REbif FLEXible Dosing in Early Multiple Sclerosis (MS)

NCT00404352 | Completed Phase 3 Results DMC

• 2 other identifiers: IMP270252006-002982-38
• Study Type: interventional
• Target: 517
• Locations: 25 countries
• Sites: 61

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.

Conditions

Multiple Sclerosis

Keywords

Rebif New Formulation; Clinical Isolated Syndrome; Multiple Sclerosis

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• 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 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

  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

  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

  Baseline, Month 36

• Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36

  Baseline, Month 36

Study Arms (3)

RNF 44 mcg three times weekly

ACTIVE COMPARATOR

Drug: RNF

RNF 44 mcg once weekly and placebo twice weekly for blinding

ACTIVE COMPARATOR

Drug: RNF; Drug: Placebo

Placebo three times weekly

PLACEBO COMPARATOR

Drug: Placebo

Interventions

RNF DRUG

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.

Also known as: Rebif

RNF 44 mcg once weekly and placebo twice weekly for blinding; RNF 44 mcg three times weekly

Placebo DRUG

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 three times weekly; RNF 44 mcg once weekly and placebo twice weekly for blinding

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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;

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead

Study Sites (67)

Research Site

Mendoza, Argentina

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Sydney, Australia

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Graz, Austria

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Innsbruck, Austria

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B-Leuven, Belgium

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Bruges, Belgium

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Pleven, Bulgaria

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Rousse, Bulgaria

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Shumen, Bulgaria

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Sofia, Bulgaria

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Varna, Bulgaria

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Montreal, Quebec, Canada

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Ontario, Canada

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Victoria British Columbia, Canada

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Karlovac, Croatia

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Osijek, Croatia

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Rijeka, Croatia

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Split, Croatia

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Zagreb, Croatia

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Hradec Králové, Czechia

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Olomouc, Czechia

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Prague, Czechia

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Tallinn, Estonia

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Tartu, Estonia

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OYS, Finland

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Vantaa, Finland

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Paris, France

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Poissy, France

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Hanover, Germany

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Henningsdorf, Germany

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Munich, Germany

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Athens, Greece

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Ness Ziona, Israel

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Safed, Israel

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Tel Litwinsky, Israel

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Catania, Italy

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Milan, Italy

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Padua, Italy

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Roma, Italy

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Riga, Latvia

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Beirut, Lebanon

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Rabat, Morocco

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Bialystok, Poland

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Lodz, Poland

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Warsaw, Poland

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Wroclaw, Poland

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Lisbon, Portugal

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Bucharest, Romania

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Iași, Romania

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Târgu Mureş, Romania

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Timișoara, Romania

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Moscow, Russia

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Nizhny Novgorod, Russia

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Novosibirsk, Russia

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Saint Petersburg, Russia

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Samara, Russia

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Saratov, Russia

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Yekaterinburg, Russia

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Riyadh, Saudi Arabia

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Belgrade, Serbia

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Niš, Serbia

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Prešov, Slovakia

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Barcelona, Spain

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Bilbao, Spain

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Madrid, Spain

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Seville, Spain

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Istanbul, Turkey (Türkiye)

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Related Publications (5)

• Kuhle J, Leppert D, Comi G, de Stefano N, Kappos L, Freedman MS, Seitzinger A, Roy S. Serum neurofilament light chain correlations in patients with a first clinical demyelinating event in the REFLEX study: a post hoc analysis. Ther Adv Neurol Disord. 2024 Mar 29;17:17562864241239101. doi: 10.1177/17562864241239101. eCollection 2024.

  PMID: 38560407 DERIVED

• 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.

  PMID: 35274413 DERIVED

• 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.

  PMID: 24413638 DERIVED

• 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.

  PMID: 24292999 DERIVED

• 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.

  PMID: 22146409 DERIVED

Related Links

• Full FDA approved prescribing information can be found here

MeSH Terms

Conditions

Multiple Sclerosis

Interventions

Interferon beta-1a

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Interferon-beta; Interferon Type I; Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Merck KGaA Communication Center
• Organization: Merck Serono, a division of Merck KGaA

service@merckgroup.com

+49-6151-72-5200

Study Officials

• Bettina M. Stubinski, MD

  Merck Serono S.A., Geneva

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 27, 2006
• First Posted: November 28, 2006
• Study Start: November 1, 2006
• Primary Completion: August 1, 2010
• Study Completion: July 1, 2011
• Last Updated: January 24, 2014
• Results First Posted: September 24, 2012

Record last verified: 2013-12

Locations

BU (5); CZ (3); CR (5); RU (7); SE (2); GR (1); ES (2); IT (4); MO (1); AU (1); SL (1); IL (3); AR (1); PT (1); FI (2); DE (3); LA (1); LE (1); RO (4); TU (1); PL (4); SA (1); CA (3); FR (2); BE (2)