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

NCT00879658 | Completed Phase 2 Results

• 2 other identifiers: CBAF312A22012008-008719-25
• Study Type: interventional
• Target: 297
• Locations: 12 countries
• Sites: 72

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).

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (15)

• Number of Confirmed Relapses - Period 1

  6 months

• Proportion of Participants With Relapse-free Patients - Period 1 + 2

  3 month

• Proportion of Participants With Relapse-free Patients - Period 1 Only

  6 months

• Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3

  3 months

• Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 Only at 6 Months

  6 months

Study Arms (6)

BAF312 10mg (period 1)

EXPERIMENTAL

Drug: BAF312

BAF312 2 mg (period 1)

EXPERIMENTAL

Drug: BAF312

BAF312 0.5 mg (period 1)

EXPERIMENTAL

Drug: BAF312

BAF312 dose between 0.1 to 8 mg period 2

EXPERIMENTAL

Drug: BAF312

BAF312 dose between 0.1 - 8 mg period 2

EXPERIMENTAL

Drug: BAF312

Placebo (period 1, 2)

PLACEBO COMPARATOR

Drug: Placebo

Interventions

BAF312 DRUG

BAF312 0.5 mg (period 1); BAF312 10mg (period 1); BAF312 2 mg (period 1); BAF312 dose between 0.1 - 8 mg period 2; BAF312 dose between 0.1 to 8 mg period 2

Placebo DRUG

Placebo (period 1, 2)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (72)

Novartis Investigative Site

Cullman, Alabama, 35058, United States

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San Francisco, California, 94143, United States

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Centennial, Colorado, 80112, United States

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Miami, Florida, 33136, United States

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Pompano Beach, Florida, 33060, United States

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Tallahassee, Florida, 32308, United States

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Tampa, Florida, 33609, United States

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Chicago, Illinois, 60637, United States

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Elk Grove Village, Illinois, 60007, United States

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Grand Rapids, Michigan, 49525, United States

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Raleigh, North Carolina, 27607, United States

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Akron, Ohio, 44320, United States

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Pittsburgh, Pennsylvania, 15213, United States

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Greenville, South Carolina, 29607, United States

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Seattle, Washington, 98122, United States

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Milwaukee, Wisconsin, 53215, United States

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Vancouver, British Columbia, V6T 1Z3, Canada

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Ottawa, Ontario, K1H 8L6, Canada

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Gatineau, Quebec, J9J 0A5, Canada

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Greenfield Park, Quebec, J4V 2J2, Canada

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Montreal, Quebec, H3A 2B4, Canada

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Helsinki, 00930, Finland

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Tampere, FIN-33520, Finland

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Turku, 20520, Finland

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Novartis Investigative Site

Berlin, 10713, Germany

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Berlin, 13439, Germany

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Dresden, 01307, Germany

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Freiburg im Breisgau, 79106, Germany

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Leipzig, 04103, Germany

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Lengerich, 49525, Germany

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München, 81675, Germany

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Novartis Investigative Site

Münster, 48149, Germany

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Novartis Investigative Site

Wiesbaden, 65191, Germany

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Novartis Investigative Site

Budapest, 1076, Hungary

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Novartis Investigative Site

Budapest, 1145, Hungary

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Novartis Investigative Site

Debrecen, 4032, Hungary

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Novartis Investigative Site

Veszprém, H-8200, Hungary

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Novartis Investigative Site

Montichiari, BS, 25018, Italy

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Novartis Investigative Site

Chieti, CH, 66100, Italy

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Novartis Investigative Site

Milan, MI, 20132, Italy

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Novartis Investigative Site

Roma, RM, 00133, Italy

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Novartis Investigative Site

Roma, RM, 00152, Italy

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Novartis Investigative Site

Roma, RM, 00189, Italy

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Novartis Investigative Site

Bergen, 5021, Norway

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Novartis Investigative Site

Drammen, 3004, Norway

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Oslo, 0424, Norway

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Novartis Investigative Site

Lodz, 90-153, Poland

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Lublin, 20-954, Poland

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Novartis Investigative Site

Warsaw, 02-957, Poland

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Novartis Investigative Site

Kazan', 420103, Russia

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Novartis Investigative Site

Moscow, 101990, Russia

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Novartis Investigative Site

Moscow, 119049, Russia

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Novartis Investigative Site

Moscow, 121359, Russia

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Novartis Investigative Site

Moscow, 125367, Russia

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Novartis Investigative Site

Moscow, 127018, Russia

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Novartis Investigative Site

Moscow, 129110, Russia

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Novartis Investigative Site

Saint Petersburg, 190013, Russia

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Novartis Investigative Site

Saint Petersburg, 197022, Russia

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Novartis Investigative Site

Seville, Andalusia, 41009, Spain

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Bilbao, Basque Country, 48013, Spain

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Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

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Novartis Investigative Site

Valencia, Valencia, 46026, Spain

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Novartis Investigative Site

Madrid, 28040, Spain

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Novartis Investigative Site

Basel, 4031, Switzerland

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Bern, 3010, Switzerland

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Lugano, 6900, Switzerland

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Zurich, 8091, Switzerland

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Novartis Investigative Site

Ankara, 06100, Turkey (Türkiye)

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Novartis Investigative Site

Haseki / Istanbul, 34096, Turkey (Türkiye)

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Novartis Investigative Site

Istanbul, 34093, Turkey (Türkiye)

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Novartis Investigative Site

Izmir, 35340, Turkey (Türkiye)

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Novartis Investigative Site

Kocaeli, 41380, Turkey (Türkiye)

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Related Publications (2)

• 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.

  PMID: 26083135 DERIVED

• 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.

  PMID: 23764350 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis; Demyelinating Diseases; Neuromyelitis Optica; Diffuse Cerebral Sclerosis of Schilder

Interventions

siponimod

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Myelitis, Transverse; Optic Neuritis; Optic Nerve Diseases; Cranial Nerve Diseases; Eye Diseases; Brain Diseases; Central Nervous System Diseases; Leukoencephalopathies

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 9, 2009
• First Posted: April 10, 2009
• Study Start: March 30, 2009
• Primary Completion: May 4, 2011
• Study Completion: May 4, 2011
• Last Updated: January 13, 2020
• Results First Posted: January 13, 2020

Record last verified: 2019-12

Locations

PL (3); FI (3); DE (9); RU (9); CA (5); ES (5); CH (4); TU (5); NO (3); US (16); HU (4); IT (6)