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Clinical Trial Results:
A Multicenter, Open-Label, Extension Study to Evaluate the Long-Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP), Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301

Summary
EudraCT number	2012-003176-39
Trial protocol	DE IT CZ HU PL SE ES IE GB FI GR FR DK
Global end of trial date	24 Sep 2018

Results information
Results version number	v2(current)
This version publication date	27 Nov 2019
First version publication date	10 Oct 2019
Other versions	v1
Version creation reason	Correction of full data set The EudraCT record is being updated to align with the updates made on ClinicalTrials.gov as a result of PRS Review comments.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

205MS303

ISRCTN number

US NCT number

NCT01797965

WHO universal trial number (UTN)

Sponsor organisation name

Biogen

Sponsor organisation address

225 Binney Street, Cambridge, Massachusetts, United States, 02142

Public contact

Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com

Scientific contact

Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

24 Sep 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

24 Sep 2018

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of the study is to assess the safety and tolerability of long-term treatment with BIIB019 (Daclizumab High Yield Process; DAC HYP) monotherapy in subjects with relapsing remitting multiple sclerosis (RRMS) who completed Study 205MS301 (NCT01064401), Study 205MS203 (NCT01051349) or Study 205MS302 (NCT01462318). Secondary objectives of this study in this study population are as follows: To describe MS-related outcomes, including MS relapse, disability progression, MS lesion formation, and subject-reported impact of MS, following long-term treatment with DAC HYP To assess the long-term immunogenicity of DAC HYP administered by prefilled syringe (PFS) To assess the safety, tolerability, and efficacy of switching to DAC HYP in subjects previously on long-term treatment with interferon β-1a (Avonex) in Study 205MS301(NCT01064401).

Protection of trial subjects

Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Feb 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

6 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 413

Country: Number of subjects enrolled

Russian Federation: 175

Country: Number of subjects enrolled

United States: 114

Country: Number of subjects enrolled

Ukraine: 133

Country: Number of subjects enrolled

Serbia: 86

Country: Number of subjects enrolled

Czech Republic: 132

Country: Number of subjects enrolled

Italy: 57

Country: Number of subjects enrolled

United Kingdom: 61

Country: Number of subjects enrolled

France: 35

Country: Number of subjects enrolled

Germany: 30

Country: Number of subjects enrolled

Hungary: 67

Country: Number of subjects enrolled

Romania: 26

Country: Number of subjects enrolled

Spain: 25

Country: Number of subjects enrolled

Brazil: 19

Country: Number of subjects enrolled

India: 21

Country: Number of subjects enrolled

Argentina: 16

Country: Number of subjects enrolled

Greece: 13

Country: Number of subjects enrolled

Sweden: 16

Country: Number of subjects enrolled

Denmark: 7

Country: Number of subjects enrolled

Moldova, Republic of: 12

Country: Number of subjects enrolled

Australia: 5

Country: Number of subjects enrolled

Canada: 10

Country: Number of subjects enrolled

Ireland: 7

Country: Number of subjects enrolled

Israel: 7

Country: Number of subjects enrolled

Mexico: 8

Country: Number of subjects enrolled

Georgia: 3

Country: Number of subjects enrolled

Switzerland: 3

Worldwide total number of subjects

1501

EEA total number of subjects

889

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1501

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled in the study at 226 investigative sites in 28 countries (United States, Canada, Western European countries, Australia, Israel, Eastern European countries, Argentina, Brazil, India, and Mexico) from 15 February 2013 to 24 September 2018.

Screening details

Subjects who completed studies: 205MS301 (NCT01064401), 205MS203 (NCT01051349), 205MS302 (NCT01462318) were eligible to enroll in this long-term extension study.

Number of subjects started

1501

Number of subjects completed

1500

Reason: Number of subjects

Adverse event, non-fatal: 1

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)

Arm description

Daclizumab High Yield Process (DAC HYP) 150 mg SC injection every 4 weeks for up to 4.6 years in this long-term extension study 303; includes subjects who previously received interferon beta-1a (IFN β-1a) 30 µg intramuscular (IM) injection once weekly in study 301 every 4 weeks for up to 144 weeks.

Arm type

Experimental

Investigational medicinal product name

DAC HYP 150 mg SC injection every 4 weeks

Investigational medicinal product code

Daclizumab High Yield Process

Other name

Pharmaceutical forms

Solution for injection/infusion in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Daclizumab High Yield Process 150 mg subcutaneous (SC) injection every 4 weeks.

DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Arm description

DAC HYP 150 mg subcutaneous (SC) injection every 4 weeks for up to 4.6 years in this long-term extension study 205MS303 (303); includes subjects who previously received DAC HYP 150 mg SC injection in Study 205MS301 (301) every 4 weeks for up to 144 weeks.

Arm type

Experimental

Investigational medicinal product name

DAC HYP 150 mg SC injection every 4 weeks

Investigational medicinal product code

Daclizumab High Yield Process

Other name

Pharmaceutical forms

Solution for injection/infusion in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Daclizumab High Yield Process 150 mg subcutaneous (SC) injection every 4 weeks.

DAC HYP 150 mg (302) /DAC HYP 150 mg (303)

Arm description

DAC HYP 150 mg SC injection every 4 weeks for up to 93.7 weeks in this long-term extension study 303 (subjects started at Week 144 of the study); includes subjects who previously received DAC HYP 150 mg SC injection in study 205MS302 (302) every 4 weeks for up to 24 weeks followed by a 20-week washout period then continued treatment for up to an additional 3 years.

Arm type

Experimental

Investigational medicinal product name

DAC HYP 150 mg SC injection every 4 weeks

Investigational medicinal product code

Daclizumab High Yield Process

Other name

Pharmaceutical forms

Solution for injection/infusion in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Daclizumab High Yield Process 150 mg subcutaneous (SC) injection every 4 weeks.

DAC HYP 150 mg (203) /DAC HYP 150 mg (303)

Arm description

DAC HYP 150 mg SC injection every 4 weeks for up to 94. 1 weeks in this long-term extension study 303 (subjects started at Week 144 of the study); includes subjects who previously received DAC HYP 150 mg SC injection in study 205MS203 (203) every 4 weeks for up to 288 weeks.

Arm type

Experimental

Investigational medicinal product name

DAC HYP 150 mg SC injection every 4 weeks

Investigational medicinal product code

Daclizumab High Yield Process

Other name

Pharmaceutical forms

Solution for injection/infusion in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Daclizumab High Yield Process 150 mg subcutaneous (SC) injection every 4 weeks.

Number of subjects in period 1 ^[1]	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Started	597	606	70	227
Completed	48	38	62	154
Not completed	549	568	8	73
Adverse event, non-fatal	104	128	4	21
Death	2	4	-	-
Reason Not Specified	280	295	-	15
Investigator decision	21	15	-	-
Lost to follow-up	9	8	1	2
Consent withdrawn	130	117	3	35
Disease progression, defined by protocol	3	1	-	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: One subject who had an adverse event and did not receive study drug is not included.

Baseline characteristics

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Reporting group title

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)

Reporting group description

Reporting group title

DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Reporting group description

Reporting group title

DAC HYP 150 mg (302) /DAC HYP 150 mg (303)

Reporting group description

Reporting group title

DAC HYP 150 mg (203) /DAC HYP 150 mg (303)

Reporting group description

Reporting group values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)	Total
Number of subjects	597	606	70	227	1500
Age, Customized
Units: Subjects
Adults (18-64 years)	597	606	70	227	1500
Sex: Female, Male
Units: Subjects
Female	394	400	42	130	966
Male	203	206	28	97	534
Race/Ethnicity, Customized
Units: Subjects
White\|	546	559	2	223	1330
Black or African American\|	5	5	3	0	13
Asian\|	11	10	0	4	25
Other\|	18	14	1	0	33
Not Reported\|	17	18	64	0	99
Age
Units: Subjects
adullt	597	606	70	227	1500

Subject analysis set title

DAC HYP 150 mg

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received DAC HYP 150 mg SC injection in study 205MS303.

Subject analysis sets values	DAC HYP 150 mg
Number of subjects	1500
Age, Customized
Units: Subjects
Adults (18-64 years)	1500
Age continuous
Units:
	±
Sex: Female, Male
Units: Subjects
Female
Male
Race/Ethnicity, Customized
Units: Subjects
White\|
Black or African American\|
Asian\|
Other\|
Not Reported\|
Age
Units: Subjects
adullt

End points

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Reporting group title

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)

Reporting group description

Reporting group title

DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Reporting group description

Reporting group title

DAC HYP 150 mg (302) /DAC HYP 150 mg (303)

Reporting group description

Reporting group title

DAC HYP 150 mg (203) /DAC HYP 150 mg (303)

Reporting group description

Subject analysis set title

DAC HYP 150 mg

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received DAC HYP 150 mg SC injection in study 205MS303.

Primary: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) ^[1]

End point description

An AE is defined as any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product. An SAE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. Safety Population consisted of all subjects who completed Study 301, 203 or 302 and had at least 1 dose of DAC HYP during Study 303.

End point type

Primary

End point timeframe

First dose of study drug in Study 303 to within 180 days of last dose (up to approximately 5.5 years)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: subjects
Subjects with AEs	541	560	53	172
Subjects with SAEs	157	190	15	38

No statistical analyses for this end point

Secondary: Annualized Relapse Rate (ARR) in the 205MS303 Treatment Period

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End point title

Annualized Relapse Rate (ARR) in the 205MS303 Treatment Period

End point description

Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist. The unadjusted ARR was calculated by tabulating the total number of relapses experienced in the group divided by the number of days up to the end of study, and the ratio then multiplied by 365.25. Relapses that occurred after subjects received alternative multiple sclerosis (MS) medications were excluded from the analyses. ARR was adjusted for relapse rate, IFN beta use, Expanded Disability Status Scale (EDSS) (<=2.5 vs >2.5) and age (<=35 vs >35) prior to start of study treatment in 205MS301, calculated using the negative binomial model. Intent-to-treat (ITT) Population consisted of all subjects who completed Study 301, 203 or 302 and received at least 1 dose of DAC HYP during Study 303.

End point type

Secondary

End point timeframe

Up to 4.6 years in the 303 study

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: relapses per year
arithmetic mean (confidence interval 95%)	0.158 (0.134 to 0.188)	0.163 (0.138 to 0.193)	0.167 (0.097 to 0.288)	0.080 (0.047 to 0.136)

No statistical analyses for this end point

Secondary: ARR in the 205MS301-303 Combined Study Period and 205MS301 Treatment Period

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End point title

ARR in the 205MS301-303 Combined Study Period and 205MS301 Treatment Period ^[2]

End point description

Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist. The unadjusted ARR was calculated by tabulating the total number of relapses experienced in the group divided by the number of days up to the end of study, and the ratio then multiplied by 365.25. Relapses that occurred after subjects received alternative MS medications were excluded from the analyses. ARR was adjusted for relapse rate, IFN beta use, EDSS (<=2.5 vs >2.5) and age (<=35 vs >35) prior to start of study treatment in 301, calculated using the negative binomial model. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303.

End point type

Secondary

End point timeframe

Up to 5.6 years combining 303 with the initial Study 301; Up to 1 year in the 301 study

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: relapses per year
arithmetic mean (confidence interval 95%)
301-303 Combined Study Period	0.247 (0.220 to 0.279)	0.175 (0.154 to 0.199)
301 Treatment Period	0.317 (0.280 to 0.360)	0.195 (0.169 to 0.225)

No statistical analyses for this end point

Secondary: Number of Subjects with Relapse in the 205MS303 Treatment Period

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End point title

Number of Subjects with Relapse in the 205MS303 Treatment Period

End point description

Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and had at least 1 dose of DAC HYP during Study 303.

End point type

Secondary

End point timeframe

Up to 4.6 years in the 303 study

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: subjects	184	172	16	35

No statistical analyses for this end point

Secondary: Number of Subjects with Relapse in the 205MS301-303 Combined Study Period

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End point title

Number of Subjects with Relapse in the 205MS301-303 Combined Study Period ^[3]

End point description

Relapses are defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Study Neurologist. 301-303 ITT Population consisted of all subjects who completed Study 301 and had at least 1 dose of DAC HYP during Study 303.

End point type

Secondary

End point timeframe

Up to 5.6 years combining 303 with the initial Study 301

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: subjects	339	261

No statistical analyses for this end point

Secondary: Number of Subjects with Sustained Disability Progression in the 205MS303 Treatment Period

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End point title

Number of Subjects with Sustained Disability Progression in the 205MS303 Treatment Period

End point description

Sustained disability progression is defined as at least a 1.0-point increase on the Expanded Disability Status Scale (EDSS) from 303 baseline EDSS ≥1.0 that is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from 303 baseline EDSS of 0, that is sustained for 24 weeks. The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10. The range of main categories include (0) =normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. Higher scores indicate more disability. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and had at least 1 dose of DAC HYP during Study 303.

End point type

Secondary

End point timeframe

Up to 4.6 years in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: subjects	95	97	2	8

No statistical analyses for this end point

Secondary: Number of Subjects with Sustained Disability Progression in the 205MS301-303 Combined Study Period

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End point title

Number of Subjects with Sustained Disability Progression in the 205MS301-303 Combined Study Period ^[4]

End point description

Sustained disability progression is defined as at least a 1.0-point increase on the Expanded Disability Status Scale (EDSS) from 303 baseline EDSS ≥1.0 that is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from 303 baseline EDSS of 0, that is sustained for 24 weeks. The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10. The range of main categories include (0) =normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. Higher scores indicate more disability. 301-303 ITT Population consisted of all subjects who completed Study 301 and had at least 1 dose of DAC HYP during Study 303.

