Efficacy Study of Arbaclofen to Treat Spasticity in Multiple Sclerosis

• Sponsor: RVL Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01743651
• Collaborator: Osmotica Pharmaceutical US LLC (Industry)
• Enrollment: 353
• Locations: 48
• Arms: 3
• Duration (Months): 17
• Patients Per Site: 7.4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This is a multicenter, randomized (1:1:1), double-blind, active and placebo controlled, parallel group study to evaluate safety, tolerability and efficacy of oral arbaclofen in MS patients with spasticity.

Eligible subjects will be removed from anti-spasticity medications for at least one week and then begin study drug treatment with daily doses increasing up to the target dose which will then be maintained for at least 12 weeks. A down-titration will then occur over two weeks.

Condition or Disease	Intervention/Treatment	Phase
Spasticity; Multiple Sclerosis	Drug: arbaclofen; Drug: baclofen; Drug: Placebo	Phase 3

Detailed Description

This is a multicenter, randomized (1:1:1), double-blind, active and placebo controlled, parallel group study to evaluate safety, tolerability and efficacy of oral arbaclofen in MS patients with spasticity.

Eligible subjects will be removed from anti-spasticity medications for at least one week and then begin study drug treatment with daily doses increasing up to the target dose which will then be maintained for at least 12 weeks. A down-titration will then occur over two weeks with the final study visit occurring at 19 weeks from start of achieving the target dose or 22 weeks from the Study Visit 1.

Study Design

• Study Type: Interventional
• Actual Enrollment: 353 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Parallel Group Study to Compare the Safety and Efficacy Arbaclofen ER Tablets to Placebo and Baclofen Tablets, USP for the Treatment of Spasticity in Patients With Multiple Sclerosis
• Study Start Date: Nov 1, 2012
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo	Drug: Placebo; arbaclofen image matched placebo tablets administered orally 2 times/day or baclofen image matched placebo capsules administered orally 4 times/day
Active Comparator: Baclofen 80 mg/day of Baclofen Tablets, USP	Drug: baclofen; 80 mg/day as 20 mg baclofen administered orally 4 times per day
Experimental: Arbaclofen 40 mg/day of Arbaclofen Tablets	Drug: arbaclofen; 40 mg/day as 20 mg arbaclofen ER administered orally 2 times per day; Other Names: OS440 AERT

Outcome Measures

Primary Outcome Measures

1. Efficacy as determined by Total Numeric Transformed Modified Ashworth scale (TNmAS) in the most affected limb. [Change in baseline from Visit 1 through Visit 9 (120 days) or end of treatment]

   Change from baseline through end of treatment in the pre-dose, morning TNmAS of the most affected limb. The most affected limb is determined at baseline using the sum of scores for three major motor groups. High scores indicate more severe spasticity.

2. Clinical Global Impression of Change (CGIC) through end of treatment [Visit 9 (120 days) or end of study]

   The CGIC is a global rating scale that captures the investigator's assessment of the subject's change in overall functional performance since starting the study. Scores range from -3 (significant worsening) to +3 (significant improvement.

Secondary Outcome Measures

1. Changes in the Multiple Sclerosis Spasticity Scale (MSSS-88) [Baseline through Visit 9 (120 days)]

   This MSSS-88 is a self-administered questionnaire for the subject to assess overall functional performance and sense of impairment with respect to the level of spasticity.

2. Changes in the TNmAS for the most affected limb [From baseline to visits 4 (22 days), 5 (36 days), 6 (50 days), 7 (71 days), and 9 (120 days)]

   The modified Ashworth Scale is a six (6)-point rating scale that measures abnormality in tone or the resistance to passive movements. Measurements are made in three muscle groups of each limb. The most affect limb is determined at baseline, based on the sum of scores from each limb. Higher scores indicate more severe spasticity.

3. Changes in the TNmAS for the sum of all limbs [Baseline to visits 4 (22 days), 5 (36 days), 6 (50 days), 7 (71 days), and 9 (120 days)]

   The sums of scores from all limbs are compared to the baseline sum. Higher scores indicate more severe spasticity.

4. Changes in Expanded Disability Status Score (EDSS) [Baseline to Visit 9 (120 Days)]

   The EDSS is based on an examination by a neurologist with a scale that ranges from zero (0) to ten (10) in half point (0.5) unit increments. Higher scores represent higher levels of disability.

5. Changes in the Lower Extremity Manual Muscle Testing (LEMMT) Scale [Baseline to Visit 4 (22 days), Visit 5 (36 days) Visit 6 (50 days) Visit 7 (71 days) and Visit 9 (120 days)]

   The LEMMT Scale is an evaluation of the function and strength of individual muscles and muscle groups based on effective performance of limb movement in relation to the forces of gravity and manual resistance. Maximum muscular strength is the maximum amount of tension or force that a muscle or muscle group can voluntarily exert in one maximal effort. Scores for each muscle or muscle group range from 0 (no detectable activity) to 5 (normal activity).

