Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (MS)CombiRx

March 6, 2014 updated by: Fred Lublin

A Multi-Center, Double-Blind, Randomized Study Comparing the Combined Use of Interferon Beta-1a and Glatiramer Acetate to Either Agent Alone in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx)

This is for a randomized clinical trial (RCT) to determine if the combined use of interferon beta-1a (IFN) and glatiramer acetate (GA) is a measurably better therapy than either agent used individually in patients with relapsing-remitting (RR) multiple sclerosis (MS).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is a multicenter, double blind, randomized trial examining combination therapy versus single agent therapy with three-year follow-up on the last patient randomized. All patients will remain on therapy until the last patient completes the study. All patients will then be transitioned, based on the findings, to open label of combination with continued follow-up or some recommendation about single agent therapy. While the study design benefits from having two arms of single agent therapy to examine the important question of whether there are differences between the single agents, the primary interest is in combination therapy. Therefore, a two-group combination versus single agent concept was used - splitting the population into single agent and combination therapy equally. The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN intramuscularly (IM) and GA subcutaneously (SC) (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).

Study Type

Interventional

Enrollment (Actual)

1008

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Alberta
      • Calgary, Alberta, Canada
        • Foothills Medical Centre
      • Edmonton, Alberta, Canada
        • Capital Health and the University of Alberta
    • Ontario
      • Ottawa, Ontario, Canada
        • Ottawa Hospital
      • Toronto, Ontario, Canada
        • St. Michael's Hospital-Multiple Sclerosis Research Center
  • United States
    • Alabama
      • Birmingham, Alabama, United States
        • University of Alabama - Birmingham
    • Arizona
      • Phoenix, Arizona, United States
        • Barrow Neurology Clinic
      • Scottsdale, Arizona, United States
        • Mayo Clinic - Scottsdale
      • Tucson, Arizona, United States, 85741
        • Northwest Neurospecialists PLLC
    • California
      • Berkeley, California, United States
        • Sutter East Bay Medical Group
      • La Habra, California, United States
        • Neurology Center North Orange County
      • Los Angeles, California, United States
        • VA West Los Angeles Healthcare Center
      • Sacramento, California, United States, 95817
        • University of California - Davis Medical Center
    • Colorado
      • Boulder, Colorado, United States
        • Alpine Clinical Research Center
      • Colorado Springs, Colorado, United States
        • Patricia Fodor P.C.
      • Denver, Colorado, United States
        • University of Colorado Health Sciences Center
    • Connecticut
      • New Haven, Connecticut, United States
        • Yale University School of Medicine
    • Florida
      • Maitland, Florida, United States
        • Neurology Associates, PA
      • Miami, Florida, United States, 33124
        • University of Miami - Neurology
    • Georgia
      • Atlanta, Georgia, United States
        • MS Center of Atlanta
      • Atlanta, Georgia, United States
        • Shepherd Center
    • Illinois
      • Chicago, Illinois, United States
        • Northwest University
      • Northbrook, Illinois, United States
        • Consultants in Neurology - Multiple Sclerosis Center
      • Peoria, Illinois, United States
        • University of Illinois College of Medicine
    • Iowa
      • Des Moines, Iowa, United States
        • Ruan Neurology Clinic and Research Center
    • Kansas
      • Kansas City, Kansas, United States
        • University of Kansas Medical Center
    • Maryland
      • Baltimore, Maryland, United States
        • Maryland Center for MS
    • Massachusetts
      • Boston, Massachusetts, United States
        • Tufts-New England Medical Center
      • Boston, Massachusetts, United States
        • University of Massachusetts Memorial Medical Center
      • Burlington, Massachusetts, United States
        • Lahey Clinic
    • Michigan
      • Detroit, Michigan, United States
        • Wayne State University
      • East Lansing, Michigan, United States
        • Michigan State University
    • Minnesota
      • Golden Valley, Minnesota, United States
        • Minneapolis Clinic - MS Center
      • Rochester, Minnesota, United States
        • Mayo Clinic - Rochester
    • Missouri
      • St. Louis, Missouri, United States
        • Washington University School of Medicine
      • St. Louis, Missouri, United States
        • St. Louis University - St. Louis VA
    • Montana
      • Billings, Montana, United States
        • Northern Rockies MS Center
    • New Hampshire
      • Lebanon, New Hampshire, United States
        • Dartmouth Medical School
    • New Jersey
      • Freehold, New Jersey, United States
        • CentraState Medical Center
    • New Mexico
      • Albuquerque, New Mexico, United States
        • University of New Mexico
    • New York
      • Albany, New York, United States
        • Albany Medical College
      • Albany, New York, United States, 12208
        • Neuro Associates of Albany, PC
      • Buffalo, New York, United States
        • The Jacobs Neurological Institute
      • Mineola, New York, United States
        • Winthrop Neurology Faculty Practice
      • New York, New York, United States, 10032
        • Columbia University Medical Center
      • New York, New York, United States, 10029
        • Icahn School of Medicine at Mount Sinai
      • New York, New York, United States
        • NYU Hospital for Joint Diseases
      • Patchogue, New York, United States
        • South Shore Neurologic Associates Inc.
      • Rochester, New York, United States
        • University of Rochester
      • Syracuse, New York, United States
        • SUNY Upstate Medical University
    • North Carolina
      • Charlotte, North Carolina, United States
        • CMC-Neuroscience & Spine Institute, Division of Neurology, MS Center
    • North Dakota
      • Fargo, North Dakota, United States
        • Meritcare Neuroscience
    • Ohio
      • Canton, Ohio, United States
        • NeuroCare Center, Inc.
      • Cleveland, Ohio, United States
        • Cleveland Clinic
      • Columbus, Ohio, United States
        • Ohio State University
      • Dayton, Ohio, United States, 45415
        • Neurology Specialists
      • Toledo, Ohio, United States
        • Medical College of Ohio
      • Uniontown, Ohio, United States
        • Oak Clinic for Multiple Sclerosis
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States
        • University of Pennsylvania
      • Pittsburgh, Pennsylvania, United States
        • Allegheny MS Treatment Center
    • Tennessee
      • Nashville, Tennessee, United States
        • Vanderbilt University Medical Center
    • Texas
      • Houston, Texas, United States
        • Baylor College of Medicine
      • Houston, Texas, United States
        • University of Texas - Houston
    • Utah
      • Salt Lake City, Utah, United States
        • University of Utah
    • Vermont
      • Bennington, Vermont, United States
        • Neurological Research Center, Inc.
      • Burlington, Vermont, United States
        • Fletcher Allen Health Care
    • Virginia
      • Richmond, Virginia, United States
        • Virginia Commonwealth University
      • Richmond, Virginia, United States
        • Neurological Associates, Inc.
    • Washington
      • Seattle, Washington, United States
        • Virginia Mason Medical Center
      • Seattle, Washington, United States
        • MS Center at Evergreen
    • Wisconsin
      • Marshfield, Wisconsin, United States
        • Marshfield Clinic
      • Milwaukee, Wisconsin, United States
        • Regional MS Center at St. Luke's Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Male and female subjects between the ages of 18 and 60 years, inclusive.
  • Diagnosis of relapsing-remitting MS by either the Poser or McDonald criteria.
  • Expanded Disability Status Scale (EDSS) score between 0 and 5.5, inclusive.
  • At least 2 exacerbations in the prior three years; one exacerbation may utilize the McDonald MRI criteria for dissemination in time (a new gadolinium [Gd]-enhancing lesion demonstrated on a scan done at least 3 months following onset of a clinical attack or a new T2 lesion or Gd-enhancing lesion on a follow-up scan after an additional 3 months).
  • Give written informed consent prior to any testing under this protocol, including screening tests and evaluations that are not considered part of the subject's routine care.

