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CompletedNCT00813709REFLEXIONUpdated Mar 8, 2017Results posted

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

A Phase 3 interventional study of RNF and RNF in Multiple Sclerosis and Clinically Isolated Syndrome, sponsored by Merck KGaA, Darmstadt, Germany. Completed at 57 sites in 24 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-03-08.

Sponsored by Merck KGaA, Darmstadt, Germany · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
402
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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).

Read the 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).

02

Conditions studied

  • Multiple Sclerosis
  • Clinically Isolated Syndrome

Keywords

  • Interferon 1-beta
  • Clinical Definite Multiple Sclerosis
03

In context

Multiple Sclerosis

3,460 studies on the registry are indexed under Multiple Sclerosis; 661 are open to participants now.

This study's enrollment of 402 is above the median of 50 across 2,342 interventional studies indexed under Multiple Sclerosis.

Browse Multiple Sclerosis studies →

Lead sponsor

Merck KGaA, Darmstadt, Germany is the lead sponsor of 269 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
402 participants (actual)

Study arms

  • Active comparator
    RNF 44 mcg thrice weekly

    Drug: RNF

  • Active comparator
    RNF 44 mcg once weekly and placebo

    Drug: RNF · Drug: Placebo

  • Active comparator
    Placebo/RNF 44 mcg thrice weekly

    Drug: RNF

Interventions

  • DrugRNF

    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.

    Also known as: Rebif®

  • DrugRNF

    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.

    Also known as: Rebif®

  • DrugRNF

    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.

    Also known as: Rebif®

  • DrugPlacebo

    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).

06

What researchers measure

Primary outcomes

  1. 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

  1. 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

  2. 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

  3. 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

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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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)

  12. 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

    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

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

  14. 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

  15. 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.

    Time frame: Baseline (Day 1 of Study 27025), Month 60

  16. Percent Change From Baseline in Brain Volume at Month 60

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

    Time frame: Baseline (Day 1 of Study 27025), Month 60

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

    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: Month 60

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

    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.

    Time frame: Baseline (Day 1 of Study 27025), Month 60

  19. Percentage of Relapse-Free Participants at Month 60

    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 60

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

    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.

    Time frame: Baseline (Day 1 of Study 27025), Month 60

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

    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 60

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

    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.

    Time frame: Month 60

  23. 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 60

07

Results

Posted Oct 28, 2013

Participant flow

Participants who were randomized in Study 27025 (NCT00404352) were eligible to enroll into extension Study 28981 (NCT00813709) whether or not they completed main study on Investigational Medicinal Product (IMP), or no treatment or received other disease-modifying drugs (DMDs) during course of main study. No re-randomization was done for this study.

Double Blind Period
Participant flow — Double Blind Period
MilestonePlacebo/RNF 44 Mcg Thrice Weekly (DB Population)RNF 44 Mcg Once Weekly (DB Population)RNF 44 Mcg Thrice Weekly (DB Population)Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice WeeklyRNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice WeeklyRNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly
Started8411799000
Treated8311498000
Completed537668000
Not completed314131000
Withdrew: Adverse event414000
Withdrew: Lost to follow-up322000
Withdrew: Switched to open label phase92618000
Withdrew: Randomized but not treated131000
Withdrew: Other1496000
Open Label Period
Participant flow — Open Label Period
MilestonePlacebo/RNF 44 Mcg Thrice Weekly (DB Population)RNF 44 Mcg Once Weekly (DB Population)RNF 44 Mcg Thrice Weekly (DB Population)Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice WeeklyRNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice WeeklyRNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly
Started000585146
Treated000575145
Completed000384135
Not completed000201011
Withdrew: Adverse event000543
Withdrew: Lack of efficacy000311
Withdrew: Randomized but not treated000101
Withdrew: Other0001156

