Clinical trial NCT00404352: REbif FLEXible Dosing in Early Multiple Sclerosis (MS)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis
Keywords: Rebif New Formulation
Clinical Isolated Syndrome
Multiple Sclerosis
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2006-11-28
Enrollment: 517
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


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

Primary outcomes:
measure: Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005)
timeFrame: Various time points from randomization up to 24 months
measure: Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005)
timeFrame: Various time points from randomization up to 36 months
Secondary outcomes:
measure: 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
timeFrame: Various time points from randomization up to 24 months
measure: 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
timeFrame: Various time points from randomization up to 36 months
measure: 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
timeFrame: Month 24 up to Month 36
measure: 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
timeFrame: Baseline, Month 36
measure: Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36
timeFrame: Baseline, Month 36
Other outcomes:
Locations:
city: Mendoza
country: Argentina
facility: Research Site
city: Sydney
country: Australia
facility: Research Site
city: Graz
country: Austria
facility: Research Site
city: Innsbruck
country: Austria
facility: Research Site
city: B-Leuven
country: Belgium
facility: Research Site
city: Brugge
country: Belgium
facility: Research Site
city: Pleven
country: Bulgaria
facility: Research Site
city: Rousse
country: Bulgaria
facility: Research Site
city: Shumen
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Varna
country: Bulgaria
facility: Research Site
city: Montreal, Quebec
country: Canada
facility: Research Site
city: Ontario
country: Canada
facility: Research Site
city: Victoria British Columbia
country: Canada
facility: Research Site
city: Karlovac
country: Croatia
facility: Research Site
city: Osijek
country: Croatia
facility: Research Site
city: Rijeka
country: Croatia
facility: Research Site
city: Split
country: Croatia
facility: Research Site
city: Zagreb
country: Croatia
facility: Research Site
city: Hradec Kralove
country: Czech Republic
facility: Research Site
city: Olomouc
country: Czech Republic
facility: Research Site
city: Prague
country: Czech Republic
facility: Research Site
city: Tallinn
country: Estonia
facility: Research Site
city: Tartu
country: Estonia
facility: Research Site
city: OYS
country: Finland
facility: Research Site
city: Vantaa
country: Finland
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Poissy Cedex
country: France
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Henningsdorf
country: Germany
facility: Research Site
city: Munich
country: Germany
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Ness Ziona
country: Israel
facility: Research Site
city: Safed
country: Israel
facility: Research Site
city: Tel-Hashomer
country: Israel
facility: Research Site
city: Catania
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Riga
country: Latvia
facility: Research Site
city: Beirut
country: Lebanon
facility: Research Site
city: Rabat
country: Morocco
facility: Research Site
city: Bialystok
country: Poland
facility: Research Site
city: Lodz
country: Poland
facility: Research Site
city: Warsaw
country: Poland
facility: Research Site
city: Wroclaw
country: Poland
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Iasi
country: Romania
facility: Research Site
city: Targu-Mures
country: Romania
facility: Research Site
city: Timisoara
country: Romania
facility: Research Site
city: Ekaterinburg
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Nizhny Novgorod
country: Russian Federation
facility: Research Site
city: Novosibirsk
country: Russian Federation
facility: Research Site
city: Saint-Petersburg
country: Russian Federation
facility: Research Site
city: Samara
country: Russian Federation
facility: Research Site
city: Saratov
country: Russian Federation
facility: Research Site
city: Riyadh
country: Saudi Arabia
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Nis
country: Serbia
facility: Research Site
city: Presov
country: Slovakia
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Bilbao
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
Study officials:
affiliation: Merck Serono S.A., Geneva
name: Bettina M. Stubinski, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.