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Clinical Trial Results:
A Phase III, Multicenter, Randomized, Double-Blind Placebo-Controlled Study to Assess the Efficacy and Safety of Tocilizumab in Subjects With Giant Cell Arteritis

Summary
EudraCT number	2011-006022-25
Trial protocol	IT SE AT DE DK GB PT NL ES BE PL
Global end of trial date

Results information
Results version number	v1
This version publication date	26 Apr 2017
First version publication date	26 Apr 2017
Other versions	v2

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

WA28119

ISRCTN number

US NCT number

NCT01791153

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 61 6878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 61 6878333, global.trial_information@roche.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

Interim

Date of interim/final analysis

11 Apr 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

11 Apr 2016

Global end of trial reached?

Main objective of the trial

The main objective for this study was to evaluate the efficacy of tocilizumab compared to placebo, in combination with a 26-week prednisone taper regimen, in participants with giant cell arteritis (GCA), as measured by the proportion of participants in sustained remission at Week 52 following induction and adherence to the protocol-defined prednisone taper regimen.

Protection of trial subjects

The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice. Approval from the Independent Ethics Committee/Institutional Review Board was obtained before study start and was documented in a letter to the Investigator specifying the date on which the committee met and granted the approval.

Background therapy

Evidence for comparator

Actual start date of recruitment

22 Jul 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 15

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

Denmark: 1

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Germany: 78

Country: Number of subjects enrolled

Italy: 29

Country: Number of subjects enrolled

Netherlands: 13

Country: Number of subjects enrolled

Norway: 4

Country: Number of subjects enrolled

Poland: 6

Country: Number of subjects enrolled

Portugal: 3

Country: Number of subjects enrolled

Spain: 12

Country: Number of subjects enrolled

Sweden: 8

Country: Number of subjects enrolled

United Kingdom: 15

Country: Number of subjects enrolled

United States: 50

Worldwide total number of subjects

250

EEA total number of subjects

198

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)

From 65 to 84 years

166

85 years and over

Subject disposition

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Recruitment details

The study consists of 2 parts: a 52-week double-blind treatment period (Part 1) followed by a 104-week open label long-term follow-up period (Part 2). Results for Part 1 are reported here. Results for Part 2 will be reported by April 2019.

Screening details

Of the 363 participants screened, a total of 251 participants were randomized into the study. One participant who was randomized to the "Tocilizumab q2w + 26 weeks prednisone taper" group withdrew on the same day of randomization and did not receive any study treatment. This participant was not included in any of the study analyses.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Part 1: Tocilizumab qw + 26 weeks prednisone taper

Arm description

Participants received tocilizumab at a dose of 162 milligrams (mg) as subcutaneous (SC) injection every week (qw) up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

RoActemra, Actemra, RO4877533

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Tocilizumab was administered at a dose of 162 mg as SC injection qw for 52 weeks in Part 1 of the study.

Investigational medicinal product name

Prednisone placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone placebo was administered daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone was administered at tapering oral doses daily for 26 weeks according to the protocol-defined schedule in Part 1 of the study.

Part 1: Tocilizumab q2w + 26 weeks prednisone taper

Arm description

Participants received tocilizumab at a dose of 162 mg as SC injection every 2 weeks (q2w) (and tocilizumab placebo q2w starting from Week 2) up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

RoActemra, Actemra, RO4877533

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Tocilizumab was administered at a dose of 162 mg as SC injection q2w for 52 weeks in Part 1 of the study.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone was administered at tapering oral doses daily for 26 weeks according to the protocol-defined schedule in Part 1 of the study.

Investigational medicinal product name

Prednisone placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone placebo was administered daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.

Investigational medicinal product name

Tocilizumab placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Tocilizumab placebo was administered as SC injection q2w (starting from Week 2) for 52 weeks in Part 1 of the study.

Part 1: Placebo + 26 weeks prednisone taper

Arm description

Participants received tocilizumab placebo as SC injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.

