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

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00813709
• Collaborator: (none)
• Enrollment: 402
• Locations: 57
• Arms: 3
• Duration (Months): 57
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

REFLEXION is a double blind extension of the study 27025 (NCT00404352) (REFLEX). The purpose of the study is to obtain long-term follow-up data in subjects with clinically definite multiple sclerosis (MS) and subjects with a first demyelinating event at high risk of converting to MS, treated with fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of interferon [IFN]-beta-1a (RNF).

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis; Clinically Isolated Syndrome	Drug: RNF; Drug: RNF; Drug: RNF; Drug: Placebo	Phase 3

Detailed Description

The objective of the study is to investigate whether RNF treatment initiated after the first clinical event versus delayed treatment results in the prolongation of time to Clinically Definite Multiple Sclerosis (CDMS) conversion up to Month 36 and up to Month 60 since randomization in Study 27025 (REFLEX). Furthermore, the study is intended to explore whether RNF treatment initiated after the first clinical event versus delayed treatment delays disability (including development of secondary progressive MS) and reduces disease activity (including the annual relapse rate [ARR]) in the long term (up to Month 36 and up to Month 60 since randomization in Study 27025 (REFLEX). The study will also assess the long-term safety profile of RNF (up to Month 36 and up to Month 60 since randomization in Study 27025 (REFLEX).

Study Design

• Study Type: Interventional
• Actual Enrollment: 402 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Double-blind Extension of the Study 27025 (REFLEX) to Obtain Long-term Follow-up Data in Patients With Clinically Definite MS and Patients With a First Demyelinating Event at High Risk of Converting to MS, Treated With Rebif® New Formulation (REFLEXION)
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: RNF 44 mcg thrice weekly	Drug: RNF; Single dose of RNF will be administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.; Other Names: Rebif®
Active Comparator: RNF 44 mcg once weekly and placebo	Drug: RNF; Single dose of RNF will be administered subcutaneously once weekly at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.; Other Names: Rebif® ; Drug: Placebo; Single dose matching placebo will be administered subcutaneously twice weekly. Placebo is supplied as a transparent, sterile solution for injection in pre-filled syringes matching the RNF pre-filled syringes, each containing 0.5 milliliter (mL).
Active Comparator: Placebo/RNF 44 mcg thrice weekly	Drug: RNF; Participants who were initially randomized in Study 27025 (REFLEX) to the placebo treatment group will be switched to single dose of RNF administered subcutaneously three times weekly at least 48 hours apart at a dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.; Other Names: Rebif®

Outcome Measures

Primary Outcome Measures

1. Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score up to 36 Months [Baseline (Day 1 of Study 27025) up to 36 Months]

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

Secondary Outcome Measures

1. Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months [Baseline (Day 1 of Study 27025) up to 36 Months]

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

2. Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, New Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Lesions Per Participant Per Scan at Month 36 [Month 36]

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

3. Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 [Baseline (Day 1 of Study 27025), Month 36]

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

4. Percent Change From Baseline in Brain Volume at Month 36 [Baseline (Day 1 of Study 27025), Month 36]

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

5. Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months [Baseline (Day 1 of Study 27025) up to CDMS conversion and/or up to 36 Months]

   The McDonald criteria use dissemination in time and space established by MRI findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new T2 or Gd+ lesion found on a repeat MRI. Dissemination in space is established by the presence of any 3 of the following: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; greater than or equal to 1 infratentorial lesion; greater than or equal to 1 juxtacortical lesion; greater than or equal to 3 periventricular lesions.

6. Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36 [Baseline (Day of Study 27025), Month 36]

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

7. Percentage of Relapse-Free Participants at Month 36 [Month 36]

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

8. Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36 [Baseline (Day of Study 27025), Month 36]

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

9. Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36 [Baseline (Day 1 of Study 27025), Month 36]

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

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

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

11. Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation [Month 24 up to Month 36 (DB treatment period for study 28981 (REFLEXION)]

    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.

12. Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score up to Month 60 [Baseline (Day 1 of Study 27025) up to 60 Months]

    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.

13. Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months [Baseline (Day 1 of Study 27025) up to 60 Months]

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

14. Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, New Gadolinium Enhanced (Gd+) Lesions and New T1 Lesions Per Participant Per Scan at Month 60 [Month 60]

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

15. Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 [Baseline (Day 1 of Study 27025), Month 60]

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

16. Percent Change From Baseline in Brain Volume at Month 60 [Baseline (Day 1 of Study 27025), Month 60]

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

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

    The McDonald criteria use dissemination in time and space established by MRI findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new T2 or Gd+ lesion found on a repeat MRI. Dissemination in space is established by the presence of any 3 of the following: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; greater than or equal to 1 infratentorial lesion; greater than or equal to 1 juxtacortical lesion; greater than or equal to 3 periventricular lesions.

18. Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60 [Baseline (Day 1 of Study 27025), Month 60]

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

19. Percentage of Relapse-Free Participants at Month 60 [Month 60]

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

20. Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60 [Baseline (Day 1 of Study 27025), Month 60]

    EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. The change in EDSS score at Month 60 was calculated as EDSS score at Month 60 minus EDSS score at baseline.

21. Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60 [Baseline (Day 1 of Study 27025), Month 60]

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

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

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

23. Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation [Month 24 up to Month 60]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Reach scheduled end of study in Study 27025 (REFLEX) (completion of 24 months participation)

• Medical assessment by the Investigator/treating physician from study 27025 that there is no objection to the subject's participation in this extension trial considering the medical experience from Study 27025 (REFLEX). Special attention should be given to laboratory abnormalities and clinically significant liver, renal and bone-marrow dysfunction

• If female, subject must:

• be neither pregnant nor breast-feeding, nor attempting to conceive

• use a highly effective method of contraception. A highly effective method of contraception is defined as those which result in a low failure rate (that is [i.e.] less than 1 percent [%] per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner

• Subject is willing to follow study procedures

• Subject has given written informed consent

Exclusion Criteria:

• Subject has any disease other than MS that could better explain the subject's signs and symptoms

• Subject has a primary progressive course of MS

• Subject has total bilirubin greater than 2.5 times upper limit of normal (ULN) at both Month 24 and at the previous visit (i.e. Month 21) (subjects with greater than 2.5 times ULN at Month 24 only are eligible for enrollment and should be managed as per label recommendations until normalization of the value)

• Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase (ALP) greater than 2.5 times the ULN values at both Month 24 and at the previous visit (i.e. Month 21) (subjects with greater than 2.5 times ULN at Month 24 only are eligible for enrollment and should be managed as per label recommendations until normalization of the value)

• Subject suffers from another current autoimmune disease

• Subject suffers from major medical or psychiatric illness (including history of, or current, severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol

• Subject has a history of seizures not adequately controlled by treatment

• Subject has cardiac disease, such as angina, congestive heart failure or arrhythmia

• Subject has a known allergy to IFN-beta or the excipient(s) of the study medication

• Subject has any condition that could interfere with the MRI evaluation

• Subject has a known allergy to gadolinium-diethylene triamine pentaacetic acid (DTPA)

