Multiple Sclerosis, Walking Impairment
Conditions
Brief summary
This study assessed the efficacy and safety of ADS-5102 (at daily doses of 137 mg or 274 mg) compared with placebo in MS patients with walking impairment.
Detailed description
This was a multicenter, 3-arm, randomized, placebo-controlled, double-blind, parallel-group study of ADS-5102 (amantadine) extended release capsules in MS subjects with walking impairment. The study consisted of a screening period (up to 3 weeks), a single-blind placebo run-in period (4 weeks; during which subjects were blinded to treatment), and a double-blind treatment period (12 weeks). For at least 30 days prior to screening, all subjects were to have received a stable regimen of MS medications, both disease-modifying and symptomatic; these medications were to continue at the same doses and regimens for the duration of the subjects' participation in the study, to the extent compatible with good neurological care. Subjects were not to have used amantadine, dalfampridine, or any 4 aminopyridine or 2,4 diaminopyridine preparation within 30 days prior to screening. Consented subjects who completed the screening period were to undergo a 4-week single-blind placebo run-in period during which they received placebo as 2 capsules once daily at bedtime. Subjects who completed the single-blind placebo run-in period and continued to meet study eligibility criteria were randomized with equal probability to 1 of 3 treatment groups: placebo or ADS-5102 at a final dose of 137 mg/day or 274 mg/day. Study drugs were administered as 2 capsules once daily at bedtime. Subjects were to return to the clinic for safety and efficacy assessments at Week 0 and Week 2 prior to randomization and at Weeks 4 (randomization and baseline visit), 6 (only safety), 8, 12, and 16 after randomization. In addition, telephone visits for safety assessments were conducted at Weeks 5 and 7. Subjects who withdrew from the study before Week 16 were to have an early termination visit that included safety follow-up and efficacy assessments, as appropriate.
Interventions
Sponsors
Adamas Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Signed a current IRB-approved informed consent form * Male or female subjects between 18 and 70 years of age, inclusive, at the time of Screening * Confirmed diagnosis of MS according to the 2017 McDonald criteria * Current medication regimen must be stable for at least 30 days prior to screening, and subject must be willing to continue the same dosing regimen for the duration of study participation * Maximum Expanded Disability Status Scale (EDSS) score during screening of 6.5 * Stable physical activity level (inclusive of prescribed physical therapy) for at least 30 days prior to screening and willing to continue without change for the duration of study participation * A score on each of two completed screening T25FW tests between 8 and 45 seconds, inclusive
Exclusion criteria
* Documented inability to tolerate amantadine * Clinically significant MS relapse with onset less than 30 days prior to screening * Receipt of dalfampridine (or any 4-aminopyridine or 2,4-diaminopyridine preparation) or amantadine within 30 days prior to screening * History of seizures within 3 years prior to screening * History of hallucinations (visual, auditory, or any other type) within 3 years prior to screening * History of bipolar disorder, schizophrenia, or psychosis, regardless of treatment * For subjects with a history of major depressive disorder, the presence of active depressive symptoms that, in the opinion of the investigator, would affect the subject's ability to complete study assessments, or which would not be in the subject's best interest to participate in the study * Presence of orthostatic hypotension at screening: a decrease in systolic blood pressure (at least 20 mm Hg) or diastolic blood pressure (at least 10 mm Hg) within 3 minutes of the subject standing up, compared to pressures obtained while sitting * If female, is pregnant or lactating * If a sexually active female, is not surgically sterile or at least 2 years post-menopausal, or does not agree to utilize a highly effective hormonal method of contraception (an IUD, or vasectomized male partner is also acceptable), in combination with a barrier method, from screening through at least 4 weeks after the completion of study treatment. If a sexually active male, does not agree to utilize condoms from