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

Relapsing Remitting Multiple Sclerosis Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00211887
• Other study ID #: GCO 02-0526
• Secondary ID: 02-0526CRCU01NS0
• Status: Completed
• Phase: Phase 3
• First received: September 13, 2005
• Last updated: March 6, 2014
• Start date: January 2005
• Est. completion date: March 2013

Study information

• Verified date: March 2014
• Source: Icahn School of Medicine at Mount Sinai
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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).

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1008
• Est. completion date: March 2013
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

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).
• 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:
• placebo
an inactive substance

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Fred Lublin	National Institute of Neurological Disorders and Stroke (NINDS)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Lublin FD, Cofield SS, Cutter GR, Conwit R, Narayana PA, Nelson F, Salter AR, Gustafson T, Wolinsky JS; CombiRx Investigators. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013 Mar;73(3):327-40. doi: 10.1 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ARR - PDEs	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	Yes
Secondary	Confirmed Progression on the Expanded Disability Status Scale	% 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	Yes
Secondary	Change in the Multiple Sclerosis Functional Composite	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	Yes
Secondary	Change in MRI Composite Score	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	Yes