Safety, Tolerability, Efficacy and Optimal Dose Finding Study of BAF312 in Patients With Relapsing-remitting Multiple Sclerosis
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).
Relapsing-remitting Multiple Sclerosis
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Phase II, Double-blind, Randomized, Multi-center, Adaptive Dose-ranging, Placebo-controlled, Parallel-group Study Evaluating Safety, Tolerability and Efficacy on MRI Lesion Parameters and Determining the Dose Response Curve of BAF312 Given Orally Once Daily in Patients With Relapsing-remitting Multiple Sclerosis.|
- Dose response relationship among five doses of BAF312 and placebo during 3 months of treatment in patients with Relapsing-Remitting Multiple Sclerosis (RRMS), as measured by the number of combined unique active [MRI] lesions (CUAL). [ Time Frame: 3 months ] [ Designated as safety issue: No ]
- 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 ]
|Study Start Date:||March 2009|
|Study Completion Date:||May 2011|
|Primary Completion Date:||May 2011 (Final data collection date for primary outcome measure)|
|Experimental: BAF312 10mg (period 1)||Drug: BAF312|
|Experimental: BAF312 2 mg (period 1)||Drug: BAF312|
|Experimental: BAF312 0.5 mg (period 1)||Drug: BAF312|
|Experimental: BAF312 dose between 0.1 to 8 mg period 2||Drug: BAF312|
|Experimental: BAF312 dose between 0.1 - 8 mg period 2||Drug: BAF312|
|Placebo Comparator: Placebo (period 1, 2)||Drug: Placebo|
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|Study Director:||Novartis Pharmaceuticals||Novartis Pharmaceuticals|