REbif FLEXible Dosing in Early Multiple Sclerosis (MS) | NCT00404352

ID	Type	Description	Link
2006-002982-38	EudraCT Number

Label	Type	Intervention Names
RNF 44 mcg three times weekly	Active Comparator	Drug: RNF
RNF 44 mcg once weekly and placebo twice weekly for blinding	Active Comparator	Drug: RNF Drug: Placebo
Placebo three times weekly	Placebo Comparator	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
RNF	Drug	Single dose of RNF administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months, or 36 months for patients enrolled in the OL extension.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005)	The McDonald criteria use dissemination in time and space established by magnetic resonance image (MRI) findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new time constant 2 (T2) or gadolinium-enhancing (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.	Various time points from randomization up to 24 months
Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005)	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 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.	Various time points from randomization up to 36 months

Secondary Outcomes

Measure	Description	Time Frame
Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score	CDMS was defined by the occurrence of a second exacerbation or relapse over 24 months in participants who presented with first clinical demyelinating event (FCDE) accompanied by an abnormal MRI scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Single, first clinical event suggestive of MS within 60 days prior to study Day 1, which is the day of randomization (clock starts 24 hours after onset). The event must be a new neurological abnormality present for at least 24 hours, either mono- or polysymptomatic, other than a paresthesia, vegetative or cerebral dysfunction
At least two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 millimeter (mm), at least one of which is ovoid or periventricular or infratentorial
EDSS 0 - 5.0 at least one time point during the screening period before start of treatment
18 and 50 years old, inclusive
Willing to follow study procedures
Written informed consent
If female, subject must:
- be neither pregnant nor breast-feeding nor attempting to conceive
- use a highly effective method of contraception. A highly effective method of contraception is defined as those which result in a low failure rate (that is [i.e.] less than 1 percent [%] per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner

Exclusion Criteria:

Diagnosis of MS (per McDonald criteria 2005)
Any other disease that could better explain the subject's signs and symptoms
Complete transverse myelitis or bilateral optic neuritis
Subject uses or has used any other approved MS disease-modifying drug (DMD)
Any investigational drug or undergone an experimental procedure within 12 weeks prior to study Day 1
Oral or systemic corticosteroids or adrenocorticotropic hormone (ACTH) within 30 days prior to study Day 1
Total bilirubin greater than 2.5 times upper limit of normal (ULN)
Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase (ALP) greater than 2.5 times the ULN
Inadequate bone marrow reserve, defined as a total white blood cell count less than 3.0 x 109 per liter (/L), platelet count less than 75 x 109/L, hemoglobin less than 100 gram per liter (g/L)
Current autoimmune disease
Major medical or psychiatric illness (including history of or current severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol
History of seizures not adequately controlled by treatment
Cardiac disease, such as angina, congestive heart failure or arrhythmia
Known allergy to IFN-beta or the excipient(s) of the study medication
Any condition that could interfere with the MRI evaluation;
Known allergy to gadolinium-diethylene triamine pentaacetic acid (DTPA)
Previously participated in this study
Participated in any clinical trial within the past 6 months
Any immunomodulatory or immunosuppressive therapy at any time prior to enrollment, including, but not limited to, the following products: any IFN, glatiramer acetate (Copolymer I), cyclophosphamide, cyclosporine, methotrexate, linomide, azathioprine, mitoxantrone, teriflunomide, laquinimod, cladribine, total lymphoid irradiation, anti-lymphocyte monoclonal antibody treatment (e.g. natalizumab, alemtuzumab/Campath, anti-cluster of differentiation 4 [CD4]), intravenous, immunoglobulins (Igs), cytokines or anti-cytokine therapy
Any experimental MS treatment prior to trial entry, including, but not limited to, any statins (if given to prevent MS) and pentoxyfylline
History of alcohol or drug abuse
Intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen
Inability to administer subcutaneous injections either by self or by caregiver
Moderate to severe renal impairment

Name	Affiliation	Role
Bettina M. Stubinski, MD	Merck Serono S.A., Geneva	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Mendoza			Argentina
Research Site

