U.S. patent application number 16/233046 was filed with the patent office on 2019-05-16 for use of rasagiline for the treatment of restless legs syndrome.
This patent application is currently assigned to Teva Pharmaceutical Industries, Ltd.. The applicant listed for this patent is Eran Blaugrund, Ruth Levy. Invention is credited to Eran Blaugrund, Ruth Levy.
Application Number | 20190142766 16/233046 |
Document ID | / |
Family ID | 38581572 |
Filed Date | 2019-05-16 |
![](/patent/app/20190142766/US20190142766A1-20190516-C00001.png)
United States Patent
Application |
20190142766 |
Kind Code |
A1 |
Blaugrund; Eran ; et
al. |
May 16, 2019 |
USE OF RASAGILINE FOR THE TREATMENT OF RESTLESS LEGS SYNDROME
Abstract
Disclosed are methods for the treatment of Restless Legs
Syndrome comprising administering an amount of
R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt
thereof.
Inventors: |
Blaugrund; Eran; (Rehovot,
IL) ; Levy; Ruth; (Tel Aviv, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Blaugrund; Eran
Levy; Ruth |
Rehovot
Tel Aviv |
|
IL
IL |
|
|
Assignee: |
Teva Pharmaceutical Industries,
Ltd.
Petach-Tikva
IL
|
Family ID: |
38581572 |
Appl. No.: |
16/233046 |
Filed: |
December 26, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16102148 |
Aug 13, 2018 |
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16233046 |
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15895962 |
Feb 13, 2018 |
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16102148 |
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15697935 |
Sep 7, 2017 |
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15895962 |
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15096038 |
Apr 11, 2016 |
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15697935 |
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14524993 |
Oct 27, 2014 |
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15096038 |
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11731493 |
Mar 30, 2007 |
8946300 |
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14524993 |
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60788617 |
Apr 3, 2006 |
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Current U.S.
Class: |
514/367 ;
514/649 |
Current CPC
Class: |
A61K 31/16 20130101;
A61P 25/14 20180101; A61K 2300/00 20130101; A61P 21/00 20180101;
A61P 25/08 20180101; A61P 25/00 20180101; A61K 31/135 20130101;
A61P 43/00 20180101; A61K 31/428 20130101 |
International
Class: |
A61K 31/135 20060101
A61K031/135; A61K 31/428 20060101 A61K031/428; A61K 31/16 20060101
A61K031/16 |
Claims
1. A pharmaceutical composition comprising in unit dosage form
R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt
thereof and at least one of pergolide, pramipexole, oxycodone,
clonazepam, carbamazepine, gabapentin, valproate, ropinirole or
clonidin.
Description
[0001] This application is a continuation of U.S. Ser. No.
14/524,993, filed Oct. 27, 2014, which is a continuation of U.S.
Ser. No. 11/731,493, filed Mar. 30, 2007, which claims benefit of
U.S. Provisional Application No. 60/788,617 filed Apr. 3, 2006, the
entire contents of each of which in their entireties are hereby
incorporated by reference.
[0002] Throughout this application various publications, published
patent applications and published patents are referenced. The
disclosures of these publications in their entireties are hereby
incorporated by reference into this application in order to more
fully describe the state of the art to which this invention
pertains.
BACKGROUND OF THE INVENTION
[0003] Restless Legs Syndrome ("RLS", also known as Ekbom Syndrome)
is a neurological condition that expresses itself as an
overwhelming urge to move the legs, usually caused by uncomfortable
or unpleasant sensations in the legs at rest. Movement of the legs
temporarily alleviates the discomfort. (Jones et al., Restless Legs
Syndrome--A Review, Eur. J. Vasc. Endovasc. Surg., December 1997,
14(6):430-2)
[0004] The sensations occur during periods of inactivity, and are
thus most intense in the evening and at night. RLS often causes
difficulty staying or falling asleep, which leads to feelings of
daytime tiredness or fatigue. RLS may cause involuntary jerking of
the limbs during sleep and sometimes during wakefulness. Because of
the nature of these symptoms, RLS is one of the most prevalent
causes of sleep disorders such as sleep disturbance and insomnia.
(Fox, G. N., Restless Legs Syndrome, American Family Physician,
January 1986, 33(1):147-52)
[0005] RLS can occur at any age but increases in frequency as
persons grow older. (Thorpy J. Michael. New Paradigms in the
treatment of restless legs syndrome. Neurology 2005; 64: S28-S33)
It afflicts about 8% of the general population. (see, rls.org/)
[0006] At least 80% of RLS patients experience periodic leg
movements (PLMs), stereotyped, repetitive flexion movements of the
legs that occur approximately every 5-90 seconds when the patient
is asleep or lying down resting. (Hening A Wayne et al. An update
on the dopaminergic treatment of restless legs syndrome and
periodic limb movement disorder. Sleep 2004, 27: 560-583.) Both the
sensations in the limbs and the PLMs can profoundly disrupt sleep
(getting to sleep and staying asleep). This can lead to excessive
daytime sleepiness as well as depression and anxiety and may have a
significant negative impact on quality of life.
[0007] Treatment of RLS can be difficult and often requires trying
different drugs and dosage regimes. (The Merck Manual, 17th Ed.