• Subject has a history of alcohol or drug abuse

• Subject has previously participated in this study

• Subject has moderate to severe renal impairment

• Subject is pregnant or lactating

• Subject has any medical, psychiatric or other conditions that compromise his/her ability to understand the subject information, to give informed consent, to comply with the study protocol, or to complete the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Mendoza		Argentina
2	Research Site	Graz		Austria
3	Research Site	Brugge		Belgium
4	Research Site	Leuven		Belgium
5	Research Site	Pleven		Bulgaria
6	Research Site	Rousse		Bulgaria
7	Research Site	Shumen		Bulgaria
8	Research Site	Sofia		Bulgaria
9	Research Site	Varna		Bulgaria
10	Research Site	Ontario		Canada
11	Research Site	Victoria British Columbia		Canada
12	Research Site	Karlovac		Croatia
13	Research Site	Osijek		Croatia
14	Research Site	Rijeka		Croatia
15	Research Site	Split		Croatia
16	Research Site	Zagreb		Croatia
17	Research Site	Hradec Kralove		Czech Republic
18	Research Site	Olomouc		Czech Republic
19	Research Site	Prague		Czech Republic
20	Research Site	Tallinn		Estonia
21	Research Site	Tartu		Estonia
22	Research Site	Oulu		Finland
23	Research Site	Paris		France
24	Research Site	Poissy Cedex		France
25	Research Site	Hannover		Germany
26	Research Site	Henningsforf		Germany
27	Research Site	Athens		Greece
28	Research Site	Safed		Israel
29	Research Site	Tel-Hashomer		Israel
30	Research Site	Milano		Italy
31	Research Site	Padova		Italy
32	Research Site	Riga		Latvia
33	Research Site	Beirut		Lebanon
34	Research Site	Rabat		Morocco
35	Research Site	Bialystok		Poland
36	Research Site	Lodz		Poland
37	Research Site	Warsaw		Poland
38	Research Site	Wroclaw		Poland
39	Research Site	Lisbon		Portugal
40	Research Site	Bucharest		Romania
41	Research Site	Iasi		Romania
42	Research Site	Targu-Mures		Romania
43	Research Site	Timisoara		Romania
44	Research Site	Ekaterinburg		Russian Federation
45	Research Site	Moscow		Russian Federation
46	Research Site	Novgorod		Russian Federation
47	Research Site	Novosibirsk		Russian Federation
48	Research Site	Saint-Petersburg		Russian Federation
49	Research Site	Samara		Russian Federation
50	Research Site	Saratov		Russian Federation
51	Reserch Site	Belgrade		Serbia
52	Research Site	Nis		Serbia
53	Research Site	Presov		Slovakia
54	Research Site	Barcelona		Spain
55	Research Site	Bilbao		Spain
56	Research Site	Madrid		Spain
57	Research Site	Seville		Spain

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, Merck Serono S.A., Geneva

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT00813709
• Other Study ID Numbers: 28981
• First Posted: Dec 23, 2008
• Last Update Posted: Mar 8, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by Merck KGaA, Darmstadt, Germany: Interferon 1-beta; Clinical Definite Multiple Sclerosis
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Interferon beta-1a

Study Results

Participant Flow

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 Detail	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
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
Period Title: Double Blind Period
STARTED	0	0	0	58	51	46
Treated	0	0	0	57	51	45
COMPLETED	0	0	0	38	41	35
NOT COMPLETED	0	0	0	20	10	11

Baseline Characteristics

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
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 Participants	133	142	127	402
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.0 (8.2)	31.4 (8.2)	31.8 (8.6)	31.4 (8.3)
Age, Customized (participants) [Number]
Less than 30 years	67 50.4%	66 46.5%	55 43.3%	188 46.8%
Greater than or equal to 30 years	66 49.6%	76 53.5%	72 56.7%	214 53.2%
Sex: Female, Male (Count of Participants)
Female	82 61.7%	88 62%	78 61.4%	248 61.7%
Male	51 38.3%	54 38%	49 38.6%	154 38.3%
Race/Ethnicity, Customized (participants) [Number]
Black	0 0%	1 0.7%	0 0%	1 0.2%
White	133 100%	141 99.3%	127 100%	401 99.8%

Outcome Measures

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
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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
Number (95% Confidence Interval) [Cumulative % of participants with CDMS]	41.3 31.1%	27.6 19.4%	27.1 21.3%

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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.555
	Confidence Interval	(2-Sided) 95%; 0.378 to 0.816
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.573
	Confidence Interval	(2-Sided) 95%; 0.391 to 0.839
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.941
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.993
	Confidence Interval	(2-Sided) 95%; 0.654 to 1.510
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
Number [% of participants with EDSS progression]	7.5 5.6%	11.8 8.3%	13.2 10.4%

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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.205
	Comments
	Method	Log Rank
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.263
	Comments
	Method	Log Rank
	Comments

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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.629
	Comments
	Method	Log Rank
	Comments

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
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

