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

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ClinicalTrials.gov Identifier: NCT00813709
Recruitment Status : Completed
First Posted : December 23, 2008
Results First Posted : October 28, 2013
Last Update Posted : March 8, 2017
Sponsor:
Information provided by (Responsible Party):
Merck KGaA, Darmstadt, Germany

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Multiple Sclerosis
Clinically Isolated Syndrome
Interventions Drug: RNF
Drug: Placebo
Enrollment 402

Recruitment Details 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.
Pre-assignment Details 517 participants randomized in Study 27025 used in this study as integrated intention to treat (ITT) population. Out of the 517, 402 participants took part in study 28981: 300 comprised the double blind (DB) population and 122 comprised the open label (OL) population (some participants (20) were included in both populations)
Arm/Group Title Placebo/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 Weekly RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly
Hide Arm/Group Description Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. Participants after having converted to CDMS during study 28981 (REFLEXION), received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. The participants who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months. Participants after having converted to CDMS during study 28981 (REFLEXION), received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. The participants who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months. Participants after having converted to CDMS during study 28981 (REFLEXION), received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. The participants who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months.
Period Title: Double Blind Period
Started 84 117 99 0 0 0
Treated 83 114 98 0 0 0
Completed 53 76 68 0 0 0
Not Completed 31 41 31 0 0 0
Reason Not Completed
Adverse Event             4             1             4             0             0             0
Lost to Follow-up             3             2             2             0             0             0
Switched to open label phase             9             26             18             0             0             0
Randomized but not treated             1             3             1             0             0             0
Other             14             9             6             0             0             0
Period Title: Open Label Period
Started 0 0 0 58 [1] 51 [2] 46 [3]
Treated 0 0 0 57 51 45
Completed 0 0 0 38 41 35
Not Completed 0 0 0 20 10 11
Reason Not Completed
Adverse Event             0             0             0             5             4             3
Lack of Efficacy             0             0             0             3             1             1
Randomized but not treated             0             0             0             1             0             1
Other             0             0             0             11             5             6
[1]
49 participants in OL period initially + 9 participants from DB converted to CDMS during the study
[2]
25 participants in OL period initially + 26 participants from DB converted to CDMS during the study
[3]
28 participants in OL period initially + 18 participants from DB converted to CDMS during the study
Arm/Group Title Placebo/RNF 44 Mcg Thrice Weekly (ITT Population) RNF 44 Mcg Once Weekly (ITT Population) RNF 44 Mcg Thrice Weekly (ITT Population) Total
Hide Arm/Group Description Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of RNF injection administered subcutaneously 3 times weekly at least 48 hours apart 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 or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months. 84 participants were initially assigned to DB RNF 44 mcg thrice weekly and 49 participants were initially assigned to OL RNF 44 mcg thrice weekly (9 participants from DB converted to CDMS and switched to OL period over course of this study) Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. 117 participants were initially assigned to DB RNF 44 mcg thrice weekly and 25 participants were initially assigned to OL RNF 44 mcg thrice weekly (26 participants from DB converted to CDMS and switched to OL period over course of this study) Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. 99 participants were initially assigned to DB RNF 44 mcg thrice weekly and 28 participants were initially assigned to OL RNF 44 mcg thrice weekly (18 participants from DB converted to CDMS and switched to OL period over course of this study) Total of all reporting groups
Overall Number of Baseline Participants 133 142 127 402
Hide Baseline Analysis Population Description
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  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 133 participants 142 participants 127 participants 402 participants
31.0  (8.2) 31.4  (8.2) 31.8  (8.6) 31.4  (8.3)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 133 participants 142 participants 127 participants 402 participants
Less than 30 years 67 66 55 188
Greater than or equal to 30 years 66 76 72 214
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 133 participants 142 participants 127 participants 402 participants