1999, 1416) The primary pharmacologic treatment of RLS is
principally with two classes of medications: dopaminergic agents
and opiate agents. (Restless Legs Syndrome Foundation, Inc. Medical
Bulletin, April 2004, pg. 15)
[0008] Nearly all patients with RLS show at least an initial
positive therapeutic response to dopamine precursor levodopa
(L-dopa) (either alone or with a dopa decarboxylase inhibitor like
carbidopa) at dosages very low compared with those prescribed in
the treatment of Parkinson's disease. (Montplaisir J. et al.,
Restless Legs Syndrome and Periodic Movements in Sleep:
Physiopathology and Treatment with L-dopa, Clin. Neuropharmacol.,
1986, 9(5):456-463) This initial response, however, is not
universally maintained. The drawback of L-dopa therapy lies in the
fact that in many patients its effectiveness tapers off and/or the
RLS problem is shifted toward the morning hours (rebound) or the
disorder is aggravated with the problem occurring event during the
day (augmentation). (Guilleminault C. et al., Dopaminergic
Treatment of Restless Legs and Rebound Phenomenon, Neurology, 1993,
43(2):445; and Allen R. P., Augmentation of the Restless Legs
Syndrome with Carbidopa/Levodopa, Sleep, 1996, 19(3):205-213)
[0009] Dopamine-receptor agonists such as pergolide and
pramipexole, known by the trade name Mirapex [available from
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn.],
provide well-established and effective treatment for RLS. However,
they have been reported to cause major side effects. (Dooley M. et
al., Pramipexole: A Review of Its Use in the Management of Early
and Advanced Parkinson's Disease, Drugs Aging, June 1998,
12(6):495-514; and Silber M. H. et al., Pergolide in the Management
of Restless Legs Syndrome: An Extended Study, Sleep, 1997,
20(10):878-882) In fact, all of the dopamine agonists can be used
to treat RLS but with a negative aspect in that, usually in the
beginning and as a function of the dosage administered, they lead
to such side effects as nausea, vomiting, dizziness, hypotension,
constipation or insomnia. (Medical Bulletin, infra at pg. 17)
[0010] Opiates are effective against RLS as well, although often at
relatively high doses. (Walters, A. S. et al., Successful Treatment
of the Idiopathic Restless Legs Syndrome in a Randomized
Double-Blind Trial of Oxycodone Versus Placebo, Sleep, 1993,
16(4):327-332) However, because of the risk of addiction and
progressive tolerance these substances are suitable for therapeutic
application to a limited extent at best.
[0011] Benzodiazepines such as clonazepam and anticonvulsants such
as gabapentin and carbamazepine have also been shown to alleviate
the symptoms of RLS. (Medical Bulletin, infra at pg. 19) However,
side effects similar to those associated with the treatments
described above limit use. Addiction and daytime sedation are
problematic with benzodiapenes, which does not prevent movement but
only prevents awakening. (Id.) High dosages are required in
anticonvulsant treatments. Furthermore, it is thought that
anticonvulsants fail to resolve the full spectrum of elements of
RLS. (Telstad W. et al., Treatment of the Restless Legs Syndrome
with Carbamazepine; A Double Blind Study, Br. Med. J. (Clin. Res.
Ed.), 1984, 288(6415):444-446)
[0012] Valproate has also shown benefit for RLS, but the side
effect of weight gain has limited its acceptance. (Dinesin H. et
al., Weight Gain During Treatment With Valproate, Acta. Neurol.
Scan., 1984, 70(2):65-69)
[0013] Clonidine, originally developed as an antihypertensive agent
and miotic, has also been examined for its effectiveness in the
treatment of RLS. While it was found that soporiferous latency was
reduced, it had no effect on the quality of sleep, the frequency of
waking up or periodic leg movement during sleep. Given that more
efficacious substances are available for monotherapy, clonidine is
not currently recommended as an alternative form of therapy except
in limited situations. (U.S. Patent Publication No. 2001/0053777,
published Dec. 20, 2001)
[0014] Therefore, there exists a need for an effective, alternative
treatment and related treatment regime options for individuals who
are afflicted with RLS. More particularly, there exists a need for
treatments that do not induce the unwanted effects observed in
modern therapeutics of RLS.
SUMMARY OF THE INVENTION
[0015] This subject invention provides a method of treating a
subject suffering from Restless Legs Syndrome which comprises
administering to the subject an amount of
R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptably salt
thereof, effective to treat the subject.
[0016] The subject invention also provides a method of alleviating
a symptom of Restless Legs Syndrome in a subject afflicted with
Restless Legs Syndrome comprising administering to the subject an
amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically
acceptable salt thereof effective to alleviate the symptom of
Restless Legs Syndrome in the subject.
[0017] The subject invention also provides a pharmaceutical
composition comprising in unit dosage form
R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt
thereof and at least one of pergolide, pramipexole, oxycodone,
clonazepam, carbamazepine, gabapentin, valproate, ropinirole or
clonidin.
[0018] The subject invention also provides a pharmaceutical
composition for use in the treatment of, or alleviation of symptoms
of, Restless Legs Syndrome, which comprises a therapeutically
effective amount of R(+)-N-propargyl-1-aminoindan or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
[0019] The subject invention also provides use of
R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for the treatment of, or
alleviation of symptoms of, Restless Legs Syndrome.
[0020] The subject invention also provides a pharmaceutical
composition comprising in unit dosage form
R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt
thereof and pramipexole.
DETAILED DESCRIPTION
[0021] The subject invention provides a method of treating a
subject suffering from Restless Legs Syndrome which comprises
administering to the subject an amount of
R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptably salt
thereof, effective to treat the subject.
[0022] The subject invention also provides a method of alleviating
a symptom of Restless Legs Syndrome in a subject afflicted with
Restless Legs Syndrome comprising administering to the subject an
amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically
acceptable salt thereof effective to alleviate the symptom of
Restless Legs Syndrome in the subject.
[0023] In an embodiment, the symptom may be any of tingling in the
legs, cramps in the legs, pain in the legs or restlessness in the
legs.
[0024] In the methods, the IRLS Rating Scale score of the subject
decreases compared to the baseline.
[0025] In an embodiment of the methods, the decrease is a 20%
decrease, preferably a 30% decrease, more preferably a 40%
decrease, yet more preferably a 50% decrease of the IRLS Rating
Scale Score.
[0026] In an embodiment, the amount of
R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable
salt thereof may be from 0.01 mg to 20 mg per day. By 0.01 mg to 20
mg it is meant that all hundredth, tenth and integer unit amounts
within the range are specifically disclosed as part of the
invention. Thus, 0.02, 0.03 . . . 0.09; 0.1, 0.2 . . . 0.9; 1, 2 .
. . 19 mg unit amounts are included as embodiments of this
invention.
[0027] In a further embodiment, the therapeutically effective
amount of R(+)-N-propargyl-1-aminoindan or of the pharmaceutically
acceptable salt thereof may be from 0.5 mg to 5 mg per day.
[0028] In a specific embodiment, the amount may be 1.0 mg. By 0.5
mg to 5 mg it is meant that all tenth and integer unit amounts
within the range are specifically disclosed as part of the
invention. Thus, 0.6, 0.7 . . . 0.9; 1, 2 . . . 4 mg unit amounts
are included as embodiments of this invention.
[0029] In an embodiment, a dose of R(+)-N-propargyl-1-aminoindan or
of the pharmaceutically acceptable salt thereof may be administered
1 to 4 times a day.
