Trial Outcomes & Findings for Long-term Follow-Up of Patients Who Participated in Study 27025 (REFLEX) (NCT NCT00813709)

NCT ID: NCT00813709

Last Updated: 2017-03-08

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 402 participants
• Primary outcome timeframe: Baseline (Day 1 of Study 27025) up to 36 Months
• Results posted on: 2017-03-08

Participant Flow

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

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)

Participant milestones

Measure	Placebo/RNF 44 Mcg Thrice Weekly (DB Population) 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.	RNF 44 Mcg Once Weekly (DB Population) 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.	RNF 44 Mcg Thrice Weekly (DB Population) 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.	Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly 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.	RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly 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.	RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly 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.
Double Blind Period STARTED	84	117	99	0	0	0
Double Blind Period Treated	83	114	98	0	0	0
Double Blind Period COMPLETED	53	76	68	0	0	0
Double Blind Period NOT COMPLETED	31	41	31	0	0	0
Open Label Period STARTED	0	0	0	58	51	46
Open Label Period Treated	0	0	0	57	51	45
Open Label Period COMPLETED	0	0	0	38	41	35
Open Label Period NOT COMPLETED	0	0	0	20	10	11

Reasons for withdrawal

Measure	Placebo/RNF 44 Mcg Thrice Weekly (DB Population) 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.	RNF 44 Mcg Once Weekly (DB Population) 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.	RNF 44 Mcg Thrice Weekly (DB Population) 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.	Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly 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.	RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly 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.	RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly 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.
Double Blind Period Adverse Event	4	1	4	0	0	0
Double Blind Period Lost to Follow-up	3	2	2	0	0	0
Double Blind Period Switched to open label phase	9	26	18	0	0	0
Double Blind Period Randomized but not treated	1	3	1	0	0	0
Double Blind Period Other	14	9	6	0	0	0
Open Label Period Adverse Event	0	0	0	5	4	3
Open Label Period Lack of Efficacy	0	0	0	3	1	1
Open Label Period Randomized but not treated	0	0	0	1	0	1
Open Label Period Other	0	0	0	11	5	6

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Placebo/RNF 44 Mcg Thrice Weekly (ITT Population) n=133 Participants 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)	RNF 44 Mcg Once Weekly (ITT Population) n=142 Participants 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)	RNF 44 Mcg Thrice Weekly (ITT Population) n=127 Participants 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 n=402 Participants Total of all reporting groups
Age, Continuous	31.0 years STANDARD_DEVIATION 8.2 • n=5 Participants	31.4 years STANDARD_DEVIATION 8.2 • n=7 Participants	31.8 years STANDARD_DEVIATION 8.6 • n=5 Participants	31.4 years STANDARD_DEVIATION 8.3 • n=4 Participants
Age, Customized Less than 30 years	67 participants n=5 Participants	66 participants n=7 Participants	55 participants n=5 Participants	188 participants n=4 Participants
Age, Customized Greater than or equal to 30 years	66 participants n=5 Participants	76 participants n=7 Participants	72 participants n=5 Participants	214 participants n=4 Participants
Sex: Female, Male Female	82 Participants n=5 Participants	88 Participants n=7 Participants	78 Participants n=5 Participants	248 Participants n=4 Participants
Sex: Female, Male Male	51 Participants n=5 Participants	54 Participants n=7 Participants	49 Participants n=5 Participants	154 Participants n=4 Participants
Race/Ethnicity, Customized Black	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Race/Ethnicity, Customized White	133 participants n=5 Participants	141 participants n=7 Participants	127 participants n=5 Participants	401 participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1 of Study 27025) up to 36 Months

Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
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	41.3 Cumulative % of participants with CDMS Interval 33.5 to 49.1	27.6 Cumulative % of participants with CDMS Interval 20.6 to 34.6	27.1 Cumulative % of participants with CDMS Interval 19.9 to 34.3

SECONDARY outcome

Timeframe: Baseline (Day 1 of Study 27025) up to 36 Months

Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months	7.5 % of participants with EDSS progression	11.8 % of participants with EDSS progression	13.2 % of participants with EDSS progression

SECONDARY outcome

Timeframe: Month 36

Population: 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.

