Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
517 participants
INTERVENTIONAL
2006-11-30
2011-07-31
Brief Summary
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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.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
QUADRUPLE
Study Groups
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RNF 44 mcg three times weekly
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.
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.
RNF 44 mcg once weekly and placebo twice weekly for blinding
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.
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.
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 three times weekly
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.
Interventions
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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.
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.
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
50 Years
ALL
No
Sponsors
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Merck KGaA, Darmstadt, Germany
INDUSTRY
Responsible Party
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Principal Investigators
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Bettina M. Stubinski, MD
Role: STUDY_DIRECTOR
Merck Serono S.A., Geneva
Locations
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Research Site
Mendoza, , Argentina
Research Site
Sydney, , Australia
Research Site
Graz, , Austria
Research Site
Innsbruck, , Austria
Research Site
B-Leuven, , Belgium
Research Site
Bruges, , Belgium
Research Site
Pleven, , Bulgaria
Research Site
Rousse, , Bulgaria
Research Site
Shumen, , Bulgaria
Research Site
Sofia, , Bulgaria
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Varna, , Bulgaria
Research Site
Montreal, Quebec, , Canada
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Ontario, , Canada
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Victoria British Columbia, , Canada
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Karlovac, , Croatia
Research Site
Osijek, , Croatia
Research Site
Rijeka, , Croatia
Research Site
Split, , Croatia
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Zagreb, , Croatia
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Hradec Králové, , Czechia
Research Site
Olomouc, , Czechia
Research Site
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
Research Site
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
Research Site
Riga, , Latvia
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Beirut, , Lebanon
Research Site
Rabat, , Morocco
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Bialystok, , Poland
Research Site
Lodz, , Poland
Research Site
Warsaw, , Poland
Research Site
Wroclaw, , Poland
Research Site
Lisbon, , Portugal
Research Site
Bucharest, , Romania
Research Site
Iași, , Romania
Research Site
Târgu Mureş, , Romania
Research Site
Timișoara, , Romania
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Moscow, , Russia
Research Site
Nizhny Novgorod, , Russia
Research Site
Novosibirsk, , Russia
Research Site
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
Research Site
Belgrade, , Serbia
Research Site
Niš, , Serbia
Research Site
Prešov, , Slovakia
Research Site
Barcelona, , Spain
Research Site
Bilbao, , Spain
Research Site
Madrid, , Spain
Research Site
Seville, , Spain
Research Site
Istanbul, , Turkey (Türkiye)
Countries
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References
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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.
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.
Related Links
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Full FDA approved prescribing information can be found here
Other Identifiers
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2006-002982-38
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
IMP27025
Identifier Type: -
Identifier Source: org_study_id
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