[0030] In a further embodiment, a dose of
R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable
salt thereof may be administered once a day.
[0031] Furthermore, an evening dose of
R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable
salt thereof may be administered to a subject 1 to 3 hours before
the subject goes to bed.
[0032] Yet furthermore, a second dose is administered to the
subject 3 to 7 hours before the evening dose.
[0033] In another embodiment, a dose of
R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable
salt thereof is administered to the subject at 3 to 7 hour
intervals throughout the day.
[0034] In an embodiment, the administration is of
R(+)-N-propargyl-1-aminoindan.
[0035] In a further embodiment, the administration is of the
pharmaceutically acceptable salt of
R(+)-N-propargyl-1-aminoindan.
[0036] The pharmaceutically acceptable salt of the methods may be
esylate, mesylate, sulfate or tartrate.
[0037] In a specific embodiment, the pharmaceutically acceptable
salt may be mesylate.
[0038] In a further embodiment, the therapeutically effective
amount of R(+)-N-propargyl-1-aminoindan mesylate may be 1.66 mg per
day.
[0039] 1 mg of the base compound R(+)-N-propargyl-1-aminoindan
amounts to 1.66 mg of R(+)-N-propargyl-1-aminoindan mesylate.
[0040] In an embodiment, the administration may be oral,
parenteral, rectal or transdermal administration.
[0041] In a further embodiment of the invention, the methods
further comprise administration of carbidopa, levodopa, pergolide,
pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin,
valproate, ropinirole or clonidin.
[0042] In an embodiment, the administration of
R(+)-N-propargyl-1-aminoindan or the salt substantially precedes
the administration of any of carbidopa, levodopa, pergolide,
pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin,
valproate, ropinirole or clonidin.
[0043] In a further embodiment, the administration of
R(T)-N-propargyl-1-aminoindan or the salt is contemporaneous with
the administration of any of carbidopa, levodopa, pergolide,
pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin,
valproate, ropinirole or clonidin.
[0044] The R(+)-N-propargyl-1-aminoindan or the pharmaceutically
acceptable salt thereof may be in a pharmaceutical composition when
used in the methods.
[0045] In an embodiment, the pharmaceutical composition is in
tablet form.
[0046] In an embodiment, the pharmaceutical composition is in a
form suitable for transdermal administration.
[0047] In an embodiment, the pharmaceutical composition is in a
form suitable for sublingual administration.
[0048] The subject invention also provides a pharmaceutical
composition comprising in unit dosage form
R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt
thereof and at least one of pergolide, pramipexole, oxycodone,
clonazepam, carbamazepine, gabapentin, valproate, ropinirole or
clonidin.
[0049] The subject invention also provides a pharmaceutical
composition comprising in unit dosage form
R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt
thereof and pramipexole.
[0050] In an embodiment, the amount of
R(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable
salt thereof is from 0.5 mg to 5 mg.
[0051] In a further embodiment, the amount of
R(+)-N-propargyl-1-aminoindan is 1 mg.
[0052] In a further embodiment, the R(+)-N-propargyl-1-aminoindan
is the pharmaceutically acceptable salt of
R(+)-N-propargyl-1-aminoindan.
[0053] In a further embodiment, the pharmaceutically acceptable
salt is esylate, mesylate, sulfate or tartrate.
[0054] In a further embodiment, the pharmaceutically acceptable
salt is mesylate.
[0055] In a further embodiment, the amount of
R(+)-N-propargyl-1-aminoindan mesylate is 1.66 mg.
[0056] In a further embodiment, the amount of pramipexole is from
0.125 mg to 0.6 mg.
[0057] In a further embodiment, the amount of pramipexole is from
0.375 mg to 6.0 mg.
[0058] In a further embodiment, the amount of pramipexole is 0.6
mg.
[0059] In a further embodiment, the pramipexole is in a
pharmaceutically acceptable salt form.
[0060] In a further embodiment, the pharmaceutically acceptable
salt form is pramipexole dihydrochloride.
[0061] In a further embodiment, the amount of pramipexole
dihydrochloride is 0.6 mg.
[0062] In a further embodiment, the amount of pramipexole
dihydrochloride is 0.75 mg.
[0063] In a further embodiment, the amount of pramipexole is from
0.125 mg to 0.6 mg.
[0064] In a further embodiment, the amount of pramipexole is from
0.375 mg to 6.0 mg.
[0065] In a further embodiment, the amount of pramipexole is 0.6
mg.
[0066] In a further embodiment, the pramipexole is in a
pharmaceutically acceptable salt form.
[0067] In a further embodiment, the pharmaceutically acceptable
salt form is pramipexole dihydrochloride.
[0068] In a further embodiment, the amount of pramipexole
dihydrochloride is 0.6 mg.
[0069] In a further embodiment, the amount of pramipexole
dihydrochloride is 0.75 mg.
[0070] The subject invention also provides a pharmaceutical
composition for use in the treatment of, or alleviation of symptoms
of, Restless Legs Syndrome, which comprises a therapeutically
effective amount of R(+)-N-propargyl-1-aminoindan or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
[0071] The subject invention also provides use of
R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for the treatment of, or
alleviation of symptoms of, Restless Legs Syndrome. Such use can
have the same embodiments as those specifically disclosed herein in
the context of a method.
[0072] The present invention thus provides the R-(+)-enantiomer of
N-propargyl-1-aminoindan ["R(+)PAI" ] of the formula (I):
##STR00001##
and pharmaceutically acceptable acid additions salts thereof for
the treatment of human patients for Restless Legs Syndrome ("RLS").
The present invention also provides pharmaceutical compositions
comprising the compound R(+)PAI, their preparations and methods of
treatment of RLS with the pharmaceutical compositions.
[0073] The subject invention also provides a method for the
treatment of RLS with rasagiline, wherein, the patient has
previously been diagnosed and treated for RLS and developed
symptoms of augmentation, i.e. a common consequence of long term
treatment in which the symptoms of RLS become more severe, occur
earlier in the evening, and spread to other parts of the body.
[0074] Rasagiline is the INN (International Nonproprietary Name)
and USAN (United States Adopted Name) of the chemical substance
R-(+)-N-propargyl-1-aminoindan.
[0075] R(+)PAI may be obtained by optical resolution of racemic
mixtures of R and S-enantiomer of N-propargyl-1-aminoindan (PAI).