Exclusion Criteria:

  • Any prior use of interferon beta or glatiramer acetate.
  • Acute exacerbation within 30 days of screening.
  • Steroids for acute exacerbations (>100 mg/day) within 30 days of study entrance or chronic systemic steroid use.
  • Evidence of progressive MS.
  • Use IVIg, azathioprine, methotrexate, cyclosporine, mitoxantrone, cyclophosphamide, mycophenolate (CellCept) or plasma exchange in the twelve weeks prior to study drug dosing.
  • Any previous treatment with natalizumab (Tysabri, Antegren), cladribine, T cell vaccine, Campath, daclizumab, rituximab, altered peptide ligand or total lymphoid irradiation.
  • Treatment with 4 aminopyridines in the four weeks prior to study drug dosing.
  • Prior treatment with any other investigational drug, unless approved by the Clinical Coordinating Center (Dr. Lublin).
  • Inability to perform the baseline MSFC (timed 25-foot walk, 9-hole peg test [9HPT], and Paced Auditory Serial Addition Test 3 [PASAT3]).
  • Inability to undergo baseline MRI scan.
  • History of any significant cardiac, hepatic, pulmonary, or renal disease, immune deficiency, or other medical conditions that would preclude therapy with interferon beta, glatiramer acetate, or participation in this study.
  • Known history of sensitivity to gadopentetate dimeglumine or mannitol.
  • History of a seizure within the 3 months prior to randomization.
  • History of suicidal ideation or an episode of severe depression within the 3 months prior to randomization.

  • Abnormal screening blood tests exceeding any of the limits defined below:

    • Alanine transaminase (ALT) or aspartate transaminase (AST) greater than two times the upper limit of normal (i.e., >2 × ULN)
    • Total white blood cell count <2,300/mm3
    • Platelet count <80,000/mm3
    • Creatinine >2 × ULN
  • Participation in another experimental clinical trial, without formal approval.
  • History of alcohol or drug abuse within the 2 years prior to randomization.
  • Female subjects who are currently pregnant, breast-feeding, or plan to become pregnant.
  • For female subjects, unless postmenopausal or surgically sterile, unwillingness to practice effective contraception, as defined by the investigator, during the study. The rhythm method is not to be used as the sole method of contraception.
  • Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition that is likely to affect the subject's returning for scheduled follow-up visits on schedule (any physical, mental, or social condition).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Interferon beta 1-a

Active Interferon B1a Weekly vs. Placebo Glatiramer Acetate

Interferon b-1a (IFN) intramuscularly weekly
Other: placebo
an inactive substance
Drug: Interferon beta 1-a
The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN IM and GA SC (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).
Other Names:
  • IFN
Active Comparator: glatiramer acetate

Placebo Interferon B1a Weekly vs. Active Glatiramer Acetate

Glatiramer acetate 20mg daily
Other: placebo
an inactive substance
Drug: glatiramer acetate
The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN IM and GA SC (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).
Other Names:
  • GA
Active Comparator: IFN and GA
Active Interferon B1a Weekly and Active Glatiramer Acetate
Drug: Interferon beta 1-a
The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN IM and GA SC (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).
Other Names:
  • IFN
Drug: glatiramer acetate
The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN IM and GA SC (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).
Other Names:
  • GA

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
ARR - PDEs
Time Frame: Baseline to Month 36
Annualized relapse rate of protocol-defined exacerbations Protocol defined relapse - an relapse seen within 7 days of onset, verified by the treating physician and independently observed as a change in EDSS by the examining physician. This relapse is defined as: the appearance of a new symptom or worsening of an old symptom, attributable to MS; accompanied by a change in the neurologic examination (defined as a 0.5 or greater increase in the EDSS over the last scheduled or unscheduled visit or a 2 point change in one functional system or a 1 point change in two functional systems, except bladder and cognitive changes); lasting at least 24 hours in the absence of fever; and preceded by stability or improvement for at least 30 days.
Baseline to Month 36

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Confirmed Progression on the Expanded Disability Status Scale
Time Frame: Baseline to Month 36

% with EDSS progression

Confirmed progression in a participant was defined as a 1.0 increase in the EDSS from baseline, when baseline <=5.0; or an increase of 0.5 from baseline, when baseline >=5.5, sustained for 6 months (2 successive quarterly visits), as assessed by the blinded EDSS examiner and confirmed centrally.
Baseline to Month 36
Change in the Multiple Sclerosis Functional Composite
Time Frame: Baseline to month 36

positive indicates improvement

The Multiple Sclerosis Functional Composite (MSFC) is a scale measuring pyramidal functions, sensory functions, cerebellar functions, bowel & bladder functions,brain stem functions, mental functions, and visual functions from 0 to 6.

0= normal 6= severe loss
Baseline to month 36
Change in MRI Composite Score
Time Frame: Baseline to month 36
MRI composite score (Z4 score) - the unweighted sum of the individual Z scores for enhanced tissue volume, T2 lesion burden, equivalence of the T1 hypointense lesion burden, normalized CSF (an inverse measure of atrophy with the appropriate sign so that all scores are directionally compatible - larger is worse) MRI enhancement status at baseline (0, 1-4, and 5 or more enhancing lesions)
Baseline to month 36

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fred Lublin

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

  • Principal Investigator: Fred Lublin, MD, Icahn School of Medicine at Mount Sinai

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2005

Primary Completion (Actual)

April 1, 2012

Study Completion (Actual)

March 1, 2013

Study Registration Dates

First Submitted

September 13, 2005

First Submitted That Met QC Criteria

September 13, 2005

First Posted (Estimate)

September 21, 2005

Study Record Updates

Last Update Posted (Estimate)

April 3, 2014

Last Update Submitted That Met QC Criteria

March 6, 2014

Last Verified

March 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GCO 02-0526
  • CRC (NINDS)
  • 02-0526
  • U01NS045719 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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