REbif FLEXible Dosing in Early Multiple Sclerosis (MS)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter Clinical Trial of Rebif New Formulation (44 Microgram [Mcg] Three Times Weekly [Tiw] and 44 Mcg Once Weekly [ow]) in Subjects at High Risk of Converting to Multiple Sclerosis (REFLEX)

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: RNF
* Drug: RNF
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RNF 44 mcg three times weekly<br> | Drug: RNF<br>* Single dose of RNF administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months, or 36 months for patients enrolled in the OL extension.<br>* Other names: Rebif;Drug: RNF<br>* Single dose of RNF administered subcutaneously once weekly at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months.<br>* Other names: Rebif;|
| Active Comparator: RNF 44 mcg once weekly and placebo twice weekly for blinding<br> | Drug: RNF<br>* Single dose of RNF administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months, or 36 months for patients enrolled in the OL extension.<br>* Other names: Rebif;Drug: RNF<br>* Single dose of RNF administered subcutaneously once weekly at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months.<br>* Other names: Rebif;Drug: Placebo<br>* Placebo was supplied as a transparent, sterile solution for injection in pre-filled syringes matching the RNF pre-filled syringes, each containing 0.5 mL.<br>|
| Placebo Comparator: Placebo three times weekly<br> | Drug: Placebo<br>* Placebo was supplied as a transparent, sterile solution for injection in pre-filled syringes matching the RNF pre-filled syringes, each containing 0.5 mL.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005) | The McDonald criteria use dissemination in time and space established by magnetic resonance image (MRI) findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new time constant 2 (T2) or gadolinium-enhancing (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. | Various time points from randomization up to 24 months | 
| Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005) | 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. | Various time points from randomization up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | CDMS was defined by the occurrence of a second exacerbation or relapse over 24 months in participants who presented with first clinical demyelinating event (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. | Various time points from randomization up to 24 months | 
| 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 | 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. | Various time points from randomization up to 36 months | 
| 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 | Number of CUA lesions, new T2 lesions, Gd+ lesions and new T1 hypointense lesions were measured by using MRI scans. | Month 24 up to Month 36 | 
| 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 | Change from baseline in lesion volume was measured by using MRI scans for T2 lesions, T1 hypointense lesions and (Gd+) lesions. | Baseline, Month 36 | 
| Change From Baseline in Expanded Disability Status Score (EDSS) Score at 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. | Baseline, Month 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rebif New Formulation, Clinical Isolated Syndrome, Multiple Sclerosis