Such a resolution can be accomplished by any conventional
resolution method, well known to a person skilled in the art, such
as those described in "Enantiomers, Racemates and Resolutions" by
J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons,
N.Y., 1981. For example, the resolution may be carried out by
preparative chromatography on a chiral column. Another example of a
suitable resolution method is the formation of diastereomeric salts
with a chiral acid such as tartaric, malic, mandelic acid or
N-acetyl derivatives of amino acids, such as N-acetyl leucine,
followed by recrystallisation to isolate the diastereomeric salt of
the desired R enantiomer.
[0076] The racemic mixture of R and S enantiomers of PAI may be
prepared, e.g. as described in WO095/11016. The racemic mixture of
PAI can also be prepared by reacting l-chloroindan or 1-bromoindan
with propargylamine. Alternatively, this racemate may be prepared
by reacting propargylamine with 1-indanone to form the
corresponding imine, followed by reduction of the carbon-nitrogen
double bond of the imine with a suitable agent, such as sodium
borohydride.
[0077] In accordance with this invention, R(+)PAI can also be
prepared directly from the optically active R-enantiomer of
l-aminoindan by reaction with propargyl bromide or propargyl
chloride in the presence of an organic or inorganic base and
optionally in the presence of a suitable solvent. A preferred
method of preparation of the aforementioned compound is the
reaction between R-1-aminoindan with propargyl chloride using
potassium bicarbonate as a base and acetonitrile as solvent.
[0078] The compound R(+)PAI may be prepared as pharmaceutical
compositions particularly useful for the treatment of RLS. Such
compositions may comprise the compound of R(+)PAI or
pharmaceutically acceptable acid addition salts thereof, together
with pharmaceutically acceptable carriers and/or excipients. In the
practice of this invention, pharmaceutically acceptable salts
include, but are not limited to, the mesylate, maleate, fumarate,
tartrate, hydrochloride, hydrobromide, esylate, p-toluensulfonate,
benzoate, acetate, phosphate and sulfate salts.
[0079] The compound pramipexole is a non-ergoline dopamine agonist
effective as an adjunct therapy to levodopa in the treatment of
patients with advanced Parkinson's disease experiencing motor
effects. It is also effective as a monotherapy in early Parkinson's
disease patients where it has shown improvement in daily living and
motor symptoms. Pramipexole has been determined to act at dopamine
D2 receptors, specifically at presynaptic dopamine D2 autoreceptors
and postsynaptic dopamine D2 receptors. (Dooley M. et al.,
Pramipexole: A Review of Its Use in the Management of Early and
Advanced Parkinson's Disease, Drugs Aging, June 1998,
12(6):495-514.
[0080] Pramipexole may be administered from 0.375 to 6.0 mg/day and
in unit dosage from 0.125 to 1.5 mg. Pramipexole may be
administered orally, intraperitoneally, subcutaneously or
intravenously. (Dooley M. et al., Pramipexole: A Review of Its Use
in the Management of Early and Advanced Parkinson's Disease, Drugs
Aging, June 1998, 12(6):495-514.
[0081] Pramipexole may be in the form of pramipexole base. In the
practice of this invention, a pharmaceutically acceptable salt form
of pramipexole includes pramipexole dihydrochloride. (Dooley M. et
al., Pramipexole: A Review of Its Use in the Management of Early
and Advanced Parkinson's Disease, Drugs Aging, June 1998,
12(6):495-514.
[0082] Pramipexole may be initially administered at a dosage which
is gradually increased until symptoms are relieved. (Dooley M. et
al., Pramipexole: A Review of Its Use in the Management of Early
and Advanced Parkinson's Disease, Drugs Aging, June 1998,
12(6):495-514.
[0083] Pramipexole may be administered 3 times daily. (Dooley M. et
al., Pramipexole: A Review of Its Use in the Management of Early
and Advanced Parkinson's Disease, Drugs Aging, June 1998,
12(6):495-514.
[0084] The compositions may be prepared as medicaments to be
administered orally, parenterally, rectally or transdermally.
Suitable forms for oral administration include tablets, compressed
or coated pills, dragees, sachets, hard or soft gelatin capsules,
sublingual tablets, syrups and suspensions; for parenteral
administration the invention provides ampoules or vials that
include an aqueous or non-aqueous solution or emulsion; for rectal
administration there are provided suppositories with hydrophilic or
hydrophobic vehicles; and for topical application as ointments and
transdermal delivery there are provided suitable delivery systems
as known in the art.
[0085] Specific examples of pharmaceutical acceptable carriers and
excipients that may be used to formulate oral dosage forms of the
present invention are described, e.g., in U.S. Pat. No. 6,126,968
to Peskin et al., issued Oct. 3, 2000. Techniques and compositions
for making dosage forms useful in the present invention are
described-in the following references: 7 Modern Pharmaceutics,
Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);
Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981);
Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition
(1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack
Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical
Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in
Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones,
James McGinity, Eds., 1995); Aqueous Polymeric Coatings for
Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences,
Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate
Carriers: Therapeutic Applications: Drugs and the Pharmaceutical
Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the
Gastrointestinal Tract (Ellis Horwood Books in the Biological
Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S.
Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the
Pharmaceutical Sciences Vol 40 (Gilbert S. Banker, Christopher T.
Rhodes, Eds.).
[0086] Tablets may contain suitable binders, lubricants,
disintegrating agents, coloring agents, flavoring agents,
flow-inducing agents, and melting agents. For instance, for oral
administration in the dosage unit form of a tablet or capsule, the
active drug component can be combined with an oral, non-toxic,
pharmaceutically acceptable, inert carrier such as lactose,
gelatin, agar, starch, sucrose, glucose, methyl cellulose,
dicalcium phosphate, calcium sulfate, mannitol, sorbitol,
microcrystalline cellulose and the like. Suitable binders include
starch, gelatin, natural sugars such as glucose or beta-lactose,
corn starch, natural and synthetic gums such as acacia, tragacanth,
or sodium alginate, povidone, carboxymethylcellulose, polyethylene
glycol, waxes, and the like. Lubricants used in these dosage forms
include sodium oleate, sodium stearate, sodium benzoate, sodium
acetate, sodium chloride, stearic acid, sodium stearyl fumarate,
talc and the like. Disintegrators include, without limitation,
starch, methyl cellulose, agar, bentonite, xanthan gum,
croscarmellose sodium, sodium starch glycolate and the like.