PubMed Identifier	Type	Citation	Retractions
38560407	Derived	Kuhle J, Leppert D, Comi G, de Stefano N, Kappos L, Freedman MS, Seitzinger A, Roy S. Serum neurofilament light chain correlations in patients with a first clinical demyelinating event in the REFLEX study: a post hoc analysis. Ther Adv Neurol Disord. 2024 Mar 29;17:17562864241239101. doi: 10.1177/17562864241239101. eCollection 2024.
35274413

Label	URL
Full FDA approved prescribing information can be found here	View source

ID	Title	Description
FG000	RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population)	Single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of interferon [IFN]-beta-1a (RNF) injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005)

The McDonald criteria use dissemination in time and space established by magnetic resonance image (MRI) findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new time constant 2 (T2) or gadolinium-enhancing (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.

Intent-to-treat (ITT) population included all participants who were randomized to the assigned study treatment.

Posted

Median

95% Confidence Interval

days

Various time points from randomization up to 24 months

ID	Title	Description
OG000	RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population)	Single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of interferon [IFN]-beta-1a (RNF) injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.
OG001	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 finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.
OG002	Placebo (DB Population)	Single dose of matching placebo 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 finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.

Units	Counts
Participants	OG000171 OG001175 OG002171

Title

Denominators

Categories

Title	Measurements
	OG000310(183 to 488) OG001182(107 to 270) OG00297(93 to 101)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		Log Rank	Log-rank test was stratified for controlling randomization stratification factors.	<0.001													No	Superiority or Other
OG001 OG002		Log Rank

Secondary

Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score

CDMS was defined by the occurrence of a second exacerbation or relapse over 24 months in participants who presented with first clinical demyelinating event (FCDE) accompanied by an abnormal MRI scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.

ITT population included all participants who were randomized to the assigned study treatment.

Posted

Median

95% Confidence Interval

days

Various time points from randomization up to 24 months

ID	Title	Description
OG000	RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population)	Single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of interferon [IFN]-beta-1a (RNF) injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.
OG001	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 finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.

Secondary

CDMS was defined by the occurrence of a second exacerbation or relapse over 36 months in participants who presented with FCDE accompanied by an abnormal MRI scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.

OL ITT population included all participants who were randomized at baseline in core REFLEX trial and entered the 12 months OLE period.

Posted

Median

95% Confidence Interval

days

Various time points from randomization up to 36 months

ID	Title	Description
OG000	RNF 44Mcg Three Times Weekly/RNF 44Mcg Three Times Weekly(OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year open label extension (OLE). Participants who had received RNF three times a week in the core REFLEX trial, were re-titrated with a 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 finally 44 mcg until 36 months in this 12 months open label extension.
OG001	RNF 44 Mcg Once Weekly/RNF 44 Mcg Three Times Weekly (OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year OLE. Participants who had received RNF once weekly in the core REFLEX trial were re-titrated with a single dose of RNF injection subcutaneously three times weekly at least 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 in this 12 months open label extension.

Secondary

Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan

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

OL ITT population included all participants who were randomized at baseline in core REFLEX trial and entered the 12 months OLE period. "n" signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.

Posted

Mean

Standard Deviation

lesions

Month 24 up to Month 36

ID	Title	Description
OG000	RNF 44Mcg Three Times Weekly/RNF 44Mcg Three Times Weekly(OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year open label extension (OLE). Participants who had received RNF three times a week in the core REFLEX trial, were re-titrated with a 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 finally 44 mcg until 36 months in this 12 months open label extension.
OG001	RNF 44 Mcg Once Weekly/RNF 44 Mcg Three Times Weekly (OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year OLE. Participants who had received RNF once weekly in the core REFLEX trial were re-titrated with a single dose of RNF injection subcutaneously three times weekly at least 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 in this 12 months open label extension.

Secondary

Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36

Change from baseline in lesion volume was measured by using MRI scans for T2 lesions, T1 hypointense lesions and (Gd+) lesions.

Posted

Mean

Standard Deviation

cubic millimeter (mm^3)

Baseline, Month 36

ID	Title	Description
OG000	RNF 44Mcg Three Times Weekly/RNF 44Mcg Three Times Weekly(OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year open label extension (OLE). Participants who had received RNF three times a week in the core REFLEX trial, were re-titrated with a 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 finally 44 mcg until 36 months in this 12 months open label extension.
OG001	RNF 44 Mcg Once Weekly/RNF 44 Mcg Three Times Weekly (OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year OLE. Participants who had received RNF once weekly in the core REFLEX trial were re-titrated with a single dose of RNF injection subcutaneously three times weekly at least 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 in this 12 months open label extension.