End point type

Secondary

End point timeframe

Up to 5.6 years combining 303 with the initial Study 301

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: subjects	144	130

No statistical analyses for this end point

Secondary: Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS303 Treatment Period

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End point title

Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS303 Treatment Period ^[5]

End point description

T2 Hyperintense Lesions were assessed by magnetic resonance imaging (MRI) and were analysed by a central MRI reader. The number of subjects with New or Newly Enlarging T2 Hyperintense Lesions relative to the 303 Baseline in the 303 Treatment Period is reported. 301-303 ITT population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. No data was collected for subjects from the 203 and 302 studies. 'n' is the number of subjects with data available at the given timepoint.

End point type

Secondary

End point timeframe

Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: subjects
Week 48 (n= 530, 499)	270	144
Week 96 (n= 376, 345)	213	130
Week 144 (n= 375, 370)	223	157
Week 192 (n= 261, 267)	173	126
Week 240 (n= 37, 45)	20	22

No statistical analyses for this end point

Secondary: Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS301 Treatment Period

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End point title

Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS301 Treatment Period ^[6]

End point description

T2 Hyperintense Lesions were assessed by MRI and were analysed by a central MRI reader. The number of subjects with New or Newly Enlarging T2 Hyperintense Lesions relative to the 301 Baseline in the 301 Treatment Period is reported. 301-303 ITT population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. 'n' is the number of subjects with data available at the given timepoint.

End point type

Secondary

End point timeframe

Baseline 301, Weeks 24, 96, 144 in Study 301

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: subjects
Week 24 (n= 586, 595)	347	314
Week 96 (n= 587, 590)	435	368
Week 144 (n= 167, 165)	126	113

No statistical analyses for this end point

Secondary: Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS303 Treatment Period

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End point title

Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS303 Treatment Period

End point description

Gd+ lesions were evaluated by MRI and were analysed by a central MRI reader. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAY HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no subjects were analysed.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 48, 96, 144, 192, 240; 203-303 and 302-303: Week 96

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: subjects
Baseline 303 (n= 591, 590, 0, 0)	180	77	999999	999999
Week 48 (n= 533, 510, 0, 0)	89	46	999999	999999
Week 96 (n= 375, 353, 147, 52)	43	23	2	8
Week 144 (n= 375, 374, 0, 0)	43	42	999999	999999
Week 192 (n= 261, 272, 0, 0)	25	29	999999	999999
Week 240 (n= 37, 44, 0, 0)	1	7	999999	999999

No statistical analyses for this end point

Secondary: Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS301 Treatment Period

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End point title

Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS301 Treatment Period ^[7]

End point description

Gd+ lesions were evaluated by MRI and were analysed by a central MRI reader. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least one dose of DAY HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint.

End point type

Secondary

End point timeframe

Baseline 301, Weeks 24, 96 and 144

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: subjects
Baseline 301 (n= 591, 595)	263	265
Week 24 (n= 593, 604)	153	119
Week 96 (n= 593, 598)	172	66
Week 144 (n= 168, 167)	49	20

No statistical analyses for this end point

Secondary: Number of Subjects with New T1 Hypointense Lesions in the 205MS303 Treatment Period

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End point title

Number of Subjects with New T1 Hypointense Lesions in the 205MS303 Treatment Period ^[8]

End point description

T1 hypointense lesions were evaluated by MRI and were analysed by a central MRI reader. The number of subjects with New T1 Hyperintense Lesions relative to the 303 Baseline in the 303 Treatment Period is reported. 301-303 ITT Population consisted of all subjects who completed Study 303 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint.

End point type

Secondary

End point timeframe

Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: subjects
Week 48 (n= 531, 510)	200	96
Week 96 (n= 376, 352)	168	91
Week 144 (n= 375, 374)	184	116
Week 192 (n= 261, 272)	152	94
Week 240 (n= 37, 44)	16	18

No statistical analyses for this end point

Secondary: Number of Subjects with New T1 Hypointense Lesions in the 205MS301 Treatment Period

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End point title

Number of Subjects with New T1 Hypointense Lesions in the 205MS301 Treatment Period ^[9]

End point description

T1 hypointense lesions were evaluated by MRI and were analysed by a central MRI reader. The number of subjects with New T1 Hyperintense Lesions relative to the 301 Baseline in the 301 Treatment Period is reported. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. 'n' is the number of subjects with data available at the given timepoint.

End point type

Secondary

End point timeframe

Baseline 301, Weeks 24, 96, 144 in Study 301

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: subjects
Week 24 (n= 585, 594)	276	244
Week 96 (n= 584, 588)	375	300
Week 144 (n= 166, 164)	111	87

No statistical analyses for this end point

Secondary: Percent Change in Brain Volume from the 205MS303 Baseline

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End point title

Percent Change in Brain Volume from the 205MS303 Baseline ^[10]

End point description

To assess brain atrophy, total brain volume was measured by MRI and was analysed by a central MRI reader. A negative percent change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 303 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. No data was collected for subjects from the 203 and 302 studies.

End point type

Secondary

End point timeframe

Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: percent change
arithmetic mean (standard deviation)
Week 48 (n= 400, 360)	-0.451 ± 0.5917	-0.355 ± 0.5100
Week 96 (n= 293, 280)	-0.713 ± 0.7288	-0.549 ± 0.6126
Week 144 (n= 290, 287)	-1.050 ± 0.8566	-0.801 ± 0.7145
Week 192 (n= 216, 222)	-1.225 ± 1.0139	-0.967 ± 0.8772
Week 240 (n= 30, 41)	-1.261 ± 1.0382	-0.852 ± 0.9890

No statistical analyses for this end point

Secondary: Percent Change in Brain Volume from 205MS301 Baseline

Top of page

End point title

Percent Change in Brain Volume from 205MS301 Baseline ^[11]

End point description

End point type

Secondary

End point timeframe

Baseline 301, Weeks 48, 96, 144, 192, 240 in Study 303

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: percent change
arithmetic mean (standard deviation)
Week 48 (n= 462, 427)	-1.535 ± 1.1975	-1.409 ± 1.1538
Week 96 (n= 338, 315)	-1.871 ± 1.3720	-1.595 ± 1.0736
Week 144 (n= 333, 333)	-2.165 ± 1.4596	-1.812 ± 1.2044
Week 192 (n= 258, 261)	-2.403 ± 1.6088	-1.970 ± 1.3439
Week 240 (n= 36, 44)	-2.415 ± 1.6005	-1.922 ± 1.2258

No statistical analyses for this end point

Secondary: Total Volume of T2 Hyperintense Lesions in the 205MS303 Treatment Period

Top of page

End point title

Total Volume of T2 Hyperintense Lesions in the 205MS303 Treatment Period

End point description

Volume of T2 hyperintense Lesions was evaluated by MRI and was analysed by a central MRI reader. ITT Population included all subjects who completed Study 301, 203 or 302 and received at least 1 dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no subjects were analysed.

End point type

Secondary

End point timeframe

Baseline 303, Weeks 48, 96, 144, 192, 240 in Study 303; 203-303 and 302-303: Week 96

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: millimeters cubed (mm^3)
arithmetic mean (standard deviation)
Baseline 303 (n= 593, 592, 0, 0)	10357.54 ± 11977.864	9323.33 ± 10777.863	999999 ± 999999	999999 ± 999999
Week 48 (n= 530, 499, 0, 0)	10738.32 ± 12358.857	9524.23 ± 10822.502	999999 ± 999999	999999 ± 999999
Week 96 (n= 376, 345, 147, 53)	11498.94 ± 12769.813	10018.09 ± 11432.768	12627.51 ± 14777.178	16116.01 ± 16791.388
Week 144 (n= 375, 370, 0, 0)	11242.79 ± 12838.060	10265.04 ± 11324.227	999999 ± 999999	999999 ± 9999999
Week 192 (n= 261, 267, 0, 0)	12453.96 ± 13643.373	10662.66 ± 11815.075	999999 ± 999999	999999 ± 999999
Week 240 (n= 37, 45, 0, 0)	9368.05 ± 12428.209	9230.78 ± 11395.493	99999 ± 999999	999999 ± 999999

No statistical analyses for this end point

Secondary: Change from Baseline in the Multiple Sclerosis Functional Composite (MSFC) Score in the 205MS303 Treatment Period

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End point title

Change from Baseline in the Multiple Sclerosis Functional Composite (MSFC) Score in the 205MS303 Treatment Period ^[12]

End point description

MSFC is a three-part, standardised, quantitative, assessment instrument consisting of (Timed 25-Foot Walk, Nine-Hole Peg Test (9HPT) and Paced Auditory Serial Addition Test (PASAT-3”). 2 timed 25-foot walk scores are averaged. 4 trials of the Peg Test (2 for each hand) are converted to the reciprocals and averaged. The number correct of the PASAT-3 is used. The composite Z-score is calculated by: Z(25-foot walk) + Z (HPT) + Z(PASAT)/3. A positive change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. No data was collected from subjects from the 203 and 302 studies.

End point type

Secondary

End point timeframe

Baseline 303, Weeks 12, 24 and 48 in Study 303

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: z-score
median (full range (min-max))
Baseline 303 (n= 596, 606)	0.24958 (-5.5818 to 1.2110)	0.30019 (-6.1660 to 1.5643)
Change to Week 12 (n= 584, 583)	0.00010 (-3.3934 to 1.6147)	-0.01021 (-4.5948 to 0.9577)
Change to Week 24 (n= 564, 554)	-0.00599 (-2.7855 to 1.6913)	-0.00010 (-3.4062 to 1.3673)
Change to Week 48 (n= 529, 507)	-0.01026 (-3.7220 to 1.7775)	-0.01897 (-3.5941 to 1.4111)

Analysis 1

Statistical analysis description

Change to Week 12

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5937

Method

ANCOVA

Confidence interval

Analysis 3

Statistical analysis description

Change to Week 48

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1884

Method

ANCOVA

Confidence interval

Analysis 2

Statistical analysis description

Change to Week 24

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6233

Method

ANCOVA

Confidence interval

Secondary: Change from 205MS301 Baseline in the MSFC Score in the 205MS301-303 Combined Study Period

Top of page

End point title

Change from 205MS301 Baseline in the MSFC Score in the 205MS301-303 Combined Study Period ^[13]

End point description

End point type

Secondary

End point timeframe

Baseline 301, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156 in the 301 study, Baseline 303, Weeks 12, 24, 48 in the 303 study

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: z-score
median (full range (min-max))
Baseline (BL) 301 (n= 596, 605)	0.14629 (-6.4963 to 1.3731)	0.14298 (-2.9163 to 1.3865)
Change from BL 301 to Week 12 for 301 (n=592, 603)	-0.00133 (-1.8674 to 6.4516)	0.02593 (-1.7953 to 2.3905)
Change from BL 301 to Week 24 for 301 (n=594, 599)	0.02377 (-1.9966 to 6.2712)	0.04728 (-4.3661 to 2.1389)
Change from BL 301 to Week 36 for 301 (n=593, 597)	0.04764 (-3.0131 to 6.2565)	0.05771 (-11.0047 to 2.1389)
Change from BL 301 to Week 48 for 301 (n=592, 601)	0.06491 (-1.6103 to 6.5816)	0.07793 (-1.3713 to 2.1024)
Change from BL 301 to Week 60 for 301 (n=589, 598)	0.06893 (-4.4756 to 6.6543)	0.08973 (-1.3564 to 1.9165)
Change from BL 301 to Week 72 for 301 (n=592, 600)	0.08645 (-3.7849 to 6.7127)	0.08690 (-5.6579 to 2.0135)
Change from BL 301 to Week 84 for 301 (n=591, 597)	0.05704 (-4.3418 to 6.6940)	0.10283 (-5.4012 to 2.0493)
Change from BL 301 to Week 96 for 301 (n=593, 600)	0.06731 (-4.1506 to 6.8296)	0.11283 (-5.8373 to 2.2536)
Change from BL 301 to Week 108 for 301(n=489, 500)	0.08020 (-4.8814 to 6.8182)	0.09868 (-5.0171 to 2.4199)
Change from BL 301 to Week 120 for 301(n=397, 395)	0.08406 (-4.4964 to 6.8441)	0.10367 (-3.4544 to 1.2502)
Change from BL 301 to Week 132 for 301(n=273, 289)	0.07712 (-4.6292 to 3.6137)	0.08682 (-3.9359 to 3.2500)
Change from BL 301 to Week 144 for 301(n=210, 203)	0.09674 (-2.1875 to 4.0089)	0.12943 (-0.8767 to 1.2626)
Change from BL 301 to Week 156 for 301 (n= 0, 1)	999999 (999999 to 999999)	-0.0272 (-0.0272 to -0.0272)
Change from BL 301 to BL 303 (n= 595, 603)	0.06638 (-1.9364 to 6.8441)	0.11003 (-5.0171 to 3.3811)
Change from BL 301 to Week 12 for 303 (n=582, 579)	0.06449 (-2.8537 to 6.9351)	0.09616 (-5.3094 to 3.3600)
Change from BL 301 to Week 24 for 303 (n=562, 550)	0.07140 (-2.7241 to 6.7870)	0.12955 (-5.0936 to 3.2141)
Change from BL 301 to Week 48 for 303 (n=527, 503)	0.05533 (-2.8215 to 7.0425)	0.09332 (-5.3475 to 3.3180)

Analysis 1

Statistical analysis description

Change from Baseline 301 to Week 12 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0204

Method

ANCOVA

Confidence interval

Analysis 2

Statistical analysis description

Change from Baseline 301 to Week 24 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0805

Method

ANCOVA

Confidence interval

Analysis 3

Statistical analysis description

Change from Baseline 301 to Week 36 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2535

Method

ANCOVA

Confidence interval

Analysis 4

Statistical analysis description

Change from Baseline 301 to Week 48 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4738

Method

ANCOVA

Confidence interval

Analysis 5

Statistical analysis description

Change from Baseline 301 to Week 60 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2302

