Multiple Sclerosis, Spasticity, Muscle
Conditions
Brief summary
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, open-label, long-term extension study to evaluate the safety and tolerability of oral AERT in patients with spasticity due to MS. Subjects from the double blind study (Study OS440-3004) may rollover into this open-label extension study, as well as de novo subjects. The maintenance dose will be 80 mg/day or the highest tolerated dose. Once the subject has reached the maintenance dose, they will remain on that dose for approximately 1 year.
Interventions
DRUGArbaclofen
Arbaclofen is the active R enantiomer of baclofen.
Sponsors
Osmotica Pharmaceutical US LLC
RVL Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects 18 to 65 years of age, inclusive. 2. An established diagnosis per McDonald Criteria (Polman et al 2011) of MS (either relapsing-remitting \[RR\] or secondary-progressive \[SP\] course) that manifests a documented history of spasticity for at least 6 months prior to Baseline. 3. Has participated in Study OS440-3004 or is a new US subject (ie, a de novo subject) who fulfills the inclusion/
Exclusion criteria
. 4. Is willing to continue on open-label treatment with AERT as described in this protocol. 5. 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 Baseline, and the subject must be willing to maintain this treatment dose for the duration of the study. If receiving AMPYRA® (dalfampridine, fampridine, 4 amino pyridine), subject must be at a stable dose for at least 3 months prior to Baseline. 6. Stable regimen for at least 1 month prior to Baseline for all medications and non pharmacological therapies that are intended to alleviate spasticity. a. De novo subjects being considered for enrollment and taking medications indicated for the treatment of spasticity (ie, baclofen, benzodiazepines, cannabinoids, carisoprodol, dantrolene, tizanidine, cyclobenzaprine, any neuroleptic, ropinoprole, tolperisone, and clonidine) must wash out from these medications for a minimum of 21 days by Baseline in order to be eligible for study treatment. De novo subjects found not to meet this criterion will be withdrawn from the study and will be considered screen failures. 7. Absence of infections, peripheral vascular disease, painful contractures, advanced arthritis, or other conditions that hinder evaluation of joint movement. 8. Creatinine clearance, as calculated by the glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease Study (MDRD) formula, of \>50 mL/minute. 9. Use of a medically highly effective form of birth control (see Section 7.8 of the protocol) during the study and for 3 months thereafter for women of child-bearing potential (including female subjects). 10. Willing to sign the informed consent form (ICF).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events, Change in Vital Signs, Clinical Laboratory Test Results, 12-lead ECGs, USP Questionnaire, and C-SSRS Results | over 1 year | Safety and tolerability will be assessed by the monitoring of adverse events volunteered, observed, and elicited by general questions in a non-suggestive manner. Changes in vital signs, clinical laboratory test results, 12-lead ECGs, the urinary symptom profile (USP) questionnaire, and the C-SSRS results will also be assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Global Impression of Change (PGIC) | week 60 | Patient Global impression of Change (PGIC) is a scale to evaluate the change in activity limitations, symptoms, emotions, and overall quality of life using scores from 1 to 7 with 1 being no change and 7 being a great deal better, and a considerable improvement that has made all the difference. Minimum value is 1 and the maximum value is 7. |
| Total Numeric-transformed Modified Ashworth Scale Score or the Most Affected Limb (TNmAS-MAL) | week 28 | The abbreviated scale title is TNmAS. It is considered the primary clinical measure of muscle spasticity in subjects with neurological conditions. It is a useful 6-point rating scale (0 to 5) to measure abnormality in tone or the resistance to passive movements. Minimum value is 0 and maximum value is 5. A higher score means a worse outcome. |
| Expanded Disability Status Scale (EDSS) | week 60 | Expanded Disability Status Scale (EDSS) is a method of quantifying disability in MS and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5-unit increments that represent higher levels of disability. A score of 0 represents a normal neurological exam, and 10 represents death due to MS. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AERT 80 mg Arbaclofen extended release tablet, 20 mg