Primary

Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005)

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 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.

Open label (OL) ITT population included all participants who were randomized at baseline in core REFLEX trial and entered the 12 months OLE period.

Posted

Median

95% Confidence Interval

days

Various time points from randomization up to 36 months

ID	Title	Description
OG000	RNF 44Mcg Three Times Weekly/RNF 44Mcg Three Times Weekly(OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year open label extension (OLE). Participants who had received RNF three times a week in the core REFLEX trial, were re-titrated with a 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 finally 44 mcg until 36 months in this 12 months open label extension.
OG001	RNF 44 Mcg Once Weekly/RNF 44 Mcg Three Times Weekly (OLE)

Secondary

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

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

Posted

Mean

Standard Deviation

unit on a scale

Baseline, Month 36

ID	Title	Description
OG000	RNF 44Mcg Three Times Weekly/RNF 44Mcg Three Times Weekly(OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year open label extension (OLE). Participants who had received RNF three times a week in the core REFLEX trial, were re-titrated with a 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 finally 44 mcg until 36 months in this 12 months open label extension.
OG001	RNF 44 Mcg Once Weekly/RNF 44 Mcg Three Times Weekly (OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year OLE. Participants who had received RNF once weekly in the core REFLEX trial were re-titrated with a single dose of RNF injection subcutaneously three times weekly at least 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 in this 12 months open label extension.

Arm/Groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population)	Single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of interferon [IFN]-beta-1a (RNF) injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.	6	171	149	171
EG001	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 finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.	8	173	156	173
EG002	Placebo (DB Population)	Single dose of matching placebo 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 finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.	12	171	133	171
EG003	RNF 44 Mcg Three Times Weekly/OL RNF 44 Mcg Three Times Weekly	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 24 months.	1	31	20	31
EG004	RNF 44 Mcg Once Weekly/OL RNF 44 Mcg Three Times Weekly	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 24 months.	0	30	20	30
EG005	Placebo/OL RNF 44 Mcg Three Times Weekly	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 24 months.	1	59	47	59
EG006	RNF 44Mcg Three Times Weekly/RNF 44Mcg Three Times Weekly(OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year open label extension (OLE). Participants who had received RNF three times a week in the core REFLEX trial, were re-titrated with a 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 finally 44 mcg until 36 months in this 12 months open label extension.	0	4	3	4
EG007	RNF 44 Mcg Once Weekly/RNF 44 Mcg Three Times Weekly (OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year OLE. Participants who had received RNF once weekly in the core REFLEX trial were re-titrated with a single dose of RNF injection subcutaneously three times weekly at least 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 in this 12 months open label extension.	0	5	2	5
EG008	Placebo/RNF 44 Mcg Three Times Weekly (OLE)	Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year OLE. Participants who had received placebo in the core REFLEX trial were re-titrated with a single dose of RNF injection subcutaneously three times weekly at least 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 in this 12 months open label extension.	0	11	5	11