Method

ANCOVA

Confidence interval

Analysis 6

Statistical analysis description

Change from Baseline 301 to Week 72 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8522

Method

ANCOVA

Confidence interval

Analysis 7

Statistical analysis description

Change from Baseline 301 to Week 84 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0431

Method

ANCOVA

Confidence interval

Analysis 8

Statistical analysis description

Change from Baseline 301 to Week 96 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0339

Method

ANCOVA

Confidence interval

Analysis 9

Statistical analysis description

Change from Baseline 301 to Week 108 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3195

Method

ANCOVA

Confidence interval

Analysis 10

Statistical analysis description

Change from Baseline 301 to Week 120 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2119

Method

ANCOVA

Confidence interval

Analysis 11

Statistical analysis description

Change from Baseline 301 to Week 132 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3619

Method

ANCOVA

Confidence interval

Analysis 12

Statistical analysis description

Change from Baseline 301 to Week 144 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.017

Method

ANCOVA

Confidence interval

Analysis 13

Statistical analysis description

Change from Baseline 301 to Baseline 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.017

Method

ANCOVA

Confidence interval

Analysis 14

Statistical analysis description

Change from Baseline 301 to Week 12 for 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0849

Method

ANCOVA

Confidence interval

Analysis 15

Statistical analysis description

Change from Baseline 301 to Week 24 for 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0057

Method

ANCOVA

Confidence interval

Analysis 16

Statistical analysis description

Change from Baseline 301 to Week 48 for 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.396

Method

ANCOVA

Confidence interval

Secondary: Change from Baseline in the Expanded Disability Status Scale (EDSS) Score in the 205MS303 Treatment Period

Top of page

End point title

Change from Baseline in the Expanded Disability Status Scale (EDSS) Score in the 205MS303 Treatment Period

End point description

The EDSS measures the disability status of people with multiple sclerosis as assessed by the Study Neurologist based on 8 functional systems that ranges from 0=normal neurologic exam; to 5=ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to 10=death due to MS. Higher scores indicate more disability. A negative change from Baseline indicates improvement. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no subjects were analysed.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 260; 203-303 and 302-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 116 in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: score on a scale
arithmetic mean (standard deviation)
Baseline 303 (n= 595, 605, 226, 70)	2.50 ± 1.468	2.44 ± 1.409	2.56 ± 1.395	2.86 ± 1.500
Change at Week 12 (n= 586, 592, 7, 2)	0.04 ± 0.464	0.02 ± 0.467	0.00 ± 0.000	0.14 ± 0.244
Change at Week 24 (n= 585, 581, 223, 70)	0.06 ± 0.570	0.03 ± 0.480	-0.06 ± 0.325	0.02 ± 0.237
Change at Week 48 (n= 551, 541, 215, 69)	0.09 ± 0.614	0.06 ± 0.495	-0.05 ± 0.455	0.00 ± 0.349
Change at Week 72 (n= 520, 495, 204, 64)	0.11 ± 0.670	0.10 ± 0.548	0.00 ± 0.542	0.04 ± 0.378
Change at Week 96 (n= 492, 469, 193, 55)	0.13 ± 0.729	0.13 ± 0.602	0.01 ± 0.486	0.04 ± 0.400
Change at Week 116 (n= 0, 0, 150, 54)	999999 ± 999999	999999 ± 999999	0.11 ± 0.572	0.05 ± 0.353
Change at Week 120 (n= 453, 441, 0, 0)	0.17 ± 0.768	0.11 ± 0.578	999999 ± 99999	999999 ± 999999
Change at Week 144 (n= 426, 417, 0, 0)	0.16 ± 0.742	0.17 ± 0.701	999999 ± 999999	999999 ± 999999
Change at Week 168 (n= 393, 381, 0, 0)	0.22 ± 0.798	0.19 ± 0.765	999999 ± 999999	999999 ± 999999
Change at Week 192 (n= 344, 348, 0, 0)	0.22 ± 0.756	0.22 ± 0.777	999999 ± 999999	999999 ± 999999
Change at Week 216 (n= 307, 315, 0, 0)	0.22 ± 0.775	0.22 ± 0.762	999999 ± 999999	999999 ± 999999
Change at Week 240 (n= 224, 223, 0, 0)	0.19 ± 0.789	0.26 ± 0.829	999999 ± 999999	999999 ± 999999
Change at Week 260 (n= 18, 12, 0, 0)	0.53 ± 1.007	-0.17 ± 0.718	999999 ± 999999	999999 ± 999999

No statistical analyses for this end point

Secondary: Number of Subjects Who Are Free from Disease Activity in the 205MS303 Treatment Period

Top of page

End point title

Number of Subjects Who Are Free from Disease Activity in the 205MS303 Treatment Period ^[14]

End point description

Subjects without clinical or radiological activity are defined as disease-free. Clinical activity includes assessment of relapses and of disease progression. Radiological activity includes assessments of Gd+ lesions and new or enlarging T2 lesions. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. No data was collected for subjects from the 203 and 302 studies.

End point type

Secondary

End point timeframe

Up to 4.6 years in Study 303

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: subjects	9	7

Analysis 1

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8417

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.902

Confidence interval

level

95%

sides

2-sided

lower limit

0.329

upper limit

2.473

Secondary: Change from Baseline in the Multiple Sclerosis Impact Scale 29 (MSIS 29) Physical and Psychological Scores in the 205MS303 Treatment Period

Top of page

End point title

Change from Baseline in the Multiple Sclerosis Impact Scale 29 (MSIS 29) Physical and Psychological Scores in the 205MS303 Treatment Period ^[15]

End point description

The 29-item MSIS-29 is a disease specific subject-reported outcome measure that has been developed and validated to examine the physical (coordination and mobility) and psychological (mental) impact of MS from a subject's perspective; it measures 20 physical items and 9 psychological items. The results for each of the physical and psychological scores are transformed to a score of 0 to 100 (worse state of health). A negative change from Baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. 'n' is the number of subjects with data available at the given timepoint. No data was collected for subjects from the 203 and 302 studies.

End point type

Secondary

End point timeframe

Baseline 303, Weeks 12, 24, 48, 96, 120 and 144

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: score on a scale
arithmetic mean (standard deviation)
Physical Scores: Baseline 303	20.61 ± 20.134	19.19 ± 19.390
Physical Scores: Change to Week 12 (n= 596, 600)	0.22 ± 11.114	-0.28 ± 9.217
Physical Scores: Change to Week 24 (n= 581, 574)	-0.46 ± 10.313	-0.88 ± 9.147
Physical Scores: Change to Week 48 (n=554, 531)	0.12 ± 11.178	0.13 ± 9.779
Physical Scores: Change to Week 96 (n= 173, 165)	2.23 ± 12.713	0.48 ± 10.617
Physical Scores: Change to Week 120 (n= 27, 26)	0.51 ± 9.062	1.44 ± 10.504
Physical Scores: Change to Week 144 (n= 1, 1)	-1.25 ± 0	-5.00 ± 0
Psychological (Psy) Scores: Baseline 303	23.46 ± 21.310	22.37 ± 20.816
Psy Scores: Change to Week 12 (n= 596, 600)	-1.06 ± 12.501	-0.34 ± 11.226
Psy Scores: Change to Week 24 (n= 581, 574)	-1.14 ± 14.154	-1.69 ± 11.576
Psy Scores: Change to Week 48 (n= 554, 531)	-0.46 ± 14.865	0.10 ± 13.648
Psy Scores: Change to Week 96 (n= 173, 165)	-0.16 ± 13.923	-0.89 ± 14.411
Psy Scores: Change to Week 120 (n= 27, 26)	-2.26 ± 10.105	0.00 ± 8.642
Psy Scores: Change to Week 144 (n= 1, 1)	8.33 ± 0	-13.89 ± 0

No statistical analyses for this end point

Secondary: Change from Baseline in Quality of Life as Assessed by the European Quality of Life, 5 Dimensions (EQ 5D) Health Scores in the 205MS303 Treatment Period

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End point title

Change from Baseline in Quality of Life as Assessed by the European Quality of Life, 5 Dimensions (EQ 5D) Health Scores in the 205MS303 Treatment Period

End point description

The EQ-5D is a self-administered questionnaire consisting of 5 domains pertaining to specific health state profile: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The subjects recorded their level of current health for each domain where: 1=no problems, 2=some problem and 3=severe problems. The health score is derived from the individual scores for each of the 5 domains transformed to a score of 0=worst health state to 1=perfect health state. A positive change from Baseline indicates improvement. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 12, 24, 48, 96, 120, 144, 192, 240; 203-303 and 302-303: Baseline 303, Weeks 48 and 96 in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: score on a scale
arithmetic mean (standard deviation)
Baseline 303	0.77 ± 0.233	0.79 ± 0.201	0.77 ± 0.213	0.71 ± 0.242
Change to Week 12 (n= 596, 600, 0, 0)	0.01 ± 0.168	-0.01 ± 0.137	999999 ± 999999	999999 ± 999999
Change to Week 24 (n= 581, 574, 0, 0)	0.01 ± 0.171	0.00 ± 0.144	999999 ± 999999	999999 ± 999999
Change to Week 48 (n= 553, 531, 225, 70)	-0.01 ± 0.185	-0.01 ± 0.152	0.00 ± 0.174	0.00 ± 0.164
Change to Week 96 (n= 497, 472, 194, 56)	0.00 ± 0.168	-0.02 ± 0.170	0.00 ± 0.184	-0.01 ± 0.162
Change to Week 120 (n= 448, 431, 0, 0)	0.01 ± 0.166	-0.01 ± 0.175	999999 ± 999999	999999 ± 999999
Change to Week 144 (n= 416, 409, 0, 0)	0.01 ± 0.187	-0.02 ± 0.172	999999 ± 999999	999999 ± 999999
Change to Week 192 (n= 332, 338, 0, 0)	0.00 ± 0.187	-0.03 ± 0.174	999999 ± 999999	999999 ± 999999
Change to Week 240 (n= 103, 105, 0, 0)	-0.01 ± 0.154	-0.06 ± 0.187	999999 ± 999999	999999 ± 999999

No statistical analyses for this end point

Secondary: Change from Baseline in Quality of Life as Assessed by the European Quality of Life, Visual Analog Scale (EQ VAS) in the 205MS303 Treatment Period

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End point title

Change from Baseline in Quality of Life as Assessed by the European Quality of Life, Visual Analog Scale (EQ VAS) in the 205MS303 Treatment Period

End point description

The subject rated their current health state using the EQ VAS 20-centimeter horizontal line from 0 (worst imaginable health state) to 100 (best imaginable health state). A positive change from baseline indicates improvement. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 12, 24, 48, 96, 120, 44, 192, 240; 203-303 and 302-303: Baseline 303, Weeks 48 and 96 in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: score on a scale
arithmetic mean (standard deviation)
Baseline 303	76.19 ± 19.534	77.74 ± 19.144	76.97 ± 19.225	72.13 ± 21.154
Change at Week 12 (n= 595, 598, 0, 0)	1.42 ± 12.753	0.25 ± 12.358	999999 ± 999999	999999 ± 999999
Change at Week 24 (n= 581, 574, 0, 0)	1.20 ± 12.135	0.74 ± 11.400	999999 ± 999999	999999 ± 999999
Change at Week 48 (n= 554, 531, 222, 70)	0.66 ± 12.966	-0.35 ± 13.543	-0.64 ± 13.440	-1.50 ± 13.604
Change at Week 96 (n= 497, 472, 190, 56)	-0.54 ± 14.963	0.56 ± 12.054	-0.95 ± 11.222	0.45 ± 11.724
Change at Week 120 (n= 448, 430, 0, 0)	0.80 ± 13.406	1.52 ± 13.492	999999 ± 999999	999999 ± 999999
Change at Week 144 (n= 416, 409, 0, 0)	0.36 ± 14.263	1.64 ± 13.648	999999 ± 999999	999999 ± 999999
Change at Week 192 (n= 332, 338, 0, 0)	0.45 ± 15.058	0.66 ± 14.921	999999 ± 999999	999999 ± 999999
Change at Week 240 (n= 103, 105, 0, 0)	-0.64 ± 11.318	-1.53 ± 13.082	999999 ± 999999	999999 ± 999999

No statistical analyses for this end point

Secondary: Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS303 Treatment Period

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End point title

Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS303 Treatment Period

End point description

Heath resource utilisation was assessed by the number of hospitalisations, emergency room visits, and unscheduled neurologist visits for MS-related and non-MS-related visits. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 24, 48, 96, 144, 192, 240; 203-303 and 302-303: Baseline 303, Weeks 48, 96 in 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: site visits
MS-related: Baseline 303 (n= 557, 549, 201, 67)	141	102	11	27
MS-related: Week 24 (n= 491, 492, 0, 0)	80	48	999999	999999
MS-related: Week 48 (n= 491, 464, 191, 54)	100	70	6	15
MS-related: Week 96 (n= 441, 420, 174, 55)	46	71	3	20
MS-related: Week 144 (n= 396, 378, 0, 0)	37	36	999999	999999
MS-related: Week 192 (n= 321, 319, 0, 0)	26	26	999999	999999
MS-related: Week 240 (n= 119, 128, 0, 0)	6	16	999999	999999
Non-MS related: Baseline 303 (n=557, 549, 201, 67)	90	97	2	15
Non-MS related: Week 24 (n= 491, 492, 0, 0)	81	56	999999	999999
Non-MS related: Week 48 (n= 491, 464, 191, 54)	111	41	5	16
Non-MS related: Week 96 (n= 441, 420, 174, 55)	90	93	10	23
Non-MS related: Week 144 (n= 396, 378, 0, 0)	52	42	999999	999999
Non-MS related: Week 192 (n= 321, 319, 0, 0)	42	39	999999	999999
Non-MS related: Week 240 (n= 119, 128, 0, 0)	10	12	999999	999999

No statistical analyses for this end point

Secondary: Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS301 Treatment Period

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End point title

Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS301 Treatment Period ^[16]

End point description

Heath resource utilisation was assessed by the number of hospitalisations, emergency room visits, and unscheduled neurologist visits for MS-related and non-MS-related visits. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint.

