Long-term Follow-Up of Patients Who Participated in Study 27025 (REFLEX)

Condition(s) targeted: Multiple Sclerosis; Clinically Isolated Syndrome

Intervention: RNF (Drug); RNF (Drug); RNF (Drug); Placebo (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Merck KGaA

Official(s) and/or principal investigator(s):
Medical Responsible, Study Director, Affiliation: Merck Serono S.A., Geneva

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).

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: 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

Secondary outcome:

Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months

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

Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36

Percent Change From Baseline in Brain Volume at Month 36

Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months

Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36

Percentage of Relapse-Free Participants at Month 36

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

Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36

Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36

Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation

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

Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months

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

Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60

Percent Change From Baseline in Brain Volume at Month 60

Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60

Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60

Percentage of Relapse-Free Participants at Month 60

Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60

Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60

Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60

Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation

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).

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Research Site, Mendoza, Argentina

Research Site, Graz, Austria

Research Site, Brugge, Belgium

Research Site, Leuven, Belgium

Research Site, Pleven, Bulgaria

Research Site, Rousse, Bulgaria

Research Site, Shumen, Bulgaria

Research Site, Sofia, Bulgaria

Research Site, Varna, Bulgaria

Research Site, Ontario, Canada

Research Site, Victoria British Columbia, Canada

Research Site, Karlovac, Croatia

Research Site, Osijek, Croatia

Research Site, Rijeka, Croatia

Research Site, Split, Croatia

Research Site, Zagreb, Croatia

Research Site, Hradec Kralove, Czech Republic

Research Site, Olomouc, Czech Republic

Research Site, Prague, Czech Republic

Research Site, Tallinn, Estonia

Research Site, Tartu, Estonia

Research Site, Oulu, Finland

Research Site, Paris, France

Research Site, Poissy Cedex, France

Research Site, Hannover, Germany

Research Site, Henningsforf, Germany

Research Site, Athens, Greece

Research Site, Safed, Israel

Research Site, Tel-Hashomer, Israel

Research Site, Milano, Italy

Research Site, Padova, Italy

Research Site, Riga, Latvia

Research Site, Beirut, Lebanon

Research Site, Rabat, Morocco

Research Site, Bialystok, Poland

Research Site, Lodz, Poland

Research Site, Warsaw, Poland

Research Site, Wroclaw, Poland

Research Site, Lisbon, Portugal

Research Site, Bucharest, Romania

Research Site, Iasi, Romania

Research Site, Targu-Mures, Romania

Research Site, Timisoara, Romania

Research Site, Ekaterinburg, Russian Federation

Research Site, Moscow, Russian Federation

Research Site, Novgorod, Russian Federation

Research Site, Novosibirsk, Russian Federation

Research Site, Saint-Petersburg, Russian Federation

Research Site, Samara, Russian Federation

Research Site, Saratov, Russian Federation

Reserch Site, Belgrade, Serbia

Research Site, Nis, Serbia

Research Site, Presov, Slovakia

Research Site, Barcelona, Spain

Research Site, Bilbao, Spain

Research Site, Madrid, Spain

Research Site, Seville, Spain

Starting date: December 2008
Last updated: July 23, 2015