OS440-3004: A Study to Investigate the Safety and Effectiveness of Arbaclofen Extended-Release Tablets for Patients With MS
Study Details
Study Description
Brief Summary
Multiple Sclerosis (MS) is an acquired inflammatory demyelinating disease of the central nervous system (CNS) that is regarded as the foremost cause of non-traumatic neurologic disability in adults in North America. Spasticity is a common complication in MS and occurs in up to 84% of patients. The main sign of spasticity is resistance to passive limb movement characterized by increased resistance to stretching, clonus, and exaggerated deep reflexes. Osmotica Pharmaceutical is currently developing arbaclofen extended-release tablets (AERT) for the treatment of spasticity in patients with MS.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of oral AERT in MS patients with spasticity. Two doses of AERT, 40 mg and 80 mg, will be compared with placebo. The treatment groups will be randomized in a 1:1:1 ratio. Eligible patients will undergo a washout period for withdrawal of all medications used for anti-spasticity and/or muscle relaxation prior to randomization. A baseline clinical evaluation will be performed (Visit 2) to confirm eligibility for study randomization, and subjects will be randomly assigned to 1 of 3 treatment arms. Subjects will remain on maintenance treatment for approximately 3 months.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: AERT 40 mg 40 mg Arbaclofen Extended-Release Tablets |
Drug: Arbaclofen
Arbaclofen Extended Release Tablet
Other Names:
|
| Active Comparator: AERT 80 mg 80 mg Arbaclofen Extended-Release Tablets |
Drug: Arbaclofen
Arbaclofen Extended Release Tablet
Other Names:
|
| Placebo Comparator: Placebo Placebo |
Drug: Placebo
Placebo comparator
|
Outcome Measures
Primary Outcome Measures
- Change From Baseline in Total Numeric-transformed Modified Ashworth Scale Score of the Most Affected Limb (TNmAS-MAL) [84 days]
Total Numeric-Transformed Modified Ashworth Scale (TNmAS) is a 6-point scale to measure abnormality in tone or the resistance to passive movements. Higher score is worse outcome. For each joint, the minimum score is 0; maximum score is 5. The values for each of the 3 main joints are summed for the limb score. The limb with the highest score is the most affected limb (MAL). The highest possible score for a limb is 15. Limb range: 0 to 15. To arrive at total limbs (TL) score the values for all 4 limbs are summed; maximum total limb score is 60. TL range: 0 to 60.
- Clinical Global Impression of Change (CGIC) [84 days]
The Clinical Global Impression of Change (CGIC) was developed to provide a brief, stand-alone assessment of the clinician's view of the subject's global functioning prior to and after initiating a study medication. The scale ranges from -3 to +3 judging whether the change is significantly worse (-3) to significantly improved (+3). Higher score is better outcome. The CGIC scale will be used to measure the overall change in the subject's condition since starting the study. There is no baseline value because the score is a measure of how the patient changed from baseline (treatment initiation).
Eligibility Criteria
Criteria
Inclusion Criteria Includes:
-
Subjects 18 to 65 years of age, inclusive.
-
An established diagnosis of MS that manifests a documented history of spasticity.
-
If receiving disease-modifying medications (eg, interferons approved for MS, glatiramer acetate, natalizumab, fingolimod, or mitoxantrone), there must be no change in dose for at least 3 months prior to Visit 1 (Screening), and the subject must be willing to maintain this treatment dose for the duration of the study. If receiving AMPYRA® (dalfampridine, fampridine, 4-amino puridine), subject must be at a stable dose for at least 3 months prior to Visit 1.
-
Stable regimen for at least 3 months prior to Visit 2 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.
-
Use of a medically highly effective form of birth control (see Section 7.8) during the study and for 3 months thereafter for women of child-bearing potential (including female subjects and female partners of non-sterile male subjects).
-
Willing to sign the informed consent form (ICF).
Exclusion Criteria Includes:
-
Any concomitant disease or disorder that has symptoms of spasticity or that may influence the subject's level of spasticity.
-
Concomitant use of medications that would potentially interfere with the actions of the study medication or outcome variables.
-
Pregnancy, lactation, or planned pregnancy during the course of the study and for 3 months after the final study visit.
-
Subject has clinically significant abnormal laboratory values, in the opinion of the investigator, at Visit 1 or Visit 2.
-
Current malignancy or history of malignancy that has not been in remission for more than 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, puts the subject at risk because of participation, influences the result of the study, or affects the subject's ability to participate.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Grodno Regional Clinical Hospital | Grodno | Belarus | ||
| 2 | Minsk City Clinical Hospital #5 | Minsk | Belarus | ||
| 3 | Minsk Scientific and Practical Center of Surgery, Transplantology and Hematology | Minsk | Belarus | ||
| 4 | Republican Research and Development Center for Neurology and Neurosurgery | Minsk | Belarus | ||
| 5 | Vitebsk Regional Diagnostic Center | Vitebsk | Belarus | ||
| 6 | University Clinical Centre of the Republic of Srpska, Clinic of Neurology | Banja Luka | Bosnia and Herzegovina | ||
| 7 | University Clinical Hospital Mostar, Clinic of Neurology | Mostar | Bosnia and Herzegovina | ||
| 8 | Multiprofile Hospital for Active Treatment - Pleven within the structure of Military Medical Academy, Sofia | Pleven | Bulgaria | ||
| 9 | University Multiprofile Hospital for Active Treatment "Dr. Georgi Stranski", Pleven, Clinic of Neurological Diseases | Pleven | Bulgaria | ||
| 10 | Medical Center "Rusemed" EOOD | Ruse | Bulgaria | ||
| 11 | Multiprofile Hospital for Active Treatment "ACIBADEM City Clinic Tokuda Hospital", Sofia, Neurology and Sleep Medicine Clinic | Sofia | Bulgaria | ||
| 12 | Multiprofile Hospital for Active Treatment of Neurology and Psychiatry "Sveti Naum", Sofia | Sofia | Bulgaria | ||
| 13 | University Multiprofile Hospital for Active Treatment "Sveti Ivan Rilski", Sofia, Clinic of Neurology Diseases | Sofia | Bulgaria | ||
| 14 | Clinical Hospital Center Osijek, Clinic of Neurology | Osijek | Croatia | ||
| 15 | Clinical Hospital Center Rijeka, Department of Neurology | Rijeka | Croatia | ||
| 16 | General Hospital Varazdin, Department of Neurology | Varaždin | Croatia | ||
| 17 | Clinical Hospital Dubrava, Department of Neurology | Zagreb | Croatia | ||
| 18 | Institute for Emergency Medicine | Chisinau | Moldova, Republic of | ||
| 19 | National Institute of Neurology and Neurosurgery | Chisinau | Moldova, Republic of | ||
| 20 | Dendryt Medical Center | Katowice | Poland | ||
| 21 | Neuro-Medic | Katowice | Poland | ||
| 22 | Medical Practice Professor K. Rejdak | Lublin | Poland | ||
| 23 | MED-Polonia, Sp. z o.o. (LLC) | Poznań | Poland | ||
| 24 | "MEDYK" Stanislaw Mazur Sp. z o.o. (LLC) Medical Centre | Rzeszów | Poland | ||
| 25 | NeuroProtect Medical Center | Warsaw | Poland | ||
| 26 | Neurology Center Krzysztof Selmaj | Łódź | Poland | ||
| 27 | Clinical Center of Serbia | Belgrade | Serbia | ||
| 28 | Clinical Hospital Center Zemun, Department of Neurology | Belgrade | Serbia | ||
| 29 | Clinical Hospital Center Zvezdara | Belgrade | Serbia | ||
| 30 | Clinical Center Kragujevac | Kragujevac | Serbia |
Sponsors and Collaborators
- RVL Pharmaceuticals, Inc.