End point type

Secondary

End point timeframe

Baseline 301, Weeks 24, 48, 72, 96, 120 and 144 in 301

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: site visits
MS-related: Baseline 301 (n= 446, 440)	277	349
MS-related: Week 24 (n= 410, 408)	76	78
MS-related: Week 48 (n= 412, 417)	77	49
MS-related: Week 72 (n= 411, 413)	60	49
MS-related: Week 96 (n= 434, 425)	88	53
MS-related: Week 120 (n= 347, 336)	55	18
MS-related: Week 144 (n= 184, 186)	13	24
Non MS-related: Baseline 301 (n= 446, 440)	93	93
Non MS-related: Week 24 (n= 410, 408)	50	45
Non MS-related: Week 48 (n= 412, 417)	65	51
Non MS-related: Week 72 (n= 411, 413)	54	69
Non MS-relate: Week 96 (n= 434, 425)	44	52
Non MS-related: Week 120 (n= 347, 336)	43	41
Non MS-related: Week 144 (n= 184, 186)	24	32

No statistical analyses for this end point

Secondary: Treatment Satisfaction as Assessed by the Subject in the 205MS303 Treatment Period

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End point title

Treatment Satisfaction as Assessed by the Subject in the 205MS303 Treatment Period ^[17]

End point description

Subjects answered the question: “How satisfied or dissatisfied are you with the ability of the medication to prevent or treat the condition?” using the following scale: Dissatisfied (Extremely dissatisfied, Very dissatisfied, Dissatisfied) or Satisfied (Somewhat satisfied, Satisfied, Very Satisfied and Extremely satisfied). The number of subjects in the Dissatisfied and Satisfied categories is reported. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. No data was collected for subjects from the 203 and 302 studies.

End point type

Secondary

End point timeframe

Baseline 303, Weeks 12, 24, 48, 72, 96, 120 in Study 303

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: subjects
Dissatisfied: Baseline 303 (n= 578, 592)	49	31
Dissatisfied: Week 12 (n= 586, 584)	46	41
Dissatisfied: Week 24 (n= 569, 559)	44	27
Dissatisfied: Week 48 (n= 530, 507)	32	35
Dissatisfied: Week 72 (n= 503, 472)	27	22
Dissatisfied: Week 96 (n= 152, 145)	19	9
Dissatisfied: Week 120 (n= 27, 24)	2	1
Satisfied: Baseline 303 (n= 578, 592)	529	561
Satisfied: Week 12 (n= 586, 584)	540	543
Satisfied: Week 24 (n= 569, 559)	525	532
Satisfied: Week 48 (n= 530, 507)	498	472
Satisfied: Week 72 (n= 503, 472)	476	450
Satisfied: Week 96 (n= 152, 145)	133	136
Satisfied: Week 120 (n= 27, 24)	25	23

No statistical analyses for this end point

Secondary: Health Related Productivity Questionnaire (HRPQ): Scheduled Work Hours in the 205MS303 Treatment Period

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End point title

Health Related Productivity Questionnaire (HRPQ): Scheduled Work Hours in the 205MS303 Treatment Period

End point description

The HRPQ was used by the subject to assess the impact of MS or its treatments on employment. The subject recorded their scheduled work hours. Data is reported by part time or full time employment. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicated that no data was collected.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: hours
arithmetic mean (standard deviation)
Part Time: Baseline 303 (n= 71, 71, 27, 9)	20.4 ± 10.60	19.5 ± 11.45	20.2 ± 6.06	23.6 ± 9.46
Part Time: Week 12 (n= 71, 69, 0, 0)	21.4 ± 10.30	22.4 ± 13.62	999999 ± 999999	999999 ± 999999
Part Time: Week 24 (n= 70, 67, 28, 11)	21.2 ± 12.80	20.6 ± 13.47	24.5 ± 5.22	23.5 ± 9.37
Part Time: Week 48 (n= 67, 68, 24, 11)	22.3 ± 11.12	21.9 ± 11.28	27.7 ± 13.79	22.7 ± 11.23
Part Time: Week 72 (n= 71, 59, 26, 9)	21.6 ± 12.44	23.0 ± 11.64	25.2 ± 6.08	22.8 ± 11.60
Part Time: Week 96 (n= 67, 58, 25, 8)	25.7 ± 17.40	19.9 ± 11.79	23.5 ± 7.98	24.8 ± 10.13
Part Time: Week 120 (n= 54, 49, 0, 0)	27.0 ± 16.13	20.8 ± 13.15	999999 ± 999999	999999 ± 999999
Part Time: Week 144 (n= 43, 48, 0, 0)	22.9 ± 14.79	21.4 ± 12.90	999999 ± 999999	999999 ± 999999
Part Time: Week 168 (n= 36, 40, 0, 0)	21.0 ± 12.06	20.3 ± 11.93	999999 ± 999999	999999 ± 999999
Part Time: Week 192 (n= 35, 36, 0, 0)	23.2 ± 12.07	23.2 ± 16.37	999999 ± 999999	999999 ± 999999
Part Time: Week 216 (n= 26, 35, 0, 0)	24.9 ± 13.18	25.3 ± 11.79	999999 ± 999999	999999 ± 999999
Part Time: Week 240 (n= 4, 0, 0, 0)	21.3 ± 8.54	999999 ± 999999	999999 ± 999999	999999 ± 999999
Full Time: Baseline 303 (n= 288, 301, 114, 41)	36.8 ± 14.23	37.4 ± 12.71	40.1 ± 10.44	39.3 ± 12.23
Full Time: Week 12 (n= 287, 306, 0, 0)	37.3 ± 14.23	38.5 ± 18.79	999999 ± 999999	999999 ± 999999
Full Time: Week 24 (n= 278, 287, 115, 39)	35.0 ± 15.43	36.4 ± 17.43	42.0 ± 7.34	37.2 ± 14.19
Full Time: Week 48 ( n= 270, 277, 103, 40)	36.0 ± 13.47	38.2 ± 20.63	41.1 ± 8.50	38.6 ± 10.90
Full Time: Week 72 (n= 255, 244, 97, 33)	36.9 ± 12.90	38.5 ± 12.21	42.0 ± 5.24	38.4 ± 9.91
Full Time: Week 96 (n= 235, 232, 92, 33)	36.0 ± 13.42	37.6 ± 12.35	41.5 ± 5.05	36.4 ± 14.36
Full Time: Week 120 (n= 224, 234, 0, 0)	37.7 ± 11.04	39.2 ± 22.80	999999 ± 999999	999999 ± 999999
Full Time: Week 144 (n= 219, 210, 0, 0)	37.3 ± 12.79	39.7 ± 12.68	999999 ± 999999	999999 ± 999999
Full Time: Week 168 (n= 180, 178, 0, 0)	37.3 ± 12.35	39.4 ± 10.36	999999 ± 999999	999999 ± 999999
Full Time: Week 192 (n= 168, 166, 0, 0)	37.7 ± 10.31	40.4 ± 9.00	999999 ± 999999	999999 ± 999999
Full Time: Week 216 (n= 155, 152, 0, 0)	37.7 ± 12.44	38.8 ± 11.68	999999 ± 999999	999999 ± 999999
Full Time: Week 240 (n= 19, 18, 0, 0)	39.8 ± 4.16	39.3 ± 12.33	999999 ± 999999	999999 ± 999999

No statistical analyses for this end point

Secondary: HRPQ: Number of Subjects where MS or Its Treatments Resulted in Missed Work in the 205MS303 Treatment Period

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End point title

HRPQ: Number of Subjects where MS or Its Treatments Resulted in Missed Work in the 205MS303 Treatment Period

End point description

The HRPQ was used by the subject to assess the impact of MS or its treatments on employment. The subject recorded whether their MS or its treatments caused them to miss work. Data is reported by part time or full time employment. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: subjects
Part Time: Baseline 303 (n= 71, 73, 27, 9)	11	7	1	1
Part Time: Week 12 (n= 73, 69, 0, 0)	10	8	999999	999999
Part Time: Week 24 (n= 70, 67, 28, 11)	12	7	2	3
Part Time: Week 48 (n= 68, 68, 24, 11)	9	7	1	2
Part Time: Week 72 (n= 72, 59, 27, 9)	7	4	2	2
Part Time: Week 96 (n= 68, 58, 25, 8)	6	5	2	2
Part Time: Week 120 (n= 54, 49, 0, 0)	11	6	999999	999999
Part Time: Week 144 (n= 43, 49, 0, 0)	4	6	999999	999999
Part Time: Week 168 (n= 36, 40, 0, 0)	5	6	999999	999999
Part Time: Week 192 (n= 35, 38, 0, 0)	5	3	999999	999999
Part Time: Week 216 (n= 26, 35, 0, 0)	1	4	999999	999999
Part Time: Week 240 (n= 4, 0, 0, 0)	1	999999	999999	999999
Full Time: Baseline 303 (n= 305, 291, 112, 41)	28	30	3	11
Full Time: Week 12 (n= 291, 305, 0, 0)	19	26	999999	999999
Full Time: Week 24 (n= 279, 288, 111, 39)	11	21	3	8
Full Time: Week 48 (n= 271, 277, 104, 40)	20	24	3	6
Full Time: Week 72 (n= 255, 245, 97, 33)	13	10	3	6
Full Time: Week 96 (n= 236, 232, 90, 33)	10	16	1	3
Full Time: Week 120 (n= 224, 235, 0, 0)	8	18	999999	999999
Full Time: Week 144 (n= 219, 210, 0, 0)	16	16	999999	999999
Full Time: Week 168 (n= 182, 178, 0, 0)	10	17	999999	999999
Full Time: Week 192 (n= 170, 166, 0, 0)	10	13	999999	999999
Full Time: Week 216 (n= 155, 152, 0, 0)	6	10	999999	999999
Full Time: Week 240 (n= 19, 18, 0, 0)	0	2	999999	999999

No statistical analyses for this end point

Secondary: HRPQ: Hours of Work Missed Due to MS or Its Treatment in the 205MS303 Treatment Period

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End point title

HRPQ: Hours of Work Missed Due to MS or Its Treatment in the 205MS303 Treatment Period

End point description

The HRPQ was used by the subject to assess the impact of MS or its treatments on employment. The subject recorded the hours they missed work due to MS or its treatments. Data is reported by part time or full time employment. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects who missed work with data available at the given timepoint. '999999' indicates that no data was collected.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: hours
arithmetic mean (standard deviation)
Part Time: Baseline 303 (n= 11, 7, 1, 1)	8.5 ± 5.82	5.6 ± 4.93	20.0 ± 0	12.0 ± 0
Part Time: Week 12 (n= 12, 8, 0, 0)	8.7 ± 8.43	8.4 ± 8.11	999999 ± 999999	999999 ± 999999
Part Time: Week 24 (n= 13, 7, 3, 2)	15.2 ± 19.31	10.1 ± 3.63	3.0 ± 1.41	8.3 ± 6.51
Part Time: Week 48 (n= 9, 7, 2, 1)	8.6 ± 4.85	12.3 ± 12.83	15.0 ± 0	4.5 ± 3.54
Part Time: Week 72 (n= 6, 4, 2, 2)	7.5 ± 7.01	10.1 ± 13.05	7.0 ± 4.24	16.0 ± 19.80
Part Time: Week 96 (n= 6, 5, 2, 2)	22.2 ± 38.48	8.7 ± 12.02	22.5 ± 3.54	5.0 ± 0.00
Part Time: Week 120 (n= 11, 6, 0, 0)	9.5 ± 5.92	7.3 ± 8.21	999999 ± 999999	999999 ± 999999
Part Time: Week 144 (n= 4, 7, 0, 0)	3.3 ± 2.22	10.3 ± 7.18	999999 ± 999999	999999 ± 999999
Part Time: Week 168 (n= 5, 6, 0, 0)	7.3 ± 7.90	5.3 ± 5.16	999999 ± 999999	999999 ± 999999
Part Time: Week 192 (n= 5, 2, 0, 0)	3.6 ± 1.14	9.0 ± 4.24	999999 ± 999999	999999 ± 999999
Part Time: Week 216 (n= 1, 5, 0, 0)	3.0 ± 0	16.4 ± 15.71	999999 ± 999999	999999 ± 999999
Part Time: Week 240 (n= 1, 0, 0, 0)	5.0 ± 0	999999 ± 999999	999999 ± 999999	999999 ± 999999
Full Time: Baseline 303 (n= 26, 30, 11, 3)	11.0 ± 11.42	15.0 ± 13.58	8.0 ± 0.00	8.8 ± 11.39
Full Time: Week 12 (n= 19, 27, 0, 0)	8.5 ± 10.13	7.9 ± 8.06	999999 ± 999999	999999 ± 999999
Full Time: Week 24 (n= 13, 23, 8, 3)	11.2 ± 13.80	12.4 ± 13.31	7.3 ± 1.15	14.1 ± 16.27
Full Time: Week 48 (n= 21, 26, 5, 3)	15.7 ± 15.50	11.7 ± 11.11	6.7 ± 3.06	12.7 ± 15.57
Full Time: Week 72 (n= 15, 11, 6, 3)	13.8 ± 11.51	7.6 ± 6.00	8.7 ± 3.06	15.0 ± 17.54
Full Time: Week 96 (n= 11, 17, 3, 1)	14.2 ± 13.19	16.1 ± 15.14	3.0 ± 0	6.7 ± 2.89
Full Time: Week 120 (n= 10, 20, 0, 0)	12.4 ± 13.88	10.7 ± 11.19	999999 ± 999999	999999 ± 999999
Full Time: Week 144 (n= 17, 16, 0, 0)	16.0 ± 14.32	13.1 ± 15.44	999999 ± 999999	999999 ± 999999
Full Time: Week 168 (n= 10, 17, 0, 0)	7.3 ± 4.45	16.9 ± 15.73	999999 ± 999999	999999 ± 999999
Full Time: Week 192 (n= 10, 13, 0, 0)	15.9 ± 11.94	10.0 ± 11.53	999999 ± 999999	999999 ± 999999
Full Time: Week 216 (n= 10, 13, 0, 0)	10.3 ± 13.98	11.2 ± 14.00	999999 ± 999999	999999 ± 999999
Full Time: Week 240 (n= 0, 2, 0, 0)	999999 ± 999999	14.5 ± 4.95	999999 ± 999999	999999 ± 999999