Female
82
  61.7%
88
  62.0%
78
  61.4%
248
  61.7%
Male
51
  38.3%
54
  38.0%
49
  38.6%
154
  38.3%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 133 participants 142 participants 127 participants 402 participants
Black 0 1 0 1
White 133 141 127 401
1.Primary Outcome
Title 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
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Overall Number of Participants Analyzed 171 175 171
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Cumulative % of participants with CDMS
41.3
(33.5 to 49.1)
27.6
(20.6 to 34.6)
27.1
(19.9 to 34.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population), RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.555
Confidence Interval (2-Sided) 95%
0.378 to 0.816
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population), RNF 44 Mcg Once Weekly (Integrated ITT Population)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.573
Confidence Interval (2-Sided) 95%
0.391 to 0.839
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection RNF 44 Mcg Once Weekly (Integrated ITT Population), RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.941
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.993
Confidence Interval (2-Sided) 95%
0.654 to 1.510
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Overall Number of Participants Analyzed 171 175 171
Measure Type: Number
Unit of Measure: % of participants with EDSS progression
7.5 11.8 13.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population), RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.205
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population), RNF 44 Mcg Once Weekly (Integrated ITT Population)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.263
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection RNF 44 Mcg Once Weekly (Integrated ITT Population), RNF 44 Mcg Thrice Weekly (Integrated ITT Population)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.629
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
3.Secondary Outcome
Title 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
Hide Description Number of CUA lesions, new T2 lesions, new Gd+ lesions and new T1 lesions were measured by using MRI scans.
Time Frame Month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure at this time point.
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Overall Number of Participants Analyzed 124 133 114
Mean (Standard Deviation)
Unit of Measure: lesions
CUA Lesions 1.02  (1.85) 1.83  (3.317) 1.63  (5.947)
New T2 Lesions 0.83  (1.545) 1.39  (2.573) 1.19  (4.217)
New Gd+ Lesions 0.17  (0.506) 0.40  (1.354) 0.41  (1.754)
New T1 Lesions 0.69  (1.721) 1.09  (2.482) 0.91  (4.143)
4.Secondary Outcome
Title Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). "n" signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Overall Number of Participants Analyzed 171 175 171
Mean (Standard Deviation)
Unit of Measure: cubic millimeter (mm^3)
T1 lesion volume at Baseline (n=171,175,171) 670.3  (1054.1) 774.8  (1288.0) 675.0  (1049.9)
T1 lesion volume Change: Month 36(n=124,133,114) 303.2  (1034.6) 272.0  (921.4) 133.3  (763.5)
T2 lesion volume at Baseline (n=171,175,171) 3334.9  (3990.4) 3853.1  (4716.7) 3110.5  (3410.7)
T2 lesion volume Change: Month 36(n=124,133,114) -3.8  (2101.8) -56.9  (2436.3) -398.1  (1415.4)
5.Secondary Outcome
Title Percent Change From Baseline in Brain Volume at Month 36
Hide Description Percent change in brain volume was measured by using MRI scans.
Time Frame Baseline (Day 1 of Study 27025), Month 36
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure at this time point.
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Overall Number of Participants Analyzed 120 132 112
Mean (Standard Deviation)
Unit of Measure: percent change
-1.02  (1.248) -0.86  (1.073) -1.14  (1.321)
6.Secondary Outcome
Title Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Overall Number of Participants Analyzed 171 175 171
Measure Type: Number
Unit of Measure: percentage of participants
84.2 76.0 66.7
7.Secondary Outcome
Title Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). "n" signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Overall Number of Participants Analyzed 171 175 171
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline (n=171,175,171) 0.0358  (0.8787) -0.0909  (1.1223) 0.0031  (1.1387)
Change at Month 36 (n=123,135,118) 0.3483  (0.6949) 0.5044  (0.7588) 0.4515  (0.9164)
8.Secondary Outcome
Title Percentage of Relapse-Free Participants at Month 36
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Overall Number of Participants Analyzed 171 175 171
Measure Type: Number
Unit of Measure: Percentage of participants
42.7 58.3 51.5
9.Secondary Outcome
Title Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). "n" signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Overall Number of Participants Analyzed 171 175 171
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline (n=171,175,171) 1.53  (0.77) 1.50  (0.72) 1.51  (0.83)
Change at Month 36 (n=120,136,116) -0.21  (0.93) -0.11  (0.96) -0.09  (0.90)
10.Secondary Outcome
Title Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). "n" signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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 36 months.
