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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

December 22, 2008
December 18, 2013
December 2008
August 2011   (final data collection date for primary outcome 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 [ 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.
Time to conversion to CDMS defined by either a second attack or a sustained increase (greater than or equal to 1.5 points) in the EDSS score (as defined in study 27025 (REFLEX)), from randomization in study 27025 (REFLEX) up to Month 36. [ Time Frame: 36 Months from randomization in study 27025 (REFLEX) ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00813709 on ClinicalTrials.gov Archive Site
  • 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.
Time to conversion to CDMS (only at M36); Time to confirmed EDSS progression (≥1.0 point, confirmed during a visit performed 6 months later); MRI endpoints; Other secondary endpoints (PASAT, relapse-free subjects...); Safety endpoints (SAEs,BAbs&Nabs.) [ Time Frame: 36 and 60 months from randomisation in study 27025 (REFLEX) ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Long-term Follow-Up of Patients Who Participated in Study 27025 (REFLEX)
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)

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).

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
  • Multiple Sclerosis
  • Clinically Isolated Syndrome
  • 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®
  • 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: 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®
  • 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: RNF 44 mcg thrice weekly
    Intervention: Drug: RNF
  • Active Comparator: RNF 44 mcg once weekly and placebo
    Interventions:
    • Drug: RNF
    • Drug: Placebo
  • Active Comparator: Placebo/RNF 44 mcg thrice weekly
    Intervention: Drug: RNF
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
402
September 2013
August 2011   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Argentina,   Austria,   Belgium,   Bulgaria,   Canada,   Croatia,   Czech Republic,   Estonia,   Finland,   France,   Germany,   Greece,   Israel,   Italy,   Latvia,   Lebanon,   Morocco,   Poland,   Portugal,   Romania,   Russian Federation,   Serbia,   Slovakia,   Spain
 
NCT00813709
28981
Not Provided
Merck KGaA
Merck KGaA
Not Provided
Study Director: Medical Responsible Merck Serono S.A., Geneva
Merck KGaA
December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP