Multiple Sclerosis, Spasticity, Muscle
Conditions
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.
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.
Interventions
DRUGArbaclofen
Arbaclofen Extended Release Tablet
DRUGPlacebo
Placebo comparator
Sponsors
Osmotica Pharmaceutical US LLC
RVL Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
Countries
Belarus, Bosnia and Herzegovina, Bulgaria, Croatia, Moldova, Poland, Serbia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AERT 40 mg 40 mg/day Arbaclofen Extended-Release Tablets | 179 |
| AERT 80 mg 80 mg/day Arbaclofen Extended-Release Tablets | 179 |
| Placebo Placebo Tablets | 178 |
| Total | 536 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 22 | 57 | 11 |
| Overall Study | MS Relapse | 2 | 1 | 0 |
| Overall Study | Unknown reason | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 18 | 13 | 8 |
Baseline characteristics
| Characteristic | AERT 40 mg | AERT 80 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 179 Participants | 179 Participants | 178 Participants | 536 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 169 Participants | 172 Participants | 171 Participants | 512 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 7 Participants | 6 Participants | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 171 Participants | 177 Participants | 174 Participants | 522 Participants |
| Sex: Female, Male Female | 108 Participants | 101 Participants | 110 Participants | 319 Participants |
| Sex: Female, Male Male | 71 Participants | 78 Participants | 68 Participants | 217 Participants |
| Total Numeric-Transformed Modified Ashworth Scale (Most Affected Limb) | 7.4 units on a scale STANDARD_DEVIATION 3.24 | 7.6 units on a scale STANDARD_DEVIATION 3.02 | 7.6 units on a scale STANDARD_DEVIATION 3.13 | 7.5 units on a scale STANDARD_DEVIATION 3.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 179 | 0 / 179 | 0 / 178 |
| other Total, other adverse events | 148 / 179 | 154 / 179 | 133 / 178 |
| serious Total, serious adverse events | 7 / 179 | 6 / 179 | 6 / 178 |
Outcome results
Primary
Change From Baseline in Total Numeric-transformed Modified Ashworth Scale Score of the Most Affected Limb (TNmAS-MAL)
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AERT 40 mg | Change From Baseline in Total Numeric-transformed Modified Ashworth Scale Score of the Most Affected Limb (TNmAS-MAL) | -1.7 units on a scale | Standard Deviation 1.97 |
| AERT 80 mg | Change From Baseline in Total Numeric-transformed Modified Ashworth Scale Score of the Most Affected Limb (TNmAS-MAL) | -2.0 units on a scale | Standard Deviation 1.78 |
| Placebo | Change From Baseline in Total Numeric-transformed Modified Ashworth Scale Score of the Most Affected Limb (TNmAS-MAL) | -1.4 units on a scale | Standard Deviation 1.82 |
Primary
Clinical Global Impression of Change (CGIC)
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AERT 40 mg | Clinical Global Impression of Change (CGIC) | 0.6 units on a scale | Standard Deviation 1 |
| AERT 80 mg | Clinical Global Impression of Change (CGIC) | 0.4 units on a scale | Standard Deviation 1.23 |
| Placebo | Clinical Global Impression of Change (CGIC) | 0.6 units on a scale | Standard Deviation 0.94 |