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

Study Overview
=================
Brief Summary
-----------------
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).

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.

Conditions
-----------------
Relapsing-remitting Multiple Sclerosis

Intervention / Treatment
-----------------
* Drug: BAF312
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAF312 10mg (period 1)<br> | Drug: BAF312<br> <br> |
| Experimental: BAF312 2 mg (period 1)<br> | Drug: BAF312<br> <br> |
| Experimental: BAF312 0.5 mg (period 1)<br> | Drug: BAF312<br> <br> |
| Experimental: BAF312 dose between 0.1 to 8 mg period 2<br> | Drug: BAF312<br> <br> |
| Experimental: BAF312 dose between 0.1 - 8 mg period 2<br> | Drug: BAF312<br> <br> |
| Placebo Comparator: Placebo (period 1, 2)<br> | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Responsiveness of BAF312 Based on the Number of Combined Unique Active MRI Lesions (CUAL) | 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. | 3 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Confirmed Relapses - Period 1 | 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). | 6 months | 
| Proportion of Participants With Relapse-free Patients - Period 1 + 2 | To explore the effect of BAF312 on the proportion of relapse-free patients (confirmed relapses only) | 3 month | 
| Proportion of Participants With Relapse-free Patients - Period 1 Only | To explore the effect of BAF312 on the proportion of relapse-free patients (confirmed relapses only) | 6 months | 
| Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3 | 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 [Gd]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. | 3 months | 
| Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 Only at 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 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. | 6 months | 
| Number of All New Gd-enhanced T1 Lesions - Period 1 +2 at Month 3 | 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]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. | 3 months | 
| Number of All Gd-enhanced T1 Lesions - Period 1 Only at 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]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. | 6 months | 
| Number of Monthly New/Enlarging T2 Lesions - Period 1 +2 at 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 new [Gd]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. | 3 months | 
| Number of Monthly New/Enlarging T2 Lesions - Period 1 Only at 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. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. | 6 months | 
| Number of Patients Without Any New MRI Disease Activity - Period 1 +2 | 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). | 3 months | 
| Number of Patients Without Any New MRI Disease Activity - Period 1 Only | 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). | 6 months | 
| Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 +2 at 3 Months | In patients with high baseline disease activity, the relative reduction in new Gd-enhanced T1 lesions compared to placebo at Month 3. High baseline disease activity is defined as >=2 Gd-enhanced T1 lesions at baseline. The number of lesions of each type was available as such 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 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. | 3 months | 
| Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 Only at 6 Months | In patients with high baseline disease activity, the relative reduction in new Gd-enhanced T1 lesions compared to placebo at Month 6. High baseline disease activity is defined as >=2 Gd-enhanced T1 lesions at baseline. 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 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. | 6 months | 
| Number of CUAL - Period 1 | Combined unique active lesions (CUAL) are defined as new Gd-enhanced T1 lesions or new or enlarging T2 lesions, withput double counting of lesions at any specific point in time. | 6 months | 
| Geometric Mean BAF312 Plasma Trough Concentrations | Geometric mean BAF312 plasma concentrations by treatment and by visit | Month 1, Month 3, Month 6 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Multiple Sclerosis (MS), Relapsing-Remitting, Demyelinating Autoimmune Diseases, Disseminated sclerosis, Encephalomyelitis disseminate, Inflammatory disease, Demyelination, Auto-inflammatory disease, Devic's disease, Balo concentric sclerosis, Schilder's diffuse sclerosis