Clinical trial NCT00813709: Long-term Follow-Up of Patients Who Participated in Study 27025 (REFLEX)
Official title: Double-blind Extension of the Study 27025 (REFLEX) to Obtain Long-term Follow-up Data in Patients With Clinically Definite MS and Patients With a First Demyelinating Event at High Risk of Converting to MS, Treated With Rebif® New Formulation (REFLEXION)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis
Clinically Isolated Syndrome
Keywords: Interferon 1-beta
Clinical Definite Multiple Sclerosis
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2008-12-23
Enrollment: 402
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: REFLEXION is a double blind extension of the study 27025 (NCT00404352) (REFLEX). The purpose of the study is to obtain long-term follow-up data in subjects with clinically definite multiple sclerosis (MS) and subjects with a first demyelinating event at high risk of converting to MS, treated with fetal bovine serum \[FBS\]-free/human serum albumin \[HSA\]-free formulation of interferon \[IFN\]-beta-1a (RNF).

Detailed description: The objective of the study is to investigate whether RNF treatment initiated after the first clinical event versus delayed treatment results in the prolongation of time to Clinically Definite Multiple Sclerosis (CDMS) conversion up to Month 36 and up to Month 60 since randomization in Study 27025 (REFLEX). Furthermore, the study is intended to explore whether RNF treatment initiated after the first clinical event versus delayed treatment delays disability (including development of secondary progressive MS) and reduces disease activity (including the annual relapse rate \[ARR\]) in the long term (up to Month 36 and up to Month 60 since randomization in Study 27025 (REFLEX). The study will also assess the long-term safety profile of RNF (up to Month 36 and up to Month 60 since randomization in Study 27025 (REFLEX).

Eligibility criteria: Inclusion Criteria:

* Reach scheduled end of study in Study 27025 (REFLEX) (completion of 24 months participation)
* Medical assessment by the Investigator/treating physician from study 27025 that there is no objection to the subject's participation in this extension trial considering the medical experience from Study 27025 (REFLEX). Special attention should be given to laboratory abnormalities and clinically significant liver, renal and bone-marrow dysfunction
* 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 vasectomized partner
* Subject is willing to follow study procedures
* Subject has given written informed consent

Exclusion Criteria:

* Subject has any disease other than MS that could better explain the subject's signs and symptoms
* Subject has a primary progressive course of MS
* Subject has total bilirubin greater than 2.5 times upper limit of normal (ULN) at both Month 24 and at the previous visit (i.e. Month 21) (subjects with greater than 2.5 times ULN at Month 24 only are eligible for enrollment and should be managed as per label recommendations until normalization of the value)
* Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase (ALP) greater than 2.5 times the ULN values at both Month 24 and at the previous visit (i.e. Month 21) (subjects with greater than 2.5 times ULN at Month 24 only are eligible for enrollment and should be managed as per label recommendations until normalization of the value)
* Subject suffers from another current autoimmune disease
* Subject suffers from 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
* Subject has a history of seizures not adequately controlled by treatment
* Subject has cardiac disease, such as angina, congestive heart failure or arrhythmia
* Subject has a known allergy to IFN-beta or the excipient(s) of the study medication
* Subject has any condition that could interfere with the MRI evaluation
* Subject has a known allergy to gadolinium-diethylene triamine pentaacetic acid (DTPA)
* Subject has a history of alcohol or drug abuse
* Subject has previously participated in this study
* Subject has moderate to severe renal impairment
* Subject is pregnant or lactating
* Subject has any medical, psychiatric or other conditions that compromise his/her ability to understand the subject information, to give informed consent, to comply with the study protocol, or to complete the study

Primary outcomes:
measure: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score up to 36 Months
timeFrame: Baseline (Day 1 of Study 27025) up to 36 Months
Secondary outcomes:
measure: Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months
timeFrame: Baseline (Day 1 of Study 27025) up to 36 Months
measure: Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, New Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Lesions Per Participant Per Scan at Month 36
timeFrame: Month 36
measure: Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36
timeFrame: Baseline (Day 1 of Study 27025), Month 36
measure: Percent Change From Baseline in Brain Volume at Month 36
timeFrame: Baseline (Day 1 of Study 27025), Month 36
measure: Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months
timeFrame: Baseline (Day 1 of Study 27025) up to CDMS conversion and/or up to 36 Months
measure: Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36
timeFrame: Baseline (Day of Study 27025), Month 36
measure: Percentage of Relapse-Free Participants at Month 36
timeFrame: Month 36
measure: Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36
timeFrame: Baseline (Day of Study 27025), Month 36
measure: Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36
timeFrame: Baseline (Day 1 of Study 27025), Month 36
measure: Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36
timeFrame: Month 36
measure: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation
timeFrame: Month 24 up to Month 36 (DB treatment period for study 28981 (REFLEXION)
measure: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score up to Month 60
timeFrame: Baseline (Day 1 of Study 27025) up to 60 Months
measure: Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months
timeFrame: Baseline (Day 1 of Study 27025) up to 60 Months
measure: Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, New Gadolinium Enhanced (Gd+) Lesions and New T1 Lesions Per Participant Per Scan at Month 60
timeFrame: Month 60
measure: Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60
timeFrame: Baseline (Day 1 of Study 27025), Month 60
measure: Percent Change From Baseline in Brain Volume at Month 60
timeFrame: Baseline (Day 1 of Study 27025), Month 60
measure: Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60
timeFrame: Month 60
measure: Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60
timeFrame: Baseline (Day 1 of Study 27025), Month 60
measure: Percentage of Relapse-Free Participants at Month 60
timeFrame: Month 60
measure: Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60
timeFrame: Baseline (Day 1 of Study 27025), Month 60
measure: Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60
timeFrame: Baseline (Day 1 of Study 27025), Month 60
measure: Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60
timeFrame: Month 60
measure: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation
timeFrame: Month 24 up to Month 60
Other outcomes:
Locations:
city: Mendoza
country: Argentina
facility: Research Site
city: Graz
country: Austria
facility: Research Site
city: Brugge
country: Belgium
facility: Research Site
city: Leuven
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: 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: Oulu
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: Henningsforf
country: Germany
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Safed
country: Israel
facility: Research Site
city: Tel-Hashomer
country: Israel
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Padova
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: Lisbon
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: 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: Belgrade
country: Serbia
facility: Reserch 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: Seville
country: Spain
facility: Research Site
Study officials:
affiliation: Merck Serono S.A., Geneva
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Comi G, De Stefano N, Freedman MS, Barkhof F, Uitdehaag BM, de Vos M, Marhardt K, Chen L, Issard D, Kappos L. Subcutaneous interferon beta-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. J Neurol Neurosurg Psychiatry. 2017 Apr;88(4):285-294. doi: 10.1136/jnnp-2016-314843. Epub 2016 Dec 30.