6. Changes in Epworth Sleepiness Scale (ESS) [Baseline to Visit 4 (22 days), Visit 5 (36 days) Visit 6 (50 days) Visit 7 (71 days) and Visit 9 (120 days)]

   The ESS is used to determine the level of daytime sleepiness. The questionnaire asks the subject to rate his or her probability of falling asleep on a scale of increasing probability from 0 to 3 in eight different situations.

7. Changes in the subject-recorded mean daily Drowsiness Numerical Rating Scale (DNRS)score for the day prior to each visit [Baseline to Visit 4 (22 days), Visit 5 (36 days) Visit 6 (50 days) Visit 7 (71 days) and Visit 9 (120 days)]

   Drowsiness will be reported by the subject using a numerical rating scale with a range of zero (0; no drowsiness) to ten (10; worst possible drowsiness). Scores will be recorded every 3 hours during the day before each designated visit.

8. Changes in the Urinary Symptom Profile (USP) Scale [Baseline to Visit 4 (22 days), Visit 5 (36 days) Visit 6 (50 days) Visit 7 (71 days) and Visit 9 (120 days)]

   The USP is a Health-Related Quality of Life questionnaire composed of 13 items assessing urinary symptoms in adults with stress, urge, overactive bladder, or urinary obstructive symptoms.

9. Clinical Global Impression of Change (CGIC) [Baseline to Visit 4 (22 days), Visit 5 (36 days) Visit 6 (50 days) Visit 7 (71 days)]

   The CGIC scores will be recorded at the designated intervals prior to Visit 9 (end of study)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients (male or female) 18 to 65 years of age, inclusive, at the time of dosing

• Have an established diagnosis (per McDonald Criteria) of Multiple Sclerosis (either relapsing remitting or secondary progressive course), that manifests spasticity for at least 6 months

• Spasticity due to MS as shown by a TNmAS score equal or greater than six (≥6) in the most affected limb.

• EDSS equal or greater than 3.0

• If receiving disease-modifying medications, these must have been at a stable dose for at least three (3) months prior to screening, and the subject must be willing to maintain this treatment for the duration of the study

• Stable regimen for at least thirty (30) days prior to study entry for all medications and non-pharmacological therapies that are intended to alleviate spasticity

• Absence of infections, peripheral vascular disease, painful contractures, advanced arthritis, or other conditions that hinder evaluation of joint movement

• Have a creatinine clearance, as calculated by Glomerular Filtration Rate using the Modification of Diet in Renal Disease (MDRD) Study equation, greater than 60mL/min.

• Use of a medically highly effective of birth control during the study and for ninety (90) days thereafter for women of child-bearing potential (including female subjects and female partners of non-sterile male subjects)

• Willing to allow his or her general practitioner and consultant, if appropriate, to be notified of participation in the study

Exclusion Criteria:

• Any concomitant disease or disorder that has symptoms of spasticity or that may influence the subject's level of spasticity

• Inability to rate their level of spasticity or distinguish it from other MS symptoms

• Acute MS exacerbation requiring treatment within twelve (12) weeks of screening

• Use of intravenous methylprednisolone within the twelve (12) weeks before visit 1

• Concomitant use of medications that would potentially interfere with the actions of the study medication or outcome variables

• Use of botulinum toxin A or B within six (6) months of visit 1

• History of allergy to baclofen or any inactive component of test or reference formulation

• Pregnancy, lactation or planned pregnancy during the course of the study and for three (3) months thereafter.

• History of unstable psychiatric disease, or current signs and symptoms of significant medical disorders such as severe, progressive, or uncontrolled pulmonary, cardiac, gastrointestinal, hepatic, renal, genitourinary, hematological, endocrine, immunologic, or neurological disease

• History of seizures

• Current significant cognitive deficit, severe or untreated anxiety, severe or untreated depression

• Subjects with abnormal micturition that requires indwelling or intermittent catheterization or with lower urinary tract symptoms (LUTS) that result in a score greater than twenty-six (>26) in the Baseline USP© questionnaire

• Current malignancy or history of malignancy that has not been in remission for more than five (5) years, except effectively treated basal cell skin carcinoma

• Any other significant disease, disorder or significant laboratory finding which, in the opinion of the investigator, put the subject at risk because of participation, influence the result of the study, or affect the subject's ability to participate

• Planned elective surgery or other procedures requiring general anesthesia during the study