[0087] Rasagiline mesylate in a 1 mg tablet is commercially
available for use in Parkinson's disease treatment as Azilect.RTM.
from Teva Pharmaceutical Industries, Ltd. (Petach Tikva, Israel)
and H. Lundbeck A/S (Copenhagen, Denmark). See, also AZILECT.RTM.,
Physician's Desk Reference (2006), 60.sup.th Edition, Thomson
Healthcare. The cognitive and behavioral adverse events of
hallucinations, confusion, depression, somnolence and other sleep
disorders in subjects treated with Azilect.RTM. are few and do not
exceed the incidence seen in subjects receiving placebo by more
than 3 percent. (Parkinson Study Group, Tyramine Challenge to
Assess the Safety of Rasagiline Monotherapy in a Placebo-Controlled
Multicenter Trial for Early Parkinson's Disease (The TEMPO Study),
Neurology, 2001, 56:A345) The most commonly reported adverse events
in rasagiline-treated subjects are pain, headache and dizziness.
Side effects typically associated with other dopaminergic
medications, such as hallucinations, somnolence, edema, nausea,
vomiting, and diarrhea, are infrequently reported in
rasagiline-treated subjects. (Stern et al., Double-Blind,
Randomized, Controlled Trial of Rasagiline as Monotherapy in Early
Parkinson's Disease Patients, Mov. Disord., 2004,
19(8):916-923)
[0088] R(+)PAI compositions may be used alone to treat RLS, or
alternatively, they may be used as an adjunct to existing RLS
treatments. R(+)PAI may be administered at different times and
separate from other RLS treatments, or as a combined pharmaceutical
composition of R(+)PAI with at least one of carbidopa, levodopa,
pergolide, pramipexole, oxycodone, clonazepam, carbamazepine,
gabapentin, valproate, ropinirole or clonidin. Thus, for example, a
pharmaceutical composition for oral use in the form of tablets or
capsules may comprise R(+)-N-propargyl-1-aminoindan, Levodopa, and
a decarboxylase inhibitor. Such a composition may comprise 0.01-20
mg of R(+)-N-propargyl-1l-aminoindan, 50-100 mg of Levodopa, and
12.5-50 mg of benserazide.
[0089] The preferred dosages of R(+)PAI in any of the disclosed
compositions may be within the following ranges: for oral or
suppository formulations 0.01-20 mg per dosage unit to be taken
daily and more preferably 0.5-5 mg per dosage unit to be taken
daily may be used; and for injectable formulations 0.05-10 mg/ml
per dosage unit to be taken daily and more preferably 0.5-3 mg/ml
per dosage unit to be taken daily may be used.
[0090] By 0.01-20 mg it is meant that all hundredth, tenth and
integer unit amounts within the range are specifically disclosed as
part of the invention. Thus, 0.02, 0.03 . . . 0.09; 0.1, 0.2 . . .
0.9; and 1, 2 . . . 19 mg unit amounts are included as embodiments
of this invention.
[0091] R(+)PAI is effective and suitable for use in the treatment
of RLS, both alone and in combination with other RLS
treatments.
[0092] Furthermore, unlike several known treatments of RLS, the use
of rasagiline as the active ingredient for treating RLS improves
the subject's condition without causing undesirable side effects.
The subject is a human subject.
EXPERIMENTAL DETAILS
Example 1
TABLE-US-00001 [0093] R(+)-N-propargyl-1-aminoindan mesylate 3.12
mg/tablet Mannitol 62.5 mg/tablet Maltodextrin (Maltrin 150) 36.0
mg/tablet Croscarmellose sodium (Ac-Di-Sol) 2.1 mg/tablet Talc 1.5
mg/tablet
Example 2
TABLE-US-00002 [0094] R(+)-N-propargyl-1-aminoindan mesylate 1.56
mg/tablet Mannitol 79.14 mg/tablet Starch 10.0 mg/tablet
Pregelatinized starch 10.0 mg/tablet Colloidal silicon dioxide 0.6
mg/tablet Talc 2.0 mg/tablet Stearic acid 2.0 mg/tablet
Example 3
TABLE-US-00003 [0095] R(+)-N-propargyl-1-aminoindan mesylate 3.12
mg/tablet Mannitol 76.58 mg/tablet Starch 10.0 mg/tablet
Pregelatinized starch 10.0 mg/tablet Colloidal silicon dioxide 0.6
mg/tablet Citric acid 1.0 mg/tablet Talc 2.0 mg/tablet
Example 4
TABLE-US-00004 [0096] R(+)-N-propargyl-1-aminoindan mesylate 3.12
mg/tablet Mannitol 69.88 mg/tablet Lactose (hydrous) 14.0 mg/tablet
Starch 14.0 mg/tablet Glyceryl Behenate (Compitrol 888 ATO) 2.0
mg/tablet
Example 6--Rat Model of RLS
TABLE-US-00005 [0097] R(+)-N-propargyl-1-aminoindan mesylate 3.12
mg/tablet Mannitol 77.28 mg/tablet Starch 10.0 mg/tablet Starch
STA-RX 1500 10.0 mg/tablet Colloidal silicon dioxide, Aerosil 0.6
mg/tablet Hydrogenated vegetable type I 2.0 mg/tablet (Sterotex
Dritex)
[0098] 6-hydroxydopamine is an agent that selectively disrupts or
destroys catecholaminergic systems. Thus, stereotaxic bilateral
6-hydroxydopamine lesions into the nucleus of dopaminergic
diencephalic spinal neurons (All) are performed to effect behavior
consistent, although not specific, with what would be expected in a
rat model of RLS. (Ondo W. G. et al., Clinical Correlates of
6-Hydroxydopamine Injections into A11 Dopaminergic Neurons in Rats:
A Possible Model for Restless Leg Syndrome, Mov. Disord., 2000,
15(1):154-8)
[0099] Multiple blindly-rated video epochs demonstrate an increased
average number of standing episodes and increased total standing
time but similar total sleep time in lesioned rats when compared
with control rats. However, treatment of the lesioned rats with
R(+)PAI mesylate results in fewer standing episodes and less total
standing time when compared with untreated lesioned rats.