Arm type

Placebo

Investigational medicinal product name

Tocilizumab placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Tocilizumab placebo was administered as SC injection qw for 52 weeks in Part 1 of the study.

Investigational medicinal product name

Prednisone placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone placebo was administered daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone was administered at tapering oral doses daily for 26 weeks according to the protocol-defined schedule in Part 1 of the study.

Part 1: Placebo + 52 weeks prednisone taper

Arm description

Arm type

Placebo

Investigational medicinal product name

Tocilizumab placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Tocilizumab placebo was administered as SC injection qw for 52 weeks in Part 1 of the study.

Investigational medicinal product name

Prednisone placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone placebo was administered daily according to the protocol-defined schedule in Part 1 of the study.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone was administered at tapering oral doses daily for 52 weeks according to the protocol-defined schedule in Part 1 of the study.

Number of subjects in period 1	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Started	100	49	50	51
Completed	85	41	44	46
Not completed	15	8	6	5
Consent withdrawn by subject	6	2	2	1
Non-Compliance	1	-	-	-
Physician decision	-	-	-	1
Adverse event, non-fatal	7	3	2	-
Lack of efficacy	1	3	2	2
Protocol deviation	-	-	-	1

Baseline characteristics

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Reporting group title

Part 1: Tocilizumab qw + 26 weeks prednisone taper

Reporting group description

Reporting group title

Part 1: Tocilizumab q2w + 26 weeks prednisone taper

Reporting group description

Reporting group title

Part 1: Placebo + 26 weeks prednisone taper

Reporting group description

Reporting group title

Part 1: Placebo + 52 weeks prednisone taper

Reporting group description

Reporting group values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper	Total
Number of subjects	100	49	50	51	250
Age Categorical
Units: Subjects
Adults (18 to 64 years)	32	17	16	17	82
From 65 to 84 years	67	31	34	34	166
85 years and over	1	1	0	0	2
Age Continuous
Units: years
arithmetic mean (standard deviation)	69.5 ( 8.5 )	69.4 ( 8.29 )	69.3 ( 8.14 )	67.8 ( 7.7 )	-
Gender Categorical
Units: Subjects
Female	78	34	38	37	187
Male	22	15	12	14	63

End points

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Reporting group title

Part 1: Tocilizumab qw + 26 weeks prednisone taper

Reporting group description

Reporting group title

Part 1: Tocilizumab q2w + 26 weeks prednisone taper

Reporting group description

Reporting group title

Part 1: Placebo + 26 weeks prednisone taper

Reporting group description

Reporting group title

Part 1: Placebo + 52 weeks prednisone taper

Reporting group description

Primary: Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 26 weeks prednisone taper)

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End point title

Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 26 weeks prednisone taper) ^[1]

End point description

Remission was defined as the absence of flare and normalization of the C-reactive protein (CRP) (less than [<] 1 milligram per deciliter [mg/dL]). Sustained remission was defined as the absence of flare following induction of remission within 12 weeks of randomization and maintained up to Week 52. Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or erythrocyte sedimentation rate (ESR) greater than or equal to (>/=) 30 millimeters per hour (mm/hr) attributable to GCA. A single CRP elevation (>/=1 mg/dL) was not considered as a sign of flare, unless the CRP remained elevated (>/=1 mg/dL) at the next study visit. Intent-to-treat (ITT) population included all participants randomized into the study who received at least one administration of study drug.

End point type

Primary

End point timeframe

Week 52

Notes
[1] - 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: The primary endpoint evaluated the proportions of patients in sustained remission in the TCZ groups compared to the 26-week placebo group. Therefore, the 52-week placebo group is not included in this analysis.

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper
Number of subjects analysed	100	49	50
Units: percentage of participants
number (not applicable)	56	53.1	14

Statistical Analysis 1

Statistical analysis description

The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (less than or equal to [</=] 30 mg/day, greater than [>] 30 mg/day).

