NCT00879658

Safety, Tolerability, Efficacy and Optimal Dose Finding Study of BAF312 in Patients With Relapsing-remitting Multiple Sclerosis

Completed Phase 2 Results posted Last updated 13 January 2020

What this trial tests

Phase 2 trial testing BAF312 in Relapsing-remitting Multiple Sclerosis in 297 participants. Completed in 4 May 2011.

Timeline

30 March 2009

Primary endpoint
4 May 2011

4 May 2011

Quick facts

Lead sponsor	Novartis Pharmaceuticals
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	297
Start date	30 March 2009
Primary completion	4 May 2011
Estimated completion	4 May 2011
Sites	72 locations across Italy, Finland, Russia, Germany, Hungary, Norway, Poland, Canada

Drugs / interventions tested

• BAF312 — full drug profile →
• Placebo

Conditions studied

• Relapsing-remitting Multiple Sclerosis — all drugs for Relapsing-remitting Multiple Sclerosis →

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

Adults 18 to 55, any sex, with Relapsing-remitting Multiple Sclerosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Dose Responsiveness of BAF312 Based on the Number of Combined Unique Active MRI Lesions (CUAL) Primary · 3 months of treatment

Combined unique active lesions (CUAL) were defined as new gadolinium \[Gd\]-enhanced lesions on T1-weighted MRI scans or new or enlarging lesions on T2-weighted MRI scans, without double-counting of lesions. ED50 is the dose that gives half of the asymptotic maximum change over placebo. ED90 is the dose that gives 90% of the asymptotic maximum change over placebo.

Dose achieving 50% reduction

Group	Value	95% CI
BAF312/Placebo	0.51	0.19 – 1.34

ED50

Group	Value	95% CI
BAF312/Placebo	0.83	0.30 – 2.27

ED90

Group	Value	95% CI
BAF312/Placebo	7.46	2.72 – 20.47

Number of Confirmed Relapses - Period 1 Secondary · 6 months

confirmed relapse: A relapse was to be confirmed by the Independent Evaluating Physician (examining neurologist) performing the EDSS. It was recommended that this occurred within 7 days of the onset of symptoms. A relapse was confirmed when it was accompanied by an increase of at least half a step (0.5) on the EDSS or an increase of 1 point on two different Functional Systems (FS) of the Expanded Disability Status Scale (EDSS) or 2 points on one of the FS (excluding Bowel/Bladder or Cerebral FS).

Group	Value	95% CI
BAF312 10mg	9
BAF312 2 mg	5
BAF312 0.5 mg	13
Placebo	13

Proportion of Participants With Relapse-free Patients - Period 1 + 2 Secondary · 3 month

To explore the effect of BAF312 on the proportion of relapse-free patients (confirmed relapses only)

Group	Value	95% CI
BAF312 10mg	0.87
BAF312 2 mg	0.93
BAF312 1.25 mg	0.93
BAF312 0.5 mg	0.79
BAF312 0.25 mg	0.86
Placebo	0.88

Proportion of Participants With Relapse-free Patients - Period 1 Only Secondary · 6 months

To explore the effect of BAF312 on the proportion of relapse-free patients (confirmed relapses only)

Group	Value	95% CI
BAF312 10mg	0.84
BAF312 2 mg	0.92
BAF312 0.5 mg	0.77
Placebo	0.72

Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3 Secondary · 3 months

Results for Month 1 through Month 3 inclusive include patients from both Period 1 and Period 2. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[G

Group	Value	95% CI
BAF312 10mg	0.2	± 0.61
BAF312 2 mg	0.4	± 1.00
BAF312 1.25 mg	0.2	± 0.48
BAF312 0.5 mg	0.9	± 2.48
BAF312 0.25 mg	0.6	± 1.16
Placebo	1.4	± 3.11

Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 Only at 6 Months Secondary · 6 months

Month 4 through Month 6 include patients from Period 1 only. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 an

Group	Value	95% CI
BAF312 10mg	0.3	± 0.57
BAF312 2 mg	0.4	± 0.96
BAF312 0.5 mg	1.4	± 4.17
Placebo	1.8	± 3.09

Number of All New Gd-enhanced T1 Lesions - Period 1 +2 at Month 3 Secondary · 3 months

The results for Month 1 through Month 3 includes patients from both Period 1 and Period 2. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]