No statistical analyses for this end point

Secondary: HRPQ: Percent Impact on Employment in the 205MS303 Treatment Period

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End point title

HRPQ: Percent Impact on Employment in the 205MS303 Treatment Period

End point description

The HRPQ was used by the subject to assess the impact of MS or its treatments on employment. The subjects assessed the percent impact of MS and its treatments on their work output using a VAS where 0= MS or its treatments had no impact on how much I accomplished to 100=MS or its treatments kept me from accomplishing anything. Data is reported by part time or full time employment. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: percent impact
arithmetic mean (standard deviation)
Part Time: Baseline 303 (n= 69, 68, 27, 9)	18.4 ± 24.18	21.1 ± 26.16	32.2 ± 34.65	19.0 ± 24.78
Part Time: Week 12 (n= 69, 66, 0, 0)	18.8 ± 24.06	16.0 ± 22.87	999999 ± 999999	999999 ± 999999
Part Time: Week 24 (n= 63, 61, 28, 11)	17.5 ± 24.30	16.8 ± 22.84	14.4 ± 14.42	26.5 ± 33.85
Part Time: Week 48 (n= 66, 66, 24, 11)	16.0 ± 23.54	14.0 ± 23.03	19.1 ± 24.17	18.8 ± 25.03
Part Time: Week 72 (n= 70, 58, 27, 9)	20.8 ± 27.63	18.8 ± 27.93	11.1 ± 10.83	23.3 ± 29.50
Part Time: Week 96 (n= 64, 57, 25, 8)	18.4 ± 24.01	16.8 ± 23.90	22.3 ± 33.41	19.1 ± 23.80
Part Time: Week 120 (n= 54, 47, 0, 0)	19.6 ± 26.58	22.4 ± 30.15	999999 ± 999999	999999 ± 999999
Part Time: Week 144 (n= 41, 49, 0, 0)	17.4 ± 23.16	15.3 ± 24.07	999999 ± 999999	999999 ± 999999
Part Time: Week 168 (n= 35, 39, 0, 0)	35.7 ± 33.82	15.3 ± 22.93	999999 ± 999999	999999 ± 999999
Part Time: Week 192 (n= 34, 35, 0, 0)	30.9 ± 33.29	21.4 ± 25.03	999999 ± 999999	999999 ± 999999
Part Time: Week 216 (n= 26, 35, 0, 0)	23.6 ± 27.73	20.3 ± 28.78	999999 ± 999999	999999 ± 999999
Part Time: Week 240 (n= 4, 0, 0, 0)	7.5 ± 15.00	999999 ± 999999	999999 ± 999999	999999 ± 999999
Full Time: Baseline 303 (n= 282, 298, 112, 41)	10.0 ± 19.52	11.8 ± 24.02	6.7 ± 16.33	13.9 ± 25.56
Full Time: Week 12 (n= 288, 301, 0, 0)	8.0 ± 17.72	10.3 ± 21.17	999999 ± 999999	999999 ± 999999
Full Time: Week 24 (n= 269, 276, 111, 39)	9.1 ± 20.13	8.3 ± 18.54	11.2 ± 25.20	12.7 ± 25.79
Full Time: Week 48 (n= 258, 271, 103, 40)	8.2 ± 19.37	9.6 ± 21.75	9.9 ± 24.25	12.2 ± 23.87
Full Time: Week 72 (n= 251, 238, 97, 33)	9.7 ± 21.40	7.8 ± 18.39	11.3 ± 22.72	14.0 ± 23.47
Full Time: Week 96 (n= 228, 227, 89, 33)	7.3 ± 18.29	8.4 ± 18.59	10.2 ± 24.63	11.1 ± 23.76
Full Time: Week 120 (n= 223, 230, 0, 0)	6.4 ± 13.87	8.6 ± 19.19	999999 ± 999999	999999 ± 999999
Full Time: Week 144 (n= 216, 205, 0, 0)	8.2 ± 18.36	7.8 ± 17.91	999999 ± 999999	999999 ± 999999
Full Time: Week 168 (n= 180, 178, 0, 0)	8.8 ± 18.53	10.1 ± 22.45	999999 ± 999999	999999 ± 999999
Full Time: Week 192 (n= 167, 166, 0, 0)	9.0 ± 19.23	7.5 ± 17.59	999999 ± 999999	999999 ± 999999
Full Time: Week 216 (n= 152, 148, 0, 0)	10.0 ± 22.36	9.3 ± 20.91	999999 ± 999999	999999 ± 999999
Full Time: Week 240 (n= 19, 18, 0, 0)	13.1 ± 23.33	7.5 ± 18.01	999999 ± 999999	999999 ± 999999

No statistical analyses for this end point

Secondary: HRPQ: Hours of Household Chores Planned to Perform in the 205MS303 Treatment Period

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End point title

HRPQ: Hours of Household Chores Planned to Perform in the 205MS303 Treatment Period

End point description

The HRPQ was used by the subject to assess the impact of MS or its treatments on performing household chores. The subject recorded their planned hours for household chores. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: hours
arithmetic mean (standard deviation)
Baseline 303 (n= 585, 597, 219, 70)	10.1 ± 10.87	10.0 ± 10.85	11.5 ± 7.94	15.8 ± 13.68
Week 12 (n= 589, 596, 0, 0)	11.8 ± 11.38	12.2 ± 12.33	999999 ± 999999	999999 ± 999999
Week 24 (n= 568, 561, 227, 70)	12.0 ± 11.75	12.6 ± 11.24	11.1 ± 7.72	14.4 ± 13.66
Week 48 (n= 552, 538, 213, 69)	11.6 ± 11.43	12.6 ± 11.39	11.6 ± 8.37	15.7 ± 14.74
Week 72 (n= 514, 486, 199, 59)	13.3 ± 12.10	13.9 ± 12.87	12.3 ± 8.94	15.0 ± 13.55
Week 96 (n= 486, 461, 191, 57)	11.9 ± 10.70	13.5 ± 12.10	12.6 ± 9.17	14.8 ± 12.20
Week 120 (n= 451, 438, 0, 0)	12.6 ± 12.09	13.1 ± 12.09	999999 ± 999999	999999 ± 999999
Week 144 (n= 426, 412, 0, 0)	13.0 ± 12.89	13.4 ± 11.99	999999 ± 999999	999999 ± 999999
Week 168 (n= 358, 361, 0, 0)	12.9 ± 12.35	13.7 ± 12.58	999999 ± 999999	999999 ± 999999
Week 192 (n= 332, 330, 0, 0)	13.4 ± 11.78	13.9 ± 12.43	999999 ± 999999	999999 ± 999999
Week 216 (n= 292, 299, 0, 0)	14.2 ± 13.01	14.0 ± 11.46	999999 ± 999999	999999 ± 999999
Week 240 (n= 42, 30, 0, 0)	13.6 ± 11.49	10.1 ± 7.89	999999 ± 999999	999999 ± 999999

No statistical analyses for this end point

Secondary: HRPQ: Number of Subjects where MS or Its Treatments Kept the Subject from Completing Chores in the 205MS303 Treatment Period

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End point title

HRPQ: Number of Subjects where MS or Its Treatments Kept the Subject from Completing Chores in the 205MS303 Treatment Period

End point description

The HRPQ was used by the subject to assess the impact of MS or its treatments on performing household chores. The subject recorded whether MS or its treatments kept them from completing household chores. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: subjects
Baseline 303 (n= 591, 600, 220, 70)	112	104	15	58
Week 12 (n= 593, 600, 0, 0)	110	111	999999	999999
Week 24 (n= 572, 565, 227, 70)	125	110	12	68
Week 48 (n= 553, 541, 213, 69)	113	93	19	66
Week 72 (n= 515, 489, 199, 59)	111	93	15	58
Week 96 (n= 487, 464, 191, 57)	94	79	16	53
Week 120 (n= 452, 439, 0, 0)	93	84	999999	999999
Week 144 (n= 427, 413, 0, 0)	91	87	999999	999999
Week 168 (n= 359, 362, 0, 0)	82	81	999999	999999
Week 192 (n= 333, 331, 0, 0)	71	65	999999	999999
Week 216 (n= 293, 299, 0, 0)	65	65	999999	999999
Week 240 (n= 42, 30, 0, 0)	2	7	999999	999999

No statistical analyses for this end point

Secondary: HRPQ: Hours not Performing Household Chores due to MS or Its Treatment in 205MS303 Treatment Period

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End point title

HRPQ: Hours not Performing Household Chores due to MS or Its Treatment in 205MS303 Treatment Period

End point description

The HRPQ was used by the subject to assess the impact of MS or its treatments on performing household chores. The subject recorded the hours where they were not able to perform household chores due to MS or its treatments. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects unable to complete chores with data available at the given timepoint. '999999' indicates that no data was collected.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: hours
arithmetic mean (standard deviation)
Baseline 303 (n= 107, 104, 58, 15)	6.4 ± 7.82	5.1 ± 5.08	5.2 ± 4.06	5.4 ± 6.25
Week 12 (n= 111, 113, 0, 0)	7.0 ± 9.35	5.9 ± 7.63	999999 ± 999999	999999 ± 999999
Week 24 (n= 124, 109, 67, 12)	6.3 ± 7.56	5.2 ± 4.59	5.0 ± 3.57	5.7 ± 7.75
Week 48 (n= 111, 89, 66, 19)	7.3 ± 11.41	4.7 ± 3.53	4.7 ± 4.21	7.9 ± 9.19
Week 72 (n= 110, 94, 59, 15)	7.2 ± 7.16	6.6 ± 10.32	5.8 ± 4.46	6.8 ± 8.03
Week 96 (n= 95, 77, 53, 17)	5.2 ± 3.93	5.1 ± 4.67	3.8 ± 3.81	8.1 ± 9.35
Week 120 (n= 92, 84, 0, 0)	6.0 ± 8.23	5.9 ± 11.13	999999 ± 999999	999999 ± 999999
Week 144 (n= 93, 87, 0, 0)	5.7 ± 4.95	6.3 ± 6.10	999999 ± 999999	999999 ± 999999
Week 168 (n= 82, 83, 0, 0)	5.8 ± 5.19	5.5 ± 5.16	999999 ± 999999	999999 ± 999999
Week 192 (n= 72, 65, 0, 0)	6.9 ± 9.01	5.7 ± 5.96	999999 ± 999999	999999 ± 999999
Week 216 (n= 66, 70, 0, 0)	6.9 ± 7.09	7.3 ± 10.97	999999 ± 999999	999999 ± 999999
Week 240 (n= 2, 8, 0, 0)	5.5 ± 6.36	9.8 ± 13.04	999999 ± 999999	999999 ± 999999

No statistical analyses for this end point

Secondary: HRPQ: Percent Impact on Performing Household chores in the 205MS303 Treatment Period

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End point title

HRPQ: Percent Impact on Performing Household chores in the 205MS303 Treatment Period

End point description

The HRPQ was used by the subject to assess the impact of MS or its treatments on performing household chores. The subject assessed the percent impact of MS and its treatments on how much they accomplished using a VAS where 0= MS or its treatments had no impact on how much I accomplished to 100=MS or its treatments kept me from accomplishing anything. ITT Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.

End point type

Secondary

End point timeframe

301-303: Baseline 303, Weeks 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240; 203-303 and 302-303: Baseline 303, Weeks 24, 48, 72, 96 in Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: percent impact
arithmetic mean (standard deviation)
Baseline 303 (n= 519, 515, 219, 69)	16.0 ± 23.16	17.5 ± 25.31	18.9 ± 24.41	25.3 ± 29.42
Week 12 (n= 578, 587, 0, 0)	16.7 ± 24.40	17.5 ± 25.38	999999 ± 999999	999999 ± 999999
Week 24 (n= 557, 552, 226, 68)	17.0 ± 25.23	16.7 ± 24.71	24.8 ± 30.25	25.5 ± 28.81
Week 48 (n= 541, 531, 210, 69)	16.9 ± 25.48	17.1 ± 26.23	21.0 ± 27.62	23.8 ± 28.52
Week 72 (n= 507, 485, 199, 59)	19.9 ± 26.83	17.8 ± 26.13	19.6 ± 23.37	25.4 ± 27.88
Week 96 (n= 482, 455, 187, 57)	16.4 ± 25.39	17.7 ± 26.18	21.4 ± 27.23	23.8 ± 29.07
Week 120 (n= 449, 435, 0, 0)	17.4 ± 25.10	16.9 ± 25.00	999999 ± 999999	999999 ± 999999
Week 144 (n= 421, 411, 0, 0)	16.5 ± 24.40	17.4 ± 25.25	999999 ± 999999	999999 ± 999999
Week 168 (n= 356, 358, 0, 0)	19.1 ± 26.03	18.2 ± 26.37	999999 ± 999999	999999 ± 999999
Week 192 (n= 330, 330, 0, 0)	18.5 ± 26.55	17.3 ± 25.07	999999 ± 999999	999999 ± 999999
Week 216 (n= 291, 298, 0, 0)	18.8 ± 26.11	18.3 ± 26.18	999999 ± 999999	999999 ± 999999
Week 240 (n= 42, 30, 0, 0)	9.6 ± 14.95	16.0 ± 26.06	999999 ± 999999	999999 ± 999999

No statistical analyses for this end point

Secondary: Number of Subjects with Clinically Significant Changes from Baseline in Clinical Laboratory Assessments in the 205MS303 Treatment Period

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End point title

Number of Subjects with Clinically Significant Changes from Baseline in Clinical Laboratory Assessments in the 205MS303 Treatment Period

End point description

Clinical Laboratory assessments included tests of hematology, blood chemistry, renal function, and thyroid function. The investigator determined if the results were clinically significant. Safety Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303.

