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

Relapsing-remitting Multiple Sclerosis Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00879658
• Other study ID #: CBAF312A2201
• Secondary ID: 2008-008719-25
• Status: Completed
• Phase: Phase 2
• Start date: March 30, 2009
• Est. completion date: May 4, 2011

Study information

• Verified date: December 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 297
• Est. completion date: May 4, 2011
• Est. primary completion date: May 4, 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Relapsing-remitting Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• BAF312

• Placebo

Locations

Country	Name	City	State
Canada	Novartis Investigative Site	Gatineau	Quebec
Canada	Novartis Investigative Site	Greenfield Park	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
Finland	Novartis Investigative Site	Helsinki
Finland	Novartis Investigative Site	Tampere
Finland	Novartis Investigative Site	Turku
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Freiburg
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Lengerich
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Muenster
Germany	Novartis Investigative Site	Wiesbaden
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Veszprem
Italy	Novartis Investigative Site	Chieti	CH
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Montichiari	BS
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Norway	Novartis Investigative Site	Bergen
Norway	Novartis Investigative Site	Drammen
Norway	Novartis Investigative Site	Oslo
Poland	Novartis Investigative Site	Lodz
Poland	Novartis Investigative Site	Lublin
Poland	Novartis Investigative Site	Warszawa
Russian Federation	Novartis Investigative Site	Kazan
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Bilbao	Pais Vasco
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Switzerland	Novartis Investigative Site	Basel
Switzerland	Novartis Investigative Site	Bern
Switzerland	Novartis Investigative Site	Lugano
Switzerland	Novartis Investigative Site	Zuerich
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Haseki / Istanbul
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Kocaeli
United States	Novartis Investigative Site	Akron	Ohio
United States	Novartis Investigative Site	Centennial	Colorado
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Cullman	Alabama
United States	Novartis Investigative Site	Elk Grove Village	Illinois
United States	Novartis Investigative Site	Grand Rapids	Michigan
United States	Novartis Investigative Site	Greenville	South Carolina
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Milwaukee	Wisconsin
United States	Novartis Investigative Site	Pittsburgh	Pennsylvania
United States	Novartis Investigative Site	Pompano Beach	Florida
United States	Novartis Investigative Site	Raleigh	North Carolina
United States	Novartis Investigative Site	San Francisco	California
United States	Novartis Investigative Site	Seattle	Washington
United States	Novartis Investigative Site	Tallahassee	Florida
United States	Novartis Investigative Site	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  Finland,  Germany,  Hungary,  Italy,  Norway,  Poland,  Russian Federation,  Spain,  Switzerland,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Geometric Mean BAF312 Plasma Trough Concentrations	Geometric mean BAF312 plasma concentrations by treatment and by visit	Month 1, Month 3, Month 6