screening through at least 4 weeks after the completion of study treatment. * Treatment with an investigational drug or device within 30 days prior to screening * Treatment with an investigational biologic within 6 months or 5 half-lives, whichever is longer, prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Timed 25 Foot Walk (T25FW, Feet/Second): the Proportion of Subjects With a ≥ 20% Increase in Walking Speed (Measured by T25FW) From Baseline at Week 16 (Responder Analysis) | 16 weeks | The T25FW is a measure of lower extremity function. The subject is directed to a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The task is immediately administered again by having the subject walk back the same distance. For this outcome measure, the result is reported as speed (feet per second). Improvement is indicated by an increase in speed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Timed 25 Foot Walk: Change From Baseline at Week 16 | 16 weeks | The T25FW is a measure of lower extremity function. The subject is directed to a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The task is immediately administered again by having the subject walk back the same distance. For this outcome measure, the result is reported as or speed (feet per second). Improvement is indicated by an increase in speed. |
| Timed Up and Go (TUG): Change From Baseline at Week 16 | 16 weeks | The TUG is a measure of lower extremity strength, balance, and coordination. The subject stands up from a chair, walks 3 meters then turns around and walks back to the chair to sit down. The result is reported in seconds. Improvement is indicated by negative change scores. |
| 2-Minute Walk Test (2MWT): Change From Baseline at Week 16 | 16 weeks | The 2MWT is a measure of lower extremity function. The subject is instructed to walk as far as possible in 2 minutes, and the distance is measured in meters. Improvement is indicated by positive change scores. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ADS-5102 137 mg ADS-5102, 137 mg: Oral capsules to be administered once daily at bedtime | 187 |
| ADS-5102 274 mg ADS-5102, 274 mg: Oral capsules to be administered once daily at bedtime | 185 |
| Placebo placebo capsules
Placebo: Oral capsules to be administered once daily at bedtime | 186 |
| Total | 558 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 15 | 40 | 7 |
| Overall Study | Could not return to clinic | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 2 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 10 | 3 |
| Overall Study | Withdrawn per physician | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | ADS-5102 137 mg | Total | Placebo | ADS-5102 274 mg |
|---|---|---|---|---|
| Age, Continuous | 54.7 years STANDARD_DEVIATION 9.13 | 54.4 years STANDARD_DEVIATION 9.37 | 54.5 years STANDARD_DEVIATION 9.75 | 54.0 years STANDARD_DEVIATION 9.27 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 24 Participants | 68 Participants | 23 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 4 Participants | 3 Participants | 0 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 | 10 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) White | 158 Participants | 473 Participants | 155 Participants | 160 Participants |
| Sex: Female, Male Female | 125 Participants | 377 Participants | 128 Participants | 124 Participants |
| Sex: Female, Male Male | 62 Participants | 181 Participants | 58 Participants | 61 Participants |
| Time since diagnosis of multiple sclerosis | 15.99 years STANDARD_DEVIATION 9.862 | 15.94 years STANDARD_DEVIATION 9.649 | 15.85 years STANDARD_DEVIATION 9.478 | 15.97 years STANDARD_DEVIATION 9.655 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 187 | 0 / 185 | 0 / 186 |
| other Total, other adverse events | 105 / 187 | 140 / 185 | 90 / 186 |
| serious Total, serious adverse events | 5 / 187 | 11 / 185 | 1 / 186 |
Outcome results
Primary
Timed 25 Foot Walk (T25FW, Feet/Second): the Proportion of Subjects With a ≥ 20% Increase in Walking Speed (Measured by T25FW) From Baseline at Week 16 (Responder Analysis)
The T25FW is a measure of lower extremity function. The subject is directed to a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The task is immediately administered again by having the subject walk back the same distance. For this outcome measure, the result is reported as speed (feet per second). Improvement is indicated by an increase in speed.
