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

• Safety and tolerability of BAF312 during 6 months and 3 months of treatment in MS patients [ Time Frame: 6 months, 3 months ] [ Designated as safety issue: Yes ]
• To explore the effect of BAF312 on the number of relapses and thereof derived measures (e.g. annualized relapse rate (ARR), proportion of relapse-free patients) [ Time Frame: 6 months, 3 months ] [ Designated as safety issue: No ]
• To explore the correlation of the course of the lymphocyte count with paraclinical measures (MRI activity) and with clinical course. [ Time Frame: 6 months, 3 months ] [ Designated as safety issue: No ]
• To determine the effect of BAF312 after 3 months and 6 months treatment on additional MRI parameters [ Time Frame: 6 months, 3 months ] [ Designated as safety issue: No ]
• To determine the steady state plasma concentrations of BAF312 in RRMS patients [ Time Frame: Month 1, Month 3, Month 6 ] [ Designated as safety issue: No ]

• Safety and tolerability (including blood pressure effects) of BAF312 during 6 months and 3 months of treatment in MS patients. [ Time Frame: 6 months, 3 months ] [ Designated as safety issue: Yes ]
• To explore the effect of BAF312 on the number of relapses and thereof derived measures (e.g. annualized relapse rate (ARR), proportion of relapse-free patients) [ Time Frame: 6 months, 3 months ] [ Designated as safety issue: No ]
• To explore the correlation of the course of the lymphocyte count with paraclinical (MRI activity) and clinical course. [ Time Frame: 6 months, 3 months ] [ Designated as safety issue: No ]
• To determine the effect of BAF312 at 6 and 3 months treatment on additional MRI parameters. [ Time Frame: 6 months, 3 months ] [ Designated as safety issue: No ]
• To determine the steady state plasma concentrations of BAF312 in RRMS patients [ Time Frame: Month 1, Month 3, Month 6 ] [ Designated as safety issue: No ]

The purpose of this study is 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 are tested for MRI efficacy. Based on an interim analysis (IA) after 3 months of treatment, two additional active doses for period 2 have been selected , thus allowing to optimize the overall determination of the dose response curve with 5 data points of active treatment, and placebo. The doses are kept blinded. The use of Modeling and Simulation allows 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 is 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) is unlikely to lead to longer term differences in outcomes [Polman, 2008]. The use of an adaptive design strategy contributes 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 may be eligible for the Extension Phase study where they receive long-term BAF312 treatment (a separate protocol).

• Drug: BAF312
• Drug: Placebo

• Experimental: BAF312 10mg (period 1)
  Intervention: Drug: BAF312
• Experimental: BAF312 2 mg (period 1)
  Intervention: Drug: BAF312
• Experimental: BAF312 0.5 mg (period 1)
  Intervention: Drug: BAF312
• Experimental: BAF312 dose between 0.1 to 8 mg period 2
  Intervention: Drug: BAF312
• Experimental: BAF312 dose between 0.1 - 8 mg period 2
  Intervention: Drug: BAF312
• Placebo Comparator: Placebo (period 1, 2)
  Intervention: Drug: Placebo

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.

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

Other protocol-defined inclusion/exclusion criteria may apply