Example 7--RLS Model Spontaneously Occurring During Sleep of
Rats
[0100] Periodic limb movements in sleep (PLMS) are often associated
with RLS. In a group of old rats 16-20 months, sleep-wake behavior
is recorded and hindlimb movements are detected by means of a
magneto-inductive device during two 12-h light periods (Baier P.C.
et al., Assessment of spontaneously occurring periodic limb
movements in sleep in the rat, J. Neurol. Sci. 2002; 198(1-2):
71-77). Periodic hindlimb movements (PHLM) during nonrapid eye
movement sleep (NREM) are identified according to modified human
criteria in some of the rats, which are then selected for the
rasagiline study. Half the rats are treated daily with rasagiline
while the other half receive vehicle. Incidence of PHLM is
determined for 3 consecutive nights, beginning 7 days after onset
of treatment. It is demonstrated that rasagiline-treated rats have
significantly fewer PHLM than vehicle-treated rats.
Example 8
[0101] The 1 mg tablet of R(+)PAI mesylate is investigated in
placebo-controlled, double-blind, randomized clinical tests
covering in a study adult patients who are suffering from moderate
to severe primary Restless Legs Syndrome.
[0102] Randomization in terms of gender, age and severity of prior
illnesses is reasonably balanced. Patients with RLS secondary to
other conditions (e.g., pregnancy, renal failure, and anemia) are
excluded.
[0103] After gradual and complete termination of any preceding
L-dopa treatment and a break in the therapy (washout) the patients
are treated with R(+)PAI.
[0104] Over a treatment period of days the patients of one group
are treated with a 0.5 mg dosage and the patients of another group
are treated with 1 mg. For a comparison the patients in the placebo
group are treated with a placebo.
[0105] Severity of symptoms is measured with a rating scale
developed by the International Restless Legs Syndrome Study Group
("IRLSSG")(http://www.irlssg.org/). Use of the scale is common for
clinical assessment, research and therapeutic trials with RLS. The
overall IRLSSG rating is derived from the individual values
discussed below.
[0106] First, an initial starting value is determined for each
patient participating in the study. This is done by adding up the
individual IRLSSG parameter values as of Day 0, i.e. before
treatment. Over the course of treatment the IRLSSG values are
compared with the starting value and any changes from that starting
value are recorded. Finally, the average improvement of the IRLSSG
value over the starting value is determined by calculating the
average of all test subjects. The resulting value is called
CAS--(complete analysis set) randomized average change from the
starting value of the overall IRLSSG rating. The term "randomized"
indicates that in terms of their different prespecified dosages the
patients are subjected to prior double-blind randomization.
Results
[0107] Between the starting value and that established after
treatment, a significant improvement of the IRLSSG values is
recorded in comparison with the placebo group.
[0108] At the end of the treatment both patient groups report that
subjective symptoms such as tingling, cramps and pain in the legs,
restlessness in the legs during the night, and difficulties falling
or remaining asleep either disappear or diminish to a tolerable
minimum.
[0109] The patients also report that the treatment does not or only
to a very minimal extent causes any hallucinations, somnolence,
edema, nausea, vomiting or diarrhea.
[0110] Accordingly, R(+)PAI is well tolerated and safe and leads to
a distinct clinical improvement in patients in a moderate to severe
stage of RLS.
[0111] An improvement of the IRLSSG value of 2 points compared to a
placebo can be considered a success. An improvement by over 3 or 6
and more rating units constitutes an all the more significant
therapeutic advance and is therefore the preferred objective of
this invention.
Example 9
[0112] This was the first clinical study in which rasagiline was
administered to RLS subjects. The dosage regimen of 1 mg/day
rasagiline was chosen based on the optimal dosage regimen for the
symptomatic treatment of PD. However, smaller doses than those
required for the treatment of PD are expected to be efficacious in
the treatment of RLS. Therefore, in the event that a subject could
not tolerate the 1 mg daily dose of rasagiline, a daily dose of 0.5
mg rasagiline was permitted. Rasagiline was administered orally as
a tablet. Both the 1 mg and 0.5 mg rasagiline tablets were beveled
round tablets, flat, white to off-white, scored on one side, plain
on the other side. Teva Pharmaceutical Industries Ltd. was
responsible for the manufacture and primary packaging of study
medications according to current Good Manufacturing Practice (cGMP)
principles and guidelines applicable to investigational medicinal
products.
TABLE-US-00006 Schedule of Activities Visit Week No. Week 12/Early
Week -2.sup.a Week 0 Week 2 Week 4 Week 8 Termination Unscheduled
(screening) (baseline) .+-.4 .+-.4 .+-.4 .+-.4 Visit.sup.b Informed
consent X Inclusion/Exclusion criteria X X Medical history X
Concomitant medications X X X X X X X IRLS X X X X X X Sleep Scale
X X X X CGI-I X X X X RLS Quality of Life Questionnaire X X X X
Adverse events X X X X X X AE follow up X Laboratory test including
-hCG.sup.c X X X Vital signs.sup.d X X X X X X X ECG X X X
Dermatological evaluation X X X Study termination X Retrieve study
drug and assess compliance X X X X X Dispense study drug X X X X X
.sup.aThe maximal interval between the screening and baseline
visits should be 14 days. If, however, results from screening
procedures are still pending after 14 days from the screening visit
and the investigator has to wait until all results are available
before determining a subject's eligibility, the interval between
the screening and baseline visits may extend up to 21 days.
.sup.bProcedures during an unscheduled visit are optional, except
vital signs. .sup.cPregnancy test relevant to women of childbearing
potential only .sup.dIncluding weight and height at screening and
weight at Visit Week 8/Early Termination
IRLS(International Restless Legs Scale)
[0113] The IRLS scale is comprised of 10 items designed to assess
the severity of sensory and motor symptoms, sleep disturbance,
daytime somnolence, and impact on activities of daily living and
mood associated with RLS. All items receive a grade in the range 0
to 4 (0=absence of a problem, 4=very severe problem) giving a
maximum score of 40.
[0114] The investigator scored subjects on the IRLS at all
scheduled study visits. The primary efficacy endpoint was based on
the change from baseline to weeks 2, 4, and 8 in IRLS scores.
IRLS Scale
[0115] Each of 10 items were graded on a scale between 0 and 4
where 0 denotes the absence of a problem, and 4 a very severe
problem. Table 1 shows the results; a low score indicates the
absence of a problem and a high score indicates a very severe
problem.