Outcome measures

PrimaryTime 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
Reported as:
Number · Cumulative % of participants with CDMS
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
Cumulative % of participants with CDMSPlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
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 Months41.3 (33.5 to 49.1)27.6 (20.6 to 34.6)27.1 (19.9 to 34.3)
Statistical analysis
  • Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) vs RNF 44 Mcg Thrice Weekly (Integrated ITT Population) · Log Rank · p = 0.002 · Hazard ratio (hr): 0.555 · 95% CI 0.378 to 0.816
  • Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) vs RNF 44 Mcg Once Weekly (Integrated ITT Population) · Log Rank · p = 0.006 · Hazard ratio (hr): 0.573 · 95% CI 0.391 to 0.839
  • RNF 44 Mcg Once Weekly (Integrated ITT Population) vs RNF 44 Mcg Thrice Weekly (Integrated ITT Population) · Log Rank · p = 0.941 · Hazard ratio (hr): 0.993 · 95% CI 0.654 to 1.510
SecondaryTime 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
Reported as:
Number · % of participants with EDSS progression
Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months
% of participants with EDSS progressionPlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months7.511.813.2
Statistical analysis
  • Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) vs RNF 44 Mcg Thrice Weekly (Integrated ITT Population) · Log Rank · p = 0.205
  • Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) vs RNF 44 Mcg Once Weekly (Integrated ITT Population) · Log Rank · p = 0.263
  • RNF 44 Mcg Once Weekly (Integrated ITT Population) vs RNF 44 Mcg Thrice Weekly (Integrated ITT Population) · Log Rank · p = 0.629
SecondaryNumber 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
Reported as:
Mean · lesions
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
lesionsPlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
CUA Lesions1.02 ± 1.851.83 ± 3.3171.63 ± 5.947
New T2 Lesions0.83 ± 1.5451.39 ± 2.5731.19 ± 4.217
New Gd+ Lesions0.17 ± 0.5060.40 ± 1.3540.41 ± 1.754
New T1 Lesions0.69 ± 1.7211.09 ± 2.4820.91 ± 4.143
SecondaryChange 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

Time frame:
Baseline (Day 1 of Study 27025), Month 36
Reported as:
Mean · cubic millimeter (mm^3)
Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36
cubic millimeter (mm^3)Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
T1 lesion volume at Baseline (n=171,175,171)670.3 ± 1054.1774.8 ± 1288.0675.0 ± 1049.9
T1 lesion volume Change: Month 36(n=124,133,114)303.2 ± 1034.6272.0 ± 921.4133.3 ± 763.5
T2 lesion volume at Baseline (n=171,175,171)3334.9 ± 3990.43853.1 ± 4716.73110.5 ± 3410.7
T2 lesion volume Change: Month 36(n=124,133,114)-3.8 ± 2101.8-56.9 ± 2436.3-398.1 ± 1415.4
SecondaryPercent 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
Reported as:
Mean · percent change
Percent Change From Baseline in Brain Volume at Month 36
percent changePlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Percent Change From Baseline in Brain Volume at Month 36-1.02 ± 1.248-0.86 ± 1.073-1.14 ± 1.321
SecondaryPercentage 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
Reported as:
Number · percentage of participants
Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months
percentage of participantsPlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months84.276.066.7
SecondaryChange 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
Reported as:
Mean · units on a scale
Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36
units on a scalePlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Baseline (n=171,175,171)0.0358 ± 0.8787-0.0909 ± 1.12230.0031 ± 1.1387
Change at Month 36 (n=123,135,118)0.3483 ± 0.69490.5044 ± 0.75880.4515 ± 0.9164
SecondaryPercentage 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
Reported as:
Number · Percentage of participants
Percentage of Relapse-Free Participants at Month 36
Percentage of participantsPlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Percentage of Relapse-Free Participants at Month 3642.758.351.5
SecondaryChange 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
Reported as:
Mean · units on a scale
Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36
units on a scalePlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Baseline (n=171,175,171)1.53 ± 0.771.50 ± 0.721.51 ± 0.83
Change at Month 36 (n=120,136,116)-0.21 ± 0.93-0.11 ± 0.96-0.09 ± 0.90
SecondaryChange 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
Reported as:
Mean · Z-score
Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36
Z-scorePlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
MFSC score at Baseline (n=171,175,171)0.0352 ± 0.58440.0071 ± 0.6653-0.0575 ± 0.6226
Change at Month 36 (n=123,135,118)0.1993 ± 0.48630.2529 ± 0.57940.3074 ± 0.6071
SecondaryNumbers 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
Reported as:
Number · participants
Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36
participantsPlacebo/RNF 44 Mcg Thrice Weekly (Integrated DB Population)RNF 44 Mcg Once Weekly (Integrated DB Population)RNF 44 Mcg Thrice Weekly (Integrated DB Population)
BAb-779788
BAb+413430
NAb-10010999
NAb+182219
SecondaryNumber 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)
Reported as:
Number · participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation
participantsPlacebo/RNF 44 Mcg Thrice Weekly (DB Population)RNF 44 Mcg Once Weekly (DB Population)RNF 44 Mcg Thrice Weekly (DB Population)
AEs796745
SAEs324
AEs leading to discontinuation202
SecondaryTime 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

