Multiple Sclerosis
Conditions
Keywords
progressive multiple sclerosis, MS, EDSS, TW25, multiple sclerosis
Brief summary
The purpose of this study is to demonstrate the superiority of MD1003 over placebo in the disability of patients suffering from progressive multiple sclerosis and especially those with gait impairment.
Interventions
DRUGPLACEBO
an inactive substance
Sponsors
MedDay Pharmaceuticals SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
PART 1: Total duration of Part 1 is 27 months. The randomized double-blind placebo-controlled period ranges from 15 to 27 months depending upon the randomization date of an individual patient. Once the last month 15 evaluation of the study has been completed, patients will switch to the active drug at the next planned visit. Participants and study personnel will remain blinded as to the original treatment assignment. Maximum duration of double-blind period per patient will be no longer than 27 months. PART 2: At the last evaluation of Part 1 (Visit 11/Month 27) all participants will be offered active treatment in an open label extension for 39 additional months (From V11/M27 to V18/M66). The purpose of the active drug extension is to further define the safety of MD1003.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patient aged 18-65 years old * Signed and dated written informed consent form in accordance with local regulations: having freely given their written informed consent to participate in the study * Diagnosis of primary or secondary progressive MS fulfilling revised McDonald criteria (2010) and Lublin criteria (2014) * Documented evidence of clinical disability progression within the 2 years prior to inclusion, i.e. a) progression of EDSS during the past two years of at least 1 point sustained for at least 6 months if inclusion EDSS is from 3.5 to 5.5 or at least 0.5 point increase sustained for at least 6 months if inclusion EDSS is from 6 to 6.5 or b) increase of TW25 by at least 20% in the last two years sustained for at least 6 months or c) other well-documented objective worsening validated by the Adjudication Committee * EDSS at inclusion from 3.5 to 6.5 * TW25 \< 40 seconds at inclusion visit * Kurtzke pyramidal functional subscore ≥2 defined as minimal disability: patient complains of motor-fatigability or reduced performance in strenuous motor tasks (motor performance grade 1) and/or BMRC grade 4 in one or two muscle groups
Exclusion criteria
* Clinical evidence of a relapse in 24 months prior to inclusion * Treatment with any product containing biotin as single ingredient within six months prior to inclusion (multivitamin supplementation authorized if biotin \< 1mg per day) * Concomitant treatment with fampridine at inclusion or in the 30 days prior to inclusion * New immunosuppressive/immunomodulatory drug initiated less than 90 days prior to inclusion * Treatment with botulinum toxin (except for cosmetic purpose) initiated within 6 months prior to inclusion * In-patient rehabilitation program within the 3 months prior to inclusion * Pregnancy, breastfeeding or women with childbearing potential without acceptable form of contraception * Men unwilling to use an acceptable form of contraception * Any general chronic handicapping/incapacitating disease other than MS * Any serious disease necessitating biological follow-up with biological tests using biotinylated antibodies or substrates * Past history of rhabdomyolysis/metabolic myopathy * Known fatty acids beta oxidation defect * Known hypersensitivity or intolerance to biotin, analogues or excipients, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption * Patients with hypersensitivity or any contra-indication to Gadolinium * Patients with uncontrolled hepatic disorder, renal or cardiovascular disease, or cancer * Laboratory tests out of normal ranges considered by the investigator as clinically significant with regards to the study continuation * Patients with history or presence of alcohol abuse or drug addiction * Untreated or uncontrolled psychiatric disorders, especially suicidal risk assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) * Participation in another research study involving an investigational product (IP) in the 90 days prior to inclusion, or planned use during the study duration * Patients likely to be non-compliant to the study procedures or for whom a long-term follow-up seems to be difficult to achieve * Relapse that occurs between inclusion and randomization visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Improved on Either Expanded Disability Status Scale (EDSS) or Time to Walk 25 Feet (TW25) | 15 months | Proportion of patients improved on either Expanded Disability Status Scale (EDSS) or time to walk 25 feet (TW25) : \- with decreased EDSS at M12 confirmed at M15 (where decreased EDSS is defined as a decrease of at least 1 point if initial EDSS from 3.5 to 5.5 and of at least 0.5 point if initial EDSS from 6 to 6.5) or \- with improved TW25 of at least 20% at Month 12 and Month15 compared to the lowest of the two EDSS and TW25\* scores among inclusion and randomization visits. \*The lowest TW25 value recorded among the four values obtained during the inclusion and randomization visits will be considered as the baseline TW25 value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to 12-Weeks Confirmed EDSS Progression | 3 to 27 months | 12-weeks EDSS progression is defined by an increase of at least 1 point for baseline EDSS 3.5 to 5.5 and of at least 0.5 point for baseline EDSS 6 to 6.5 with respective confirmation 12 weeks later. Date of 12-weeks confirmed EDSS progression will be the first date of an EDSS progression (as defined above) that is confirmed 12 weeks later. |
| CGI-I Score (Clinical Global Impression of Change - Improvement), Evaluated Both by the Patient (SGI) and by the Evaluating Physician (CGI) | 15 months | — |
| Mean Change in TW25 Between M0 and M15 | 15 months | — |
Other
| Measure | Time frame |
|---|---|
| Brain MRI Changes Between M0 and M15 | 15 months |
| Symbol Digit Modalities Test (SDMT) | 15 months |
| Remote Monitoring of Ambulation | 27 months |
| (MSQOL54) & (CAREQOL-MS) Subscores and Composite Scores | 15 months |
| Subscores of the Kurtzke Functional Score | 15 months |
Countries
Australia, Belgium, Canada, Czechia, Germany, Hungary, Italy, Poland, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months.
