E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Secondary progressive multiple sclerosis |
|
E.1.1.1 | Medical condition in easily understood language |
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 |
Primary objective Core part: To demonstrate the efficacy of Siponimod (BAF312) relative to placebo in delaying the time to 3-month confirmed disability progression in patients with secondary progressive multiple sclerosis (SPMS) as measured by expanded disability status scale (EDSS)
|
|
E.2.2 | Secondary objectives of the trial |
First key secondary objective Core part: To demonstrate the efficacy of Siponimod relative to placebo in delaying the time to 3-month confirmed worsening of at least 20% from Baseline in the timed 25-foot walk test (T25W)
Second key secondary objective Core part: To demonstrate the efficacy of Siponimod relative to placebo in reducing the increase in T2 lesion volume from Baseline
For further secondary objectives please see protocol
Extension part: To evaluate the long-term safety, tolerability and efficacy of BAF312
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Exploratory blood and CSF biomarker sub-study
(2012-7-12, Version 00)
- Characterization of changes in biomarker levels in the CSF and peripheral blood during study course
2. Exploratory cognitive sub-study
(2012-7-12, Version 00)
- Exploration of cognitive impairment in SPMS patients
- Investigation of relationship between cognitive test performance and certain brain imaging findings
3. Exploratory optical coherence tomography (OCT) sub-study
(2012-7-12, Version 00)
-Exploration of the utility of retinal layer thickness as a marker of axonal degeneration and disability progression in SPMS
4. Magnetic resonance imaging (MRI) sub-study
(2012-07-12, Version 00)
-Exploration of the use of MRI techniques that may provide additional information about the extent and nature of structural damage due to demyelination or axonal loss, in patients with SPMS treated with Siponimod and placebo, respectively
-In addition to the conventional MRI, MTR (magnetization transfer ratio) and high resolution structural imaging will be implemented at centers meeting pre-specified technical requirements to evaluate structural integrity of the brain lesions visible on conventional MRI and in the normal appearing brain tissue as well as the grey matter volume of the patients participating in the CBAF312A2304 study
5. Exploratory fluorescence-activated cell sorting (FACS) sub-study
(2012-07-12, Version 00)
-Investigation of the influence of pre-treatment peripheral lymphocyte composition on the on-treatment absolute lymphocyte count (ALC)
-Increase understanding of the effect of Siponimod on different lymphocyte subpopulations, follow their longitudinal changes on treatment and relate these changes to the clinical and MR outcomes |
|
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male or female patients aged 18 to 60 years (inclusive) at screening
3. Prior history of relapsing-remitting MS (RRMS) according to the 2010 Revised McDonald criteria (Polman et al. 2011)
4. Secondary progressive course of MS (SPMS), defined by a progressive increase in disability (of at least 6 months duration) in the absence of relapses or independent of, relapses (Lublin et al. 1996, 2003, Rovaris et al. 2006)
• Attestation by the investigator in a written statement that the disease has entered the progressive stage (according to the study definition) at least 6 months prior to enrollment
5. Disability status at Screening with an EDSS score of 3.0 to 6.5(inclusive)
6. Documented EDSS progression in the 2 years prior to study of ≥1 point for patients with EDSS <6.0 at screening, and ≥0.5 point for patients with EDSS ≥6.0 at screening. Should documented EDSS scores not be available, a written summary of the clinical evidence of disability progression in the previous 2 years, and retrospective assessment of EDSS score from data up to 2 years prior to screening must be submitted for central review.
7. No evidence of relapse or corticosteroid treatment within 3 months prior to randomization
Note 1: A central review of the available clinical evidence of disability progression will be required for patients without documented pre-trial EDSS assessments. This will be completed by submitting a disability progression form for central adjudication. The central adjudication will be led by Professor Polman and team located at the VU Medical Centre in Amsterdam. The adjudication process is outlined in a separate charter. |
|
E.4 | Principal exclusion criteria |
Women of child bearing potential must use reliable forms of contraception.
Diagnosis of Macular edema during screening period
Any medically unstable condition determined by investigator
Unable to undergo MRI scans
Hypersensitivity to any study drugs or drugs of similar class
Other protocol-defined inclusion criteria may apply
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Core part: The delay in time to 3-month confirmed disability progression by Siponimod (BAF312) relative to placebo as measured by expanded disability status scale (EDSS)
Confirmed disability is defined as an increase of score of 1 point in patients with baseline score of 3.0-5.0 and 0.5 point increase with baseline score of 5.5 to 6.5. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline, every three months up to the maximum of 3 years |
|
E.5.2 | Secondary end point(s) |
Core part: The first key secondary endpoint is the delay in time to 3-month confirmed worsening of at least 20% from Baseline in the timed 25-foot walk test (T25W) by Siponimod (BAF312) compared to placebo.
The second key secondary endpoint is the efficacy of Siponimod (BAF312) relative to placebo in reducing the increase in T2 lesion volume from Baseline.
For further secondary endpoints please see protocol. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Baseline, every three months up to the maximum of 3 years
2) Baseline, every year up to the maximum of 3 years |
|
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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Extension part: Tolerability. |
|
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 | Yes |
E.8.1.7.1 | Other trial design description |
Actually: Core part = double blind (up to the 3 years) and extension part = open-label (7 years) |
|
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 173 |
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 |
Egypt |
Israel |
United States |
Austria |
Estonia |
France |
Latvia |
Lithuania |
Poland |
Sweden |
Bulgaria |
Netherlands |
Romania |
Spain |
Switzerland |
Czechia |
Germany |
Greece |
Italy |
Belgium |
Hungary |
Ireland |
Portugal |
Russian Federation |
Slovakia |
Turkey |
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 | 10 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |