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

Merck KGaA, Darmstadt, Germany402 enrolled

Overview

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).

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

402

Conditions

Multiple Sclerosis Clinically Isolated Syndrome

Interventions

RNFDRUG

Single dose of RNF will be 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 60 months.

RNFDRUG

Single dose of RNF will be 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 60 months.

RNFDRUG

Participants who were initially randomized in Study 27025 (REFLEX) to the placebo treatment group will be switched to single dose of RNF administered subcutaneously three times weekly at least 48 hours apart at a dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (57)

Outcomes

Primary Outcomes

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

CDMS was defined by the occurrence of a second attack or relapse over 36 months in participants who presented with clinically isolated syndrome (CIS) accompanied by an abnormal magnetic resonance imaging (MRI) scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis \[MS\]) was calculated. Time to conversion to CDMS was represented by Kaplan-Meier estimates of the cumulative percentage (%) of participants with CDMS.

Time frame: Baseline (Day 1 of Study 27025) up to 36 Months

Secondary Outcomes

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

EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. A confirmed EDSS progression was defined EDSS greater than or equal to 1.0 point confirmed during a visit performed 6 months later. Time to confirmed EDSS progression was represented by Kaplan-Meier estimates of the cumulative percentage (%) of participants with confirmed EDSS progression.

Time frame: Baseline (Day 1 of Study 27025) 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

Number of CUA lesions, new T2 lesions, new Gd+ lesions and new T1 lesions were measured by using MRI scans.

Time frame: Month 36

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

Change from baseline in lesion volume was measured by using MRI scans for T1 hypointense lesions and T2 lesions at Month 36

Data from ClinicalTrials.gov

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PlaceboDRUG

Single dose matching placebo will be administered subcutaneously twice weekly. Placebo is supplied as a transparent, sterile solution for injection in pre-filled syringes matching the RNF pre-filled syringes, each containing 0.5 milliliter (mL).

Research Site

Mendoza, Argentina

Research Site

Graz, Austria

Research Site

Bruges, 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

...and 47 more locations

Time frame: Baseline (Day 1 of Study 27025), Month 36

Percent Change From Baseline in Brain Volume at Month 36

Percent change in brain volume was measured by using MRI scans.

Time frame: Baseline (Day 1 of Study 27025), Month 36

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

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 new 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.

Time frame: Baseline (Day 1 of Study 27025) up to CDMS conversion and/or up to 36 Months

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

The Paced Auditory Serial Addition Test (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Score ranges from '0-60'. Higher scores reflect better neurological function and a positive change from baseline indicates improvement.

Time frame: Baseline (Day of Study 27025), Month 36

Percentage of Relapse-Free Participants at Month 36

A relapse was defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, lasting for 24 hours and with a previous period for more than 30 days with a stable or an improving condition.

Time frame: Month 36

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

EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. The change in EDSS score at Month 36 was calculated as EDSS score at Month 36 minus EDSS score at baseline.

Time frame: Baseline (Day of Study 27025), Month 36

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

The MSFC is a multidimensional clinical outcome measure which consists of three sub-tests; Timed 25-Foot Walk, 9-Hole Peg Test and Paced Auditory Serial Addition Test-3(PASAT-3). The Timed 25-Foot Walk is a quantitative measure of lower extremity function. The 9-Hole Peg Test is a quantitative measure of upper extremity (arm and hand) function. The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Standardized results (Z-scores) of these sub-tests and the overall MSFC Z-score as an average of these three Z-scores was calculated. Higher Z-scores reflect better neurological function and a positive change from baseline indicates improvement. An increase in score indicates an improvement (range -3 to +3).

Time frame: Baseline (Day 1 of Study 27025), Month 36

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

BAbs are all antibodies which are capable of binding to the investigational drug molecule (RNF) irrespective of their binding site. NAbs are defined as a subgroup of BAbs which bind to the active sites of the RNF and therefore neutralize its potency. NAbs were detected using a viral cytopathic assay. BAbs were measured by using an ELISA (Enzyme-linked immunosorbent assay).

Time frame: Month 36

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

An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition.

Time frame: Month 24 up to Month 36 (DB treatment period for study 28981 (REFLEXION)

CDMS was defined by the occurrence of a second attack or relapse over 60 months in participants who presented with clinically isolated syndrome (CIS) accompanied by an abnormal magnetic resonance imaging (MRI) scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis \[MS\]) was calculated. Time to conversion to CDMS was represented by Kaplan-Meier estimates of the cumulative percentage (%) of participants with CDMS.

Time frame: Baseline (Day 1 of Study 27025) up to 60 Months

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

Time frame: Baseline (Day 1 of Study 27025) 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

Number of CUA lesions, new T2 lesions, new Gd+ Lesions and new T1 lesions were measured by using MRI scans.

Time frame: Month 60

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

Change from baseline in lesion volume was measured by using MRI scans for T1 hypointense lesions and T2 lesions.