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

Confidence interval

level

99.5%

sides

2-sided

lower limit

upper limit

Statistical Analysis 2

Statistical analysis description

The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

39.06

Confidence interval

level

99.5%

sides

2-sided

lower limit

12.46

upper limit

65.66

Secondary: Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 52 weeks prednisone taper)

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End point title

Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 52 weeks prednisone taper) ^[2]

End point description

Remission was defined as the absence of flare and normalization of the CRP (<1 mg/dL). Sustained remission was defined as the absence of flare following induction of remission within 12 weeks of randomization and maintained up to Week 52. Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or ESR >/=30 mm/hr attributable to GCA. A single CRP elevation (>/=1 mg/dL) was not considered as a sign of flare, unless the CRP remained elevated (>/=1 mg/dL) at the next study visit. ITT population.

End point type

Secondary

End point timeframe

Week 52

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: The key secondary endpoint evaluated the proportions of patients in sustained remission in the TCZ groups compared to the 52-week placebo group. Therefore, the 26-week placebo group is not included in this analysis.

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Number of subjects analysed	100	49	51
Units: percentage of participants
number (not applicable)	56	53.1	17.6

Statistical Analysis 1

Statistical analysis description

The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Confidence interval

Statistical Analysis 2

Statistical analysis description

The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

Difference in response rates

Point estimate

38.35

Confidence interval

level

99.5%

sides

2-sided

lower limit

17.89

upper limit

58.81

Notes
[3] - The tocilizumab group was to be considered as non-inferior to the placebo group if the lower limit of the two-sided 99.5% confidence interval was >/= -22.5%.

Statistical Analysis 3

Statistical analysis description

The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

Cochran-Mantel-Haenszel

Confidence interval

Statistical Analysis 4

Statistical analysis description

The treatment groups were compared using a Cochran-Mantel-Haenszel model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

Method

Parameter type

Difference in response rates

Point estimate

35.41

Confidence interval

level

99.5%

sides

2-sided

lower limit

10.41

upper limit

60.41

Notes
[4] - The tocilizumab group was to be considered as non-inferior to the placebo group if the lower limit of the two-sided 99.5% confidence interval was >/= -22.5%.

Secondary: Time to First GCA Disease Flare

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End point title

Time to First GCA Disease Flare

End point description

Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or ESR >/=30 mm/hr attributable to GCA. Participants who withdrew from the study prior to Week 52 were censored from the time of withdrawal. ITT population. Value "99999" in results indicates that data could not be calculated due to low number of participants who had an event.

End point type

Secondary

End point timeframe

Up to 52 weeks

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Number of subjects analysed	100	49	50	51
Units: days
median (confidence interval 99%)	99999 (99999 to 99999)	99999 (99999 to 99999)	165 (120 to 260)	295 (168 to 99999)

Statistical Analysis 1

Statistical analysis description

The treatment groups were compared using a Cox proportional hazards model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.23

Confidence interval

level

99%

sides

2-sided

lower limit

0.11

upper limit

0.46

Statistical Analysis 2

Statistical analysis description

The treatment groups were compared using a Cox proportional hazards model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0011

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.39

Confidence interval

level

99%

sides

2-sided

lower limit

0.18

upper limit

0.82

Statistical Analysis 3

Statistical analysis description

The treatment groups were compared using a Cox proportional hazards model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0001

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.28

Confidence interval

level

99%

sides

2-sided

lower limit

0.12

upper limit

0.66

Statistical Analysis 4

Statistical analysis description

The treatment groups were compared using a Cox proportional hazards model adjusted for the stratification factor of starting prednisone dose (</=30 mg/day, >30 mg/day).

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0316

Method

Cox proportional hazards model

Parameter type

Hazard ratio (HR)

Point estimate

0.48

Confidence interval

level

99%

sides

2-sided

lower limit

0.2

upper limit

1.16

Secondary: Total Cumulative Prednisone Dose

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End point title

Total Cumulative Prednisone Dose

End point description

The median total cumulative prednisone dose over the 52 weeks for each treatment group and the corresponding 95% confidence intervals are presented. ITT Population.

