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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT00813709
First received: December 22, 2008
Last updated: December 18, 2013
Last verified: December 2013
  Purpose

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).


Condition Intervention Phase
Multiple Sclerosis
Clinically Isolated Syndrome
Drug: RNF
Drug: Placebo
Phase 3

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

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • 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 [ Time Frame: Baseline (Day 1 of Study 27025) up to 36 Months ] [ Designated as safety issue: No ]
    CDMS was defined by the occurrence of a second exacerbation 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.


Secondary Outcome Measures:
  • Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months [ Time Frame: Baseline (Day 1 of Study 27025) up to 36 Months ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Month 36 ] [ Designated as safety issue: No ]
    Number of CUA lesions, new T2 lesions, new Gd+ lesions and new T1 lesions were measured by using MRI scans.

  • Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 [ Time Frame: Baseline (Day 1 of Study 27025), Month 36 ] [ Designated as safety issue: No ]
    Change from baseline in lesion volume was measured by using MRI scans for T1 hypointense lesions and T2 lesions at Month 36

  • Percent Change From Baseline in Brain Volume at Month 36 [ Time Frame: Baseline (Day 1 of Study 27025), Month 36 ] [ Designated as safety issue: No ]
    Percent change in brain volume was measured by using MRI scans.

  • Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months [ Time Frame: Baseline (Day 1 of Study 27025) up to CDMS conversion and/or up to 36 Months ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36 [ Time Frame: Baseline (Day of Study 27025), Month 36 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Relapse-Free Participants at Month 36 [ Time Frame: Month 36 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36 [ Time Frame: Baseline (Day of Study 27025), Month 36 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36 [ Time Frame: Baseline (Day 1 of Study 27025), Month 36 ] [ Designated as safety issue: No ]
    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).

  • Numbers of Participants With Positive Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 [ Time Frame: Month 36 ] [ Designated as safety issue: No ]
    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).

  • Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation [ Time Frame: Month 24 up to Month 36 (DB treatment period for study 28981 (REFLEXION) ] [ Designated as safety issue: Yes ]
    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 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 Frame: Baseline (Day 1 of Study 27025) up to 60 Months ] [ Designated as safety issue: No ]
    CDMS was defined by the occurrence of a second exacerbation 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 to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months [ Time Frame: Baseline (Day 1 of Study 27025) up to 60 Months ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Month 60 ] [ Designated as safety issue: No ]
    Number of CUA lesions, new T2 lesions, new Gd+ Lesions and new T1 lesions were measured by using MRI scans.

  • Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 [ Time Frame: Baseline (Day 1 of Study 27025), Month 60 ] [ Designated as safety issue: No ]
    Change from baseline in lesion volume was measured by using MRI scans for T1 hypointense lesions and T2 lesions.

  • Percent Change From Baseline in Brain Volume at Month 60 [ Time Frame: Baseline (Day 1 of Study 27025), Month 60 ] [ Designated as safety issue: No ]
    Percent Change in brain volume was measured by using MRI scans.

  • Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60 [ Time Frame: Month 60 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60 [ Time Frame: Baseline (Day 1 of Study 27025), Month 60 ] [ Designated as safety issue: No ]
    The 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.

  • Percentage of Relapse-Free Participants at Month 60 [ Time Frame: Month 60 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60 [ Time Frame: Baseline (Day 1 of Study 27025), Month 60 ] [ Designated as safety issue: No ]
    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 60 was calculated as EDSS score at Month 60 minus EDSS score at baseline.

  • Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60 [ Time Frame: Baseline (Day 1 of Study 27025), Month 60 ] [ Designated as safety issue: No ]
    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).

  • Numbers of Participants With Positive Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 [ Time Frame: Month 60 ] [ Designated as safety issue: No ]
    BAbs are all antibodies which are capable of binding to the 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.

  • Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation [ Time Frame: Month 24 up to Month 60 ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 402
Study Start Date: December 2008
Study Completion Date: September 2013
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: RNF 44 mcg thrice weekly Drug: RNF
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.
Other Name: Rebif®
Active Comparator: RNF 44 mcg once weekly and placebo Drug: RNF
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.
Other Name: Rebif®
Drug: Placebo
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).
Active Comparator: Placebo/RNF 44 mcg thrice weekly Drug: RNF
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.
Other Name: Rebif®

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00813709

  Show 57 Study Locations
Sponsors and Collaborators
Merck KGaA
Investigators
Study Director: Medical Responsible Merck Serono S.A., Geneva
  More Information

No publications provided

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT00813709     History of Changes
Other Study ID Numbers: 28981
Study First Received: December 22, 2008
Results First Received: November 27, 2012
Last Updated: December 18, 2013
Health Authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Austria: Agency for Health and Food Safety
Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Bulgaria: Bulgarian Drug Agency
Canada: Canadian Institutes of Health Research
Croatia: Ministry of Health and Social Care
Czech Republic: State Institute for Drug Control
Estonia: The State Agency of Medicine
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Greece: Ministry of Health and Welfare
Israel: Ministry of Health
Italy: Ethics Committee
Latvia: State Agency of Medicines
Morocco: Ministry of Public Health
Poland: Ministry of Health
Portugal: National Pharmacy and Medicines Institute
Romania: National Medicines Agency
Russia: Ministry of Health of the Russian Federation
Serbia and Montenegro: Agency for Drugs and Medicinal Devices
Slovakia: State Institute for Drug Control
Spain: Spanish Agency of Medicines

Keywords provided by Merck KGaA:
Interferon 1-beta
Clinical Definite Multiple Sclerosis

Additional relevant MeSH terms:
Multiple Sclerosis
Sclerosis
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Pathologic Processes
Interferon beta 1a
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 27, 2014