Overall Number of Participants Analyzed 171 175 171
Mean (Standard Deviation)
Unit of Measure: Z-score
MFSC score at Baseline (n=171,175,171) 0.0352  (0.5844) 0.0071  (0.6653) -0.0575  (0.6226)
Change at Month 36 (n=123,135,118) 0.1993  (0.4863) 0.2529  (0.5794) 0.3074  (0.6071)
11.Secondary Outcome
Title Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36
Hide Description 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
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Hide Analysis Population Description
Data has been presented as per planned analysis for integrated DB population which included all participants who received at least one dose of DB treatment in REFLEX study 27025 (NCT00404352). 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure at this time point.
Arm/Group Title Placebo/RNF 44 Mcg Thrice Weekly (Integrated DB Population) RNF 44 Mcg Once Weekly (Integrated DB Population) RNF 44 Mcg Thrice Weekly (Integrated DB Population)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first.
Overall Number of Participants Analyzed 118 131 118
Measure Type: Number
Unit of Measure: participants
BAb- 77 97 88
BAb+ 41 34 30
NAb- 100 109 99
NAb+ 18 22 19
12.Secondary Outcome
Title Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation
Hide Description 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)
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Hide Analysis Population Description
DB Safety Population 28981 (REFLEXION) included all the participants who discontinued DB treatment in REFLEX study 27025 (NCT00404352) and were enrolled in 28981 (REFLEXION) study and received at least one dose of DB treatment in this study. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Placebo/RNF 44 Mcg Thrice Weekly (DB Population) RNF 44 Mcg Once Weekly (DB Population) RNF 44 Mcg Thrice Weekly (DB Population)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first.
Overall Number of Participants Analyzed 84 117 99
Measure Type: Number
Unit of Measure: participants
AEs 79 67 45
SAEs 3 2 4
AEs leading to discontinuation 2 0 2
13.Secondary Outcome
Title 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
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Overall Number of Participants Analyzed 171 175 171
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Cumulative % of participants with CDMS
44.6
(36.6 to 52.6)
40.7
(32.8 to 48.6)
39.2
(30.8 to 47.6)
14.Secondary Outcome
Title Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Overall Number of Participants Analyzed 171 175 171
Measure Type: Number
Unit of Measure: % of participants with EDSS progression
11.0 18.7 18.4
15.Secondary Outcome
Title 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
Hide Description Number of CUA lesions, new T2 lesions, new Gd+ Lesions and new T1 lesions were measured by using MRI scans.
Time Frame Month 60
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). "n" signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
Arm/Group Title Placebo/RNF 44 Mcg Thrice Weekly (ITT Population) RNF 44 Mcg Once Weekly (ITT Population) RNF 44 Mcg Thrice Weekly (ITT Population)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of RNF injection administered subcutaneously 3 times weekly at least 48 hours apart 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 or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. 84 participants were initially assigned to DB RNF 44 mcg thrice weekly and 49 participants were initially assigned to OL RNF 44 mcg thrice weekly (4 participants from DB converted to CDMS and switched to OL period over course of this study)
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. 117 participants were initially assigned to DB RNF 44 mcg thrice weekly and 25 participants were initially assigned to OL RNF 44 mcg thrice weekly (10 participants from DB converted to CDMS and switched to OL period over course of this study)
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. 99 participants were initially assigned to DB RNF 44 mcg thrice weekly and 28 participants were initially assigned to OL RNF 44 mcg thrice weekly (6 participants from DB converted to CDMS and switched to OL period over course of this study)
Overall Number of Participants Analyzed 171 175 171
Mean (Standard Deviation)
Unit of Measure: lesions
CUA Lesions (n=102, 121, 110) 1.46  (3.394) 1.60  (3.542) 1.94  (4.803)
New T2 Lesions (n=102, 121, 110) 1.17  (2.576) 1.17  (2.628) 1.35  (3.284)
New Gd+ Lesions (n=102, 121, 110) 0.24  (0.823) 0.36  (1.225) 0.48  (1.618)
New T1 Lesions (n=102, 120, 110) 0.57  (1.656) 0.69  (1.659) 0.71  (1.917)