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
Reported as:
Number · Cumulative % of participants with CDMS
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
Cumulative % of participants with CDMSPlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
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 6044.6 (36.6 to 52.6)40.7 (32.8 to 48.6)39.2 (30.8 to 47.6)
SecondaryTime to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 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 60 Months
Reported as:
Number · % of participants with EDSS progression
Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months
% of participants with EDSS progressionPlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months11.018.718.4
SecondaryNumber 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
Reported as:
Mean · lesions
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
lesionsPlacebo/RNF 44 Mcg Thrice Weekly (ITT Population)RNF 44 Mcg Once Weekly (ITT Population)RNF 44 Mcg Thrice Weekly (ITT Population)
CUA Lesions (n=102, 121, 110)1.46 ± 3.3941.60 ± 3.5421.94 ± 4.803
New T2 Lesions (n=102, 121, 110)1.17 ± 2.5761.17 ± 2.6281.35 ± 3.284
New Gd+ Lesions (n=102, 121, 110)0.24 ± 0.8230.36 ± 1.2250.48 ± 1.618
New T1 Lesions (n=102, 120, 110)0.57 ± 1.6560.69 ± 1.6590.71 ± 1.917
SecondaryChange 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.

Time frame:
Baseline (Day 1 of Study 27025), Month 60
Reported as:
Mean · mm^3
Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60
mm^3Placebo/RNF 44 Mcg Thrice Weekly (ITT Population)RNF 44 Mcg Once Weekly (ITT Population)RNF 44 Mcg Thrice Weekly (ITT Population)
T1 lesion volume at Baseline (n=171,175,171)670.3 ± 1054.1774.8 ± 1288.0675.0 ± 1049.9
Change at Month 60 (n=102,120,110)415.0 ± 1080.3412.3 ± 1020.8261.8 ± 1006.1
T2 lesion volume at Baseline (n=171,175,171)3334.9 ± 3990.43853.1 ± 4716.73110.5 ± 3410.7
Change at Month 60 (n=102,121,110)119.4 ± 2225.225.0 ± 2827.1-188.5 ± 2576.1
SecondaryPercent Change From Baseline in Brain Volume at Month 60

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

Time frame:
Baseline (Day 1 of Study 27025), Month 60
Reported as:
Mean · percent change
Percent Change From Baseline in Brain Volume at Month 60
percent changePlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Percent Change From Baseline in Brain Volume at Month 60-1.82 ± 1.494-1.54 ± 1.378-2.03 ± 1.644
SecondaryPercentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60

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:
Month 60
Reported as:
Number · percentage of participants
Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60
percentage of participantsPlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 6084.282.972.5
SecondaryChange From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60

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.

Time frame:
Baseline (Day 1 of Study 27025), Month 60
Reported as:
Mean · units on a scale
Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60
units on a scalePlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Baseline (n=171, 175, 171)0.0358 ± 0.8787-0.0909 ± 1.12230.0031 ± 1.1387
Change at Month 60 (n=112, 132, 118)0.4109 ± 0.68440.4785 ± 0.98860.4608 ± 0.8630
SecondaryPercentage of Relapse-Free Participants at Month 60

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 60
Reported as:
Number · percentage of participants
Percentage of Relapse-Free Participants at Month 60
percentage of participantsPlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Percentage of Relapse-Free Participants at Month 6034.545.140.9
SecondaryChange From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60

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.

Time frame:
Baseline (Day 1 of Study 27025), Month 60
Reported as:
Mean · units on a scale
Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60
units on a scalePlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Baseline (n=171,175,171)1.53 ± 0.771.50 ± 0.721.51 ± 0.83
Change at Month 60 (n=111,133,117)-0.11 ± 0.94-0.01 ± 1.010.04 ± 1.02
SecondaryChange From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60

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 60
Reported as:
Mean · Z-score
Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60
Z-scorePlacebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population)RNF 44 Mcg Once Weekly (Integrated ITT Population)RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
MFSC score at Baseline (n=171,175,171)0.0352 ± 0.58440.0071 ± 0.6653-0.0575 ± 0.6226
Change at Month 60 (n=112,132,132)0.2290 ± 0.48240.2213 ± 0.56020.2192 ± 0.6229
SecondaryNumbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60

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.

Time frame:
Month 60
Reported as:
Number · participants
Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60
participantsPlacebo/RNF 44 Mcg Thrice Weekly (Integrated DB Population)RNF 44 Mcg Once Weekly (Integrated DB Population)RNF 44 Mcg Thrice Weekly (Integrated DB Population)
BAb-8999100
BAb+253015
BAb (Missing)110
NAb-97110102
NAb+182013
SecondaryNumber 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 60
Reported as:
Number · participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation
participantsPlacebo/RNF 44 Mcg Thrice Weekly (DB Population)RNF 44 Mcg Once Weekly (DB Population)RNF 44 Mcg Thrice Weekly (DB Population)
AEs709684
SAEs779
AEs leading to discontinuation302