End point type

Secondary

End point timeframe

Up to 52 weeks

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Number of subjects analysed	100	49	50	51
Units: mg
median (confidence interval 95%)	1862 (1582 to 1942)	1862 (1568 to 2239.5)	3296 (2729.5 to 4023.5)	3817.5 (2817.5 to 4425.5)

Statistical Analysis 1

Statistical analysis description

The treatment groups were compared using a Van Elteren's test stratified by starting prednisone dose (<=30 mg/day, > 30 mg/day).

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Van Elteren's test

Confidence interval

Statistical Analysis 3

Statistical analysis description

The treatment groups were compared using a Van Elteren's test stratified by starting prednisone dose (<=30 mg/day, > 30 mg/day).

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0003

Method

Van Elteren's test

Confidence interval

Statistical Analysis 2

Statistical analysis description

The treatment groups were compared using a Van Elteren's test stratified by starting prednisone dose (<=30 mg/day, > 30 mg/day).

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Van Elteren's test

Confidence interval

Statistical Analysis 4

Statistical analysis description

The treatment groups were compared using a Van Elteren's test stratified by starting prednisone dose (<=30 mg/day, > 30 mg/day).

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Van Elteren's test

Confidence interval

Secondary: Change From Baseline in Short Form (SF)-36 Questionnaire Score at Week 52

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End point title

Change From Baseline in Short Form (SF)-36 Questionnaire Score at Week 52

End point description

The SF-36 is a standardized questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical Component Score (PCS) and Mental Component Score (MCS). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). A positive change from baseline indicates improvement. No imputation was used for missing data. Data was set to missing for participants who received escape therapy. ITT population. Here, 'Number of Subject Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Number of subjects analysed	97	49	48	49
Units: units on a scale
arithmetic mean (standard deviation)
PCS: Baseline (n=97,49,48,49)	43.1 ( 9.43 )	40.62 ( 8 )	42.65 ( 10.87 )	41.12 ( 9.97 )
PCS: Change at Week 52 (n=59,26,9,18)	5.37 ( 7.38 )	2.71 ( 8.86 )	2.08 ( 12.11 )	-2.8 ( 6.98 )
MCS: Baseline (n=97,49,48,49)	42.77 ( 12.43 )	47.67 ( 12.59 )	42.73 ( 12.13 )	40.45 ( 13.73 )
MCS: Change at Week 52 (n=59,26,9,18)	8.21 ( 10.35 )	1.98 ( 7.17 )	4.99 ( 7.54 )	2.6 ( 10.56 )

Statistical Analysis 1

Statistical analysis description

MCS: Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.8067

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

0.61

Confidence interval

level

99%

sides

2-sided

lower limit

-5.86

upper limit

7.07

Statistical Analysis 2

Statistical analysis description

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0252

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

4.44

Confidence interval

level

99%

sides

2-sided

lower limit

-0.69

upper limit

9.56

Statistical Analysis 3

Statistical analysis description

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.8374

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

-0.56

Confidence interval

level

99%

sides

2-sided

lower limit

-7.64

upper limit

6.53

Statistical Analysis 4

Statistical analysis description

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1468

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

3.27

Confidence interval

level

99%

sides

2-sided

lower limit

-2.59

upper limit

9.14

Statistical Analysis 5

Statistical analysis description

PCS: Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.057

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

4.38

Confidence interval

level

99%

sides

2-sided

lower limit

-1.58

upper limit

10.34

Statistical Analysis 6

Statistical analysis description

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0024

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

5.59

Confidence interval

level

99%

sides

2-sided

lower limit

0.86

upper limit

10.32

Statistical Analysis 7

Statistical analysis description

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2218

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

3.04

Confidence interval

level

99%

sides

2-sided

lower limit

-3.43

upper limit

9.51

Statistical Analysis 8

Statistical analysis description

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0412

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

4.25

Confidence interval

level

99%

sides

2-sided

lower limit

-1.14

upper limit

9.64

Secondary: Change From Baseline in Patient Global Assessment (PGA) of Disease Activity Assessed Using Visual Analogue Scale (VAS) at Week 52