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

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=124 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=133 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=114 Participants 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.
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 CUA Lesions	1.02 lesions Standard Deviation 1.85	1.83 lesions Standard Deviation 3.317	1.63 lesions Standard Deviation 5.947
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 New T2 Lesions	0.83 lesions Standard Deviation 1.545	1.39 lesions Standard Deviation 2.573	1.19 lesions Standard Deviation 4.217
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 New Gd+ Lesions	0.17 lesions Standard Deviation 0.506	0.40 lesions Standard Deviation 1.354	0.41 lesions Standard Deviation 1.754
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 New T1 Lesions	0.69 lesions Standard Deviation 1.721	1.09 lesions Standard Deviation 2.482	0.91 lesions Standard Deviation 4.143

SECONDARY outcome

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

Population: 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.

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

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 T1 lesion volume at Baseline (n=171,175,171)	670.3 cubic millimeter (mm^3) Standard Deviation 1054.1	774.8 cubic millimeter (mm^3) Standard Deviation 1288.0	675.0 cubic millimeter (mm^3) Standard Deviation 1049.9
Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 T1 lesion volume Change: Month 36(n=124,133,114)	303.2 cubic millimeter (mm^3) Standard Deviation 1034.6	272.0 cubic millimeter (mm^3) Standard Deviation 921.4	133.3 cubic millimeter (mm^3) Standard Deviation 763.5
Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 T2 lesion volume at Baseline (n=171,175,171)	3334.9 cubic millimeter (mm^3) Standard Deviation 3990.4	3853.1 cubic millimeter (mm^3) Standard Deviation 4716.7	3110.5 cubic millimeter (mm^3) Standard Deviation 3410.7
Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 T2 lesion volume Change: Month 36(n=124,133,114)	-3.8 cubic millimeter (mm^3) Standard Deviation 2101.8	-56.9 cubic millimeter (mm^3) Standard Deviation 2436.3	-398.1 cubic millimeter (mm^3) Standard Deviation 1415.4

SECONDARY outcome

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

Population: 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.

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

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=120 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=132 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=112 Participants 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.
Percent Change From Baseline in Brain Volume at Month 36	-1.02 percent change Standard Deviation 1.248	-0.86 percent change Standard Deviation 1.073	-1.14 percent change Standard Deviation 1.321

SECONDARY outcome

Timeframe: Baseline (Day 1 of Study 27025) up to CDMS conversion and/or up to 36 Months

Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months	84.2 percentage of participants	76.0 percentage of participants	66.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day of Study 27025), Month 36

Population: 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.

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36 Baseline (n=171,175,171)	0.0358 units on a scale Standard Deviation 0.8787	-0.0909 units on a scale Standard Deviation 1.1223	0.0031 units on a scale Standard Deviation 1.1387
Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36 Change at Month 36 (n=123,135,118)	0.3483 units on a scale Standard Deviation 0.6949	0.5044 units on a scale Standard Deviation 0.7588	0.4515 units on a scale Standard Deviation 0.9164

SECONDARY outcome

Timeframe: Month 36

Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Percentage of Relapse-Free Participants at Month 36	42.7 Percentage of participants	58.3 Percentage of participants	51.5 Percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day of Study 27025), Month 36

Population: 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.

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36 Baseline (n=171,175,171)	1.53 units on a scale Standard Deviation 0.77	1.50 units on a scale Standard Deviation 0.72	1.51 units on a scale Standard Deviation 0.83
Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36 Change at Month 36 (n=120,136,116)	-0.21 units on a scale Standard Deviation 0.93	-0.11 units on a scale Standard Deviation 0.96	-0.09 units on a scale Standard Deviation 0.90

SECONDARY outcome

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

Population: 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.

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).

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36 MFSC score at Baseline (n=171,175,171)	0.0352 Z-score Standard Deviation 0.5844	0.0071 Z-score Standard Deviation 0.6653	-0.0575 Z-score Standard Deviation 0.6226
Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36 Change at Month 36 (n=123,135,118)	0.1993 Z-score Standard Deviation 0.4863	0.2529 Z-score Standard Deviation 0.5794	0.3074 Z-score Standard Deviation 0.6071

SECONDARY outcome

Timeframe: Month 36

Population: 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.

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).

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=118 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=131 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=118 Participants 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.
Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 BAb-	77 participants	97 participants	88 participants
Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 BAb+	41 participants	34 participants	30 participants
Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 NAb-	100 participants	109 participants	99 participants
Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 NAb+	18 participants	22 participants	19 participants

SECONDARY outcome

Timeframe: Month 24 up to Month 36 (DB treatment period for study 28981 (REFLEXION)

Population: 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.