Group	Value	95% CI
BAF312 10mg	0.5	± 0.99
BAF312 2 mg	0.8	± 1.46
BAF312 1.25 mg	0.3	± 0.68
BAF312 0.5 mg	1.5	± 3.92
BAF312 0.25 mg	1.0	± 1.54
Placebo	2.0	± 3.78

Number of All Gd-enhanced T1 Lesions - Period 1 Only at 6 Months Secondary · 6 months

The results for Month 4 through Month 6 inclusive includes patients from Period 1 only. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- e

Group	Value	95% CI
BAF312 10mg	0.3	± 0.77
BAF312 2 mg	0.6	± 1.37
BAF312 0.5 mg	1.1	± 3.78
Placebo	3.0	± 5.88

Number of Monthly New/Enlarging T2 Lesions - Period 1 +2 at 3 Months Secondary · 3 months

The results for Month 1 through Month 3 inclusive include patients from both Period 1 and Period 2. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly n

Group	Value	95% CI
BAF312 10mg	0.4	± 0.99
BAF312 2 mg (Period 1)	0.4	± 1.00
BAF312 1.25 mg	0.2	± 0.64
BAF312 0.5 mg	1.0	± 3.08
BAF312 0.25 mg	0.8	± 1.39
Placebo	1.5	± 3.17

Number of Monthly New/Enlarging T2 Lesions - Period 1 Only at 6 Months Secondary · 6 months

Month 4 through Month 6 inclusive include patients from Period 1 only. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions.

Group	Value	95% CI
BAF312 10mg	0.4	± 0.91
BAF312 2 mg	0.4	± 1.18
BAF312 0.5 mg	0.9	± 2.97
Placebo	2.1	± 3.66

Number of Patients Without Any New MRI Disease Activity - Period 1 +2 Secondary · 3 months

The proportion of patients who were free of new Gd-enhanced T1 lesions, and/or free of new or enlarging T2 lesions, i.e. free of new MRI activity (CUAL).

Group	Value	95% CI
BAF312 10mg	15
BAF312 2 mg	18
BAF312 1.25 mg	20
BAF312 0.5 mg	13
BAF312 0.25 mg	20
Placebo	11

Number of Patients Without Any New MRI Disease Activity - Period 1 Only Secondary · 6 months

The proportion of patients who were free of new Gd-enhanced T1 lesions, and/or free of new or enlarging T2 lesions, i.e. free of new MRI activity (CUAL).

Group	Value	95% CI
BAF312 10mg	12
BAF312 2 mg	16
BAF312 0.5 mg	11
Placebo	6

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 2.5 years.. Reporting threshold: 3%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

BAF312 10 mg

Serious: 3/50 (6%)

Deaths: 0/50

BAF312 2 mg

Serious: 4/49 (8%)

Deaths: 0/49

BAF312 1.25 mg

Serious: 2/42 (5%)

Deaths: 1/42

BAF312 0.5 mg

Serious: 8/43 (19%)

Deaths: 0/43

BAF312 0.25 mg

Serious: 0/51 (0%)

Deaths: 0/51

Placebo

Serious: 0/61 (0%)

Deaths: 0/61

Serious adverse events (15 terms)

Reaction	System	BAF312 10 mg	BAF312 2 mg	BAF312 1.25 mg	BAF312 0.5 mg	BAF312 0.25 mg	Placebo
Atrioventricular block second degree	Cardiac disorders	—	—	—	—	—	—
Bradycardia	Cardiac disorders	—	—	—	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—	—	—	—
Death	General disorders	—	—	—	—	—	—
Perineal abscess	Infections and infestations	—	—	—	—	—	—
Pyelonephritis acute	Infections and infestations	—	—	—	—	—	—
Intentional overdose	Injury, poisoning and procedural complications	—	—	—	—	—	—
Myopathy	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—
Benign intracranial hypertension	Nervous system disorders	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—
Multiple sclerosis relapse	Nervous system disorders	—	—	—	—	—	—
Optic neuritis	Nervous system disorders	—	—	—	—	—	—
Schizophreniform disorder	Psychiatric disorders	—	—	—	—	—	—

Other adverse events (69 terms — click to expand)