Arbaclofen: Arbaclofen is the active R enantiomer of baclofen. | 323 |
| Total | 323 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 40 |
| Overall Study | MS relapse | 10 |
| Overall Study | reason not specified | 5 |
| Overall Study | Withdrawal by Subject | 50 |
Baseline characteristics
| Characteristic | AERT 80 mg |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 323 Participants |
| Body Mass Index (BMI) | 24.825 kg/m^2 STANDARD_DEVIATION 4.776 |
| Expanded Disability Status Scale (EDSS) | 4.98 units on a scale STANDARD_DEVIATION 1.29 |
| Height | 169.6 cm STANDARD_DEVIATION 8.94 |
| Patient Global Impression of Change (PGIC) | 3.3 units on a scale STANDARD_DEVIATION 1.61 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 312 Participants |
| Sex: Female, Male Female | 190 Participants |
| Sex: Female, Male Male | 133 Participants |
| Total Numeric-Transformed Modified Ashworth Scale-Most Affected Limb (TNmAS-MAL) | 6.3 units on a scale STANDARD_DEVIATION 3.25 |
| Total Numeric-Transformed Modified Ashworth Scale-Total Limbs (TNmAS-TL) | 13.0 units on a scale STANDARD_DEVIATION 8.06 |
| Weight | 71.67 kg STANDARD_DEVIATION 15.704 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 323 |
| other Total, other adverse events | 278 / 323 |
| serious Total, serious adverse events | 21 / 323 |
Outcome results
Primary
Number of Participants With Adverse Events, Change in Vital Signs, Clinical Laboratory Test Results, 12-lead ECGs, USP Questionnaire, and C-SSRS Results
Safety and tolerability will be assessed by the monitoring of adverse events volunteered, observed, and elicited by general questions in a non-suggestive manner. Changes in vital signs, clinical laboratory test results, 12-lead ECGs, the urinary symptom profile (USP) questionnaire, and the C-SSRS results will also be assessed.
Time frame: over 1 year
Population: Safety population included all subjects who received at least one dose of study treatment and had at least one-post dose visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AERT 80 mg | Number of Participants With Adverse Events, Change in Vital Signs, Clinical Laboratory Test Results, 12-lead ECGs, USP Questionnaire, and C-SSRS Results | 276 Participants |
Secondary
Expanded Disability Status Scale (EDSS)
Expanded Disability Status Scale (EDSS) is a method of quantifying disability in MS and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5-unit increments that represent higher levels of disability. A score of 0 represents a normal neurological exam, and 10 represents death due to MS.
Time frame: week 60
Population: Safety population included all subjects who received at least one dose of study treatment and had at least one-post dose visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AERT 80 mg | Expanded Disability Status Scale (EDSS) | 5.01 units on a scale | Standard Deviation 1.3 |
Secondary
Patient Global Impression of Change (PGIC)
Patient Global impression of Change (PGIC) is a scale to evaluate the change in activity limitations, symptoms, emotions, and overall quality of life using scores from 1 to 7 with 1 being no change and 7 being a great deal better, and a considerable improvement that has made all the difference. Minimum value is 1 and the maximum value is 7.
Time frame: week 60
Population: Safety population included all subjects who received at least one dose of study treatment and had at least one-post dose visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AERT 80 mg | Patient Global Impression of Change (PGIC) | 2.7 units on a scale | Standard Deviation 1.63 |
Secondary
Total Numeric-transformed Modified Ashworth Scale Score or the Most Affected Limb (TNmAS-MAL)
The abbreviated scale title is TNmAS. It is considered the primary clinical measure of muscle spasticity in subjects with neurological conditions. It is a useful 6-point rating scale (0 to 5) to measure abnormality in tone or the resistance to passive movements. Minimum value is 0 and maximum value is 5. A higher score means a worse outcome.
Time frame: week 28
Population: Safety population included all subjects who received at least one dose of study treatment and had at least one-post dose visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AERT 80 mg | Total Numeric-transformed Modified Ashworth Scale Score or the Most Affected Limb (TNmAS-MAL) | 5.6 units on a scale | Standard Deviation 3.22 |