Time frame: 16 weeks
Population: Intent-to-treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ADS-5102 137 mg | Timed 25 Foot Walk (T25FW, Feet/Second): the Proportion of Subjects With a ≥ 20% Increase in Walking Speed (Measured by T25FW) From Baseline at Week 16 (Responder Analysis) | 0.176 proportion of responders |
| ADS-5102 274 mg | Timed 25 Foot Walk (T25FW, Feet/Second): the Proportion of Subjects With a ≥ 20% Increase in Walking Speed (Measured by T25FW) From Baseline at Week 16 (Responder Analysis) | 0.211 proportion of responders |
| Placebo | Timed 25 Foot Walk (T25FW, Feet/Second): the Proportion of Subjects With a ≥ 20% Increase in Walking Speed (Measured by T25FW) From Baseline at Week 16 (Responder Analysis) | 0.113 proportion of responders |
p-value: 0.081195% CI: [-0.008, 0.136]Farrington-Manning score test
p-value: 0.010495% CI: [0.023, 0.174]Farrington-Manning score test
Secondary
2-Minute Walk Test (2MWT): Change From Baseline at Week 16
The 2MWT is a measure of lower extremity function. The subject is instructed to walk as far as possible in 2 minutes, and the distance is measured in meters. Improvement is indicated by positive change scores.
Time frame: 16 weeks
Population: Intent-to-treat: subjects with available data at Week 16
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ADS-5102 137 mg | 2-Minute Walk Test (2MWT): Change From Baseline at Week 16 | 6.306 meters | Standard Error 1.2422 |
| ADS-5102 274 mg | 2-Minute Walk Test (2MWT): Change From Baseline at Week 16 | 5.692 meters | Standard Error 1.3537 |
| Placebo | 2-Minute Walk Test (2MWT): Change From Baseline at Week 16 | 2.163 meters | Standard Error 1.2158 |
p-value: 0.017695% CI: [0.726, 7.56]Mixed Models Analysis
p-value: 0.05395% CI: [-0.046, 7.104]Mixed Models Analysis
Secondary
Timed 25 Foot Walk: Change From Baseline at Week 16
The T25FW is a measure of lower extremity function. The subject is directed to a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The task is immediately administered again by having the subject walk back the same distance. For this outcome measure, the result is reported as or speed (feet per second). Improvement is indicated by an increase in speed.
Time frame: 16 weeks
Population: Intent-to-treat: subjects with available data at Week 16
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ADS-5102 137 mg | Timed 25 Foot Walk: Change From Baseline at Week 16 | 0.19 feet/second | Standard Error 0.034 |
| ADS-5102 274 mg | Timed 25 Foot Walk: Change From Baseline at Week 16 | 0.19 feet/second | Standard Error 0.034 |
| Placebo | Timed 25 Foot Walk: Change From Baseline at Week 16 | 0.07 feet/second | Standard Error 0.033 |
p-value: 0.016295% CI: [0.02, 0.21]Mixed Models Analysis
p-value: 0.014295% CI: [0.02, 0.22]Mixed Models Analysis
Secondary
Timed Up and Go (TUG): Change From Baseline at Week 16
The TUG is a measure of lower extremity strength, balance, and coordination. The subject stands up from a chair, walks 3 meters then turns around and walks back to the chair to sit down. The result is reported in seconds. Improvement is indicated by negative change scores.
Time frame: 16 weeks
Population: Intent-to-treat: subjects with available data at Week 16
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ADS-5102 137 mg | Timed Up and Go (TUG): Change From Baseline at Week 16 | -1.35 seconds | Standard Error 0.384 |
| ADS-5102 274 mg | Timed Up and Go (TUG): Change From Baseline at Week 16 | -0.60 seconds | Standard Error 0.415 |
| Placebo | Timed Up and Go (TUG): Change From Baseline at Week 16 | -0.56 seconds | Standard Error 0.377 |
p-value: 0.142495% CI: [-1.85, 0.27]Mixed Models Analysis
p-value: 0.946795% CI: [-1.14, 1.06]Mixed Models Analysis