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

Study Overview
=================
Brief 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).

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).

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)

Conditions
-----------------
Relapsing Remitting Multiple Sclerosis

Intervention / Treatment
-----------------
* Drug: Interferon beta 1-a
* Drug: glatiramer acetate
* Other: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Interferon beta 1-a<br>Active Interferon B1a Weekly vs. Placebo Glatiramer Acetate Interferon b-1a (IFN) intramuscularly weekly | Drug: Interferon beta 1-a<br>* 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).<br>* Other names: IFN;Other: placebo<br>* an inactive substance<br>|
| Active Comparator: glatiramer acetate<br>Placebo Interferon B1a Weekly vs. Active Glatiramer Acetate Glatiramer acetate 20mg daily | Drug: glatiramer acetate<br>* 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).<br>* Other names: GA;Other: placebo<br>* an inactive substance<br>|
| Active Comparator: IFN and GA<br>Active Interferon B1a Weekly and Active Glatiramer Acetate | Drug: Interferon beta 1-a<br>* 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).<br>* Other names: IFN;Drug: glatiramer acetate<br>* 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).<br>* Other names: GA;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Multiple Sclerosis, Clinical trial, treatment trial, autoimmune disease, Relapsing Remitting, MS Treatment, interferon beta-1a, glatiramer acetate