Reaction	System	BAF312 10 mg	BAF312 2 mg	BAF312 1.25 mg	BAF312 0.5 mg	BAF312 0.25 mg	Placebo
Headache	Nervous system disorders	—	—	—	—	—	—
Bradycardia	Cardiac disorders	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—
Vertigo	Ear and labyrinth disorders	—	—	—	—	—	—
Lymphopenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—	—
Sinusitis	Infections and infestations	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—
Lymphocyte count decreased	Investigations	—	—	—	—	—	—
Somnolence	Nervous system disorders	—	—	—	—	—	—
Atrioventricular block first degree	Cardiac disorders	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—
Toothache	Gastrointestinal disorders	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—
Chills	General disorders	—	—	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—	—	—
Oral herpes	Infections and infestations	—	—	—	—	—	—
Pharyngitis	Infections and infestations	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Melanocytic naevus	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—
Migraine	Nervous system disorders	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Atrioventricular block second degree	Cardiac disorders	—	—	—	—	—	—
Palpitations	Cardiac disorders	—	—	—	—	—	—
Sinus bradycardia	Cardiac disorders	—	—	—	—	—	—
Dry eye	Eye disorders	—	—	—	—	—	—
Eye pain	Eye disorders	—	—	—	—	—	—
Visual impairment	Eye disorders	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—
Abdominal pain lower	Gastrointestinal disorders	—	—	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—	—	—

Most-reported serious reactions: Atrioventricular block second degree, Bradycardia, Myocardial infarction, Death, Perineal abscess, Pyelonephritis acute, Intentional overdose, Myopathy.

Data from ClinicalTrials.gov NCT00879658 adverse events section.

Sponsor's own description

The purpose of this study was to determine the dose-response curve for the MRI-based efficacy of BAF312 compared with placebo in patients with Relapsing-Remitting Multiple Sclerosis (RRMS), and to characterize its safety and tolerability for the selection of an optimal dose in a later phase III study.

Study Design Rationale An adaptive design was chosen to characterize the dose response curve of BAF312. In a first period of study ("Period 1"), three doses of BAF312 and placebo were tested for MRI efficacy. Based on an interim analysis (IA) after 3 months of treatment, two additional active doses for period 2 wereselected , thus allowing to optimize the overall determination of the dose response curve with 5 data points of active treatment, and placebo. The doses were kept blinded. The use of Modeling and Simulation allowed to establish the full range and dynamics of the dose-response curve in silico, and hence the definition of the optimal dose for later phase III studies.

The choice of placebo as treatment control was essential to obtain information on the specific compared to non-specific effects of active treatment and provides the best way of evaluating the efficacy and of assessing the true safety and tolerability profile of BAF312. Short-term placebo exposure (6 (Period 1) or 3 (Period 2) months, respectively) was unlikely to lead to longer term differences in outcomes \[Polman, 2008\]. The use of an adaptive design strategy contributed to a significant reduction of placebo exposure, both in terms of the number of patients and duration, as compared to conventional trial models.

Patients having completed the study within the protocol might be eligible for the Extension Phase study where they receive long-term BAF312 treatment (a separate protocol).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond.
   Kunkel GT, Maceyka M, Milstien S, Spiegel S. · · 2013 · cited 377× · PMID 23954895 · DOI 10.1038/nrd4099
2. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study.
   Selmaj K, Li DK, Hartung HP, Hemmer B, et al · · 2013 · cited 175× · PMID 23764350 · DOI 10.1016/s1474-4422(13)70102-9
3. Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects.
   Chun J, Giovannoni G, Hunter SF. · · 2021 · cited 115× · PMID 33289881 · DOI 10.1007/s40265-020-01431-8
4. Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery.
   Park SJ, Im DS. · · 2017 · cited 103× · PMID 28035084 · DOI 10.4062/biomolther.2016.160
5. Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis.
   Chaudhry BZ, Cohen JA, Conway DS. · · 2017 · cited 99× · PMID 28812220 · DOI 10.1007/s13311-017-0565-4
6. Progressive multiple sclerosis: latest therapeutic developments and future directions.
   Faissner S, Gold R. · · 2019 · cited 57× · PMID 31598138 · DOI 10.1177/1756286419878323
7. The S1P-S1PR Axis in Neurological Disorders-Insights into Current and Future Therapeutic Perspectives.
   Lucaciu A, Brunkhorst R, Pfeilschifter JM, Pfeilschifter W, et al · · 2020 · cited 53× · PMID 32580348 · DOI 10.3390/cells9061515
8. Sphingosine 1-Phosphate Receptors: Do They Have a Therapeutic Potential in Cardiac Fibrosis?
   Vestri A, Pierucci F, Frati A, Monaco L, et al · · 2017 · cited 38× · PMID 28626422 · DOI 10.3389/fphar.2017.00296