TABLE-US-00007 TABLE 1 Descriptive Statistics of IRLS Rating Scale
and Change from Baseline Over Time IRLS Total Me- IRLS Total
(Absolute Change) IRLS Total (Percent Change) N Mean SD Min dian
Max N Mean SD Min Median Max N Mean SD Min Median Max Week 2 32.00
8.49 26.00 32.00 38.00 2 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00
0.00 0.00 BASE- LINE VISIT 2 29.00 12.73 20.00 29.00 38.00 2 -3.00
4.24 -6.00 -3.00 0.00 2 -11.54 16.32 -23.08 -11.54 0.00 WEEK 2
VISIT 2 25.50 17.68 13.00 25.50 38.00 2 -6.50 9.19 -13.00 -6.50
0.00 2 -25.00 35.36 -50.00 -25.00 0.00 WEEK 4 VISIT 1 12.00 12.00
12.00 12.00 1 -14.00 -14.00 -14.00 -14.00 1 -53.85 -53.85 -53.85
-53.85 WEEK 8
Clinical Global Impression-Global Improvement (CGI-I)
[0116] The CGI-I scale is a single item scale on which the
investigator rated a subject's symptoms as very much improved, much
improved, minimally improved, not changed, minimally worse, much
worse, or very much worse. Subjects were scored on this scale at
weeks 2, 4, and 8. The mean score at each of these time points was
calculated as a secondary efficacy endpoint. Table 2 shows the
results of the CGI-I Rating Scale. Subjects are scored on a scale
of 1-7, where 1 indicates the subject's symptoms are very much
improved and 7 indicates the subject's symptoms are very much
worse.
TABLE-US-00008 TABLE 2 Descriptive Statistics of CGI-I Rating Scale
CGI-I Total Week N Mean SD Min Median Max VISIT WEEK 2 2 3.50 0.71
3.00 3.50 4.00 VISIT WEEK 4 2 3.50 2.12 2.00 3.50 5.00 VISIT WEEK 8
1 1.00 1.00 1.00 1.00
RLS QoL Questionnaire
[0117] The Restless Leg Syndrome Quality of Life questionnaire (RLS
QoL) assesses the impact of RLS on daily life, emotional
well-being, social life and work life. It is an 18-item
questionnaire with a total score ranging 0 to 100. Table 3 shows
the results of this questionnaire. The lower the score, the greater
the impact of RLS on quality of life.
TABLE-US-00009 TABLE 3 Descriptive Statistics of IRLS QoL Rating
Scale and Change from Baseline Over Time IRLS QoL Total IRLS QoL
Total (Absolute Change) IRLS QoL Total (Percent Change) Week N Mean
SD Min Median Max N Mean SD Min Median Max N Mean SD Min Median Max
BASELINE 2 46.25 30.05 25.00 46.25 67.50 2 0.00 0.00 0.00 0.00 0.00
2 0.00 0.00 0.00 0.00 0.00 VISIT WEEK 4 2 62.92 41.84 33.33 62.92
92.50 2 16.67 11.79 8.33 16.67 25.00 2 35.19 2.62 33.33 35.19 37.04
VISIT WEEK 8 1 92.50 92.50 92.50 92.50 1 25.00 25.00 25.00 25.00 1
37.04 37.04 37.04 37.04
[0118] (Abetz L. et al. Validation of the restless legs syndrome
quality of life questionnaire. Value in Health, 2005; 8(2):
157-167)
[0119] The RLS QoL questionnaire was completed by the investigator
at the baseline and Week 4, and 8 visits. The change from baseline
to each post-baseline study visit was calculated as an additional
efficacy endpoint.
Sleep Scale:
[0120] The Sleep Scale is a 12-item scale that provides a
comprehensive view across almost all dimensions of sleep including
daytime somnolence, sleep disturbance, sleep adequacy and sleep
quantity. The investigator scored subjects on this scale at the
baseline and Week 4,and 8 visits. The change from baseline to each
post-baseline study visit was calculated as a secondary efficacy
endpoint. (Hays, R. D. & Steward, A. L. (1992). Sleep measures.
In A. L. Stewart & J. E. Ware (eds.), Measuring functioning and
well-being: The Medical Outcomes Study approach (pp. 235-259),
Durham, N.C.: Duke University Press.
[0121] Tables 4-12 show the results of the Sleep Rating Scale and
change from baseline over time for each of the 9 dimensions scored
by the Sleep Rating Scale. N is the number of participants in the
study. A low score indicates the absence of problems and a high
score indicates a very severe problem.
TABLE-US-00010 TABLE 4 Descriptive Statistics of Sleep Rating Scale
and Change from Baseline Over Time Sleep Disturbance Scale Me-
Sleep Disturbance (Absolute Change) Sleep Disturbance (Percent
Change) Week N Mean SD Min dian Max N Mean SD Min dian Max N Mean
SD Min Median Max BASE- 2 41.25 5.30 37.50 41.25 45.00 2 0.00 0.00
0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 0.00 LINE VISIT 2 33.75 15.91
22.50 33.75 45.00 2 -7.50 10.61 -15.00 -7.50 0.00 2 -20.00 28.28
-40.00 -20.00 0.00 WEEK 4 VISIT 1 21.25 21.25 21.25 21.25 1 -16.25
-16.25 -16.25 -16.25 1 -43.33 -43.33 -43.33 -43.33 WEEK 8
TABLE-US-00011 TABLE 5 Descriptive Statistics of Sleep Rating Scale
and Change from Baseline Over Time Snoring Scale Sleep Snoring
(Absolute Change) Sleep Snoring (Percent Change) Week N Mean SD Min
Median Max N Mean SD Min Median Max N Mean SD Min Median Max
BASELINE 2 40.00 56.57 0.00 40.00 80.00 2 0.00 0.00 0.00 0.00 0.00
1 0.00 0.00 0.00 0.00 VISIT 2 40.00 56.57 0.00 40.00 80.00 2 0.00
0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 WEEK 4 VISIT 1 100.00
100.00 100.00 100.00 1 20.00 20.00 20.00 20.00 1 25.00 25.00 25.00
25.00 WEEK 8
TABLE-US-00012 TABLE 6 Descriptive Statistics of Sleep Rating Scale