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=84 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=117 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=99 Participants 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.
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation AEs	79 participants	67 participants	45 participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation SAEs	3 participants	2 participants	4 participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation AEs leading to discontinuation	2 participants	0 participants	2 participants

SECONDARY outcome

Timeframe: Baseline (Day 1 of Study 27025) up to 60 Months

Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
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	44.6 Cumulative % of participants with CDMS Interval 36.6 to 52.6	40.7 Cumulative % of participants with CDMS Interval 32.8 to 48.6	39.2 Cumulative % of participants with CDMS Interval 30.8 to 47.6

SECONDARY outcome

Timeframe: Baseline (Day 1 of Study 27025) up to 60 Months

Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months	11.0 % of participants with EDSS progression	18.7 % of participants with EDSS progression	18.4 % of participants with EDSS progression

SECONDARY outcome

Timeframe: Month 60

Population: 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.

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

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
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 CUA Lesions (n=102, 121, 110)	1.46 lesions Standard Deviation 3.394	1.60 lesions Standard Deviation 3.542	1.94 lesions Standard Deviation 4.803
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 New T1 Lesions (n=102, 120, 110)	0.57 lesions Standard Deviation 1.656	0.69 lesions Standard Deviation 1.659	0.71 lesions Standard Deviation 1.917
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 New T2 Lesions (n=102, 121, 110)	1.17 lesions Standard Deviation 2.576	1.17 lesions Standard Deviation 2.628	1.35 lesions Standard Deviation 3.284
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 New Gd+ Lesions (n=102, 121, 110)	0.24 lesions Standard Deviation 0.823	0.36 lesions Standard Deviation 1.225	0.48 lesions Standard Deviation 1.618

SECONDARY outcome

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

Population: 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.

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

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 T1 lesion volume at Baseline (n=171,175,171)	670.3 mm^3 Standard Deviation 1054.1	774.8 mm^3 Standard Deviation 1288.0	675.0 mm^3 Standard Deviation 1049.9
Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 Change at Month 60 (n=102,120,110)	415.0 mm^3 Standard Deviation 1080.3	412.3 mm^3 Standard Deviation 1020.8	261.8 mm^3 Standard Deviation 1006.1
Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 T2 lesion volume at Baseline (n=171,175,171)	3334.9 mm^3 Standard Deviation 3990.4	3853.1 mm^3 Standard Deviation 4716.7	3110.5 mm^3 Standard Deviation 3410.7
Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 Change at Month 60 (n=102,121,110)	119.4 mm^3 Standard Deviation 2225.2	25.0 mm^3 Standard Deviation 2827.1	-188.5 mm^3 Standard Deviation 2576.1

SECONDARY outcome

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

Population: 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.

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

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=98 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=120 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=110 Participants 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.
Percent Change From Baseline in Brain Volume at Month 60	-1.82 percent change Standard Deviation 1.494	-1.54 percent change Standard Deviation 1.378	-2.03 percent change Standard Deviation 1.644

SECONDARY outcome

Timeframe: Month 60

Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60	84.2 percentage of participants	82.9 percentage of participants	72.5 percentage of participants

SECONDARY outcome

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

Population: 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.

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60 Change at Month 60 (n=112, 132, 118)	0.4109 units on a scale Standard Deviation 0.6844	0.4785 units on a scale Standard Deviation 0.9886	0.4608 units on a scale Standard Deviation 0.8630
Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60 Baseline (n=171, 175, 171)	0.0358 units on a scale Standard Deviation 0.8787	-0.0909 units on a scale Standard Deviation 1.1223	0.0031 units on a scale Standard Deviation 1.1387

SECONDARY outcome

Timeframe: Month 60

Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Percentage of Relapse-Free Participants at Month 60	34.5 percentage of participants	45.1 percentage of participants	40.9 percentage of participants

SECONDARY outcome

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

Population: 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.

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60 Baseline (n=171,175,171)	1.53 units on a scale Standard Deviation 0.77	1.50 units on a scale Standard Deviation 0.72	1.51 units on a scale Standard Deviation 0.83
Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60 Change at Month 60 (n=111,133,117)	-0.11 units on a scale Standard Deviation 0.94	-0.01 units on a scale Standard Deviation 1.01	0.04 units on a scale Standard Deviation 1.02

SECONDARY outcome

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

Population: 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.

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).