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Appendicitis	Infections and infestations	MedDRA 13.0	Systematic Assessment	EG0003 events3 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG0030 events0 affected31 at risk EG0040 events0 affected30 at risk EG0050 events0 affected59 at risk EG0060 affected4 at risk EG0070 affected5 at risk EG0080 affected11 at risk
Tonsillitis	Infections and infestations	MedDRA 13.0	Systematic Assessment	EG0001 events1 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Varicella	Infections and infestations	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0011 events1 affected173 at risk EG0020 events0 affected171 at risk EG003
Gastrointestinal motility disorder	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0021 events1 affected171 at risk EG003
Inguinal hernia	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0021 events1 affected171 at risk EG003
Pancreatic necrosis	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0021 events1 affected171 at risk EG003
Breast cancer stage III	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0021 events1 affected171 at risk EG003
Ovarian germ cell teratoma benign	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0021 events1 affected171 at risk EG003
Testis cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0021 events1 affected171 at risk EG003
Ovarian cyst	Reproductive system and breast disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0022 events2 affected171 at risk EG003
Cervical polyp	Reproductive system and breast disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0011 events1 affected173 at risk EG0020 events0 affected171 at risk EG003
Muscle rupture	Injury, poisoning and procedural complications	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0011 events1 affected173 at risk EG0020 events0 affected171 at risk EG003
Post procedural hematoma	Injury, poisoning and procedural complications	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0021 events1 affected171 at risk EG003
Tibia fracture	Injury, poisoning and procedural complications	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0011 events1 affected173 at risk EG0020 events0 affected171 at risk EG003
Acute myocardial infarction	Cardiac disorders	MedDRA 13.0	Systematic Assessment	EG0001 events1 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Angina unstable	Cardiac disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0021 events1 affected171 at risk EG003
Deafness congenital	Congenital, familial and genetic disorders	MedDRA 13.0	Systematic Assessment	EG0001 events1 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Dermoid cyst	Congenital, familial and genetic disorders	MedDRA 13.0	Systematic Assessment	EG0001 events1 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Abortion spontaneous	Pregnancy, puerperium and perinatal conditions	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0011 events1 affected173 at risk EG0021 events1 affected171 at risk EG003
Nasal septum deviation	Respiratory, thoracic and mediastinal disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0011 events1 affected173 at risk EG0020 events0 affected171 at risk EG003
Tonsillar disorder	Respiratory, thoracic and mediastinal disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0011 events1 affected173 at risk EG0020 events0 affected171 at risk EG003
Iron deficiency anemia	Blood and lymphatic system disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0011 events1 affected173 at risk EG0020 events0 affected171 at risk EG003
Hypoacusis	Ear and labyrinth disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0011 events1 affected173 at risk EG0020 events0 affected171 at risk EG003
Ischemic stroke	Nervous system disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0021 events1 affected171 at risk EG003
Cholelithiasis	Hepatobiliary disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Psychotic disorder	Psychiatric disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Influenza like illness	General disorders	MedDRA 13.0	Systematic Assessment	EG000218 events93 affected171 at risk EG001374 events122 affected173 at risk EG00250 events34 affected171 at risk EG0039 events8 affected31 at risk EG0046 events3 affected30 at risk EG00531 events24 affected59 at risk EG0061 affected4 at risk EG0071 affected5 at risk EG0081 affected11 at risk
Injection site erythema	General disorders	MedDRA 13.0	Systematic Assessment	EG00076 events50 affected171 at risk EG00149 events34 affected173 at risk EG0023 events3 affected171 at risk EG003
Pyrexia	General disorders	MedDRA 13.0	Systematic Assessment	EG00013 events6 affected171 at risk EG00129 events22 affected173 at risk EG00212 events9 affected171 at risk EG003
Fatigue	General disorders	MedDRA 13.0	Systematic Assessment	EG00025 events13 affected171 at risk EG00112 events5 affected173 at risk EG00226 events11 affected171 at risk EG003
Chills	General disorders	MedDRA 13.0	Systematic Assessment	EG00026 events11 affected171 at risk EG00127 events9 affected173 at risk EG00211 events5 affected171 at risk EG003
Asthenia	General disorders	MedDRA 13.0	Systematic Assessment	EG00011 events9 affected171 at risk EG0019 events6 affected173 at risk EG0025 events5 affected171 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA 13.0	Systematic Assessment	EG00021 events17 affected171 at risk EG00130 events23 affected173 at risk EG00249 events22 affected171 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA 13.0	Systematic Assessment	EG00037 events17 affected171 at risk EG00119 events13 affected173 at risk EG00234 events20 affected171 at risk EG003
