Clinical trial NCT00879658: Safety, Tolerability, Efficacy and Optimal Dose Finding Study of BAF312 in Patients With Relapsing-remitting Multiple Sclerosis
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Relapsing-remitting Multiple Sclerosis
Keywords: 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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-04-10
Enrollment: 297
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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

Primary outcomes:
measure: Dose Responsiveness of BAF312 Based on the Number of Combined Unique Active MRI Lesions (CUAL)
timeFrame: 3 months of treatment
Secondary outcomes:
measure: Number of Confirmed Relapses - Period 1
timeFrame: 6 months
measure: Proportion of Participants With Relapse-free Patients - Period 1 + 2
timeFrame: 3 month
measure: Proportion of Participants With Relapse-free Patients - Period 1 Only
timeFrame: 6 months
measure: Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3
timeFrame: 3 months
measure: Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 Only at 6 Months
timeFrame: 6 months
measure: Number of All New Gd-enhanced T1 Lesions - Period 1 +2 at Month 3
timeFrame: 3 months
measure: Number of All Gd-enhanced T1 Lesions - Period 1 Only at 6 Months
timeFrame: 6 months
measure: Number of Monthly New/Enlarging T2 Lesions - Period 1 +2 at 3 Months
timeFrame: 3 months
measure: Number of Monthly New/Enlarging T2 Lesions - Period 1 Only at 6 Months
timeFrame: 6 months
measure: Number of Patients Without Any New MRI Disease Activity - Period 1 +2
timeFrame: 3 months
measure: Number of Patients Without Any New MRI Disease Activity - Period 1 Only
timeFrame: 6 months
measure: Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 +2 at 3 Months
timeFrame: 3 months
measure: Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 Only at 6 Months
timeFrame: 6 months
measure: Number of CUAL - Period 1
timeFrame: 6 months
measure: Geometric Mean BAF312 Plasma Trough Concentrations
timeFrame: Month 1, Month 3, Month 6
Other outcomes:
Locations:
city: Cullman
country: United States
facility: Novartis Investigative Site
state: Alabama
city: San Francisco
country: United States
facility: Novartis Investigative Site
state: California
city: Centennial
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Pompano Beach
country: United States
facility: Novartis Investigative Site
state: Florida
city: Tallahassee
country: United States
facility: Novartis Investigative Site
state: Florida
city: Tampa
country: United States
facility: Novartis Investigative Site
state: Florida
city: Chicago
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Elk Grove Village
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Grand Rapids
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Raleigh
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Akron
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Pittsburgh
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Greenville
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Milwaukee
country: United States
facility: Novartis Investigative Site
state: Wisconsin
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Ottawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Gatineau
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Greenfield Park
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Helsinki
country: Finland
facility: Novartis Investigative Site
city: Tampere
country: Finland
facility: Novartis Investigative Site
city: Turku
country: Finland
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Lengerich
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Muenster
country: Germany
facility: Novartis Investigative Site
city: Wiesbaden
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Veszprem
country: Hungary
facility: Novartis Investigative Site
city: Montichiari
country: Italy
facility: Novartis Investigative Site
state: BS
city: Chieti
country: Italy
facility: Novartis Investigative Site
state: CH
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Bergen
country: Norway
facility: Novartis Investigative Site
city: Drammen
country: Norway
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Lodz
country: Poland
facility: Novartis Investigative Site
city: Lublin
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Bilbao
country: Spain
facility: Novartis Investigative Site
state: Pais Vasco
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Basel
country: Switzerland
facility: Novartis Investigative Site
city: Bern
country: Switzerland
facility: Novartis Investigative Site
city: Lugano
country: Switzerland
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Haseki / Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Kocaeli
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Mercier F, Bornkamp B, Ohlssen D, Wallstroem E. Characterization of dose-response for count data using a generalized MCP-Mod approach in an adaptive dose-ranging trial. Pharm Stat. 2015 Jul-Aug;14(4):359-67. doi: 10.1002/pst.1693. Epub 2015 Jun 17.
citation: Selmaj K, Li DK, Hartung HP, Hemmer B, Kappos L, Freedman MS, Stuve O, Rieckmann P, Montalban X, Ziemssen T, Auberson LZ, Pohlmann H, Mercier F, Dahlke F, Wallstrom E. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013 Aug;12(8):756-67. doi: 10.1016/S1474-4422(13)70102-9. Epub 2013 Jun 11.