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=175 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=171 Participants 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.
Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60 MFSC score at Baseline (n=171,175,171)	0.0352 Z-score Standard Deviation 0.5844	0.0071 Z-score Standard Deviation 0.6653	-0.0575 Z-score Standard Deviation 0.6226
Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60 Change at Month 60 (n=112,132,132)	0.2290 Z-score Standard Deviation 0.4824	0.2213 Z-score Standard Deviation 0.5602	0.2192 Z-score Standard Deviation 0.6229

SECONDARY outcome

Timeframe: Month 60

Population: 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.

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=115 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=130 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=115 Participants 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.
Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 BAb-	89 participants	99 participants	100 participants
Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 BAb+	25 participants	30 participants	15 participants
Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 BAb (Missing)	1 participants	1 participants	0 participants
Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 NAb-	97 participants	110 participants	102 participants
Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 NAb+	18 participants	20 participants	13 participants

SECONDARY outcome

Timeframe: Month 24 up to Month 60

Population: 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.

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.

Outcome measures

Measure	Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=84 Participants 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.	RNF 44 Mcg Once Weekly (Integrated ITT Population) n=117 Participants 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.	RNF 44 Mcg Thrice Weekly (Integrated ITT Population) n=99 Participants 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.
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation AEs leading to discontinuation	3 participants	0 participants	2 participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation AEs	70 participants	96 participants	84 participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation SAEs	7 participants	7 participants	9 participants

Adverse Events

Placebo/RNF 44 Mcg Thrice Weekly (DB Population)

Serious events: 7 serious events

Other events: 69 other events

Deaths: 0 deaths

RNF 44 Mcg Once Weekly (DB Population)

Serious events: 7 serious events

Other events: 97 other events

Deaths: 0 deaths

RNF 44 Mcg Thrice Weekly (DB Population)

Serious events: 9 serious events

Other events: 84 other events

Deaths: 0 deaths

Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly

Serious events: 2 serious events

Other events: 46 other events

Deaths: 0 deaths

RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly

Serious events: 3 serious events

Other events: 37 other events

Deaths: 0 deaths

RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly

Serious events: 4 serious events

Other events: 36 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo/RNF 44 Mcg Thrice Weekly (DB Population) n=84 participants at risk 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.	RNF 44 Mcg Once Weekly (DB Population) n=117 participants at risk 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.	RNF 44 Mcg Thrice Weekly (DB Population) n=99 participants at risk 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.	Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly n=58 participants at risk 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.	RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly n=51 participants at risk 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.	RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly n=46 participants at risk 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma in situ	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Abscess intestinal	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Diverticulitis	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Viral infection	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Appendicitis	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.85% 1/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.2% 1/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Endometritis	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.85% 1/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Peritonsillar abscess	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Salpingo-oophoritis	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cervix carcinoma stage 0	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign neoplasm of thyroid gland	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.2% 1/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.85% 1/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Nervous system disorders Lumbar radiculopathy	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.2% 1/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Pregnancy, puerperium and perinatal conditions Abortion missed	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.85% 1/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.2% 1/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Pregnancy, puerperium and perinatal conditions Foetal distress syndrome	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Cardiac disorders Angina stable	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Eye disorders Eye haemorrhage	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.0% 1/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Gastrointestinal disorders Enterovesical fistula	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Gastrointestinal disorders Haematemesis	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Gastrointestinal disorders Melaena	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Gastrointestinal disorders Abdominal pain	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.0% 1/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.7% 1/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Congenital, familial and genetic disorders Foetal chromosome abnormality	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.85% 1/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Ear and labyrinth disorders Vestibular disorder	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.85% 1/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Injury, poisoning and procedural complications Fibula fracture	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Injury, poisoning and procedural complications Post procedural fistula	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Renal and urinary disorders Nephrolithiasis	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Renal and urinary disorders Renal colic	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Skin and subcutaneous tissue disorders Urticaria	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Surgical and medical procedures Appendicectomy	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.85% 1/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Vascular disorders Venous insufficiency	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.85% 1/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Vascular disorders Hypertension	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.0% 1/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Cardiac disorders Acute coronary syndrome	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.7% 1/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.

