REbif FLEXible Dosing in Early Multiple Sclerosis (MS) (REFLEX)

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)

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.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: RNF; Drug: RNF; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 517
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Mendoza, Argentina
    • Research Site
• Australia
  • Sydney, Australia
    • Research Site
• Austria
  • Graz, Austria
    • Research Site
  • Innsbruck, Austria
    • Research Site
• Belgium
  • B-Leuven, Belgium
    • Research Site
  • Brugge, Belgium
    • Research Site
• Bulgaria
  • Pleven, Bulgaria
    • Research Site
  • Rousse, Bulgaria
    • Research Site
  • Shumen, Bulgaria
    • Research Site
  • Sofia, Bulgaria
    • Research Site
  • Varna, Bulgaria
    • Research Site
• Canada
  • Montreal, Quebec, Canada
    • Research Site
  • Ontario, Canada
    • Research Site
  • Victoria British Columbia, Canada
    • Research Site
• Croatia
  • Karlovac, Croatia
    • Research Site
  • Osijek, Croatia
    • Research Site
  • Rijeka, Croatia
    • Research Site
  • Split, Croatia
    • Research Site
  • Zagreb, Croatia
    • Research Site
• Czech Republic
  • Hradec Kralove, Czech Republic
    • Research Site
  • Olomouc, Czech Republic
    • Research Site
  • Prague, Czech Republic
    • Research Site
• Estonia
  • Tallinn, Estonia
    • Research Site
  • Tartu, Estonia
    • Research Site
• Finland
  • OYS, Finland
    • Research Site
  • Vantaa, Finland
    • Research Site
• France
  • Paris, France
    • Research Site
  • Poissy Cedex, France
    • Research Site
• Germany
  • Hannover, Germany
    • Research Site
  • Henningsdorf, Germany
    • Research Site
  • Munich, Germany
    • Research Site
• Greece
  • Athens, Greece
    • Research Site
• Israel
  • Ness Ziona, Israel
    • Research Site
  • Safed, Israel
    • Research Site
  • Tel-Hashomer, Israel
    • Research Site
• Italy
  • Catania, Italy
    • Research Site
  • Milano, Italy
    • Research Site
  • Padova, Italy
    • Research Site
  • Roma, Italy
    • Research Site
• Latvia
  • Riga, Latvia
    • Research Site
• Lebanon
  • Beirut, Lebanon
    • Research Site
• Morocco
  • Rabat, Morocco
    • Research Site
• Poland
  • Bialystok, Poland
    • Research Site
  • Lodz, Poland
    • Research Site
  • Warsaw, Poland
    • Research Site
  • Wroclaw, Poland
    • Research Site
• Portugal
  • Lisboa, Portugal
    • Research Site
• Romania
  • Bucharest, Romania
    • Research Site
  • Iasi, Romania
    • Research Site
  • Targu-Mures, Romania
    • Research Site
  • Timisoara, Romania
    • Research Site
• Russian Federation
  • Ekaterinburg, Russian Federation
    • Research Site
  • Moscow, Russian Federation
    • Research Site
  • Nizhny Novgorod, Russian Federation
    • Research Site
  • Novosibirsk, Russian Federation
    • Research Site
  • Saint-Petersburg, Russian Federation
    • Research Site
  • Samara, Russian Federation
    • Research Site
  • Saratov, Russian Federation
    • Research Site
• Saudi Arabia
  • Riyadh, Saudi Arabia
    • Research Site
• Serbia
  • Belgrade, Serbia
    • Research Site
  • Nis, Serbia
    • Research Site
• Slovakia
  • Presov, Slovakia
    • Research Site
• Spain
  • Barcelona, Spain
    • Research Site
  • Bilbao, Spain
    • Research Site
  • Madrid, Spain
    • Research Site
  • Sevilla, Spain
    • Research Site
• Turkey
  • Istanbul, Turkey
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RNF 44 mcg three times weekly	Drug: RNF; 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.; Other Names: Rebif; Drug: RNF; 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.; Other Names: Rebif
Active Comparator: RNF 44 mcg once weekly and placebo twice weekly for blinding	Drug: RNF; 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.; Other Names: Rebif; Drug: RNF; 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.; Other Names: Rebif; Drug: Placebo; 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.
Placebo Comparator: Placebo three times weekly	Drug: Placebo; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Bettina M. Stubinski, MD, Merck Serono S.A., Geneva

Publications and helpful links

General Publications

• Battaglini M, Vrenken H, Tappa Brocci R, Gentile G, Luchetti L, Versteeg A, Freedman MS, Uitdehaag BMJ, Kappos L, Comi G, Seitzinger A, Jack D, Sormani MP, Barkhof F, De Stefano N. Evolution from a first clinical demyelinating event to multiple sclerosis in the REFLEX trial: Regional susceptibility in the conversion to multiple sclerosis at disease onset and its amenability to subcutaneous interferon beta-1a. Eur J Neurol. 2022 Jul;29(7):2024-2035. doi: 10.1111/ene.15314. Epub 2022 Apr 4.
• Freedman MS, De Stefano N, Barkhof F, Polman CH, Comi G, Uitdehaag BM, Casset-Semanaz F, Hennessy B, Lehr L, Stubinski B, Jack DL, Kappos L. Patient subgroup analyses of the treatment effect of subcutaneous interferon beta-1a on development of multiple sclerosis in the randomized controlled REFLEX study. J Neurol. 2014 Mar;261(3):490-9. doi: 10.1007/s00415-013-7222-6. Epub 2014 Jan 12.
• De Stefano N, Comi G, Kappos L, Freedman MS, Polman CH, Uitdehaag BM, Hennessy B, Casset-Semanaz F, Lehr L, Stubinski B, Jack DL, Barkhof F. Efficacy of subcutaneous interferon beta-1a on MRI outcomes in a randomised controlled trial of patients with clinically isolated syndromes. J Neurol Neurosurg Psychiatry. 2014 Jun;85(6):647-53. doi: 10.1136/jnnp-2013-306289. Epub 2013 Nov 29.
• Comi G, De Stefano N, Freedman MS, Barkhof F, Polman CH, Uitdehaag BM, Casset-Semanaz F, Hennessy B, Moraga MS, Rocak S, Stubinski B, Kappos L. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol. 2012 Jan;11(1):33-41. doi: 10.1016/S1474-4422(11)70262-9. Epub 2011 Dec 4. Erratum In: Lancet Neurol. 2012 Feb;11(2):125.

Helpful Links

• Full FDA approved prescribing information can be found here

Study record dates

Study Major Dates

• Study Start: November 1, 2006
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: November 27, 2006
• First Submitted That Met QC Criteria: November 27, 2006
• First Posted (Estimate): November 28, 2006

Study Record Updates

• Last Update Posted (Estimate): January 24, 2014
• Last Update Submitted That Met QC Criteria: December 18, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Rebif New Formulation; Clinical Isolated Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Immunologic Factors; Adjuvants, Immunologic; Interferon beta-1a
• Other Study ID Numbers: IMP27025; 2006-002982-38 (EudraCT Number)