Safety, Tolerability, Efficacy and Optimal Dose Finding Study of BAF312 in Patients With Relapsing-remitting Multiple Sclerosis
Safety, Tolerability, Efficacy and Optimal Dose Finding Study of BAF312 in Patients With Relapsing-remitting Multiple Sclerosis
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).
Key inclusion Criteria:

 -  Diagnosis of Multiple Sclerosis (MS) as defined by revised McDonald criteria.

 -  A relapsing-remitting course of disease with at least 1 documented relapse during the
 previous year, or 2 documented relapses during the previous 2 years, or a positive
 gadolinium (Gd)-enhanced MRI scan at screening (in case the first MRI scan obtained at
 screening is negative, a second scan may be obtained 1 month later.)

 -  An Expanded Disability Status Scale (EDSS) score of 0-5.0 inclusive at randomization.

 -  Neurologically stable with no evidence of relapse or corticosteroid treatment within
 30 days prior to randomization.

 -  Patients who decline initiation or continuation of treatment with available disease
 modifying drugs for MS, for whatever reason, after having been informed about their
 respective benefits and possible adverse events by the investigator.

 Key exclusion Criteria:

 -  A manifestation of another type of MS than RRMS

 -  History of chronic disease of the immune system other than MS

 -  Malignancies, diabetes, significant cardiovascular, pulmonary and hepatic diseases and
 conditions

 -  Active infections