Other adverse events

Measure	Placebo/RNF 44 Mcg Thrice Weekly (DB Population) n=84 participants at risk 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.	RNF 44 Mcg Once Weekly (DB Population) n=117 participants at risk 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.	RNF 44 Mcg Thrice Weekly (DB Population) n=99 participants at risk 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.	Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly n=58 participants at risk 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.	RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly n=51 participants at risk 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.	RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly n=46 participants at risk 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.
Blood and lymphatic system disorders Leukopenia	10.7% 9/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.7% 2/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.0% 2/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	7.8% 4/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.2% 1/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Blood and lymphatic system disorders Lymphopenia	4.8% 4/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.85% 1/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.1% 5/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Blood and lymphatic system disorders Neutropenia	9.5% 8/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.6% 3/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.1% 5/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	7.8% 4/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.2% 1/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Ear and labyrinth disorders Vertigo	6.0% 5/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.85% 1/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.1% 5/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.4% 2/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.9% 3/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Gastrointestinal disorders Diarrhoea	3.6% 3/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.8% 8/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.0% 3/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Gastrointestinal disorders Toothache	6.0% 5/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.4% 4/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	4.0% 4/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Gastrointestinal disorders Dyspepsia	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.5% 3/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Gastrointestinal disorders Nausea	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.9% 3/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	4.3% 2/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
General disorders Influenza like illness	53.6% 45/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	33.3% 39/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	17.2% 17/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	19.0% 11/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	23.5% 12/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	21.7% 10/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
General disorders Injection site erythema	20.2% 17/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.1% 6/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	8.1% 8/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.9% 4/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	15.7% 8/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	4.3% 2/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
General disorders Chills	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.9% 3/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	4.3% 2/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
General disorders Fatigue	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.9% 2/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.5% 3/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Bronchitis	3.6% 3/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	4.3% 5/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.1% 6/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.9% 4/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.0% 1/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	4.3% 2/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Cystitis	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.2% 3/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.2% 1/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Influenza	3.6% 3/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.8% 8/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	7.1% 7/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.9% 4/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.9% 2/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.5% 3/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Nasopharyngitis	14.3% 12/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	12.0% 14/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	9.1% 9/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	10.3% 6/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	13.7% 7/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	8.7% 4/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Pharyngitis	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.4% 2/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	8.7% 4/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Upper respiratory tract infection	11.9% 10/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	9.4% 11/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	10.1% 10/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	10.3% 6/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	9.8% 5/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	10.9% 5/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Infections and infestations Urinary tract infection	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.8% 8/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.0% 3/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.4% 2/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.9% 3/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	8.7% 4/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Injury, poisoning and procedural complications Overdose	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.4% 2/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	15.7% 8/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.2% 1/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Investigations Alanine aminotransferase increased	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.7% 1/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.9% 2/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.5% 3/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Investigations Aspartate aminotransferase increased	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.7% 1/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.9% 2/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.5% 3/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Investigations Blood creatine phosphokinase increased	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.9% 4/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.0% 1/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.4% 2/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.9% 3/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Musculoskeletal and connective tissue disorders Back pain	6.0% 5/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.0% 7/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.1% 6/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	8.6% 5/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.9% 2/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	10.9% 5/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.9% 4/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.0% 1/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.2% 1/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Nervous system disorders Headache	13.1% 11/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	16.2% 19/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	16.2% 16/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.9% 4/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	11.8% 6/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	19.6% 9/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Nervous system disorders Dizziness	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.7% 1/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.0% 1/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.5% 3/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Nervous system disorders Migraine	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.7% 1/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.9% 3/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Psychiatric disorders Anxiety	3.6% 3/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.0% 7/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	4.0% 4/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.4% 2/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.5% 3/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Psychiatric disorders Depression	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.1% 6/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.0% 2/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Nervous system disorders Insomnia	1.2% 1/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.0% 7/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	4.0% 4/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.4% 2/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.0% 1/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	8.7% 4/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.2% 3/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	3.9% 2/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	4.3% 2/46 • Month 24 to 60 for both DB safety population and OL safety population 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.
Vascular disorders Hypertension	6.0% 5/84 • Month 24 to 60 for both DB safety population and OL safety population 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.	6.0% 7/117 • Month 24 to 60 for both DB safety population and OL safety population 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.	1.0% 1/99 • Month 24 to 60 for both DB safety population and OL safety population 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.	0.00% 0/58 • Month 24 to 60 for both DB safety population and OL safety population 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.	5.9% 3/51 • Month 24 to 60 for both DB safety population and OL safety population 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.	2.2% 1/46 • Month 24 to 60 for both DB safety population and OL safety population 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.

Additional Information

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• Principal investigator is a sponsor employee 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.
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Restriction type: OTHER