Outcome Measure Data

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)
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.
Measure Participants	124	133	114
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
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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
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
Description	Percent change in brain volume was measured by using MRI scans.
Time Frame	Baseline (Day 1 of Study 27025), Month 36

Outcome Measure Data

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)
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.
Measure Participants	120	132	112
Mean (Standard Deviation) [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
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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
Number [percentage of participants]	84.2 63.3%	76.0 53.5%	66.7 52.5%

7. Secondary Outcome

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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
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
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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
Number [Percentage of participants]	42.7 32.1%	58.3 41.1%	51.5 40.6%

9. Secondary Outcome

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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
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
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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
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
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

Outcome Measure Data

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)
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.
Measure Participants	118	131	118
BAb-	77 57.9%	97 68.3%	88 69.3%
BAb+	41 30.8%	34 23.9%	30 23.6%
NAb-	100 75.2%	109 76.8%	99 78%
NAb+	18 13.5%	22 15.5%	19 15%

12. Secondary Outcome

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

Outcome Measure Data

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)
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.
Measure Participants	84	117	99
AEs	79 59.4%	67 47.2%	45 35.4%
SAEs	3 2.3%	2 1.4%	4 3.1%
AEs leading to discontinuation	2 1.5%	0 0%	2 1.6%

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
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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
Number (95% Confidence Interval) [Cumulative % of participants with CDMS]	44.6 33.5%	40.7 28.7%	39.2 30.9%

14. Secondary Outcome

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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
Number [% of participants with EDSS progression]	11.0 8.3%	18.7 13.2%	18.4 14.5%

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
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

Outcome Measure Data

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)
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)
Measure Participants	171	175	171
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
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

Outcome Measure Data

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)
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)
Measure Participants	171	175	171
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
Description	Percent Change in brain volume was measured by using MRI scans.
Time Frame	Baseline (Day 1 of Study 27025), Month 60

Outcome Measure Data

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)
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.
Measure Participants	98	120	110
Mean (Standard Deviation) [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
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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
Number [percentage of participants]	84.2 63.3%	82.9 58.4%	72.5 57.1%

19. Secondary Outcome

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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
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
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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
Number [percentage of participants]	34.5 25.9%	45.1 31.8%	40.9 32.2%

21. Secondary Outcome

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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
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
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

Outcome Measure Data

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)
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.
Measure Participants	171	175	171
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
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

Outcome Measure Data

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)
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.
Measure Participants	115	130	115
BAb-	89 66.9%	99 69.7%	100 78.7%
BAb+	25 18.8%	30 21.1%	15 11.8%
BAb (Missing)	1 0.8%	1 0.7%	0 0%
NAb-	97 72.9%	110 77.5%	102 80.3%
NAb+	18 13.5%	20 14.1%	13 10.2%

24. Secondary Outcome

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

Outcome Measure Data

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)
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.
Measure Participants	84	117	99
AEs	70 52.6%	96 67.6%	84 66.1%
SAEs	7 5.3%	7 4.9%	9 7.1%
AEs leading to discontinuation	3 2.3%	0 0%	2 1.6%