End point type

Secondary

End point timeframe

Up to 4.6 years Study 303

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	70	227
Units: subjects	0	0	0	0

No statistical analyses for this end point

Secondary: Local Tolerability as assessed by Subject-reported Injection Site Pain VAS

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End point title

Local Tolerability as assessed by Subject-reported Injection Site Pain VAS

End point description

The VAS is a 10 cm-long horizontal line labeled with 2 extremes of pain at either end: 0 =no pain on the left and 100=very painful on the right. The subject rates their perceived pain of each injection by placing a vertical mark on the line to indicate the level of pain. Safety Population included all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects in this study who received DAC HYP with data available for analysis. Local tolerability of the DAC HYP injection was assessed for all subjects who received DAC HYP in Study 303 and is independent of the treatment previously received.

End point type

Secondary

End point timeframe

After the first and fourth injections in 303, approximately Week 0 and Week 12

End point values	DAC HYP 150 mg
Number of subjects analysed	1500
Units: score on scale
arithmetic mean (standard deviation)
First Injection, Post-dose (n= 97)	1.7 ± 2.46
Fourth Injection, Post-dose (n=87)	1.6 ± 2.34

No statistical analyses for this end point

Secondary: Number of Subjects in Local Tolerability Clinician Injection Site Assessment Categories

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End point title

Number of Subjects in Local Tolerability Clinician Injection Site Assessment Categories

End point description

The investigator assessed the injection site after the first dose and before the fourth dose for the presence of erythema (None, Mild, Moderate, Severe), pigmentation (None, Hypo, Hyper), Induration (None, Mild, Moderate, Severe), Tenderness (None, Mild, Moderate, Severe) and Temperature (Normal, Warm, Hot). The number of subjects in each grade is reported. Safety Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. This outcome measure was assessed for all subjects who received at least one dose of DAC HYP combined. 'n' is the number of subjects with data available at the given timepoint. Local tolerability of the DAC HYP injection was assessed for all subjects who received DAC HYP in Study 303 and is independent of the treatment previously received.

End point type

Secondary

End point timeframe

After the first and fourth injections in 303, approximately Week 0 and Week 12

End point values	DAC HYP 150 mg
Number of subjects analysed	1500
Units: subjects
First Injection Post-dose, Erythema: None (n= 97)	87
First Injection Post-dose, Erythema: Mild (n= 97)	8
First Injection Post-dose,Erythema:Moderate (n=97)	2
First Injection Post-dose, Erythema: Severe (n=97)	0
Fourth Injection Pre-dose, Erythema: None (n= 87)	87
Fourth Injection Pre-dose, Erythema: Mild (n= 87)	0
Fourth Injection Pre-dose,Erythema:Moderate (n=87)	0
Fourth Injection Pre-dose, Erythema: Severe (n=87)	0
First Injection Post-dose,Pigmentation:None (n=97)	90
First Injection Post-dose,Pigmentation:Hypo (n=97)	7
First Injection Post-dose,Pigmentation:Hyper(n=97)	0
Fourth Injection Pre-dose,Pigmentation:None (n=87)	87
Fourth Injection Pre-dose,Pigmentation:Hypo (n=87)	0
Fourth Injection Pre-dose,Pigmentation:Hyper(n=87)	0
First Injection Post-dose, Induration: None (n=93)	89
First Injection Post-dose, Induration: Mild (n=93)	4
First Injection Postdose,Induration:Moderate(n=93)	0
First Injection Post-dose,Induration:Severe (n=93)	0
Fourth Injection Pre-dose, Induration: None (n=87)	87
Fourth Injection Pre-dose, Induration: Mild (n=87)	0
Fourth Injection Predose,Induration:Moderate(n=87)	0
Fourth Injection Pre-dose,Induration:Severe (n=87)	0
First Injection Post-dose, Tenderness: None (n=97)	94
First Injection Post-dose, Tenderness: Mild (n=97)	3
First Injection Postdose,Tenderness:Moderate(n=97)	0
First Injection Post-dose,Tenderness:Severe (n=97)	0
Fourth Injection Pre-dose, Tenderness: None (n=87)	87
Fourth Injection Pre-dose, Tenderness: Mild (n=87)	0
Fourth Injection Predose,Tenderness:Moderate(n=87)	0
Fourth Injection Pre-dose,Tenderness:Severe (n=87)	0
First Injection Postdose,Temperature:Normal (n=97)	97
First Injection Post-dose,Temperature:Warm (n=97)	0
First Injection Post-dose,Temperature: Hot (n= 97)	0
Fourth Injection Pre-dose,Temperature:Normal(n=87)	87
Fourth Injection Pre-dose,Temperature:Warm (n=87)	0
Fourth Injection Pre-dose, Temperature: Hot (n=87)	0

No statistical analyses for this end point

Secondary: Number of Subjects with Anti-BIIB019 Binding Antibodies (ADAbs) in the 205MS303 Treatment Period

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End point title

Number of Subjects with Anti-BIIB019 Binding Antibodies (ADAbs) in the 205MS303 Treatment Period

End point description

Blood samples were collected for ADAbs and were analysed using a laboratory test. The number of subjects ADAb positive at any post-baseline timepoint is reported. Safety Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. Number of subjects analyzed is the number of subjects with evaluable data for this outcome measure.

End point type

Secondary

End point timeframe

Up to 4.6 years in the 303 Treatment Period

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	603	35	68
Units: subjects	113	48	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with Anti-BIIB019 Neutralizing Antibodies (Nabs) in the 205MS303 Treatment Period

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End point title

Number of Subjects with Anti-BIIB019 Neutralizing Antibodies (Nabs) in the 205MS303 Treatment Period

End point description

Blood samples were collected for NAbs and were analysed using a laboratory test. The number of subjects NAb positive at any post-baseline timepoint is reported. Safety Population consisted of all subjects who completed Study 301, 203 or 302 and received at least one dose of DAC HYP in Study 303. Number of subjects analyzed is the number of subjects with evaluable data for this outcome measure.

End point type

Secondary

End point timeframe

Up to 4.6 years in the 303 Treatment Period

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606	35	67
Units: subjects	45	21	0	0

No statistical analyses for this end point

Secondary: Change from 205MS303 Baseline in the Symbol Digit Modalities Test (SDMT) Score in the 205MS303 Treatment Period

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End point title

Change from 205MS303 Baseline in the Symbol Digit Modalities Test (SDMT) Score in the 205MS303 Treatment Period ^[18]

End point description

SDMT is a screening test for cognitive impairment. Subjects are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). A positive change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. 'n' is the number of subjects with data available at the given timepoint. No data is collected for subjects from 203 and 302 studies.

End point type

Secondary

End point timeframe

Baseline 303, Weeks 144, 168, 192, 240 in 303

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	408	400
Units: score on a scale
arithmetic mean (standard deviation)
Baseline 303	52.0 ± 15.13	52.4 ± 16.08
Change at Week 144 (n= 321, 315)	-3.0 ± 11.38	-3.5 ± 11.91
Change at Week 168 (n= 327, 340)	-1.9 ± 11.59	-3.7 ± 13.10
Change at Week 192 (n= 314, 318)	-2.5 ± 12.02	-2.8 ± 12.92
Change at Week 240 (n= 24, 16)	2.0 ± 10.78	-2.0 ± 15.38

No statistical analyses for this end point

Secondary: Change from 205MS301 Baseline in the SDMT Score in the 205MS301-303 Combined Study Period

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End point title

Change from 205MS301 Baseline in the SDMT Score in the 205MS301-303 Combined Study Period ^[19]

End point description

SDMT is a screening test for cognitive impairment. Subjects are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). A positive change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least one dose of DAC HYP in Study 303. 'n' is the number of subjects with data available at the given timepoint.

End point type

Secondary

End point timeframe

Baseline 301, Weeks 24, 48, 72, 96, 120, 144 in 301; Weeks 144, 168, 192, 216, 240 in 303

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	577	584
Units: score on a scale
arithmetic mean (standard deviation)
Baseline (BL) 301	47.8 ± 16.18	48.4 ± 16.32
Change from BL 301 at Week 24 for 301 (n=572, 575)	1.3 ± 11.20	1.1 ± 12.42
Change from BL 301 at Week 48 for 301 (n=568, 577)	2.7 ± 12.31	2.2 ± 12.01
Change from BL 301 at Week 72 for 301 (n=568, 573)	3.0 ± 13.12	3.6 ± 12.98
Change from BL 301 at Week 96 for 301 (n=574, 579)	3.0 ± 13.04	4.1 ± 13.09
Change from BL 301 at Week 120 for 301(n=416, 437)	3.5 ± 13.53	5.4 ± 12.75
Change from BL 301 at Week 144 for 301(n=237, 238)	3.2 ± 13.38	6.6 ± 13.15
Change from BL 301 at Week 144 for 303(n=308, 297)	0.7 ± 14.95	1.3 ± 13.92
Change from BL 301 at Week 168 for 303(n=315, 321)	2.0 ± 14.78	1.6 ± 14.86
Change from BL 301 at Week 192 for 303(n=300, 302)	1.7 ± 15.81	2.1 ± 15.35
Change from BL 301 at Week 216 for 303(n=255, 265)	4.7 ± 15.91	4.5 ± 14.59
Change from BL 301 at Week 240 for 303(n=24, 16)	3.8 ± 11.41	8.8 ± 9.42

No statistical analyses for this end point

Secondary: Change from Baseline in 3-Second Paced Auditory Serial Addition Test (PASAT 3) Score in the 205MS303 Treatment Period

Top of page

End point title

Change from Baseline in 3-Second Paced Auditory Serial Addition Test (PASAT 3) Score in the 205MS303 Treatment Period ^[20]

End point description

The PASAT 3 assesses auditory information processing speed. A random series of numbers from 1 to 9, inclusive, are presented and the subject is instructed to consecutively add pairs of numbers so that each number is added to the one that immediately preceded it. In the 3- second PASAT, numbers are presented at a rate of 1 every 3 seconds. The total possible score is the number of correct responses from 0 to 60 (best). A positive change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed Study 301 and received at least 1 dose of DAC HYP during Study 303. 'n' is the number of subjects with data available at the given timepoint. No data was collected for subjects from the 203 and 302 studies.

End point type

Secondary

End point timeframe

Baseline 303, Weeks 12, 24, 48, 120, 144, 168, 192, 216, 240 in Study 303

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: score on a scale
median (full range (min-max))
Baseline 303 (n= 595, 604)	54.0 (0 to 60)	54.0 (3 to 60)
Change to Week 12 (n= 584, 584)	0.0 (-40 to 19)	0.0 (-23 to 25)
Change to Week 24 (n= 564, 557)	0.0 (-26 to 26)	0.0 (-27 to 39)
Change to Week 48 (n= 530, 509)	0.0 (-41 to 21)	0.0 (-21 to 41)
Change to Week 120 (n= 1, 2)	-3.0 (-3 to -3)	-1.0 (-2 to 0)
Change to Week 144 (n= 305, 301)	-1.0 (-34 to 23)	-1.0 (-31 to 35)
Change to Week 168 (n= 327, 334)	0.0 (-35 to 21)	0.0 (-30 to 25)
Change to Week 192 (n= 315, 319)	0.0 (-33 to 26)	0.0 (-42 to 40)
Change to Week 216 (n= 266, 279)	0.0 (-22 to 16)	0.0 (-23 to 39)
Change to Week 240 (n= 24, 16)	0.0 (-8 to 12)	-2.0 (-9 to 6)

Analysis 1

Statistical analysis description

Change to Week 12

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3813

Method

ANCOVA

Confidence interval

Analysis 2

Statistical analysis description

Change to Week 24

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1679

Method

ANOVA

Confidence interval

Analysis 3

Statistical analysis description

Change to Week 48

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5634

Method

ANCOVA

Confidence interval

Analysis 4

Statistical analysis description

Change to Week 144

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7003

Method

ANCOVA

Confidence interval

Analysis 5

Statistical analysis description

Change to Week 168

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7812

Method

ANCOVA

Confidence interval

Analysis 6

Statistical analysis description

Change to Week 192

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3246

Method

ANCOVA

Confidence interval

Analysis 7

Statistical analysis description

Change to Week 216

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6423

Method

ANCOVA

Confidence interval

Analysis 8

Statistical analysis description

Change to Week 240

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0288

Method

ANCOVA

Confidence interval

Secondary: Change from Baseline in 3-Second Paced Auditory Serial Addition Test (PASAT 3) Score in the 205MS301-303 Combined Study Period

Top of page

End point title

Change from Baseline in 3-Second Paced Auditory Serial Addition Test (PASAT 3) Score in the 205MS301-303 Combined Study Period ^[21]

End point description

The PASAT 3 assesses auditory information processing speed. A random series of numbers from 1 to 9, inclusive, are presented and the subject is instructed to consecutively add pairs of numbers so that each number is added to the one that immediately preceded it. In the 3- second PASAT, numbers are presented at a rate of 1 every 3 seconds. The total possible score is the number of correct responses from 0 to 60 (best). A positive change from baseline indicates improvement. 301-303 ITT Population consisted of all subjects who completed study 301 and had at least 1 dose of DAC HYP during study 303. 'n' is the number of subjects with data available at the given timepoint. '999999' indicates that no data was collected.

