as 2 months or
longer, such as 3 months or longer, such as 4 months or longer,
such as 5 months or longer, such as 6 months or longer, such as
about 1 year. [0201] E112. The use according to any of embodiments
110-111, wherein said observation period following initial
assessment is 1-2 weeks such as about 2 weeks. [0202] E113. The use
according to any of embodiments 91-112, wherein said medicament is
to be taken as-needed, such as on each day the patient perceives a
risk of drinking alcohol, preferably 1-2 hours prior to the
anticipated time of drinking. [0203] E114. Use of nalmefene for the
manufacture of a medicament for reduction of alcohol consumption in
a patient with alcohol dependence, wherein said use comprises the
following steps:
[0204] a) manufacturing a medicament comprising nalmefene,
[0205] b) identifying a patient with alcohol dependence i) who has
a high DRL, and/or ii) who maintains the DRL of alcohol consumption
after an observation period following initial assessment, and
[0206] c) administering said medicament to the patient identified
in step b), wherein said medicament is to be administered
as-needed, such as on each day the patient perceives a risk of
drinking alcohol, preferably 1-2 hours prior to the anticipated
time of drinking. [0207] E115. The use according to embodiment 114,
wherein said observation period following initial assessment is 1-2
weeks, such as 2 weeks. [0208] E116. The use according to any of
embodiments 114-115, wherein said patient identified in step b) has
a DRL corresponding to consumption >60 g/day of pure alcohol for
men and >40 g/day for women. [0209] E117. The use according to
any of embodiments 114-116, wherein said high DRL in identified in
step b) i) has been assessed by calculating mean daily alcohol
consumption in g/day over a period preceding assessment, wherein
said period is 1 week or longer, such as 2 weeks or longer, such as
3 weeks or longer, such as 4 weeks or longer, such as 1 month or
longer such as 2 months or longer, such as 3 months or longer, such
as 4 months or longer, such as 5 months or longer, such as 6 months
or longer, such as about 1 year. [0210] E118. Nalmefene according
to any of embodiments 114-117, wherein wherein said maintained DRL
in step b) ii) is assessed by calculating mean daily alcohol
consumption in g/day over said observation period. [0211] E119. The
use according to any of embodiments 91-118, wherein said patient
does not require immediate detoxification and/or wherein said
patient does not have physical withdrawal symptoms. [0212] E120.
The use according to any of embodiments 91-119, wherein said
patient is subject to ongoing motivational support. [0213] E121.
The use according to any of embodiments 91-120, wherein said
patient is subject to counseling focused on enhanced treatment
adherence and reduced alcohol consumption. [0214] E122. The use
according to embodiment 121, wherein said counseling is performed
according to the BRENDA model. [0215] E123. The use according to
any of embodiments 91-122, wherein said patient is a patient for
whom immediate abstinence is not a treatment goal. [0216] E124. The
use according to any of embodiments 91-123, wherein said medicament
is to be used for a treatment period of 6 -12 months such as 6
months. [0217] E125. The use according to any of embodiments
91-124, wherein said patient is an adult or an adolescent. [0218]
E126. The use according to any of embodiments 91-125, wherein said
patient is 12 years or older, such as 14 years or older, such as 16
years or older, such as 18 years or older. [0219] E127. The use
according to any of embodiments 91-126, wherein said medicament
comprises nalmefene in a dose of 10-20 mg such as 10 mg, 11 mg, 12
mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg.