Influenza	Infections and infestations	MedDRA 13.0	Systematic Assessment	EG00012 events9 affected171 at risk EG00117 events10 affected173 at risk EG00220 events17 affected171 at risk EG003
Pharyngitis	Infections and infestations	MedDRA 13.0	Systematic Assessment	EG00010 events9 affected171 at risk EG0019 events5 affected173 at risk EG00211 events10 affected171 at risk EG003
Viral upper respiratory tract infection	Infections and infestations	MedDRA 13.0	Systematic Assessment	EG00019 events9 affected171 at risk EG00112 events6 affected173 at risk EG00218 events8 affected171 at risk EG003
Headache	Nervous system disorders	MedDRA 13.0	Systematic Assessment	EG000145 events46 affected171 at risk EG001129 events37 affected173 at risk EG002135 events46 affected171 at risk EG003
Paresthesia	Nervous system disorders	MedDRA 13.0	Systematic Assessment	EG00016 events7 affected171 at risk EG00117 events8 affected173 at risk EG00227 events16 affected171 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 13.0	Systematic Assessment	EG00021 events12 affected171 at risk EG00117 events11 affected173 at risk EG0028 events8 affected171 at risk EG003
Toothache	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0007 events6 affected171 at risk EG00112 events10 affected173 at risk EG0029 events6 affected171 at risk EG003
Diarrhea	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0005 events4 affected171 at risk EG0015 events4 affected173 at risk EG0029 events9 affected171 at risk EG003
Depression	Psychiatric disorders	MedDRA 13.0	Systematic Assessment	EG00017 events14 affected171 at risk EG00110 events9 affected173 at risk EG00210 events10 affected171 at risk EG003
Anxiety	Psychiatric disorders	MedDRA 13.0	Systematic Assessment	EG00010 events10 affected171 at risk EG00121 events7 affected173 at risk EG00220 events14 affected171 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA 13.0	Systematic Assessment	EG00015 events14 affected171 at risk EG00112 events11 affected173 at risk EG0026 events5 affected171 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA 13.0	Systematic Assessment	EG00011 events10 affected171 at risk EG00110 events9 affected173 at risk EG0023 events3 affected171 at risk EG003
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 13.0	Systematic Assessment	EG0006 events6 affected171 at risk EG00113 events9 affected173 at risk EG00214 events11 affected171 at risk EG003
Neutropenia	Blood and lymphatic system disorders	MedDRA 13.0	Systematic Assessment	EG00015 events13 affected171 at risk EG0017 events6 affected173 at risk EG0021 events1 affected171 at risk EG003
Injection site pain	General disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Blood creatine phosphokinase increased	Investigations	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Leukopenia	Blood and lymphatic system disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Hypertension	Vascular disorders	MedDRA 13.0	Systematic Assessment	EG0000 events0 affected171 at risk EG0010 events0 affected173 at risk EG0020 events0 affected171 at risk EG003
Cervicobrachial syndrome	Nervous system disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Migraine	Nervous system disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Syncope	Nervous system disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Lymphopenia	Blood and lymphatic system disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Iron deficiency anaemia	Blood and lymphatic system disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Hyperthyroidism	Endocrine disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Aphthous stomatitis	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Facial bones fracture	Injury, poisoning and procedural complications	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Contusion	Injury, poisoning and procedural complications	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Anti-thyroid antibody positive	Investigations	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Rhinitis	Infections and infestations	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Melanocytic naevus	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Nervousness	Psychiatric disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Vulvovaginal pruritus	Reproductive system and breast disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Skin irritation	Skin and subcutaneous tissue disorders	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003
Limb injury	Injury, poisoning and procedural complications	MedDRA 13.0	Systematic Assessment	EG0000 affected171 at risk EG0010 affected173 at risk EG0020 affected171 at risk EG003

ID	Term
D020278	Demyelinating Autoimmune Diseases, CNS
D020274	Autoimmune Diseases of the Nervous System
D009422	Nervous System Diseases
D003711	Demyelinating Diseases
D001327	Autoimmune Diseases
D007154	Immune System Diseases

ID	Term
D016899	Interferon-beta
D007370	Interferon Type I
D007372	Interferons
D016207	Cytokines
D036341	Intercellular Signaling Peptides and Proteins
D010455	Peptides
D000602	Amino Acids, Peptides, and Proteins
D011506	Proteins
D001685	Biological Factors

ID	Title	Description
BG000	RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population)	Single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of interferon [IFN]-beta-1a (RNF) injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.
BG001	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 finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.
BG002	Placebo (DB Population)	Single dose of matching placebo 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 finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.
BG003	Total	Total of all reporting groups