Mechanistic Studies of Phase III Trial With BAF312 in Secondary Progressive Multiple Sclerosis

Mechanistic Studies of Phase III Trial With BAF312 in Secondary Progressive Multiple Sclerosis (AMS04)

The primary goal of this study is to evaluate the effects of BAF312 (siponimod) on select immune and neuronal (nerve) cells by examining laboratory specimens (blood and/or spinal fluid) at multiple time points, prior to, and following the initiation of BAF312 or placebo treatment, in patients with Secondary Progressive Multiple Sclerosis (SPMS) who are enrolled in a clinical trial (NCT01665144) to evaluate the effectiveness and safety of BAF312.

Study Overview

• Status: Completed
• Conditions: Secondary Progressive Multiple Sclerosis
• Intervention / Treatment: Procedure: Blood Draw; Procedure: CSF collection by lumbar puncture (Optional)

Detailed Description

This study is complementary to a multi-center, randomized, double-blind,parallel-group, placebo-controlled, variable treatment duration study comparing the efficacy and safety of BAF312 to placebo in patients with SPMS (NCT01665144). Investigators will explore both immunological and neuroprotective mechanisms of BAF312 (siponimod), a novel agent in the setting of a SPMS clinical trial.

This study is part of a multi-center study, with the University of Michigan serving as the central site.

• Study Type: Observational
• Enrollment (Actual): 36

Contacts and Locations

Study Locations

• United States
  • California
    • Berkeley, California, United States, 94705
      • Jordan Research & Education Institute: Sutter Alta Bates Summit
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Sacramento, California, United States, 95817
      • University of California, Davis
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System -Multiple Sclerosis Center
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Golden Valley, Minnesota, United States, 55422
      • Minneapolis Clinic of Neurology
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico: Health Sciences Center
  • New York
    • Patchogue, New York, United States, 11772
      • South Shore Neurologic Associates - Multiple Sclerosis Care Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Carolinas Medical Center (CMC)
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic: Mellen Center for Multiple Sclerosis
  • Oregon
    • Portland, Oregon, United States, 97225
      • Providence Multiple Sclerosis Center
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Neuroscience Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 56 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Ambulatory participants with Secondary Progressive Multiple Sclerosis (SPMS) enrolled in the EXPAND trial (BAF312 treated and placebo [control] participants) may be enrolled in this study after the EXPAND baseline visit has occurred provided that the subject has not passed the Month 12 time point.

-Refer to ClinicalTrials.gov record NCT01665144.

Description

Inclusion Criteria:

• Participants enrolled in the multicenter, randomized, double-blind, parallel-group, placebo-controlled, variable treatment duration study comparing the efficacy and safety of BAF312 to placebo in patients with Secondary Progressive Multiple Sclerosis (SPMS) Protocol No. CBAF312A2304 (sponsored by Novartis). Refer to ClinicalTrials.gov record NCT01665144.
• Subjects enrolled at one of the participating AMS04 study sites located in the United States.
• Subject must be able to provide written informed consent.

Exclusion Criteria:

• Subjects with severe bleeding disorders, platelet count less than (<)50,000/microliters (μL), and/or who are currently on full anticoagulant therapy will be excluded from the optional CSF collections.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Subjects Assigned to BAF312; Patients with secondary progressive multiple sclerosis (SPMS) randomized to receive BAF312 (siponimod). Refer to ClinicalTrials.gov record NCT01665144 for more information.	Procedure: Blood Draw; Blood draws (65 mLs [~4 tablespoons] per blood draw) at 4 time points: Prior to study medication initiation, and at +6, +12 and+24 months post treatment initiation.; Other Names: Phlebotomy; Venipuncture; Procedure: CSF collection by lumbar puncture (Optional); For participants who volunteer to donate CSF samples: up to 25 mLs (<2 tablespoons): prior to study medication initiation, and at month 24 post treatment initiation.; Other Names: CSF by LP; cerebrospinal fluid collected by lumbar puncture
Subjects Assigned to Placebo (Controls); Patients with secondary progressive multiple sclerosis (SPMS) randomized to receive placebo. Refer to ClinicalTrials.gov record NCT01665144 for more information.	Procedure: Blood Draw; Blood draws (65 mLs [~4 tablespoons] per blood draw) at 4 time points: Prior to study medication initiation, and at +6, +12 and+24 months post treatment initiation.; Other Names: Phlebotomy; Venipuncture; Procedure: CSF collection by lumbar puncture (Optional); For participants who volunteer to donate CSF samples: up to 25 mLs (<2 tablespoons): prior to study medication initiation, and at month 24 post treatment initiation.; Other Names: CSF by LP; cerebrospinal fluid collected by lumbar puncture

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in frequency of MBP-reactive Th17 cells	Evaluation (BAF312 versus placebo) of dominant cytokines produced by myelin basic protein (MBP)-stimulated peripheral blood mononuclear cells (PBMCs), measured by ELISpot.	From baseline to the follow-up time points (Open label phase + 6 months and OLP +12 months).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in frequency of polyclonal CD4+ Th17, Th1, Th2, and Treg cells	Compare BAF312 and Placebo (Control) Groups	From baseline to the follow-up time points (Open label phase + 6 months and OLP +12 months).
Change in chemokine and cytokines levels	Compare BAF312 and Placebo (Control) Groups	From baseline to the follow-up time points (Open label phase + 6 months and OLP +12 months).
Change in Regulatory B Cells	Compare BAF312 and Placebo (Control) Groups	From baseline to the follow-up time points (Open label phase + 6 months and OLP +12 months).
Changes of clinical status and lymphocyte subgroups	Compare BAF312 and Placebo (Control) Groups	From baseline to the follow-up time points (Open label phase + 6 months and OLP +12 months).

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Novartis Pharmaceuticals; Autoimmunity Centers of Excellence
• Investigators: Study Chair: Yang Mao-Draayer, MD, PhD, Multiple Sclerosis Center - University of Michigan Health System; Study Chair: David Fox, MD, Division of Rheumatology - University of Michigan Health System

Publications and helpful links

General Publications

• Wu Q, Mills EA, Wang Q, Dowling CA, Fisher C, Kirch B, Lundy SK, Fox DA, Mao-Draayer Y; AMS04 Study Group. Siponimod enriches regulatory T and B lymphocytes in secondary progressive multiple sclerosis. JCI Insight. 2020 Feb 13;5(3):e134251. doi: 10.1172/jci.insight.134251.

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Autoimmunity Centers of Excellence (ACE)
• Relevant Clinical Trials.gov Record: NCT01665144

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Actual): July 12, 2017
• Study Completion (Actual): July 12, 2017

Study Registration Dates

• First Submitted: December 31, 2014
• First Submitted That Met QC Criteria: December 31, 2014
• First Posted (Estimate): January 5, 2015

Study Record Updates

• Last Update Posted (Actual): November 9, 2020
• Last Update Submitted That Met QC Criteria: November 5, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: clinical research; autoimmunity; blood draw; mechanistic studies; cerebrospinal fluid (CSF) by lumbar puncture (optional)
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Neoplastic Processes; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Neoplasm Metastasis
• Other Study ID Numbers: DAIT AMS04

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No