Adverse events

Collected over Month 24 to 60 for both DB safety population and OL safety population. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo/RNF 44 Mcg Thrice Weekly (DB Population)—7/84 (8.3%)69/84 (82.1%)
RNF 44 Mcg Once Weekly (DB Population)—7/117 (6%)97/117 (82.9%)
RNF 44 Mcg Thrice Weekly (DB Population)—9/99 (9.1%)84/99 (84.8%)
Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly—2/58 (3.4%)46/58 (79.3%)
RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly—3/51 (5.9%)37/51 (72.5%)
RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly—4/46 (8.7%)36/46 (78.3%)
Most frequent serious events
Showing 10 of 34
Most frequent serious events
EventPlacebo/RNF 44 Mcg Thrice Weekly (DB Population)RNF 44 Mcg Once Weekly (DB Population)RNF 44 Mcg Thrice Weekly (DB Population)Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice WeeklyRNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice WeeklyRNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly
AppendicitisInfections and infestations0/841/1170/990/580/511/46
Benign neoplasm of thyroid glandNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/840/1170/990/580/511/46
Lumbar radiculopathyNervous system disorders0/840/1170/990/580/511/46
Abortion missedPregnancy, puerperium and perinatal conditions0/841/1170/990/580/511/46
Eye haemorrhageEye disorders0/840/1171/990/581/510/46
Abdominal painGastrointestinal disorders0/840/1170/990/581/510/46
HypertensionVascular disorders0/840/1170/990/581/510/46
Abdominal pain upperGastrointestinal disorders0/840/1170/991/580/510/46
Acute coronary syndromeCardiac disorders0/840/1170/991/580/510/46
Peritonsillar abscessInfections and infestations1/840/1170/990/580/510/46
Most frequent other events
Showing 10 of 34
Most frequent other events
EventPlacebo/RNF 44 Mcg Thrice Weekly (DB Population)RNF 44 Mcg Once Weekly (DB Population)RNF 44 Mcg Thrice Weekly (DB Population)Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice WeeklyRNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice WeeklyRNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly
Influenza like illnessGeneral disorders45/8439/11717/9911/5812/5110/46
Injection site erythemaGeneral disorders17/846/1178/994/588/512/46
HeadacheNervous system disorders11/8419/11716/994/586/519/46
OverdoseInjury, poisoning and procedural complications0/840/1170/992/588/511/46
NasopharyngitisInfections and infestations12/8414/1179/996/587/514/46
Upper respiratory tract infectionInfections and infestations10/8411/11710/996/585/515/46
Back painMusculoskeletal and connective tissue disorders5/847/1176/995/582/515/46
LeukopeniaBlood and lymphatic system disorders9/842/1172/990/584/511/46
NeutropeniaBlood and lymphatic system disorders8/843/1175/990/584/511/46
PharyngitisInfections and infestations0/840/1170/992/580/514/46

Baseline characteristics

Baseline data was presented for ITT population (402 participants) which included participants who had completed the REFLEX Study 27025 (NCT00404352) and were enrolled in this extension Study 28981 (REFLEXION).

Age, Continuous
Age, Continuous(years)Placebo/RNF 44 Mcg Thrice Weekly (ITT Population)RNF 44 Mcg Once Weekly (ITT Population)RNF 44 Mcg Thrice Weekly (ITT Population)Total
Mean31.0 ± 8.231.4 ± 8.231.8 ± 8.631.4 ± 8.3
Age, Customized
Age, Customized(participants)Placebo/RNF 44 Mcg Thrice Weekly (ITT Population)RNF 44 Mcg Once Weekly (ITT Population)RNF 44 Mcg Thrice Weekly (ITT Population)Total
Less than 30 years676655188
Greater than or equal to 30 years667672214
Sex: Female, Male
Sex: Female, Male(Participants)Placebo/RNF 44 Mcg Thrice Weekly (ITT Population)RNF 44 Mcg Once Weekly (ITT Population)RNF 44 Mcg Thrice Weekly (ITT Population)Total
Female828878248
Male515449154
Race/Ethnicity, Customized
Race/Ethnicity, Customized(participants)Placebo/RNF 44 Mcg Thrice Weekly (ITT Population)RNF 44 Mcg Once Weekly (ITT Population)RNF 44 Mcg Thrice Weekly (ITT Population)Total
Black0101
White133141127401
08

Study locations

57 sites
  • 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
09

References and documents

Publications

  • 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. PubMed 28039317 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Mar 8, 2017, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00813709
Lead sponsor
Merck KGaA, Darmstadt, Germany
Responsible party
Sponsor
First posted
Dec 23, 2008
Start date
Dec 2008
Primary completion
Aug 2011
Completion
Sep 2013
Results posted
Oct 28, 2013
Last update
Mar 8, 2017

Study contacts

Medical Responsible
study director · Merck Serono S.A., Geneva
View the source record on ClinicalTrials.gov ↗

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