End point type

Secondary

End point timeframe

Baseline 301, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156 in the 301 study, Baseline 303, Weeks 12, 24, 48, 120, 144,168, 192, 216, 240 in 303 study

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the baseline period are applicable to this endpoint.

End point values	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)
Number of subjects analysed	597	606
Units: score on a scale
median (full range (min-max))
Baseline 301 (n= 596, 605)	50.0 (0 to 60)	51.0 (9 to 60)
Change from BL 301 to Week 12 for 301 (n=593, 603)	0.0 (-58 to 40)	1.0 (-59 to 25)
Change from BL 301 to Week 24 for 301 (n=594, 600)	0.5 (-26 to 31)	1.0 (-32 to 22)
Change from BL 301 to Week 36 for 301 (n=594, 599)	1.0 (-29 to 30)	1.0 (-37 to 28)
Change from BL 301 to Week 48 for 301 (n=592, 602)	1.0 (-25 to 42)	1.0 (-38 to 30)
Change from BL 301 to Week 60 for 301 (n=589, 599)	1.0 (-46 to 40)	2.0 (-34 to 37)
Change from BL 301 to Week 72 for 301 (n=592, 600)	2.0 (-20 to 40)	2.0 (-21 to 41)
Change from BL 301 to Week 84 for 301 (n=591, 598)	2.0 (-31 to 39)	2.0 (-41 to 29)
Change from BL 301 to Week 96 for 301 (n=594, 600)	2.0 (-28 to 41)	2.0 (-25 to 38)
Change from BL 301 to Week 108 for 301(n=489, 500)	1.0 (-27 to 43)	2.0 (-25 to 40)
Change from BL 301 to Week 120 for 301(n=397, 397)	2.0 (-27 to 35)	2.0 (-31 to 41)
Change from BL 301 to Week 132 for 301(n=273, 289)	2.0 (-30 to 35)	2.0 (-19 to 38)
Change from BL 301 to Week 144 for 301(n=210, 204)	2.0 (-25 to 31)	3.0 (-21 to 31)
Change from BL 301 to Week 156 for 301(n=0, 1)	999999 (999999 to 999999)	-4.0 (-4 to -4)
Change from BL 301 to BL 303 (n=595, 603)	2.0 (-34 to 44)	2.0 (-41 to 45)
Change from BL 301 to Week 12 for 303 (n=582, 580)	2.0 (-38 to 43)	2.0 (-26 to 41)
Change from BL 301 to Week 24 for 303 (n=562, 553)	2.0 (-31 to 40)	2.0 (-27 to 43)
Change from BL 301 to Week 48 for 303 (n=528, 505)	2.0 (-47 to 44)	2.0 (-24 to 41)
Change from BL 301 to Week 120 for 303(n=1, 2)	15.0 (15 to 15)	3.0 (1 to 5)
Change from BL 301 to Week 144 for 303(n=303, 298)	1.0 (-32 to 37)	2.0 (-24 to 38)
Change from BL 301 to Week 168 for 303(n=325, 330)	2.0 (-36 to 42)	2.0 (-29 to 42)
Change from BL 301 to Week 192 for 303(n=313, 316)	2.0 (-40 to 42)	2.0 (-21 to 42)
Change from BL 301 to Week 216 for 303(n=265, 277)	2.0 (-27 to 40)	2.0 (-30 to 41)
Change from BL 301 to Week 240 for 303(n=24, 16)	1.5 (-10 to 26)	0.5 (-11 to 23)

Analysis 1

Statistical analysis description

Change from Baseline 301 to Week 12 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2567

Method

ANCOVA

Confidence interval

Analysis 2

Statistical analysis description

Change from Baseline 301 to Week 24 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6152

Method

ANCOVA

Confidence interval

Analysis 3

Statistical analysis description

Change from Baseline 301 to Week 36 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2024

Method

ANCOVA

Confidence interval

Analysis 4

Statistical analysis description

Change from Baseline 301 to Week 48 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9988

Method

ANCOVA

Confidence interval

Analysis 5

Statistical analysis description

Change from Baseline 301 to Week 60 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7962

Method

ANCOVA

Confidence interval

Analysis 6

Statistical analysis description

Change from Baseline 301 to Week 72 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8486

Method

ANCOVA

Confidence interval

Analysis 7

Statistical analysis description

Change from Baseline 301 to Week 84 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4478

Method

ANCOVA

Confidence interval

Analysis 8

Statistical analysis description

Change from Baseline 301 to Week 96 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.325

Method

ANCOVA

Confidence interval

Analysis 9

Statistical analysis description

Change from Baseline 301 to Week 108 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.129

Method

ANCOVA

Confidence interval

Analysis 10

Statistical analysis description

Change from Baseline 301 to Week 120 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7295

Method

ANCOVA

Confidence interval

Analysis 11

Statistical analysis description

Change from Baseline 301 to Week 132 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8647

Method

ANCOVA

Confidence interval

Analysis 12

Statistical analysis description

Change from Baseline 301 to Week 144 for 301

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2183

Method

ANCOVA

Confidence interval

Analysis 13

Statistical analysis description

Change from Baseline 301 to Baseline 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3945

Method

ANCOVA

Confidence interval

Analysis 14

Statistical analysis description

Change from Baseline 301 to Week 12 for 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5068

Method

ANCOVA

Confidence interval

Analysis 15

Statistical analysis description

Change from Baseline 301 to Week 24 for 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1669

Method

ANCOVA

Confidence interval

Analysis 16

Statistical analysis description

Change from Baseline 301 to Week 48 for 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5038

Method

ANCOVA

Confidence interval

Analysis 17

Statistical analysis description

Change from Baseline 301 to Week 144 for 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6001

Method

ANCOVA

Confidence interval

Analysis 18

Statistical analysis description

Change from Baseline 301 to Week 168 for 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8617

Method

ANCOVA

Confidence interval

Analysis 19

Statistical analysis description

Change from Baseline 301 to Week 192 for 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.259

Method

ANCOVA

Confidence interval

Analysis 20

Statistical analysis description

Change from Baseline 301 to Week 216 for 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5159

Method

ANCOVA

Confidence interval

Analysis 21

Statistical analysis description

Change from Baseline 301 to Week 240 for 303

Comparison groups

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303) v DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Number of subjects included in analysis

1203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6123

Method

ANCOVA

Confidence interval

Adverse events

Top of page

Timeframe for reporting adverse events

First dose of study drug in study 205MS303 to within 180 days of last dose (up to approximately 5.5 years)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)

Reporting group description

DAC HYP 150 mg SC injection every 4 weeks for up to 4.6 years in this long-term extension study 303; includes subjects who previously received interferon beta-1a (IFN β-1a) 30 µg intramuscular (IM) injection once weekly in study 301 every 4 weeks for up to 144 weeks.

Reporting group title

DAC HYP 150 mg (301) /DAC HYP 150 mg (303)

Reporting group description

Reporting group title

DAC HYP 150 mg (302) /DAC HYP 150 mg (303)

Reporting group description

Reporting group title

DAC HYP 150 mg (203) /DAC HYP 150 mg (303)

Reporting group description

Serious adverse events	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Total subjects affected by serious adverse events
subjects affected / exposed	157 / 597 (26.30%)	190 / 606 (31.35%)	15 / 70 (21.43%)	38 / 227 (16.74%)
number of deaths (all causes)	2	4	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anorectal human papilloma virus infection
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
B-cell lymphoma
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Benign neoplasm of thyroid gland
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	3 / 597 (0.50%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 3	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial cancer
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fibroadenoma of breast
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metaplastic breast carcinoma
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cancer
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian fibroma
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Parathyroid tumour benign
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Testicular neoplasm
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 597 (0.00%)	4 / 606 (0.66%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyosarcoma
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Granulomatosis with polyangiitis
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Kawasaki's disease
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Varicose vein
subjects affected / exposed	2 / 597 (0.34%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Abdominoplasty
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Female sterilisation
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hospitalisation
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immunosuppressant drug therapy
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mastectomy
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blighted ovum
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foetal growth restriction
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Premature delivery
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inflammation
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multi-organ disorder
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 597 (0.50%)	3 / 606 (0.50%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	1 / 3	2 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sarcoidosis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Serum sickness
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Adnexal torsion
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical dysplasia
subjects affected / exposed	2 / 597 (0.34%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysfunctional uterine bleeding
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metrorrhagia
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian adhesion
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst ruptured
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic prolapse
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial hyperreactivity
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis chronic
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Choking
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngeal necrosis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary sarcoidosis
subjects affected / exposed	0 / 597 (0.00%)	3 / 606 (0.50%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tracheal fistula
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Acute stress disorder
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anxiety
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bipolar i disorder
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	2 / 597 (0.34%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Personality disorder
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Somatoform disorder
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	2 / 597 (0.34%)	3 / 606 (0.50%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 597 (0.17%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 597 (0.17%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diagnostic procedure
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Protein urine present
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accident
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 597 (0.17%)	7 / 606 (1.16%)	1 / 70 (1.43%)	2 / 227 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 7	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 597 (0.00%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 597 (0.00%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intentional overdose
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint injury
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ligament injury
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 597 (0.00%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Snake bite
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 597 (0.00%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular hypertrophy
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain compression
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebellar syndrome
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral venous thrombosis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis autoimmune
subjects affected / exposed	3 / 597 (0.50%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	2 / 597 (0.34%)	3 / 606 (0.50%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Guillain-barre syndrome
subjects affected / exposed	2 / 597 (0.34%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple sclerosis
subjects affected / exposed	3 / 597 (0.50%)	3 / 606 (0.50%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple sclerosis relapse
subjects affected / exposed	61 / 597 (10.22%)	65 / 606 (10.73%)	3 / 70 (4.29%)	17 / 227 (7.49%)
occurrences causally related to treatment / all	4 / 113	4 / 117	0 / 4	0 / 20
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscle spasticity
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myasthenia gravis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neurological symptom
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Optic neuritis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 597 (0.17%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Agranulocytosis
subjects affected / exposed	1 / 597 (0.17%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Granulocytopenia
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	2 / 597 (0.34%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	2 / 2	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	2 / 597 (0.34%)	3 / 606 (0.50%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 2	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	4 / 597 (0.67%)	10 / 606 (1.65%)	1 / 70 (1.43%)	2 / 227 (0.88%)
occurrences causally related to treatment / all	2 / 4	11 / 13	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoid tissue hyperplasia
subjects affected / exposed	4 / 597 (0.67%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	3 / 4	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphopenia
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 597 (0.00%)	2 / 606 (0.33%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Pernicious anaemia
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pseudolymphoma
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	3 / 597 (0.50%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Acute vestibular syndrome
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Eye haemorrhage
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Iritis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anorectal disorder
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coeliac disease
subjects affected / exposed	0 / 597 (0.00%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 597 (0.00%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	2 / 597 (0.34%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Functional gastrointestinal disorder
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gingivitis ulcerative
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inflammatory bowel disease
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	2 / 597 (0.34%)	2 / 606 (0.33%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	2 / 597 (0.34%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	3 / 597 (0.50%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peptic ulcer haemorrhage
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis necrotising
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tongue necrosis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	2 / 597 (0.34%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	5 / 597 (0.84%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic hepatitis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	4 / 597 (0.67%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	4 / 4	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic necrosis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis cholestatic
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis toxic
subjects affected / exposed	1 / 597 (0.17%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver injury
subjects affected / exposed	0 / 597 (0.00%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Alopecia scarring
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis atopic
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis contact
subjects affected / exposed	3 / 597 (0.50%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug eruption
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eczema
subjects affected / exposed	2 / 597 (0.34%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erythema
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erythema multiforme
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erythema nodosum
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Henoch-schonlein purpura
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hidradenitis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pemphigoid
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perivascular dermatitis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Photosensitivity reaction
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pityriasis rosea
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psoriasis
subjects affected / exposed	3 / 597 (0.50%)	2 / 606 (0.33%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	3 / 4	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash generalised
subjects affected / exposed	0 / 597 (0.00%)	3 / 606 (0.50%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	2 / 597 (0.34%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rosacea
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seborrhoeic dermatitis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stevens-johnson syndrome
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxic epidermal necrolysis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxic skin eruption
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus ureteric
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertonic bladder
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 597 (0.00%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal cyst
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure chronic
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urogenital fistula
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vesicoureteric reflux
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperparathyroidism primary
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fibromyalgia
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Juvenile idiopathic arthritis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ligament laxity
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteochondrosis
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psoriatic arthropathy
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seronegative arthritis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Still's disease adult onset
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Systemic sclerosis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tendonitis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tenosynovitis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Anal abscess
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 597 (0.17%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bartholin's abscess
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Brucellosis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chlamydial infection
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic hepatitis c
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Genitourinary tract infection
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis e
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 597 (0.00%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lyme disease
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	1 / 70 (1.43%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myelitis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Parotitis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	5 / 597 (0.84%)	8 / 606 (1.32%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	1 / 5	3 / 8	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pneumonia cytomegaloviral
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	2 / 597 (0.34%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 597 (0.17%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reiter's syndrome
subjects affected / exposed	0 / 597 (0.00%)	0 / 606 (0.00%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 597 (0.17%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 597 (0.00%)	2 / 606 (0.33%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	2 / 597 (0.34%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	6 / 597 (1.01%)	3 / 606 (0.50%)	2 / 70 (2.86%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	4 / 7	0 / 4	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	2 / 597 (0.34%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal infection
subjects affected / exposed	0 / 597 (0.00%)	1 / 606 (0.17%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperamylasaemia
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Type 1 diabetes mellitus
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	1 / 597 (0.17%)	0 / 606 (0.00%)	0 / 70 (0.00%)	0 / 227 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	IFN β-1a 30 µg (301)/DAC HYP 150 mg (303)	DAC HYP 150 mg (301) /DAC HYP 150 mg (303)	DAC HYP 150 mg (302) /DAC HYP 150 mg (303)	DAC HYP 150 mg (203) /DAC HYP 150 mg (303)
Total subjects affected by non serious adverse events
subjects affected / exposed	463 / 597 (77.55%)	476 / 606 (78.55%)	42 / 70 (60.00%)	116 / 227 (51.10%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	45 / 597 (7.54%)	48 / 606 (7.92%)	3 / 70 (4.29%)	16 / 227 (7.05%)
occurrences all number	59	65	3	22
Aspartate aminotransferase increased
subjects affected / exposed	40 / 597 (6.70%)	48 / 606 (7.92%)	2 / 70 (2.86%)	11 / 227 (4.85%)
occurrences all number	48	72	2	15
Liver function test abnormal
subjects affected / exposed	32 / 597 (5.36%)	30 / 606 (4.95%)	2 / 70 (2.86%)	6 / 227 (2.64%)
occurrences all number	32	34	2	6
Nervous system disorders
Headache
subjects affected / exposed	57 / 597 (9.55%)	56 / 606 (9.24%)	7 / 70 (10.00%)	16 / 227 (7.05%)
occurrences all number	93	92	13	31
Multiple sclerosis relapse
subjects affected / exposed	179 / 597 (29.98%)	169 / 606 (27.89%)	15 / 70 (21.43%)	36 / 227 (15.86%)
occurrences all number	339	282	28	51
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	47 / 597 (7.87%)	71 / 606 (11.72%)	3 / 70 (4.29%)	7 / 227 (3.08%)
occurrences all number	65	93	4	12
General disorders and administration site conditions
Fatigue
subjects affected / exposed	40 / 597 (6.70%)	41 / 606 (6.77%)	3 / 70 (4.29%)	4 / 227 (1.76%)
occurrences all number	45	51	3	5
Pyrexia
subjects affected / exposed	45 / 597 (7.54%)	43 / 606 (7.10%)	3 / 70 (4.29%)	7 / 227 (3.08%)
occurrences all number	77	58	3	13
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	42 / 597 (7.04%)	35 / 606 (5.78%)	2 / 70 (2.86%)	10 / 227 (4.41%)
occurrences all number	51	48	2	16
Toothache
subjects affected / exposed	17 / 597 (2.85%)	14 / 606 (2.31%)	4 / 70 (5.71%)	3 / 227 (1.32%)
occurrences all number	18	17	4	3
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	13 / 597 (2.18%)	16 / 606 (2.64%)	4 / 70 (5.71%)	4 / 227 (1.76%)
occurrences all number	19	16	4	5
Eczema
subjects affected / exposed	32 / 597 (5.36%)	46 / 606 (7.59%)	1 / 70 (1.43%)	5 / 227 (2.20%)
occurrences all number	52	71	2	6
Erythema
subjects affected / exposed	31 / 597 (5.19%)	27 / 606 (4.46%)	0 / 70 (0.00%)	1 / 227 (0.44%)
occurrences all number	33	35	0	1
Rash
subjects affected / exposed	39 / 597 (6.53%)	64 / 606 (10.56%)	0 / 70 (0.00%)	9 / 227 (3.96%)
occurrences all number	52	88	0	11
Psychiatric disorders
Depression
subjects affected / exposed	45 / 597 (7.54%)	38 / 606 (6.27%)	1 / 70 (1.43%)	1 / 227 (0.44%)
occurrences all number	52	43	1	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	45 / 597 (7.54%)	38 / 606 (6.27%)	3 / 70 (4.29%)	7 / 227 (3.08%)
occurrences all number	49	53	3	7
Back pain
subjects affected / exposed	65 / 597 (10.89%)	51 / 606 (8.42%)	3 / 70 (4.29%)	10 / 227 (4.41%)
occurrences all number	78	73	3	11
Pain in extremity
subjects affected / exposed	34 / 597 (5.70%)	40 / 606 (6.60%)	2 / 70 (2.86%)	2 / 227 (0.88%)
occurrences all number	42	48	2	3
Infections and infestations
Bronchitis
subjects affected / exposed	29 / 597 (4.86%)	36 / 606 (5.94%)	3 / 70 (4.29%)	1 / 227 (0.44%)
occurrences all number	35	39	3	1
Influenza
subjects affected / exposed	46 / 597 (7.71%)	35 / 606 (5.78%)	1 / 70 (1.43%)	4 / 227 (1.76%)
occurrences all number	56	44	1	4
Nasopharyngitis
subjects affected / exposed	121 / 597 (20.27%)	125 / 606 (20.63%)	6 / 70 (8.57%)	18 / 227 (7.93%)
occurrences all number	267	283	9	25
Oral herpes
subjects affected / exposed	42 / 597 (7.04%)	35 / 606 (5.78%)	3 / 70 (4.29%)	6 / 227 (2.64%)
occurrences all number	84	61	5	10
Pharyngitis
subjects affected / exposed	53 / 597 (8.88%)	47 / 606 (7.76%)	1 / 70 (1.43%)	9 / 227 (3.96%)
occurrences all number	68	61	2	13
Sinusitis
subjects affected / exposed	41 / 597 (6.87%)	26 / 606 (4.29%)	1 / 70 (1.43%)	4 / 227 (1.76%)
occurrences all number	60	36	1	4
Tonsillitis
subjects affected / exposed	34 / 597 (5.70%)	14 / 606 (2.31%)	4 / 70 (5.71%)	2 / 227 (0.88%)
occurrences all number	48	18	4	2
Upper respiratory tract infection
subjects affected / exposed	116 / 597 (19.43%)	114 / 606 (18.81%)	13 / 70 (18.57%)	26 / 227 (11.45%)
occurrences all number	226	216	19	36
Urinary tract infection
subjects affected / exposed	77 / 597 (12.90%)	58 / 606 (9.57%)	4 / 70 (5.71%)	10 / 227 (4.41%)
occurrences all number	111	109	7	12

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
24 Sep 2018	Study was terminated early because the subject population under study was no longer the same as indicated for use in the majority of countries.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Multicenter, Open-Label, Extension Study to Evaluate the Long-Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP), Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Annualized Relapse Rate (ARR) in the 205MS303 Treatment Period

Secondary: Annualized Relapse Rate (ARR) in the 205MS303 Treatment Period

Secondary: ARR in the 205MS301-303 Combined Study Period and 205MS301 Treatment Period

Secondary: ARR in the 205MS301-303 Combined Study Period and 205MS301 Treatment Period

Secondary: Number of Subjects with Relapse in the 205MS303 Treatment Period

Secondary: Number of Subjects with Relapse in the 205MS303 Treatment Period

Secondary: Number of Subjects with Relapse in the 205MS301-303 Combined Study Period

Secondary: Number of Subjects with Relapse in the 205MS301-303 Combined Study Period

Secondary: Number of Subjects with Sustained Disability Progression in the 205MS303 Treatment Period

Secondary: Number of Subjects with Sustained Disability Progression in the 205MS303 Treatment Period

Secondary: Number of Subjects with Sustained Disability Progression in the 205MS301-303 Combined Study Period

Secondary: Number of Subjects with Sustained Disability Progression in the 205MS301-303 Combined Study Period

Secondary: Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS303 Treatment Period

Secondary: Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS303 Treatment Period

Secondary: Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS301 Treatment Period

Secondary: Number of Subjects with New or Newly Enlarging T2 Hyperintense Lesions in the 205MS301 Treatment Period

Secondary: Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS303 Treatment Period

Secondary: Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS303 Treatment Period

Secondary: Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS301 Treatment Period

Secondary: Number of Subjects with Gadolinium-enhancing (Gd+) Lesions in the 205MS301 Treatment Period

Secondary: Number of Subjects with New T1 Hypointense Lesions in the 205MS303 Treatment Period

Secondary: Number of Subjects with New T1 Hypointense Lesions in the 205MS303 Treatment Period

Secondary: Number of Subjects with New T1 Hypointense Lesions in the 205MS301 Treatment Period

Secondary: Number of Subjects with New T1 Hypointense Lesions in the 205MS301 Treatment Period

Secondary: Percent Change in Brain Volume from the 205MS303 Baseline

Secondary: Percent Change in Brain Volume from the 205MS303 Baseline

Secondary: Percent Change in Brain Volume from 205MS301 Baseline

Secondary: Percent Change in Brain Volume from 205MS301 Baseline

Secondary: Total Volume of T2 Hyperintense Lesions in the 205MS303 Treatment Period

Secondary: Total Volume of T2 Hyperintense Lesions in the 205MS303 Treatment Period

Secondary: Change from Baseline in the Multiple Sclerosis Functional Composite (MSFC) Score in the 205MS303 Treatment Period

Secondary: Change from Baseline in the Multiple Sclerosis Functional Composite (MSFC) Score in the 205MS303 Treatment Period

Secondary: Change from 205MS301 Baseline in the MSFC Score in the 205MS301-303 Combined Study Period

Secondary: Change from 205MS301 Baseline in the MSFC Score in the 205MS301-303 Combined Study Period

Secondary: Change from Baseline in the Expanded Disability Status Scale (EDSS) Score in the 205MS303 Treatment Period

Secondary: Change from Baseline in the Expanded Disability Status Scale (EDSS) Score in the 205MS303 Treatment Period

Secondary: Number of Subjects Who Are Free from Disease Activity in the 205MS303 Treatment Period

Secondary: Number of Subjects Who Are Free from Disease Activity in the 205MS303 Treatment Period

Secondary: Change from Baseline in the Multiple Sclerosis Impact Scale 29 (MSIS 29) Physical and Psychological Scores in the 205MS303 Treatment Period

Secondary: Change from Baseline in the Multiple Sclerosis Impact Scale 29 (MSIS 29) Physical and Psychological Scores in the 205MS303 Treatment Period

Secondary: Change from Baseline in Quality of Life as Assessed by the European Quality of Life, 5 Dimensions (EQ 5D) Health Scores in the 205MS303 Treatment Period

Secondary: Change from Baseline in Quality of Life as Assessed by the European Quality of Life, 5 Dimensions (EQ 5D) Health Scores in the 205MS303 Treatment Period

Secondary: Change from Baseline in Quality of Life as Assessed by the European Quality of Life, Visual Analog Scale (EQ VAS) in the 205MS303 Treatment Period

Secondary: Change from Baseline in Quality of Life as Assessed by the European Quality of Life, Visual Analog Scale (EQ VAS) in the 205MS303 Treatment Period

Secondary: Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS303 Treatment Period

Secondary: Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS303 Treatment Period

Secondary: Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS301 Treatment Period

Secondary: Direct Health Resource Utilisation (HRU): Number of Unscheduled Site Visits in the 205MS301 Treatment Period

Secondary: Treatment Satisfaction as Assessed by the Subject in the 205MS303 Treatment Period

Secondary: Treatment Satisfaction as Assessed by the Subject in the 205MS303 Treatment Period

Secondary: Health Related Productivity Questionnaire (HRPQ): Scheduled Work Hours in the 205MS303 Treatment Period

Secondary: Health Related Productivity Questionnaire (HRPQ): Scheduled Work Hours in the 205MS303 Treatment Period

Secondary: HRPQ: Number of Subjects where MS or Its Treatments Resulted in Missed Work in the 205MS303 Treatment Period

Secondary: HRPQ: Number of Subjects where MS or Its Treatments Resulted in Missed Work in the 205MS303 Treatment Period

Secondary: HRPQ: Hours of Work Missed Due to MS or Its Treatment in the 205MS303 Treatment Period

Secondary: HRPQ: Hours of Work Missed Due to MS or Its Treatment in the 205MS303 Treatment Period

Secondary: HRPQ: Percent Impact on Employment in the 205MS303 Treatment Period

Secondary: HRPQ: Percent Impact on Employment in the 205MS303 Treatment Period

Secondary: HRPQ: Hours of Household Chores Planned to Perform in the 205MS303 Treatment Period

Secondary: HRPQ: Hours of Household Chores Planned to Perform in the 205MS303 Treatment Period

Secondary: HRPQ: Number of Subjects where MS or Its Treatments Kept the Subject from Completing Chores in the 205MS303 Treatment Period

Secondary: HRPQ: Number of Subjects where MS or Its Treatments Kept the Subject from Completing Chores in the 205MS303 Treatment Period

Secondary: HRPQ: Hours not Performing Household Chores due to MS or Its Treatment in 205MS303 Treatment Period

Secondary: HRPQ: Hours not Performing Household Chores due to MS or Its Treatment in 205MS303 Treatment Period

Secondary: HRPQ: Percent Impact on Performing Household chores in the 205MS303 Treatment Period

Secondary: HRPQ: Percent Impact on Performing Household chores in the 205MS303 Treatment Period

Secondary: Number of Subjects with Clinically Significant Changes from Baseline in Clinical Laboratory Assessments in the 205MS303 Treatment Period

Secondary: Number of Subjects with Clinically Significant Changes from Baseline in Clinical Laboratory Assessments in the 205MS303 Treatment Period

Clinical Trial Results:
A Multicenter, Open-Label, Extension Study to Evaluate the Long-Term Safety and Efficacy of BIIB019, Daclizumab High Yield Process (DAC HYP), Monotherapy in Subjects With Multiple Sclerosis Who Have Completed Study 205MS301