E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-relapsing Secondary Progressive Multiple Sclerosis |
|
E.1.1.1 | Medical condition in easily understood language |
Non-relapsing Secondary Progressive Multiple Sclerosis |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063400 |
E.1.2 | Term | Secondary progressive multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in
NRSPMS |
|
E.2.2 | Secondary objectives of the trial |
- To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic resonance
imaging (MRI) lesions, cognitive performance, physical function, and quality of life
- To evaluate safety and tolerability of SAR442168
- To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites in NRSPMS and its relationship to efficacy and safety
- To evaluate pharmacodynamics (PD) of SAR442168 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- 18 to 60 years of age inclusive
- Diagnosis of nonrelapsing secondary progressive multiple sclerosis according to the 2017 McDonald criteria
- Expanded disability status scale (EDSS) between 3.0 to 6.5 points inclusive, at screening
- The participant must have documented evidence of disability progression observed during the 12 months before screening
- Absence of clinical relapses for at least 24 months
- The participant must have, at screening, disease duration from the onset of MS symptoms of:
-- <20 years in participants with EDSS scores at screening >5.0;
OR <10 years in participants with EDSS scores at screening ≤5.0
- Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
- Participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a woman of child bearing potential (WOCBP)
OR
- Is a WOCBP and agrees to use an acceptable contraceptive method |
|
E.4 | Principal exclusion criteria |
- The participant has conditions that would adversely affect study participation such as short life expectancy.
- History of organ transplant.
- Evidence of infection with human immuodeficiency virus (HIV), progressive multifocal leukoencephalopathy (PML), active hepatitis B or C, active or latent tuberculosis or other active infections that would adversely affect study participation.
- History of malignancy within 5 years prior to screening.
- History of alchohol or drug abuse within 1 year prior to screening.
- Hospitalized for psychiatric disease within 2 years prior to screening.
- Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at screening
- Bleeding disorder, known platelet dysfunction or platelet count <150 000/μL at screening.
-- A history of significant bleeding event within 6 months prior to
screening, according to the Investigator's judgment such as, but not
limited to cerebral or gastrointestinal bleeding.
- Lymphocyte count below the lower limit of normal at screening.
- Recent live (attenuated) vaccine within 2 months before the first treatment visit.
- Recent major surgery (within 4 weeks of screening) or planned major surgery during the study.
- The participant has received medications/treatments for MS within a specified time frame.
- Receiving strong inducers or inhibitors of cytochrome P450 3A (CYP3A) or CYP2C8 hepatic enzymes.
- Receiving anticoagulant or antiplatelet therapy (such as aspirin, clopidogrel, warfarin).
- Contraindications to magnetic resonance imaging (MRI).
NOTE: Other Inclusion/Exclusion criteria may apply. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
6-month confirmed disability progression (CDP) ; Time to onset of 6 months CDP defined as follows:
-Increase of ≥1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is ≤5.0, or
-Increase of ≥0.5 point when the baseline EDSS score is >5.0 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to approximately 48 months |
|
E.5.2 | Secondary end point(s) |
1 - 3-months change in T25-FW and 9-HPT ; Time to onset of sustained 20% increase in the timed 25 foot walk (T25-FW) and the 9-hole peg test (9-HPT) for at least 3 months
2 - 3-month CDP ; Time to onset of 3-month CDP as assessed by EDSS score
3 - T2 hyperintense lesion by MRI ; Total number of new or enlarging T2 hyperintense lesions as detected by MRI
4 - Time to confirmed disability improvement (CDI) ; Time to CDI defined as ≥1.0 point decrease on the EDSS score from baseline confirmed over at least 6 months
5 - Brain volume loss (BVL) ; Percent change in Brain volume loss (BVL) as detected by brain MRI at the EOS compared to month 6
6 - Change in cognitive function ; Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test (SDMT) and by the California Verbal Learning Test (CVLT-II)
7 - Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) ; Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS
8 - Safety and Tolerability ; Number of participants with adverse events (AEs), Serious AEs, AEs leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)
9 - Population pharmacokinetics ; Plasma concentration of SAR442168 and relevant metabolites(population PK assessment) at Months 6, 9, and 12
10 - Change in plasma neurofilament light chain (NfL) ; Change in NfL levels at the EOS compared to baseline
11 - Changes in serum Immunoglobulin level ; Changes in serum Immunoglobulin level at the EOS compared to baseline
12 - Change in lymphocyte phenotype subsets ; Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline
13 - Change in serum chitinase-3 like protein 1 (Chi3L1) ; Change in serum chitinase-3 like protein 1 (Chi3L1) at the EOS compared to baseline |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2 : Up to approximately 48 months
3, 4, 5, 6, 7, 10, 11, 12, 13 : From Baseline up to approximately 48 months
8 : From Screening until end of study up to approximately 48 months
9 : Months 6, 9 and 12 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 144 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Canada |
China |
India |
Israel |
Japan |
United States |
Austria |
Finland |
France |
Lithuania |
Poland |
Bulgaria |
Netherlands |
Romania |
Spain |
Czechia |
Germany |
Greece |
Italy |
Belarus |
Belgium |
Denmark |
Hungary |
Norway |
Portugal |
Russian Federation |
Turkey |
Ukraine |
United Kingdom |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |