REbif FLEXible Dosing in Early Multiple Sclerosis (MS)

Phase 3

Completed

Conditions: Multiple Sclerosis

Interventions: Drug: RNF
Drug: Placebo

Registration Number: NCT00404352

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: The study is a 24 months randomized, double-blind, Placebo-controlled, multi-center clinical trial with an optional 12 months open label extension.

The primary objective of the study is to evaluate the effect of fetal bovine serum \[FBS\]-free/human serum albumin \[HSA\]-free formulation of Interferon \[IFN\] beta-1a (RNF) 44 microgram (three times weekly and once weekly) versus placebo on the time to conversion to McDonald multiple sclerosis (MS) criteria (2005) in subjects with a first clinical demyelinating event at high risk of converting to MS.

The main secondary objective of study is to evaluate the effect of RNF 44 microgram (three times weekly and once weekly) versus placebo on the "Time to conversion to clinically definite MS (CDMS)" in subjects with a first clinical demyelinating event at high risk of converting to MS.

At the end of 24 month double-blind core REFLEX trial, subjects who will not convert to CDMS and decide to receive open-label (OL) treatment will be enrolled into an open-label, 12 month extension period to evaluate the effect of RNF 44 mcg three times weekly treatment on the time to conversion to McDonald MS and time to conversion to CDMS.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 517

Inclusion Criteria

Single, first clinical event suggestive of MS within 60 days prior to study Day 1, which is the day of randomization (clock starts 24 hours after onset). The event must be a new neurological abnormality present for at least 24 hours, either mono- or polysymptomatic, other than a paresthesia, vegetative or cerebral dysfunction
At least two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 millimeter (mm), at least one of which is ovoid or periventricular or infratentorial
EDSS 0 - 5.0 at least one time point during the screening period before start of treatment
18 and 50 years old, inclusive
Willing to follow study procedures
Written informed consent
If female, subject must:
- be neither pregnant nor breast-feeding nor attempting to conceive
- use a highly effective method of contraception. A highly effective method of contraception is defined as those which result in a low failure rate (that is [i.e.] less than 1 percent [%] per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner

Exclusion Criteria

Diagnosis of MS (per McDonald criteria 2005)
Any other disease that could better explain the subject's signs and symptoms
Complete transverse myelitis or bilateral optic neuritis
Subject uses or has used any other approved MS disease-modifying drug (DMD)
Any investigational drug or undergone an experimental procedure within 12 weeks prior to study Day 1
Oral or systemic corticosteroids or adrenocorticotropic hormone (ACTH) within 30 days prior to study Day 1
Total bilirubin greater than 2.5 times upper limit of normal (ULN)
Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase (ALP) greater than 2.5 times the ULN
Inadequate bone marrow reserve, defined as a total white blood cell count less than 3.0 x 109 per liter (/L), platelet count less than 75 x 109/L, hemoglobin less than 100 gram per liter (g/L)
Current autoimmune disease
Major medical or psychiatric illness (including history of or current severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol
History of seizures not adequately controlled by treatment
Cardiac disease, such as angina, congestive heart failure or arrhythmia
Known allergy to IFN-beta or the excipient(s) of the study medication
Any condition that could interfere with the MRI evaluation;
Known allergy to gadolinium-diethylene triamine pentaacetic acid (DTPA)
Previously participated in this study
Participated in any clinical trial within the past 6 months
Any immunomodulatory or immunosuppressive therapy at any time prior to enrollment, including, but not limited to, the following products: any IFN, glatiramer acetate (Copolymer I), cyclophosphamide, cyclosporine, methotrexate, linomide, azathioprine, mitoxantrone, teriflunomide, laquinimod, cladribine, total lymphoid irradiation, anti-lymphocyte monoclonal antibody treatment (e.g. natalizumab, alemtuzumab/Campath, anti-cluster of differentiation 4 [CD4]), intravenous, immunoglobulins (Igs), cytokines or anti-cytokine therapy
Any experimental MS treatment prior to trial entry, including, but not limited to, any statins (if given to prevent MS) and pentoxyfylline
History of alcohol or drug abuse
Intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen
Inability to administer subcutaneous injections either by self or by caregiver
Moderate to severe renal impairment

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RNF 44 mcg once weekly and placebo twice weekly for blinding	RNF	-
RNF 44 mcg three times weekly	RNF	-
RNF 44 mcg once weekly and placebo twice weekly for blinding	Placebo	-
Placebo three times weekly	Placebo	-

Primary Outcome Measures

Name	Time	Method
Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005)	Various time points from randomization up to 36 months	The McDonald criteria use dissemination in time and space established by MRI findings to provide a clinical diagnosis for MS. Dissemination in time is established by a T2 or Gd+ lesion found on a repeat MRI. Dissemination in space is established by the presence of any 3 of the following: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; greater than or equal to 1 infratentorial lesion; greater than or equal to 1 juxtacortical lesion; greater than or equal to 3 periventricular lesions.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36	Baseline, Month 36	EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. The change in EDSS at Month 36 was calculated as EDSS at Month 36 minus EDSS at baseline.
Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score	Various time points from randomization up to 36 months	CDMS was defined by the occurrence of a second exacerbation or relapse over 36 months in participants who presented with FCDE accompanied by an abnormal MRI scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.
Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan	Month 24 up to Month 36	Number of CUA lesions, new T2 lesions, Gd+ lesions and new T1 hypointense lesions were measured by using MRI scans.
Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36	Baseline, Month 36	Change from baseline in lesion volume was measured by using MRI scans for T2 lesions, T1 hypointense lesions and (Gd+) lesions.