- Osmotica Pharmaceutical US LLC
Investigators
- Study Director: David Jacobs, MD, Vice President
Study Documents (Full-Text)
More Information
Publications
None provided.- OS440-3004
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | AERT 40 mg | AERT 80 mg | Placebo |
|---|---|---|---|
| Arm/Group Description | 40 mg//day Arbaclofen Extended-Release Tablets | 80 mg/day Arbaclofen Extended-Release Tablets | Placebo Tablets |
| Period Title: Overall Study | |||
| STARTED | 179 | 179 | 178 |
| COMPLETED | 137 | 107 | 159 |
| NOT COMPLETED | 42 | 72 | 19 |
Baseline Characteristics
| Arm/Group Title | AERT 40 mg | AERT 80 mg | Placebo | Total |
|---|---|---|---|---|
| Arm/Group Description | 40 mg/day Arbaclofen Extended-Release Tablets | 80 mg/day Arbaclofen Extended-Release Tablets | Placebo Tablets | Total of all reporting groups |
| Overall Participants | 179 | 179 | 178 | 536 |
| Age (Count of Participants) | ||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
179
100%
|
179
100%
|
178
100%
|
536
100%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
108
60.3%
|
101
56.4%
|
110
61.8%
|
319
59.5%
|
| Male |
71
39.7%
|
78
43.6%
|
68
38.2%
|
217
40.5%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
2
1.1%
|
0
0%
|
1
0.6%
|
3
0.6%
|
| Not Hispanic or Latino |
169
94.4%
|
172
96.1%
|
171
96.1%
|
512
95.5%
|
| Unknown or Not Reported |
8
4.5%
|
7
3.9%
|
6
3.4%
|
21
3.9%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
1
0.6%
|
1
0.2%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
4
2.2%
|
0
0%
|
2
1.1%
|
6
1.1%
|
| White |
171
95.5%
|
177
98.9%
|
174
97.8%
|
522
97.4%
|
| More than one race |
1
0.6%
|
0
0%
|
1
0.6%
|
2
0.4%
|
| Unknown or Not Reported |
3
1.7%
|
2
1.1%
|
0
0%
|
5
0.9%
|
| Total Numeric-Transformed Modified Ashworth Scale (Most Affected Limb) (units on a scale) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [units on a scale] |
7.4
(3.24)
|
7.6
(3.02)
|
7.6
(3.13)
|
7.5
(3.1)
|
Outcome Measures
| Title | Change From Baseline in Total Numeric-transformed Modified Ashworth Scale Score of the Most Affected Limb (TNmAS-MAL) |
|---|---|
| Description | Total Numeric-Transformed Modified Ashworth Scale (TNmAS) is a 6-point scale to measure abnormality in tone or the resistance to passive movements. Higher score is worse outcome. For each joint, the minimum score is 0; maximum score is 5. The values for each of the 3 main joints are summed for the limb score. The limb with the highest score is the most affected limb (MAL). The highest possible score for a limb is 15. Limb range: 0 to 15. To arrive at total limbs (TL) score the values for all 4 limbs are summed; maximum total limb score is 60. TL range: 0 to 60. |
| Time Frame | 84 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | AERT 40 mg | AERT 80 mg | Placebo |
|---|---|---|---|
| Arm/Group Description | 40 mg/day Arbaclofen Extended-Release Tablets | 80 mg/day Arbaclofen Extended-Release Tablets | Placebo Tablets |
| Measure Participants | 179 | 179 | 178 |
| Mean (Standard Deviation) [units on a scale] |
-1.7
(1.97)
|
-2.0
(1.78)
|
-1.4
(1.82)
|
| Title | Clinical Global Impression of Change (CGIC) |
|---|---|
| Description | The Clinical Global Impression of Change (CGIC) was developed to provide a brief, stand-alone assessment of the clinician's view of the subject's global functioning prior to and after initiating a study medication. The scale ranges from -3 to +3 judging whether the change is significantly worse (-3) to significantly improved (+3). Higher score is better outcome. The CGIC scale will be used to measure the overall change in the subject's condition since starting the study. There is no baseline value because the score is a measure of how the patient changed from baseline (treatment initiation). |
| Time Frame | 84 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | AERT 40 mg | AERT 80 mg | Placebo |
|---|---|---|---|
| Arm/Group Description | 40 mg/day Arbaclofen Extended-Release Tablets | 80 mg/day Arbaclofen Extended-Release Tablets | Placebo Tablets P |