and Change from Baseline Over Time Sleep Short of Breath Sleep
Short of Breath Short of Breath Scale (Absolute Change) (Percent
Change) Week N Mean SD Min Median Max N Mean SD Min Median Max N
Mean SD Min Median Max BASELINE 2 0.00 0.00 0.00 0.00 0.00 2 0.00
0.00 0.00 0.00 0.00 0 VISIT WEEK 4 2 0.00 0.00 0.00 0.00 0.00 2
0.00 0.00 0.00 0.00 0.00 0 VISIT WEEK 8 1 0.00 0.00 0.00 0.00 1
0.00 0.00 0.00 0.00 0
TABLE-US-00013 TABLE 7 Descriptive Statistics of Sleep Rating Scale
and Change from Baseline Over Time Sleep Adequacy Sleep Adequacy
(Absolute Change) Sleep Adequacy (Percent Change) Week N Mean SD
Min Median Max N Mean SD Min Median Max N Mean SD Min Median Max
BASELINE 2 40.00 28.28 20.00 40.00 60.00 2 0.00 0.00 0.00 0.00 0.00
2 0.00 0.00 0.00 0.00 0.00 VISIT 2 55.00 49.50 20.00 55.00 90.00 2
15.00 21.21 0.00 15.00 30.00 2 25.00 35.36 0.00 25.00 50.00 WEEK 4
VISIT 1 100.00 100.00 100.00 100.00 1 40.00 40.00 40.00 40.00 1
66.67 66.67 66.67 66.67 WEEK 8
TABLE-US-00014 TABLE 8 Descriptive Statistics of Sleep Rating Scale
and Change from Baseline Over Time Somnolence Scale Sleep
Somnolence (Absolute Change) Sleep Somnolence (Percent Change) Week
N Mean SD Min Median Max N Mean SD Min Median Max N Mean SD Min
Median Max BASELINE 2 40.00 37.71 13.33 40.00 66.67 2 0.00 0.00
0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 0.00 VISIT 2 40.00 47.14 6.67
40.00 73.33 2 -0.00 9.43 -6.67 -0.00 6.67 2 -20.00 42.43 -50.00
-20.00 10.00 WEEK 4 VISIT 1 13.33 13.33 13.33 13.33 1 0.00 0.00
0.00 0.00 1 0.00 0.00 0.00 0.00 WEEK 8
TABLE-US-00015 TABLE 9 Descriptive Statistics of Sleep Rating Scale
and Change from Baseline Over Time Sleep Problems Index I Sleep
Problems Index I Me- (Absolute Change) Sleep Problems Index I
(Percent Change) Week N Mean SD Min dian Max N Mean SD Min Median
Max N Mean SD Min Median Max BASE- 2 33.33 23.57 16.67 33.33 50.00
2 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 0.00 LINE VISIT 2
26.67 33.00 3.33 26.67 50.00 2 -6.67 9.43 -13.33 -6.67 0.00 2
-40.00 56.57 -80.00 -40.00 0.00 WEEK 4 VISIT 1 0.00 0.00 0.00 0.00
1 -16.67 -16.67 -16.67 -16.67 1 -100.00 -100.00 -100.00 -100.00
WEEK 8
TABLE-US-00016 TABLE 10 Descriptive Statistics of Sleep Rating
Scale and Change from Baseline Over Time Sleep Problems Index II
Sleep Problems Index II Sleep Problems Index II Me- (Absolute
Change) (Percent Change) Week N Mean SD Min dian Max N Mean SD Min
Median Max N Mean SD Min Median Max BASE- 2 40.56 18.07 27.78 40.56
53.33 2 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 0.00 LINE
VISIT 2 33.89 27.50 14.44 33.89 53.33 2 -6.67 9.43 -13.33 -6.67
0.00 2 -24.00 33.94 -48.00 -24.00 0.00 WEEK 4 VISIT 1 11.67 11.67
11.67 11.67 1 -16.11 -16.11 -16.11 -16.11 1 -58.00 -58.00 -58.00
-58.00 WEEK 8
TABLE-US-00017 TABLE 11 Descriptive Statistics of Sleep Rating
Scale and Change from Baseline Over Time Sleep Quantity (raw score)
Sleep Quantity (Absolute Change) Sleep Quantity (Percent Change)
Week N Mean SD Min Median Max N Mean SD Min Median Max N Mean SD
Min Median Max BASELINE 1 7.00 7.00 7.00 7.00 1 0.00 0.00 0.00 0.00
1 0.00 0.00 0.00 0.00 VISIT 1 7.00 7.00 7.00 7.00 1 0.00 0.00 0.00
0.00 1 0.00 0.00 0.00 0.00 WEEK 4 VISIT 1 7.00 7.00 7.00 7.00 1
0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 WEEK 8
TABLE-US-00018 TABLE 12 Descriptive Statistics of Sleep Rating
Scale and Change from Baseline Over Time Optimal Sleep Scale
Optimal Sleep (Absolute Change) Optimal Sleep (Percent Change) Week
N Mean SD Min Median Max N Mean SD Min Median Max N Mean SD Min
Median Max BASELINE 1 1.00 1.00 1.00 1.00 1 0.00 0.00 0.00 0.00 1
0.00 0.00 0.00 0.00 VISIT 1 1.00 1.00 1.00 1.00 1 0.00 0.00 0.00
0.00 1 0.00 0.00 0.00 0.00 WEEK 4 VISIT 1 1.00 1.00 1.00 1.00 1
0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 WEEK 8
CONCLUSION
[0122] To date, 2 subjects have been enrolled in this open label
pilot study of rasagiline's efficacy in Restless Legs Syndrome.
These subjects had a mean baseline IRLS Rating Scale score of 32.
After 2 weeks the mean score had decrease to 29. At 4 weeks, one
subject had a score of 13 (indicating a 50% decrease from
baseline). Another subject discontinued participation in the study,
at week 4, with a score of 38, unchanged from this subject's
baseline score. By 8 weeks, the remaining subject's IRLS score had
decreased to 12 (a 54% decrease from baseline). Additionally, by
eight weeks this subject had indicated that the RLS symptoms were
"Very Much Improved" on the CGI-I rating scale. Also, by eight
weeks this subject had an improvement of 37% in the IRLS Quality of
Life Questionnaire compared to baseline. In addition, by eight
weeks, this subject had an improvement of 58% in the Sleep Problems
Index II statistic measured as part of the Sleep Scale. In summary,
in at least a subset of RLS patients, rasagiline has been shown to
have a clinically significant effect on the symptoms of RLS.
* * * * *
References