16.Secondary Outcome
Title Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). "n" signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
Arm/Group Title Placebo/RNF 44 Mcg Thrice Weekly (ITT Population) RNF 44 Mcg Once Weekly (ITT Population) RNF 44 Mcg Thrice Weekly (ITT Population)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of RNF injection administered subcutaneously 3 times weekly at least 48 hours apart 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 or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. 84 participants were initially assigned to DB RNF 44 mcg thrice weekly and 49 participants were initially assigned to OL RNF 44 mcg thrice weekly (4 participants from DB converted to CDMS and switched to OL period over course of this study)
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. 117 participants were initially assigned to DB RNF 44 mcg thrice weekly and 25 participants were initially assigned to OL RNF 44 mcg thrice weekly (10 participants from DB converted to CDMS and switched to OL period over course of this study)
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. 99 participants were initially assigned to DB RNF 44 mcg thrice weekly and 28 participants were initially assigned to OL RNF 44 mcg thrice weekly (6 participants from DB converted to CDMS and switched to OL period over course of this study)
Overall Number of Participants Analyzed 171 175 171
Mean (Standard Deviation)
Unit of Measure: mm^3
T1 lesion volume at Baseline (n=171,175,171) 670.3  (1054.1) 774.8  (1288.0) 675.0  (1049.9)
Change at Month 60 (n=102,120,110) 415.0  (1080.3) 412.3  (1020.8) 261.8  (1006.1)
T2 lesion volume at Baseline (n=171,175,171) 3334.9  (3990.4) 3853.1  (4716.7) 3110.5  (3410.7)
Change at Month 60 (n=102,121,110) 119.4  (2225.2) 25.0  (2827.1) -188.5  (2576.1)
17.Secondary Outcome
Title Percent Change From Baseline in Brain Volume at Month 60
Hide Description Percent Change in brain volume was measured by using MRI scans.
Time Frame Baseline (Day 1 of Study 27025), Month 60
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure at this time point.
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Overall Number of Participants Analyzed 98 120 110
Mean (Standard Deviation)
Unit of Measure: percent change
-1.82  (1.494) -1.54  (1.378) -2.03  (1.644)
18.Secondary Outcome
Title Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Overall Number of Participants Analyzed 171 175 171
Measure Type: Number
Unit of Measure: percentage of participants
84.2 82.9 72.5
19.Secondary Outcome
Title Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). "n" signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Overall Number of Participants Analyzed 171 175 171
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline (n=171, 175, 171) 0.0358  (0.8787) -0.0909  (1.1223) 0.0031  (1.1387)
Change at Month 60 (n=112, 132, 118) 0.4109  (0.6844) 0.4785  (0.9886) 0.4608  (0.8630)
20.Secondary Outcome
Title Percentage of Relapse-Free Participants at Month 60
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Overall Number of Participants Analyzed 171 175 171
Measure Type: Number
Unit of Measure: percentage of participants
34.5 45.1 40.9
21.Secondary Outcome
Title Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). "n" signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Overall Number of Participants Analyzed 171 175 171
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline (n=171,175,171) 1.53  (0.77) 1.50  (0.72) 1.51  (0.83)
Change at Month 60 (n=111,133,117) -0.11  (0.94) -0.01  (1.01) 0.04  (1.02)
22.Secondary Outcome
Title Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). "n" signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
Arm/Group Title 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)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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.
Overall Number of Participants Analyzed 171 175 171
Mean (Standard Deviation)
Unit of Measure: Z-score
MFSC score at Baseline (n=171,175,171) 0.0352  (0.5844) 0.0071  (0.6653) -0.0575  (0.6226)
Change at Month 60 (n=112,132,132) 0.2290  (0.4824) 0.2213  (0.5602) 0.2192  (0.6229)
23.Secondary Outcome
Title Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Data has been presented as per planned analysis for integrated DB population which included all participants who received at least one dose of DB treatment in REFLEX study 27025 (NCT00404352). 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure at this time point.