| Measure Participants | 179 | 179 | 178 |
| Mean (Standard Deviation) [units on a scale] |
0.6
(1.0)
|
0.4
(1.23)
|
0.6
(0.94)
|
Adverse Events
| Time Frame | Adverse event data collected over 92 day period. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | AERT 40 mg | AERT 80 mg | Placebo | |||
| Arm/Group Description | 40 mg/day Arbaclofen Extended-Release Tablets | 80 mg/day Arbaclofen Extended-Release Tablets | Placebo Tablets | |||
All Cause Mortality |
||||||
| AERT 40 mg | AERT 80 mg | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/179 (0%) | 0/179 (0%) | 0/178 (0%) | |||
Serious Adverse Events |
||||||
| AERT 40 mg | AERT 80 mg | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 7/179 (3.9%) | 6/179 (3.4%) | 6/178 (3.4%) | |||
| Ear and labyrinth disorders | ||||||
| Vertigo | 0/179 (0%) | 0 | 1/179 (0.6%) | 1 | 0/178 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Vomiting | 0/179 (0%) | 0 | 1/179 (0.6%) | 1 | 0/178 (0%) | 0 |
| General disorders | ||||||
| Withdrawal Syndrome | 0/179 (0%) | 0 | 0/179 (0%) | 0 | 1/178 (0.6%) | 1 |
| Immune system disorders | ||||||
| Urosepsis | 0/179 (0%) | 0 | 0/179 (0%) | 0 | 1/178 (0.6%) | 1 |
| Injury, poisoning and procedural complications | ||||||
| Contusion | 1/179 (0.6%) | 1 | 0/179 (0%) | 0 | 0/178 (0%) | 0 |
| Hip Fracture | 1/179 (0.6%) | 1 | 0/179 (0%) | 0 | 0/178 (0%) | 0 |
| Joint Injury | 0/179 (0%) | 0 | 1/179 (0.6%) | 1 | 0/178 (0%) | 0 |
| Pneumothorax | 1/179 (0.6%) | 1 | 0/179 (0%) | 0 | 0/178 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Schwannoma | 0/179 (0%) | 0 | 0/179 (0%) | 0 | 1/178 (0.6%) | 1 |
| Nervous system disorders | ||||||
| Multiple Sclerosis Relapse | 2/179 (1.1%) | 2 | 3/179 (1.7%) | 3 | 0/178 (0%) | 0 |
| Restless Leg Syndrome | 1/179 (0.6%) | 1 | 0/179 (0%) | 0 | 0/178 (0%) | 0 |
| Somnolence | 0/179 (0%) | 0 | 0/179 (0%) | 0 | 1/178 (0.6%) | 1 |
| Status Epilepticus | 1/179 (0.6%) | 1 | 0/179 (0%) | 0 | 0/178 (0%) | 0 |
| Trigeminal Neuralgia | 0/179 (0%) | 0 | 0/179 (0%) | 0 | 1/178 (0.6%) | 1 |
| Psychiatric disorders | ||||||
| Delirium | 1/179 (0.6%) | 1 | 0/179 (0%) | 0 | 0/178 (0%) | 0 |
| Depression Suicidal | 0/179 (0%) | 0 | 1/179 (0.6%) | 1 | 0/178 (0%) | 0 |
| Somatic Symptom Disorder | 0/179 (0%) | 0 | 1/179 (0.6%) | 1 | 0/178 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Pulmonary Embolism | 1/179 (0.6%) | 1 | 0/179 (0%) | 0 | 0/178 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||
| Toxic Skin Eruption | 0/179 (0%) | 0 | 0/179 (0%) | 0 | 1/178 (0.6%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||
| AERT 40 mg | AERT 80 mg | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 148/179 (82.7%) | 154/179 (86%) | 133/178 (74.7%) | |||
| Ear and labyrinth disorders | ||||||
| Vertigo | 5/179 (2.8%) | 5 | 9/179 (5%) | 9 | 4/178 (2.2%) | 4 |
| Gastrointestinal disorders | ||||||
| Nausea | 40/179 (22.3%) | 40 | 30/179 (16.8%) | 30 | 28/178 (15.7%) | 28 |
| Vomiting | 14/179 (7.8%) | 14 | 19/179 (10.6%) | 19 | 16/178 (9%) | 16 |
| General disorders | ||||||
| Asthenia | 24/179 (13.4%) | 24 | 37/179 (20.7%) | 37 | 27/178 (15.2%) | 27 |
| Gait Disturbance | 2/179 (1.1%) | 2 | 14/179 (7.8%) | 14 | 6/178 (3.4%) | 6 |
| Fatigue | 4/179 (2.2%) | 4 | 10/179 (5.6%) | 10 | 7/178 (3.9%) | 7 |
| Musculoskeletal and connective tissue disorders | ||||||
| Muscular Weakness | 43/179 (24%) | 43 | 40/179 (22.3%) | 40 | 27/178 (15.2%) | 27 |
| Nervous system disorders | ||||||
| Dizziness | 27/179 (15.1%) | 27 | 35/179 (19.6%) | 35 | 20/178 (11.2%) | 20 |
| Somnolence | 20/179 (11.2%) | 20 | 27/179 (15.1%) | 27 | 19/178 (10.7%) | 19 |
| Headache | 4/179 (2.2%) | 4 | 6/179 (3.4%) | 6 | 12/178 (6.7%) | 12 |
| Renal and urinary disorders | ||||||
| Urinary Tract Disorder | 56/179 (31.3%) | 56 | 57/179 (31.8%) | 57 | 67/178 (37.6%) | 67 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | Vice President, Regulatory Affairs and Quality |
|---|---|
| Organization | RVL Pharmaceuticals, Inc. |
| Phone | 908-809-1300 |
| Regulatory@RVLpharma.com |
- OS440-3004