REbif FLEXible Dosing in Early Multiple Sclerosis (MS)
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Intervention: RNF; RNF; Placebo
Intervention description: 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.; 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.; 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.
Intervention MeSH terms: Interferon beta-1a
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 517.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: No
Keywords: Rebif New Formulation; Clinical Isolated Syndrome; Multiple Sclerosis

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.
    

Eligibility criteria:

        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