Primary Core: to demonstrate the efficacy of BAF312 relative to placebo in delaying the time to 3-month confirmed disability progression, measured by EDSS. Main secondary objectives Core: to demonstrate the efficacy in delaying the time to 3-month…
ID
Source
Brief title
Condition
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Expanded Disability Status Score (EDSS).
Secondary outcome
Timed 25-Foot walk (T25W), Nine Hole Peg Test (9-HPT), Paced Auditory Serial
Addition Test (PASAT), MS Relapse, MRI, Symbol Digital Modalities Test (SDMT),
Brief Visuospatial Memory Test-Revised (BVMT-R), Low Contract Visual Acuity
(LCVA), adverse events, questionnaires QoL and Colombia Suicide Severity
Rating, PK, pharmacogenomics (optional), biomarkers.
Background summary
For the treatment of secondary progressive MS mitoxantrone and interferon B-1b
are being used. Mitoxantrone is approved for the treatment of SPMS in the
Netherlands. However, there are no convincing data demonstrating the efficacy
of mitoxantrone in SPMS patients without superimposed relapses and the risks
associated with mitoxantrone (heart failure, leukemia) limit the use of the
product. IFNβ-1b carries an indication for SPMS with active disease, evidenced
by relapses. a considerable medical need remains to find therapies that will be
effective in delaying disability progression in patients with SPMS without
relapses.
Fingolimod has been registered for very active relapsing-remitting MS.
Siponimod (BAF312) is a novel S1P receptor modulator that leads to the
reduction of peripheral lymphocyte counts in blood. The mechanism of action is
similar to that of the S1P receptor modulator fingolimod, but BAF312 belongs to
a different chemical class. Whereas fingolimod acts as an agonist on four out
of five S1P receptors (namely S1P1, S1P3, S1P4, and S1P5); BAF312 is a
S1P1/S1P5-selective agonist. In contrast to fingolimod, BAF312 does not require
a phosphorylation step in vivo. The half-life of BAF312 compared to fingolimod
is shorter (approximately 30 h versus 200 h), therefore drug effects cease more
rapidly after discontinuation. For example, 90% recovery of the baseline
lymphocyte counts after treatment withdrawal from steady state conditions
should be achieved in one week at a daily BAF312 dose of 2 mg. In contrast, in
the case of fingolimod the return to 90% of the baseline lymphocyte counts
after discontinuation of 0.5 mg fingolimod takes ~12 weeks. The BAF312
mode of action in MS is believed to include S1P1-mediated prevention of
effector lymphocyte recirculation from lymphatic tissue to inflammatory lesions
in the CNS. In addition, there may be direct beneficial effects in the CNS
mediated by S1P1 and/or S1P5.
In this phase III study, effects of BAF312 (efficacy, safety and tolerability)
will be compared to those of placebo, for up to maiximum 3 years.
Placebo-controlled trials are considered to be ethical for those with forms of
the disease lacking established effective treatment. This is followed by an
open-label extension part; all patients treated ith BAF312 to investigate
long-term safety and tolerability.
Study objective
Primary Core: to demonstrate the efficacy of BAF312 relative to placebo in
delaying the time to 3-month confirmed disability progression, measured by
EDSS.
Main secondary objectives Core: to demonstrate the efficacy in delaying the
time to 3-month confirmed worsening of at least 20% from Baseline in the timed
25-foot walk test and in reducing the increase in T2 lesion volume from
Baseline to the end of the study.
Extension: To evaluate the long-term safety and tolerability of BAF312
Study design
Multicenter, randomized, double-blind, parallel-group phase III study.
Discontinuation of current MS treatment (if any).
Core:
Randomization (2:1):
• BAF312 2 mg daily
• Placebo
In case of unacceptable reduction of lymphocytes: dose adjustment (once). In
case of recurrence: temporary interruption of treatment.
Estimated treatment duration (depending of time of enrollment) approx. 23-36
months. Maximum: 36 months (3 years).
Followed by an open-label extension part; all patients treated ith BAF312 up to
maximum of 7 years.
1530 patients.
Intervention
Core: Treatment with BAF312 or placebo. Extension: Treatment with BAF312.
Study burden and risks
Risks: Adverse effects of study medication.
Core:
Burden: Visits screening, day (D) 1,7,28, month (M) 3, thereafter every 3 M.
Duration 1-8 h. Some visits: fasting.