[0220] E128. The use according to embodiment 127, wherein said
medicament comprises nalmefene in a dose of 18 mg. [0221] E129. The
use according to any of embodiments 91-128, wherein said medicament
comprises nalmefene in the form of a pharmaceutically acceptable
acid addition salt. [0222] E130. The use according to embodiment
129, wherein said medicament comprises nalmefene in the form the
hydrochloride salt. [0223] E131. The use according to embodiment
130, wherein said medicament comprises nalmefene in the form the
hydrochloride dihydrate. [0224] E132. The use according to any of
embodiments 91-131, wherein said said medicament comprises
nalmefene in a crystalline form. [0225] E133. The use according to
any of embodiments 91-132, wherein said medicament comprises an
oral dose form such as tablets or capsules. [0226] E134. The use
according to any of embodiments 91-133, wherein said medicament
comprises a further active ingredient. [0227] E135. The use
according to any of embodiments 91-134, wherein said patient does
not fall into one or more of the following categories: patients
taking opioid analgesics, opioid-addicted patients without
successful withdrawal, patients with acute symptoms of opioid
withdrawal, patients for whom recent use of opioids is suspected,
patients with moderate or severe hepatic impairment, patients with
moderate or severe renal impairment, patients with current or
recent opioid addiction, patients with a recent history of acute
alcohol withdrawal syndrome (including hallucinations, seizures,
and delirium tremens).
EXAMPLES
[0228] The invention will be illustrated by the following
non-limiting examples.
[0229] The efficacy of nalmefene on the reduction of alcohol
consumption in patients with alcohol dependence (DSM-IV) was
evaluated in two efficacy studies (Study 12014A and Study 12023A).
Both studies were randomised, double blind, two-parallel group,
placebo controlled, and after 6 months of treatment, patients
receiving nalmefene were re-randomised to receive either placebo or
nalmefene in a 1 month run out period. The efficacy of nalmefene
was also evaluated in a randomised, double blind, two parallel
group, placebo controlled 1 year safety study (Study 12013A). The
studies included 1941 patients, 1144 of whom were treated with
nalmefene 18 mg in an as-needed dosing regimen.
[0230] The studies were conducted applying an outpatient setting
without preceding detoxification. Higher CIWA withdrawal scores at
Screening as well as a history of delirium tremens and seizures
would be indicative for the necessity of prior inpatient
detoxification. Patients with abuse of substance other than alcohol
and subjects with significant depressive or psychotic co-morbidity
were excluded.
[0231] The studies included outpatients, aged .gtoreq.18 years,
with a primary diagnosis of alcohol dependence. A patient was
eligible for participation in the study if, in the 4 weeks
preceding the Screening Visit (Baseline period), he/she had >6
HDDs, at least a medium DRL (calculated as mean daily alcohol
consumption in g/day i.e. >40 g/day for men and >20 g/day for
women calculated as mean daily alcohol consumption over the 4 week
period preceding the screening visit), and .ltoreq.14 consecutive
abstinent days. The timeline followback (TLFB) method was used to
obtain estimates of the patient's daily drinking.
[0232] The studies were conducted over a 34 week period (12 visits)
in total and consisted of four sequential periods: a 2-week
screening period, a 24-week double-blind treatment period, a 4-week
double-blind placebo-controlled run-out in each of the treatment
arms and finally a 4-week safety follow-up. One to two weeks after
the Screening Visit the patients were randomised 1:1 to 24 weeks of
as-needed, double-blind treatment (Main Treatment Period: MTP) with
nalmefene (18 mg) or placebo. The patients who completed 24 weeks
of double-blind treatment entered a 4-week, double-blind Run-out
Period (ROP). The patients randomised to nalmefene were
re-randomised 1:1 to receive nalmefene (18 mg, as-needed) or
placebo and the patients randomised to placebo continued on
placebo.
[0233] The Timeline Follow-back (TLFB) method was used to collect
self-reported drinking data (alcohol consumption).
[0234] At the initial visit, the patients' clinical status, social
situation, and alcohol consumption pattern were evaluated (based on
patient reporting). After a 1- to 2-week observation period the
drinking risk level was re-assessed (i.e. the can daily alcohol
consumption over the 1-2 week assessment period was calculated),
and treatment with nalmefene was initiated together with counseling
with focus on motivating the patients to adhere to the treatment
and to change their drinking behavior. In all the studies, a
motivational and adherence enhancing intervention, according to the
BRENDA model, was administered to all the patients to support the
patients in changing their behavior and to enhance adherence to
treatment.
[0235] The patients' alcohol intake (g/day) was estimated based on
national definitions of standard units (subsequently converted into
grams of alcohol). To define the standard units, a standard drink
conversion card was distributed to each patient at the Screening
Visit. Each patient was also provided with a calendar that he/she
could use to support his/her input to the TLFB, or he/she could use
a personal calendar, if preferred. For all the variables derived
from the TLFB data, baseline was defined as the month (that is 4
weeks/28 consecutive days) preceding the Screening Visit. The
investigational medicinal product (IMP) was taken as-needed. Each
patient was instructed to take a maximum of one tablet on each day
the patient perceived a risk of drinking alcohol, preferably 1 to 2
hours prior to the anticipated time of drinking. If the patient had
started drinking alcohol without taking nalmefene, the patient was
to take one tablet as soon as possible. The dates when nalmefene
was taken/not taken were recorded using the TLFB method. The chosen
comparator was placebo
[0236] The demographic data for each study are provided in tables
2-4 below. Table 5 summarizes the number of patients in the
efficacy analysis for each patient group.
TABLE-US-00003 TABLE 2 Patient Demographics (APRS) - Study 12014A
Placebo Nalmefene Total Number of Patients 298 306 604 Age (years)
N 298 306 604 MEAN 52.12 51.02 51.56 STD 9.08 10.12 9.63 MIN 24.00
24.00 24.00 MAX 75.00 72.00 75.00 MEDIAN 52.00 51.00 52.00 Age
group (years) n (%) <25 1 (0.3) 1 (0.3) 2 (0.3) >=25 and 6
(2.0) 14 (4.6) 20 (3.3) <35 >=35 and 54 (18.1) 65 (21.2) 119
(19.7) <45 >=45 and 115 (38.6) 108 (35.3) 223 (36.9) <55
>=55 and 97 (32.6) 87 (28.4) 154 (30.5) <55 >=65 25 (8.4)
31 (10.1) 56 (9.3) Sex n (%) F 96 (32.2) 102 (33.3) 198 (32.8) M
202 (67.8) 204 (66.7) 406 (67.2) Race n (%) BLACK 1 (0.3) 306 (100)
1 (0.2) CAUCASIAN 297 (99.7) 306 (100) 603 (99.8)
TABLE-US-00004 TABLE 3 Patient Demographics (APRS) - Study 12023A
Placebo Nalmefene Total Number of Patients 360 358 718 Age (years)
N 360 358 718 MEAN 44.41 45.10 44.75 STD 10.66 10.69 10.67 MIN
20.00 20.00 20.00 MAX 69.00 72.00 72.00 MEDIAN 45.00 45.00 45.00
Age group (years) n (%) <25 7 (1.9) 9 (2.5) 16 (2.2) >=25 and
69 (19.2) 57 (15.9) 126 (17.5) <35 >=35 and 99 (27.5) 106
(29.6) 205 (28.6) <45 >=45 and 123 (34.2) 116 (32.4) 239
(33.3) <55 >=55 and 52 (14.4) 57 (15.9) 109 (15.2) <65
>=65 10 (2.8) 13 (3.6) 23 (3.2) Sex n (%) F 104 (28.9) 92 (25.7)
196 (27.3) M 256 (71.1) 266 (74.3) 522 (72.7) Race n (%) ASIAN 2
(0.6) 2 (0.3) BLACK 2 (0.6) 3 (0.8) 5 (0.7) CAUCASIAN 357 (99.2)
353 (98.6) 710 (98.9) OTHER 1 (0.3) 1 (0.1)
TABLE-US-00005 TABLE 4 Patient Demographics (APRS) - Study 12013A
Placebo Nalmefene Total Number of Patients 166 509 675 Age (years)
N 166 509 675 MEAN 44.27 44.26 44.26 STD 11.99 11.24 11.42 MIN
18.00 19.00 18.00 MAX 72.00 77.00 77.00 MEDIAN 44.00 44.00 44.00
Age group (years) n (%) <25 8 (4.8) 14 (2.8) 22 (3.3) >=25
and 30 (18.1) 91 (17.9) 121 (17.9) <35 >=35 and 47 (28.3) 160
(31.4) 207 (30.7) <45 >=45 and 44 (26.5) 153 (30.1) 197
(29.2) <55 >=55 and 30 (18.1) 64 (12.6) 94 (13.9) <65
>=65 7 (4.2) 27 (5.3) 34 (5.0) Sex n (%) F 39 (23.5) 116 (22.8)
155 (23.0) M 127 (76.5) 393 (77.2) 520 (77.0) Race n (%) ASIAN 1
(0.2) 1 (0.1) BLACK 1 (0.2) 1 (0.1) CAUCASIAN 165 (99.4) 506 (99.4)
671 (99.4) OTHER 1 (0.6) 1 (0.2) 2 (0.3)
TABLE-US-00006 TABLE 5 Number of patients in efficacy analysis
Study Population Placebo Nalmefene 12014A Total population 289 290
High DRL at baseline 230 222 Total excl. ERs 231 246 High DRL at
baseline & 167 171 randomisation 12023A Total population 326
329 High DRL at baseline 247 265 Total excl. ERs 221 216 High DRL
at baseline & 155 148 randomisation 12013A Total population 137
415 High DRL at baseline 88 252 Total excl. ERs 79 258 High DRL at
baseline & 42 141 randomisation
[0237] The efficacy of nalmefene was measured using two co-primary
endpoints: the change in the monthly number of heavy drinking days
(HDDs) and the change in the mean daily total alcohol consumption
(TAC) per month (=28 days). A HDD was defined as a day with a
consumption .gtoreq.60 g alcohol for men and .gtoreq.40 g for
women. Data obtained at month 6 are listed in Table 6 below. The
change in HDD and TAC over time in patients treated with nalmefene
or placebo is furthermore reflected in FIGS. 1-12.
TABLE-US-00007 TABLE 6 Results (Mixed model repeated measures
(MMRM) analysis) at Month 6. Mean difference to placebo in the
change from baseline Study Endpoint Population to month 6 p-value
12014A HDD Total population -2.3 days/month 0.002 High DRL at
baseline -2.6 days/month 0.006 Total excl. ERs -3.1 days/month
<0.001 High DRL at -3.7 days/month 0.001 baseline &
randomisation TAC Total population -11.0 g/day <0.001 High DRL
at baseline -12.2 g/day <0.001 Total excl. ERs -14.5 g/day
<0.001 High DRL at -18.3 g/day <0.001 baseline &
randomisation 12023A HDD Total population -1.7 days/month 0.012
High DRL at baseline -2.1 days/month 0.010 Total excl. ERs -2.0
days/month 0.012 High DRL at -2.7 days/month 0.025 baseline &
randomisation TAC Total population -5.0 g/day 0.088 High DRL at
baseline -6.6 g/day 0.062 Total excl. ERs -7.0 g/day 0.037 High DRL
at -10.3 g/day 0.040 baseline & randomisation 12013A HDD Total
population -0.9 days/month 0.160 High DRL at baseline -1.1
days/month 0.253 Total excl. ERs -1.4 days/month 0.082 High DRL at
-2.6 days/month 0.071 baseline & randomisation TAC Total
population -3.5 g/day 0.232 High DRL at baseline -5.6 g/day 0.219
Total excl. ERs -7.9 g/day 0.036 High DRL -15.3 g/day 0.031 at
baseline & randomisation
[0238] Table 6 indicates that in all three studies the difference
between nalmefene and placebo measured in HDDs and TAG was more
pronounced in the group of patents with High DRL at baseline than
in the total study population.
[0239] Table 6 also indicates that in all three studies the
difference between nalmefene and placebo measured in HDDs and TAC
was more pronounced in the group of patients excluding ERs than in
the total study population.
[0240] Finally, table 6 clearly indicates that in all three studies
the difference between nalmefene and placebo measured in HDDs and
TAC was more pronounced in the group of patients with High DRL at
baseline and randomization (i.e. patients with High DRL excluding
ERs) than in the total study population.
* * * * *