Arm/Group Title Placebo/RNF 44 Mcg Thrice Weekly (Integrated DB Population) RNF 44 Mcg Once Weekly (Integrated DB Population) RNF 44 Mcg Thrice Weekly (Integrated DB Population)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.
Overall Number of Participants Analyzed 115 130 115
Measure Type: Number
Unit of Measure: participants
BAb- 89 99 100
BAb+ 25 30 15
BAb (Missing) 1 1 0
NAb- 97 110 102
NAb+ 18 20 13
24.Secondary Outcome
Title Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
DB Safety Population 28981 (REFLEXION) included all the participants who discontinued DB treatment in REFLEX study 27025 (NCT00404352) and were enrolled in 28981 (REFLEXION) study and received at least one dose of DB treatment in this study. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Placebo/RNF 44 Mcg Thrice Weekly (DB Population) RNF 44 Mcg Once Weekly (DB Population) RNF 44 Mcg Thrice Weekly (DB Population)
Hide Arm/Group Description:
Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.
Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.
Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.
Overall Number of Participants Analyzed 84 117 99
Measure Type: Number
Unit of Measure: participants
AEs 70 96 84
SAEs 7 7 9
AEs leading to discontinuation 3 0 2
Time Frame Month 24 to 60 for both DB safety population and OL safety population
Adverse Event Reporting Description An adverse event (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.
 
Arm/Group Title Placebo/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 Weekly RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly
Hide Arm/Group Description Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first. Participants after having converted to CDMS during study 28981 (REFLEXION), received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. The participants who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months. Participants after having converted to CDMS during study 28981 (REFLEXION), received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. The participants who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months. Participants after having converted to CDMS during study 28981 (REFLEXION), received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart 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. The participants who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months.
All-Cause Mortality
Placebo/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 Weekly RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo/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 Weekly RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   7/84 (8.33%)   7/117 (5.98%)   9/99 (9.09%)   2/58 (3.45%)   3/51 (5.88%)   4/46 (8.70%) 
Cardiac disorders             
Angina stable * 1  0/84 (0.00%)  0/117 (0.00%)  1/99 (1.01%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Acute coronary syndrome * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  1/58 (1.72%)  0/51 (0.00%)  0/46 (0.00%) 
Congenital, familial and genetic disorders             
Foetal chromosome abnormality * 1  0/84 (0.00%)  1/117 (0.85%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Ear and labyrinth disorders             
Vestibular disorder * 1  0/84 (0.00%)  1/117 (0.85%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Eye disorders             
Eye haemorrhage * 1  0/84 (0.00%)  0/117 (0.00%)  1/99 (1.01%)  0/58 (0.00%)  1/51 (1.96%)  0/46 (0.00%) 
Gastrointestinal disorders             
Enterovesical fistula * 1  0/84 (0.00%)  0/117 (0.00%)  1/99 (1.01%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Haematemesis * 1  1/84 (1.19%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Melaena * 1  1/84 (1.19%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Abdominal pain * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  1/51 (1.96%)  0/46 (0.00%) 
Abdominal pain upper * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  1/58 (1.72%)  0/51 (0.00%)  0/46 (0.00%) 
Infections and infestations             