(Nearly) every visit: physical examination, blood draw (screening 50 ml, others
approx. 15 ml).
Pregnancy tests: every month (partly at home).
Ophthalmic examination: screening, M 3, thereafter every year (visual acuity
every 6 M).
ECG: screening, D 1,7, M 3 thereafter every year.
Ambulant ECG monitoring during the first 6 treatment days.
Pulmonary function test: screening, M3, thereafter every year.
T25W: screening, D 1, thereafter every 3 M.
9-HPT: screening, M 3, thereafter every 3 M.
Other MS related tests: screening and every 6 M.
MRI brain: screening and every year.
CT/MRI lungs: screening and M 24.
Questionnaires: screening, D 28, M3, thereafter every 3 M.
Diary: Intake study medication and results pregnancy test at home.
Extension:
Visits Day 1,7, Month 1,3,6,9,12, then bi-annually, end of treatment visit,
follow-up visit 1 month post-treatment. Duration: 1-8 hours per visit. Some
visits: Patient should be fasting.
Physical Examination: Each visit.
EDSS: As of month 3 each visit.
Blood- and urine collection: (Nearly) each visit (not at Day 7 and Follow-up
visit). ca. 25 ml blood per visit.
Dermatological Exam: Month 12, then yearly and at end of treatment visit.
Ophthalmologic Exam: Month 3,6,12, daarna jaarlijks en op end of treatment
visit.
ECG: Day 1,7, Month 3,12, then yearly, at end of treatment and follow-up visit.
Pulmonary Function Test: Maand 3,6,12, then yearly, at end of treatment visit
and follow-up visit.
T25W: Month 3,6,9,12, then each visit up to month 18 from then every year (not
at follow-up visit).
SDMT: Month 6, as of month 12 each visit up to month 18 from then every year
(not at follow-up visit).
MRI brain: Month 12, then 2-yearly and at end of treatment visit.
Completion Questionnaire(s): As of Month 1 each visit up to month 18 from then
every year
Completion diary: Daily during treatment period.
Raapopseweg 1
Arnhem 6824 LZ
NL
Raapopseweg 1
Arnhem 6824 LZ
NL
Listed location countries
Age
Inclusion criteria
Core part:
• 18 to 60 years (inclusive).
• History of relapsing-remitting MS according to the 2010 Revised McDonald
criteria.
• Secondary progressive course of MS.
• EDSS score of 3.0 to 6.5 (inclusive).
• Documented EDSS progression in the 2 years prior to study of >=1 point for
patients with EDSS <6.0 at baseline, and >=0.5 point for patients with EDSS >=6.0
at baseline. 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.
• No evidence of relapse or corticosteroid treatment within 3 months prior to
randomization., Patients who completed the Core Part on:
* double-blind treatment
* open-label BAF312
* abbreviated schedule of assessments (with the exception of patients with
BAF312-related AE or SAE)
are eligible to enter the extension part.
Exclusion criteria
• Active chronic disease (or stable but treated with immune therapy) of the
immune system other than MS.
• Diagnosis of macular edema during pre-randomization phase (patients with a
history of macular edema will be allowed to enter the study provided that they
do not have macular edema at the ophthalmic examination at the Screening Visit).
• Negative for varicella-zoster virus IgG antibodies at Screening.
• Live or live-attenuated vaccines within 2 months prior to randomization.
• Have been treated with: BAF312, fingolimod within 2 months (M) or for more
than 6 M, intravenous immunoglobulin within 2 M, dimethyl fumarate within 2 M,
natalizumab within 6 M, immunosuppressive/chemotherapeutic medications within 6
M, cyclophosphamide within 12 M, rituximab, ofatumumab, ocrelizumab, cladribine
within 24 M, mitoxantrone during previous 24 M or evidence of cardiotoxicity
following mitoxantrone or a cumulative life-time dose of more than 60 mg/m2,
teriflunomide within 2Y (unless teriflunomide plasma concentration is zero or
without relevant biological significance) OR within 2W following successful
accelerated elimination procedure as described in the product label
• Abnormalities in the Suicidal Ideation section of the eC-SSRS (see protocol
for details)
• Homozygosity for CYP2C9*3 (will be tested at Screening), or refusal to test
for CYP2C9*3 haplotype.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | EUCTR2012-003056-36-BG en NCT01665144 |
| EudraCT | EUCTR2012-003056-36-NL |
| CCMO | NL42105.029.12 |