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. 2021 Nov 16;2021(11):CD013647. doi: 10.1002/14651858.CD013647.pub2

Selmaj 2013.

Study characteristics
Methods An adaptive, dose‐ranging, randomised, phase 2 study
Multicentre study was done at 73 specialised MS centres in Canada, USA, Russia, and 9 European countries (Finland, Germany, Hungary, Italy, Norway, Poland, Spain, Switzerland, and Turkey)
Recruitment period: 30 March 2009‐22 October 2010
Population included in data analyses:

  1. participants in cohort 1 (1:1:1:1) to receive once‐daily siponimod 10 mg, 2 mg, or 0.5 mg, or placebo for 6 months

  2. participants in cohort 2 (4:4:1) to siponimod 1.25 mg, siponimod 0.25 mg, or placebo once‐daily for 3 months


2 participant cohorts were tested sequentially, and an interim analysis was performed at 3 months
Participants 297 participants with RRMS
Inclusion criteria:

  1. people aged 18–55 years

  2. have had at least 1 documented relapse during the previous year

  3. at least 2 documented relapses during the previous 2 years, or ≥ 1 gadolinium‐enhancing lesions on MRI at screening

  4. an EDSS score of 0–5.0


Key exclusion criteria:

  1. relapse or corticosteroid treatment in the 30 days before randomisation

  2. active infection

  3. macular oedema

  4. diabetes mellitus, immunosuppression (related to drugs or disease)

  5. cancer (apart from successfully treated basal or squamous‐cell carcinoma of the skin)

  6. heart disease, lung disease, or liver disease


MS disease characteristics at baseline were generally balanced between treatment groups.
Age (mean ± SD): siponimod 10 mg = 36.4 ± 8.4 years, siponimod 2 mg = 37.4 ± 8.9 years, siponimod 1.25 mg = 35.4 ± 8.9 years, siponimod 0.5 mg = 36.0 ± 8.8 years, siponimod 0.25 mg = 37.4 ± 8.4 years, placebo = 35.4 ± 8.6 years
Sex (women): siponimod 10 mg = 30 (60%), siponimod 2 mg = 34 (69%), siponimod 1.25 mg = 31 (74%), siponimod 0.5 mg = 30 (70%), siponimod 0.25 mg = 42 (82%), placebo = 45 (73%)
Time from first symptoms of MS (mean ± SD): siponimod 10 mg = 6.0 ± 6.1 years, siponimod 2 mg = 7.2 ± 6.8 years, siponimod 1.25 mg = 7.2 ± 6.6 years, siponimod 0.5 mg = 8.7 ± 7.3 years, siponimod 0.25 mg = 7.7 ± 5.7 years, placebo = 8.0 ± 6.6 years
Number of relapses in previous year (mean ± SD): siponimod 10 mg = 1.4 ± 0.8 years, siponimod 2 mg = 1.3 ± 0.6 years, siponimod 1.25 mg = 1.3 ± 0.6 years, siponimod 0.5 mg = 1.5 ± 0.9 years, siponimod 0.25 mg = 1.4 ± 0.8 years, placebo = 1.3 ± 0.6 years
Number of relapses in previous 2 years (mean ± SD): siponimod 10 mg = 2.0 ± 1.0 years, siponimod 2 mg = 2.1 ± 1.0 years, siponimod 1.25 mg = 1.8 ± 0.8 years, siponimod 0.5 mg = 1.8 ± 1.0 years, siponimod 0.25 mg = 2.0 ± 0.9 years, placebo = 1.8 ± 0.7 years
Number of participants with gadolinium‐enhancing T1 lesions: siponimod 10 mg = 22/50 (44%), siponimod 2 mg = 26/48 (54%), siponimod 1.25 mg = 22/42 (52%), siponimod 0.5 mg = 23/43 (53%), siponimod 0.25 mg = 23/51 (45%), placebo = 35/61 (57%)
EDSS total score (mean ± SD): siponimod 10 mg = 2.3 ± 1.0, siponimod 2 mg = 2.4 ± 1.2, siponimod 1.25 mg = 2.0 ± 1.0, siponimod 0.5 mg = 2.2 ± 1.3, siponimod 0.25 mg = 2.3 ± 1.1, placebo = 2.3 ± 1.1
Interventions Participants were randomly assigned to 1 of the 2 groups:

  1. cohort 1: were randomly allocated (1:1:1:1) to receive siponimod 10 mg, 2 mg, or 0.5 mg, or placebo once‐daily for 6 months

  2. cohort 2: were randomly allocated (4:4:1) to siponimod 1.25 mg, siponimod 0.25 mg, or placebo once‐daily for 3 months


Cohort 1:
Experimental group 1: siponimod 10 mg once daily (n = 50)
Experimental group 2: siponimod 2 mg once daily (n = 49)
Experimental group 3: siponimod 0.5 mg once daily (n = 43)
Control group: matching placebo once daily (n = 45)
Cohort 2:
Experimental group 4: siponimod 1.25 mg once daily (n = 42)
Experimental group 5: siponimod 0.25 mg once daily (n = 51)
Control group: matching placebo once daily (n = 16)
Outcomes Primary outcome measure

  1. The dose‐response relation of the 5 doses of siponimod compared with placebo during 3 months of treatment


Assessed by percentage reduction in monthly number of combined unique active lesions at 3 months for siponimod versus placebo
Secondary outcome measures

  1. The effect of siponimod on the number of monthly CUALs

  2. Number of monthly new and all gadolinium‐enhancing T1 lesions

  3. Number of monthly new gadolinium‐enhancing T1 lesions in participants with high disease activity

  4. Number of monthly new or newly enlarged T2 lesions

  5. The proportion of participants without any new MRI activity (CUALs)

  6. ARRs

  7. Proportion of participants who were free of relapses

  8. The safety and tolerability of siponimod (including cardiac events)

  9. Determination of steady‐state blood‐plasma concentrations of siponimod
Notes The study was sponsored by Novartis Pharmaceuticals. Novartis Pharma AG was involved in the study design, and some authors of this paper are employed by Novartis and contributed to its preparation. The study design was approved by the steering committee (appendix) who, in conjunction with Novartis Pharma AG, collected and analysed the data, and contributed to the interpretation of the results
ClinicalTrials.gov number: NCT00879658
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Quote: "A central interactive voice‐response system automated the random assignment of patient numbers to randomisation numbers; the randomisation number was linked to a treatment group and a unique medication number".
Sequence generation was adequate.
Allocation concealment (selection bias) Low risk Quote: "A central interactive voice‐response system automated the random assignment of patient numbers to randomisation numbers; the randomisation number was linked to a treatment group and a unique medication number".
Allocation concealment was adequate
Blinding of participants and personnel (performance bias)
All outcomes Low risk Quote: "Patients, investigator staff, the independent assessing physician, the independent first‐dose administrator, and sponsor staff involved in the conduct of the study remained masked to treatment allocation from the time of randomisation until database lock".
Participants and personnel were blinded to the allocated interventions
Blinding of outcome assessment (detection bias)
All outcomes Low risk Quote: "Patients, investigator staff, the independent assessing physician, the independent first‐dose administrator, and sponsor staff involved in the conduct of the study remained masked to treatment allocation from the time of randomisation until database lock".
Incomplete outcome data (attrition bias)
All outcomes High risk Quote: "We included 188 patients in cohort 1 and 109 in cohort 2; 148 (79%) of individuals in cohort 1 and 104 (95%) individuals in cohort 2 completed the study on the study. Overall, 45 (15.2%) participants withdrew from study, 18.3% (40/188) in cohort 1, 4.6% (5/109) in cohort 2 group.
Selective reporting (reporting bias) High risk  Did not provide enough information to assess reporting bias, no full protocol or statistical analysis plan was available in the public domain.
Other bias Unclear risk Quote: "1. Novartis Pharma AG was involved in the study design, and some authors of this paper are employed by Novartis and contributed to its preparation.
2.Novartis Pharma AG provided funding for editorial assistance by Oxford PharmaGenesis (Oxford, UK), handling of data by Quintiles, and central laboratory monitoring by CoreLab Partners".
It is not clear whether this would have affected the results.

AE: adverse event; ARR: annualised relapse rate; CDP: confirmed disability progression; CUAL: combined unique active lesions; EDSS: Expanded Disability Status Scale; MRI: magnetic resonance imaging; MS: multiple sclerosis; RRMS: relapsing remitting multiple sclerosis; SAE: serious adverse event; SD: standard deviation; SPMS: secondary progressive multiple sclerosis;