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End point title

Change From Baseline in Patient Global Assessment (PGA) of Disease Activity Assessed Using Visual Analogue Scale (VAS) at Week 52

End point description

Participants assessed their current disease activity on a 0-100 millimeter (mm) VAS, where 0 mm = no disease activity and 100 mm = maximum disease activity. A negative change from baseline indicates improvement. ITT population. Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Number of subjects analysed	100	49	49	51
Units: mm
arithmetic mean (standard deviation)
Baseline (n=100,49,49,51)	43.61 ( 25.66 )	46.65 ( 25.6 )	35.73 ( 28.15 )	47.78 ( 27.8 )
Change at Week 52 (n=60,26,11,18)	-19.68 ( 33.64 )	-22.69 ( 22.41 )	-8.45 ( 24.81 )	-10 ( 35.12 )

Statistical Analysis 1

Statistical analysis description

Change at Week 52: Repeated measures model used for analysis included the following covariates and interactions: treatment, starting prednisone dose (<=30mg/day, >30mg/day), visit, treatment-by-visit interaction, starting dose-by-visit interaction, baseline score and baseline score-by-visit interaction.

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

149

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0312

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

-15.6

Confidence interval

level

99%

sides

2-sided

lower limit

-34.3

upper limit

3.1

Statistical Analysis 2

Statistical analysis description

Comparison groups

Part 1: Tocilizumab qw + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0476

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

-11.8

Confidence interval

level

99%

sides

2-sided

lower limit

-27.2

upper limit

3.6

Statistical Analysis 3

Statistical analysis description

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 26 weeks prednisone taper

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0059

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

-21.9

Confidence interval

level

99%

sides

2-sided

lower limit

-42.4

upper limit

-1.4

Statistical Analysis 4

Statistical analysis description

Comparison groups

Part 1: Tocilizumab q2w + 26 weeks prednisone taper v Part 1: Placebo + 52 weeks prednisone taper

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0081

Method

Repeated measures model

Parameter type

Differences in Least Square Means

Point estimate

-18.2

Confidence interval

level

99%

sides

2-sided

lower limit

-35.8

upper limit

-0.5

Secondary: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State of Tocilizumab

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End point title

Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State of Tocilizumab ^[5]

End point description

AUCtau is the model-predicted area under the tocilizumab serum concentration versus time curve from time zero to the end of dosing interval. AUCtau is measured in microgram*day per milliliter (mcg*day/mL). Pharmacokinetics (PK)-evaluable population included all participants who received at least one tocilizumab injection and had at least one PK sample with detectable results taken at any time during the study.

End point type

Secondary

End point timeframe

Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0])

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: This endpoint evaluated the concentrations of TCZ in serum samples and is therefore not applicable for the two treatment arms in which patients received placebo.

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper
Number of subjects analysed	100	49
Units: mcg*day/mL
arithmetic mean (standard deviation)	499.2 ( 210.4 )	227.2 ( 165.4 )

No statistical analyses for this end point

Secondary: Maximum Serum Concentration at Steady State (Cmax,ss) of Tocilizumab

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End point title

Maximum Serum Concentration at Steady State (Cmax,ss) of Tocilizumab ^[6]

End point description

Cmax,ss is maximum model-predicted serum steady state concentration of tocilizumab measured in micrograms per milliliter (mcg/mL). PK-evaluable population.

End point type

Secondary

End point timeframe

Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0])

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: This endpoint evaluated the concentrations of TCZ in serum samples and is therefore not applicable for the two treatment arms in which patients received placebo.

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper
Number of subjects analysed	100	49
Units: mcg/mL
arithmetic mean (standard deviation)	73 ( 30.4 )	19.3 ( 12.8 )

No statistical analyses for this end point

Secondary: Minimum Serum Concentration at Steady State (Cmin,ss) of Tocilizumab

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End point title

Minimum Serum Concentration at Steady State (Cmin,ss) of Tocilizumab ^[7]

End point description

Cmin,ss is minimum model-predicted serum steady state concentration of tocilizumab measured in mcg/mL. PK-evaluable population.

End point type

Secondary

End point timeframe

Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0])

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: This endpoint evaluated the concentrations of TCZ in serum samples and is therefore not applicable for the two treatment arms in which patients received placebo.

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper
Number of subjects analysed	100	49
Units: mcg/mL
arithmetic mean (standard deviation)	68.1 ( 29.5 )	11.1 ( 10.3 )

No statistical analyses for this end point

Secondary: Minimum Observed Serum Concentration (Ctrough) of Tocilizumab

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End point title

Minimum Observed Serum Concentration (Ctrough) of Tocilizumab ^[8]

End point description

Ctrough is minimum observed serum concentration of tocilizumab measured in mcg/mL. PK-evaluable population. Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.

End point type

Secondary

End point timeframe

Predose (Hour 0) at Baseline and Week 52

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: This endpoint evaluated the concentrations of TCZ in serum samples and is therefore not applicable for the two treatment arms in which patients received placebo.

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper
Number of subjects analysed	99	48
Units: mcg/mL
arithmetic mean (standard deviation)
Baseline (n= 99, 48)	0.07 ( 0.72 )	0 ( 0.02 )
Week 52 (n= 72, 33)	67.93 ( 34.4 )	12.22 ( 10.02 )

No statistical analyses for this end point

Secondary: Serum Interleukin-6 (IL-6) Level

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End point title

Serum Interleukin-6 (IL-6) Level

End point description

Safety population. Here, 'n' signifies the number of participants evaluable at specified time point for different arms, respectively

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Number of subjects analysed	100	49	50	51
Units: picograms per milliliter (pg/mL)
arithmetic mean (standard deviation)
Baseline (n=91,44,50,47)	8.79 ( 10.01 )	16.29 ( 31.23 )	12.73 ( 18.04 )	8.31 ( 9.47 )
Week 52 (n=69,32,28,30)	65.99 ( 84.92 )	52.7 ( 33.1 )	35.96 ( 149.65 )	10.85 ( 15.17 )

No statistical analyses for this end point

Secondary: Serum Soluble IL-6 Receptor (sIL-6R) Level

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End point title

Serum Soluble IL-6 Receptor (sIL-6R) Level

End point description

Safety population. Here, 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Number of subjects analysed	100	49	50	51
Units: nanograms per milliliter (ng/mL)
arithmetic mean (standard deviation)
Baseline (n=99,48,50,50)	51.34 ( 61.98 )	50.82 ( 63.51 )	42.07 ( 11.32 )	40.37 ( 10.84 )
Week 52 (n=73,33,33,31)	600.53 ( 217.52 )	464.3 ( 153.64 )	76.44 ( 149.2 )	64.8 ( 105.13 )

No statistical analyses for this end point

Secondary: Erythrocyte Sedimentation Rate (ESR)

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End point title

Erythrocyte Sedimentation Rate (ESR)

End point description

ESR is a laboratory test that provides a nonspecific measure of inflammation. The test assesses the rate at which red blood cells fall in a test tube. Normal range is 0-30 mm/hr. A higher rate is consistent with inflammation. Safety population. Here, 'n' signifies the number of participants evaluable at specified time point for different arms, respectively

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Number of subjects analysed	100	49	50	51
Units: mm/hr
median (inter-quartile range (Q1-Q3))
Baseline (n=99,49,50,51)	19 (10 to 35)	15 (10 to 30)	23 (9 to 36)	20 (8 to 38)
Week 52 (n=76,35,35,33)	3 (2 to 5)	5 (2 to 7)	20 (11 to 36)	24 (10 to 37)

No statistical analyses for this end point

Secondary: C-Reactive Protein (CRP) Level

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End point title

C-Reactive Protein (CRP) Level

End point description

The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. Safety population. Here, 'n' signifies the number of participants evaluable at specified time point for different arms, respectively.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Number of subjects analysed	100	49	50	51
Units: milligrams per liter (mg/L)
median (inter-quartile range (Q1-Q3))
Baseline (n=100,49,50,51)	3.67 (1.02 to 9.26)	4.52 (1.55 to 9.75)	3.64 (1.2 to 9.59)	3.56 (1.17 to 7.24)
Week 52 (n=76,35,35,33)	0.3 (0.2 to 0.59)	0.33 (0.2 to 0.72)	4.9 (2.25 to 9.25)	8.12 (2.02 to 14.4)