• Subject who is inappropriate for placebo medication in the judgment of the Investigator

• History of substance abuse within the past twelve (12) months

• Current chronic use of long acting opioids or round the clock use of short acting opioids for the treatment of pain

• Participation in another research study within thirty (30) days of Screening

• Patients who are uncooperative or unwilling to sign consent form

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Osmotica Study Site-138	Cullman	Alabama	United States	35058
2	Osmotica Site-143	Long Beach	California	United States	92845
3	Osmotica Study Site-123	Aurora	Colorado	United States	80045
4	Osmotica Study Site-110	Bradenton	Florida	United States	34205
5	Osmotica Study Site-142	Maitland	Florida	United States	32751
6	Osmotica Study Site-119	Ormond Beach	Florida	United States	32174
7	Osmotica Study Site-120	Pompano Beach	Florida	United States	33060
8	Osmotica Study Site-109	Tampa	Florida	United States	33606
9	Osmotica Study Site-126	Northbrook	Illinois	United States	60096
10	Osmotica Study Site-108	Fort Wayne	Indiana	United States	46805
11	Osmotica Study Site-116	Lenexa	Kansas	United States	66214
12	Osmotica Study Site-124	Baltimore	Maryland	United States	21201
13	Osmotica Study Site-136	Springfield	Massachusetts	United States	01104
14	Osmotica Study Site-101	Ann Arbor	Michigan	United States	48104
15	Osmotica Study Site-115	Johnson City	New York	United States	13790
16	Osmotica Study Site-113	New York	New York	United States	10016
17	Osmotica Study Site-141	New York	New York	United States	10019
18	Osmotica Study Site-125	New York	New York	United States	10029
19	Osmotica Study Site-106	Charlotte	North Carolina	United States	28204
20	Osmotica Study Site-131	Cincinnati	Ohio	United States	45219
21	Osmotica Study Site-127	Pittsburgh	Pennsylvania	United States	15212
22	Osmotica Study Site-112	San Antonio	Texas	United States	78229
23	Osmotica Study Site-133	Salt Lake City	Utah	United States	84103
24	Osmotica Study Site-129	Seattle	Washington	United States	98122
25	Osmotica SIte-144	Tacoma	Washington	United States	98405
26	Osmotica Study Site-509	Pyatigorsk	Stavropol Krai	Russian Federation
27	Osmotica Study Site-510	Tonnel'nyy	Stavropol Krai	Russian Federation
28	Osmotica Site-511	Krasnoyarsk		Russian Federation
29	Osmotica Study Site-508	Krasnoyarsk		Russian Federation
30	Osmotica Study Site-510	Krasnoyarsk		Russian Federation
31	Osmotica Study Site-501	Moscow		Russian Federation
32	Osmotica Study Site-502	Moscow		Russian Federation
33	Osmotica Study Site-506	Sestroretsk		Russian Federation
34	Osmotica Study Site-507	St Petersburg		Russian Federation
35	Osmotica Study Site-503	St. Petersburg		Russian Federation
36	Osmotica Study Site-505	St. Petersburg		Russian Federation
37	Osmotica Study Site 614	Chernigov		Ukraine	14001
38	Osmotica Study Site-602	Dnipropetrovsk		Ukraine	49005
39	Osmotica Study Site-603	Dnipropetrovsk		Ukraine	49022
40	Osmotica Study Site-609	Dnipropetrovsk		Ukraine	53012
41	Osmotica Study Site-611	Donetsk		Ukraine	83003
42	Osmotica Study Site-613	Ivano-Frankivsk		Ukraine	76008
43	Osmotica Site-605	Kharkov		Ukraine	61068
44	Osmotica Study Site-610	Kharkov		Ukraine	61103
45	Osmotica Study Site-604	Kharkov		Ukraine
46	Osmotica Study Site-606	Lviv		Ukraine
47	Osmotica Study Site-608	Odessa		Ukraine
48	Osmotica Study Site-615	Uzhgorod		Ukraine	88018

Sponsors and Collaborators

• RVL Pharmaceuticals, Inc.
• Osmotica Pharmaceutical US LLC

Investigators

• Study Chair: Praveen Tyle, PhD, Osmotica Pharmaceutical

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: RVL Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01743651
• Other Study ID Numbers: OS440-3002
• First Posted: Dec 6, 2012
• Last Update Posted: Apr 25, 2022
• Last Verified: May 1, 2014

• Keywords provided by RVL Pharmaceuticals, Inc.: spasticity; multiple sclerosis; arbaclofen
• Additional relevant MeSH terms: Muscle Spasticity; Multiple Sclerosis; Sclerosis; Baclofen

Study Results

No Results Posted as of Apr 25, 2022