PLACEBO: an inactive substance | 316 |
| MD1003 MD1003 capsule, 1 capsule tid (morning,noon and evening) for 15 months and up to 27 months.
MD1003 100mg capsule | 326 |
| Total | 642 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind Treatment Period | Adverse Event | 11 | 11 |
| Double-Blind Treatment Period | Death | 0 | 1 |
| Double-Blind Treatment Period | Lack of Efficacy | 4 | 12 |
| Double-Blind Treatment Period | Lost to Follow-up | 0 | 1 |
| Double-Blind Treatment Period | Protocol Violation | 1 | 4 |
| Double-Blind Treatment Period | Suicidal risk, etc. | 2 | 8 |
| Double-Blind Treatment Period | Withdrawal by Subject | 31 | 28 |
| Open Label Extension | Adverse Event | 0 | 3 |
| Open Label Extension | Other | 0 | 3 |
| Open Label Extension | Withdrawal by Subject | 0 | 4 |
Baseline characteristics
| Characteristic | Placebo | MD1003 | Total |
|---|---|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 7.6 | 52.6 years STANDARD_DEVIATION 7.79 | 52.7 years STANDARD_DEVIATION 7.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 12 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 293 Participants | 302 Participants | 595 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 14 Participants | 12 Participants | 26 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 8 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 10 Participants | 19 Participants |
| Race (NIH/OMB) White | 291 Participants | 306 Participants | 597 Participants |
| Region of Enrollment Australia | 6 participants | 8 participants | 14 participants |
| Region of Enrollment Belgium | 4 participants | 7 participants | 11 participants |
| Region of Enrollment Canada | 35 participants | 37 participants | 72 participants |
| Region of Enrollment Czechia | 26 participants | 31 participants | 57 participants |
| Region of Enrollment Germany | 48 participants | 42 participants | 90 participants |
| Region of Enrollment Hungary | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Italy | 5 participants | 7 participants | 12 participants |
| Region of Enrollment Poland | 11 participants | 12 participants | 23 participants |
| Region of Enrollment Spain | 30 participants | 31 participants | 61 participants |
| Region of Enrollment Sweden | 9 participants | 9 participants | 18 participants |
| Region of Enrollment Turkey | 2 participants | 2 participants | 4 participants |
| Region of Enrollment United Kingdom | 31 participants | 30 participants | 61 participants |
| Region of Enrollment United States | 109 participants | 109 participants | 218 participants |
| Sex: Female, Male Female | 170 Participants | 175 Participants | 345 Participants |
| Sex: Female, Male Male | 146 Participants | 151 Participants | 297 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 311 | 1 / 331 |
| other Total, other adverse events | 264 / 311 | 277 / 331 |
| serious Total, serious adverse events | 82 / 311 | 87 / 331 |
Outcome results
Primary
Proportion of Patients Improved on Either Expanded Disability Status Scale (EDSS) or Time to Walk 25 Feet (TW25)
Proportion of patients improved on either Expanded Disability Status Scale (EDSS) or time to walk 25 feet (TW25) : \- with decreased EDSS at M12 confirmed at M15 (where decreased EDSS is defined as a decrease of at least 1 point if initial EDSS from 3.5 to 5.5 and of at least 0.5 point if initial EDSS from 6 to 6.5) or \- with improved TW25 of at least 20% at Month 12 and Month15 compared to the lowest of the two EDSS and TW25\* scores among inclusion and randomization visits. \*The lowest TW25 value recorded among the four values obtained during the inclusion and randomization visits will be considered as the baseline TW25 value.
Time frame: 15 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Patients Improved on Either Expanded Disability Status Scale (EDSS) or Time to Walk 25 Feet (TW25) | 9.2 percent |
| MD1003 | Proportion of Patients Improved on Either Expanded Disability Status Scale (EDSS) or Time to Walk 25 Feet (TW25) | 12.0 percent |
Secondary
CGI-I Score (Clinical Global Impression of Change - Improvement), Evaluated Both by the Patient (SGI) and by the Evaluating Physician (CGI)
Time frame: 15 months
Secondary
Mean Change in TW25 Between M0 and M15
Time frame: 15 months
Secondary
Time to 12-Weeks Confirmed EDSS Progression
12-weeks EDSS progression is defined by an increase of at least 1 point for baseline EDSS 3.5 to 5.5 and of at least 0.5 point for baseline EDSS 6 to 6.5 with respective confirmation 12 weeks later. Date of 12-weeks confirmed EDSS progression will be the first date of an EDSS progression (as defined above) that is confirmed 12 weeks later.
Time frame: 3 to 27 months
Other Pre-specified
Brain MRI Changes Between M0 and M15
Time frame: 15 months
Other Pre-specified
(MSQOL54) & (CAREQOL-MS) Subscores and Composite Scores
Time frame: 15 months
Other Pre-specified
Remote Monitoring of Ambulation
Time frame: 27 months
Other Pre-specified
Subscores of the Kurtzke Functional Score
Time frame: 15 months
Other Pre-specified
Symbol Digit Modalities Test (SDMT)
Time frame: 15 months