Abscess intestinal * 1  0/84 (0.00%)  0/117 (0.00%)  1/99 (1.01%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Diverticulitis * 1  0/84 (0.00%)  0/117 (0.00%)  1/99 (1.01%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Viral infection * 1  0/84 (0.00%)  0/117 (0.00%)  1/99 (1.01%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Appendicitis * 1  0/84 (0.00%)  1/117 (0.85%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  1/46 (2.17%) 
Endometritis * 1  0/84 (0.00%)  1/117 (0.85%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Peritonsillar abscess * 1  1/84 (1.19%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Salpingo-oophoritis * 1  1/84 (1.19%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Injury, poisoning and procedural complications             
Fibula fracture * 1  1/84 (1.19%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Post procedural fistula * 1  1/84 (1.19%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Musculoskeletal and connective tissue disorders             
Osteoarthritis * 1  0/84 (0.00%)  0/117 (0.00%)  1/99 (1.01%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Cervix carcinoma stage 0 * 1  0/84 (0.00%)  0/117 (0.00%)  1/99 (1.01%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Benign neoplasm of thyroid gland * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  1/46 (2.17%) 
Malignant melanoma in situ * 1  0/84 (0.00%)  0/117 (0.00%)  1/99 (1.01%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Uterine leiomyoma * 1  1/84 (1.19%)  1/117 (0.85%)  1/99 (1.01%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Nervous system disorders             
Lumbar radiculopathy * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  1/46 (2.17%) 
Pregnancy, puerperium and perinatal conditions             
Abortion missed * 1  0/84 (0.00%)  1/117 (0.85%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  1/46 (2.17%) 
Abortion spontaneous * 1  0/84 (0.00%)  0/117 (0.00%)  1/99 (1.01%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Foetal distress syndrome * 1  0/84 (0.00%)  0/117 (0.00%)  1/99 (1.01%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Renal and urinary disorders             
Nephrolithiasis * 1  1/84 (1.19%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Renal colic * 1  1/84 (1.19%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Skin and subcutaneous tissue disorders             
Urticaria * 1  1/84 (1.19%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Surgical and medical procedures             
Appendicectomy * 1  0/84 (0.00%)  1/117 (0.85%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Vascular disorders             
Venous insufficiency * 1  0/84 (0.00%)  1/117 (0.85%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Hypertension * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  1/51 (1.96%)  0/46 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA Version 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo/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 Weekly RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   69/84 (82.14%)   97/117 (82.91%)   84/99 (84.85%)   46/58 (79.31%)   37/51 (72.55%)   36/46 (78.26%) 
Blood and lymphatic system disorders             
Leukopenia * 1  9/84 (10.71%)  2/117 (1.71%)  2/99 (2.02%)  0/58 (0.00%)  4/51 (7.84%)  1/46 (2.17%) 
Lymphopenia * 1  4/84 (4.76%)  1/117 (0.85%)  5/99 (5.05%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Neutropenia * 1  8/84 (9.52%)  3/117 (2.56%)  5/99 (5.05%)  0/58 (0.00%)  4/51 (7.84%)  1/46 (2.17%) 
Ear and labyrinth disorders             
Vertigo * 1  5/84 (5.95%)  1/117 (0.85%)  5/99 (5.05%)  2/58 (3.45%)  3/51 (5.88%)  0/46 (0.00%) 
Gastrointestinal disorders             
Diarrhoea * 1  3/84 (3.57%)  8/117 (6.84%)  3/99 (3.03%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Toothache * 1  5/84 (5.95%)  4/117 (3.42%)  4/99 (4.04%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Dyspepsia * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  0/51 (0.00%)  3/46 (6.52%) 
Nausea * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  3/51 (5.88%)  2/46 (4.35%) 
General disorders             
Influenza like illness * 1  45/84 (53.57%)  39/117 (33.33%)  17/99 (17.17%)  11/58 (18.97%)  12/51 (23.53%)  10/46 (21.74%) 