Adverse Events

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
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/84 (8.3%)		7/117 (6%)		9/99 (9.1%)		2/58 (3.4%)		3/51 (5.9%)		4/46 (8.7%)
Cardiac disorders
Angina stable	0/84 (0%)		0/117 (0%)		1/99 (1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Acute coronary syndrome	0/84 (0%)		0/117 (0%)		0/99 (0%)		1/58 (1.7%)		0/51 (0%)		0/46 (0%)
Congenital, familial and genetic disorders
Foetal chromosome abnormality	0/84 (0%)		1/117 (0.9%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Ear and labyrinth disorders
Vestibular disorder	0/84 (0%)		1/117 (0.9%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Eye disorders
Eye haemorrhage	0/84 (0%)		0/117 (0%)		1/99 (1%)		0/58 (0%)		1/51 (2%)		0/46 (0%)
Gastrointestinal disorders
Enterovesical fistula	0/84 (0%)		0/117 (0%)		1/99 (1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Haematemesis	1/84 (1.2%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Melaena	1/84 (1.2%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Abdominal pain	0/84 (0%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		1/51 (2%)		0/46 (0%)
Abdominal pain upper	0/84 (0%)		0/117 (0%)		0/99 (0%)		1/58 (1.7%)		0/51 (0%)		0/46 (0%)
Infections and infestations
Abscess intestinal	0/84 (0%)		0/117 (0%)		1/99 (1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Diverticulitis	0/84 (0%)		0/117 (0%)		1/99 (1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Viral infection	0/84 (0%)		0/117 (0%)		1/99 (1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Appendicitis	0/84 (0%)		1/117 (0.9%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		1/46 (2.2%)
Endometritis	0/84 (0%)		1/117 (0.9%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Peritonsillar abscess	1/84 (1.2%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Salpingo-oophoritis	1/84 (1.2%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Injury, poisoning and procedural complications
Fibula fracture	1/84 (1.2%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Post procedural fistula	1/84 (1.2%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/84 (0%)		0/117 (0%)		1/99 (1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma stage 0	0/84 (0%)		0/117 (0%)		1/99 (1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Benign neoplasm of thyroid gland	0/84 (0%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		1/46 (2.2%)
Malignant melanoma in situ	0/84 (0%)		0/117 (0%)		1/99 (1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Uterine leiomyoma	1/84 (1.2%)		1/117 (0.9%)		1/99 (1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Nervous system disorders
Lumbar radiculopathy	0/84 (0%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		1/46 (2.2%)
Pregnancy, puerperium and perinatal conditions
Abortion missed	0/84 (0%)		1/117 (0.9%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		1/46 (2.2%)
Abortion spontaneous	0/84 (0%)		0/117 (0%)		1/99 (1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Foetal distress syndrome	0/84 (0%)		0/117 (0%)		1/99 (1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Renal and urinary disorders
Nephrolithiasis	1/84 (1.2%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Renal colic	1/84 (1.2%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Skin and subcutaneous tissue disorders
Urticaria	1/84 (1.2%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Surgical and medical procedures
Appendicectomy	0/84 (0%)		1/117 (0.9%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Vascular disorders
Venous insufficiency	0/84 (0%)		1/117 (0.9%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Hypertension	0/84 (0%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		1/51 (2%)		0/46 (0%)