Injection site erythema * 1  17/84 (20.24%)  6/117 (5.13%)  8/99 (8.08%)  4/58 (6.90%)  8/51 (15.69%)  2/46 (4.35%) 
Chills * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  3/51 (5.88%)  2/46 (4.35%) 
Fatigue * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  0/58 (0.00%)  2/51 (3.92%)  3/46 (6.52%) 
Infections and infestations             
Bronchitis * 1  3/84 (3.57%)  5/117 (4.27%)  6/99 (6.06%)  4/58 (6.90%)  1/51 (1.96%)  2/46 (4.35%) 
Cystitis * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  3/58 (5.17%)  0/51 (0.00%)  1/46 (2.17%) 
Influenza * 1  3/84 (3.57%)  8/117 (6.84%)  7/99 (7.07%)  4/58 (6.90%)  2/51 (3.92%)  3/46 (6.52%) 
Nasopharyngitis * 1  12/84 (14.29%)  14/117 (11.97%)  9/99 (9.09%)  6/58 (10.34%)  7/51 (13.73%)  4/46 (8.70%) 
Pharyngitis * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  2/58 (3.45%)  0/51 (0.00%)  4/46 (8.70%) 
Upper respiratory tract infection * 1  10/84 (11.90%)  11/117 (9.40%)  10/99 (10.10%)  6/58 (10.34%)  5/51 (9.80%)  5/46 (10.87%) 
Urinary tract infection * 1  1/84 (1.19%)  8/117 (6.84%)  3/99 (3.03%)  2/58 (3.45%)  3/51 (5.88%)  4/46 (8.70%) 
Injury, poisoning and procedural complications             
Overdose * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  2/58 (3.45%)  8/51 (15.69%)  1/46 (2.17%) 
Investigations             
Alanine aminotransferase increased * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  1/58 (1.72%)  2/51 (3.92%)  3/46 (6.52%) 
Aspartate aminotransferase increased * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  1/58 (1.72%)  2/51 (3.92%)  3/46 (6.52%) 
Blood creatine phosphokinase increased * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  4/58 (6.90%)  1/51 (1.96%)  0/46 (0.00%) 
Musculoskeletal and connective tissue disorders             
Arthralgia * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  2/58 (3.45%)  3/51 (5.88%)  0/46 (0.00%) 
Back pain * 1  5/84 (5.95%)  7/117 (5.98%)  6/99 (6.06%)  5/58 (8.62%)  2/51 (3.92%)  5/46 (10.87%) 
Pain in extremity * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  4/58 (6.90%)  1/51 (1.96%)  1/46 (2.17%) 
Nervous system disorders             
Headache * 1  11/84 (13.10%)  19/117 (16.24%)  16/99 (16.16%)  4/58 (6.90%)  6/51 (11.76%)  9/46 (19.57%) 
Dizziness * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  1/58 (1.72%)  1/51 (1.96%)  3/46 (6.52%) 
Migraine * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  1/58 (1.72%)  3/51 (5.88%)  0/46 (0.00%) 
Insomnia * 1  1/84 (1.19%)  7/117 (5.98%)  4/99 (4.04%)  2/58 (3.45%)  1/51 (1.96%)  4/46 (8.70%) 
Psychiatric disorders             
Anxiety * 1  3/84 (3.57%)  7/117 (5.98%)  4/99 (4.04%)  2/58 (3.45%)  0/51 (0.00%)  3/46 (6.52%) 
Depression * 1  1/84 (1.19%)  6/117 (5.13%)  2/99 (2.02%)  0/58 (0.00%)  0/51 (0.00%)  0/46 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Oropharyngeal pain * 1  0/84 (0.00%)  0/117 (0.00%)  0/99 (0.00%)  3/58 (5.17%)  2/51 (3.92%)  2/46 (4.35%) 
Vascular disorders             
Hypertension * 1  5/84 (5.95%)  7/117 (5.98%)  1/99 (1.01%)  0/58 (0.00%)  3/51 (5.88%)  1/46 (2.17%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA Version 16.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Sponsor has the right to publish any results communication in connection with the study. The PI shall submit any communications including study results to the sponsor for review 30 working days prior to communication submission. The sponsor can request the PI to modify or delete any sponsor's proprietary information. If the PI refuses the modification, the submission shall be postponed for 60 days from PI refusal, to provide the sponsor the opportunity to file a patent or seek legal remedies.
Results Point of Contact
Name/Title: Merck KGaA Communication Center
Organization: Merck Serono, a division of Merck KGaA
Phone: +49-6151-72-5200
Responsible Party: Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier: NCT00813709     History of Changes
Other Study ID Numbers: 28981
First Submitted: December 22, 2008
First Posted: December 23, 2008
Results First Submitted: November 27, 2012
Results First Posted: October 28, 2013
Last Update Posted: March 8, 2017