Other (Not Including 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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	69/84 (82.1%)		97/117 (82.9%)		84/99 (84.8%)		46/58 (79.3%)		37/51 (72.5%)		36/46 (78.3%)
Blood and lymphatic system disorders
Leukopenia	9/84 (10.7%)		2/117 (1.7%)		2/99 (2%)		0/58 (0%)		4/51 (7.8%)		1/46 (2.2%)
Lymphopenia	4/84 (4.8%)		1/117 (0.9%)		5/99 (5.1%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Neutropenia	8/84 (9.5%)		3/117 (2.6%)		5/99 (5.1%)		0/58 (0%)		4/51 (7.8%)		1/46 (2.2%)
Ear and labyrinth disorders
Vertigo	5/84 (6%)		1/117 (0.9%)		5/99 (5.1%)		2/58 (3.4%)		3/51 (5.9%)		0/46 (0%)
Gastrointestinal disorders
Diarrhoea	3/84 (3.6%)		8/117 (6.8%)		3/99 (3%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Toothache	5/84 (6%)		4/117 (3.4%)		4/99 (4%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Dyspepsia	0/84 (0%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		0/51 (0%)		3/46 (6.5%)
Nausea	0/84 (0%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		3/51 (5.9%)		2/46 (4.3%)
General disorders
Influenza like illness	45/84 (53.6%)		39/117 (33.3%)		17/99 (17.2%)		11/58 (19%)		12/51 (23.5%)		10/46 (21.7%)
Injection site erythema	17/84 (20.2%)		6/117 (5.1%)		8/99 (8.1%)		4/58 (6.9%)		8/51 (15.7%)		2/46 (4.3%)
Chills	0/84 (0%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		3/51 (5.9%)		2/46 (4.3%)
Fatigue	0/84 (0%)		0/117 (0%)		0/99 (0%)		0/58 (0%)		2/51 (3.9%)		3/46 (6.5%)
Infections and infestations
Bronchitis	3/84 (3.6%)		5/117 (4.3%)		6/99 (6.1%)		4/58 (6.9%)		1/51 (2%)		2/46 (4.3%)
Cystitis	0/84 (0%)		0/117 (0%)		0/99 (0%)		3/58 (5.2%)		0/51 (0%)		1/46 (2.2%)
Influenza	3/84 (3.6%)		8/117 (6.8%)		7/99 (7.1%)		4/58 (6.9%)		2/51 (3.9%)		3/46 (6.5%)
Nasopharyngitis	12/84 (14.3%)		14/117 (12%)		9/99 (9.1%)		6/58 (10.3%)		7/51 (13.7%)		4/46 (8.7%)
Pharyngitis	0/84 (0%)		0/117 (0%)		0/99 (0%)		2/58 (3.4%)		0/51 (0%)		4/46 (8.7%)
Upper respiratory tract infection	10/84 (11.9%)		11/117 (9.4%)		10/99 (10.1%)		6/58 (10.3%)		5/51 (9.8%)		5/46 (10.9%)
Urinary tract infection	1/84 (1.2%)		8/117 (6.8%)		3/99 (3%)		2/58 (3.4%)		3/51 (5.9%)		4/46 (8.7%)
Injury, poisoning and procedural complications
Overdose	0/84 (0%)		0/117 (0%)		0/99 (0%)		2/58 (3.4%)		8/51 (15.7%)		1/46 (2.2%)
Investigations
Alanine aminotransferase increased	0/84 (0%)		0/117 (0%)		0/99 (0%)		1/58 (1.7%)		2/51 (3.9%)		3/46 (6.5%)
Aspartate aminotransferase increased	0/84 (0%)		0/117 (0%)		0/99 (0%)		1/58 (1.7%)		2/51 (3.9%)		3/46 (6.5%)
Blood creatine phosphokinase increased	0/84 (0%)		0/117 (0%)		0/99 (0%)		4/58 (6.9%)		1/51 (2%)		0/46 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/84 (0%)		0/117 (0%)		0/99 (0%)		2/58 (3.4%)		3/51 (5.9%)		0/46 (0%)
Back pain	5/84 (6%)		7/117 (6%)		6/99 (6.1%)		5/58 (8.6%)		2/51 (3.9%)		5/46 (10.9%)
Pain in extremity	0/84 (0%)		0/117 (0%)		0/99 (0%)		4/58 (6.9%)		1/51 (2%)		1/46 (2.2%)
Nervous system disorders
Headache	11/84 (13.1%)		19/117 (16.2%)		16/99 (16.2%)		4/58 (6.9%)		6/51 (11.8%)		9/46 (19.6%)
Dizziness	0/84 (0%)		0/117 (0%)		0/99 (0%)		1/58 (1.7%)		1/51 (2%)		3/46 (6.5%)
Migraine	0/84 (0%)		0/117 (0%)		0/99 (0%)		1/58 (1.7%)		3/51 (5.9%)		0/46 (0%)
Insomnia	1/84 (1.2%)		7/117 (6%)		4/99 (4%)		2/58 (3.4%)		1/51 (2%)		4/46 (8.7%)
Psychiatric disorders
Anxiety	3/84 (3.6%)		7/117 (6%)		4/99 (4%)		2/58 (3.4%)		0/51 (0%)		3/46 (6.5%)
Depression	1/84 (1.2%)		6/117 (5.1%)		2/99 (2%)		0/58 (0%)		0/51 (0%)		0/46 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/84 (0%)		0/117 (0%)		0/99 (0%)		3/58 (5.2%)		2/51 (3.9%)		2/46 (4.3%)
Vascular disorders
Hypertension	5/84 (6%)		7/117 (6%)		1/99 (1%)		0/58 (0%)		3/51 (5.9%)		1/46 (2.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.