No statistical analyses for this end point

Secondary: Percentage of Participants With Anti-Tocilizumab Antibodies

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End point title

Percentage of Participants With Anti-Tocilizumab Antibodies

End point description

All samples were tested by screening assay, and those samples that were positive were further analyzed by a confirmation assay to confirm specificity. Percentage of participants who has a positive confirmation assay result any time after the initial drug administration with a negative confirmation assay result at baseline was reported. Safety population included all participants who received at least one administration of study drug and provided at least one post-dose safety assessment. Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Baseline up to Week 52

End point values	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Number of subjects analysed	95	46	49	47
Units: percentage of participants
number (not applicable)	1.1	6.5	2	2.1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 52 weeks

Adverse event reporting additional description

Safety population

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Part 1: Tocilizumab qw + 26 weeks prednisone taper

Reporting group description

Participants received tocilizumab at a dose of 162 mg as SC injection qw for 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks.

Reporting group title

Part 1: Tocilizumab q2w + 26 weeks prednisone taper

Reporting group description

Participants received tocilizumab at a dose of 162 mg as SC injection q2w for 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks.

Reporting group title

Part 1: Placebo + 26 weeks prednisone taper

Reporting group description

Participants received tocilizumab placebo as SC injection for 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks.

Reporting group title

Part 1: Placebo + 52 weeks prednisone taper

Reporting group description

Serious adverse events	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Total subjects affected by serious adverse events
subjects affected / exposed	15 / 100 (15.00%)	7 / 49 (14.29%)	11 / 50 (22.00%)	13 / 51 (25.49%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (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
Malignant melanoma
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Ovarian adenoma
subjects affected / exposed	0 / 100 (0.00%)	1 / 49 (2.04%)	0 / 50 (0.00%)	0 / 51 (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
Hypertension
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (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
Temporal arteritis
subjects affected / exposed	1 / 100 (1.00%)	1 / 49 (2.04%)	1 / 50 (2.00%)	1 / 51 (1.96%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Hypertensive crisis
subjects affected / exposed	2 / 100 (2.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Dry gangrene
subjects affected / exposed	0 / 100 (0.00%)	1 / 49 (2.04%)	0 / 50 (0.00%)	0 / 51 (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
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Hypersensitivity
subjects affected / exposed	0 / 100 (0.00%)	1 / 49 (2.04%)	0 / 50 (0.00%)	0 / 51 (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
Respiratory, thoracic and mediastinal disorders
Nasal inflammation
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal pain
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Dyspnoea exertional
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Pleural effusion
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Pulmonary embolism
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Dyspnoea
subjects affected / exposed	0 / 100 (0.00%)	1 / 49 (2.04%)	0 / 50 (0.00%)	0 / 51 (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
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Stress
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Injury, poisoning and procedural complications
Postoperative wound complication
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (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
Alcohol poisoning
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Laceration
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Tendon rupture
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Meniscus injury
subjects affected / exposed	0 / 100 (0.00%)	1 / 49 (2.04%)	0 / 50 (0.00%)	0 / 51 (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
Aortic valve stenosis
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Cardiac failure
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Cardiac failure chronic
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Supraventricular tachycardia
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Tachyarrhythmia
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Nervous system disorders
Paraesthesia
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Headache
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Thrombotic stroke
subjects affected / exposed	0 / 100 (0.00%)	1 / 49 (2.04%)	0 / 50 (0.00%)	0 / 51 (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
Eye disorders
Glaucoma
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastritis erosive
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Renal and urinary disorders
Renal impairment
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fibromyalgia
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Osteoarthritis
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Tendon pain
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Infections and infestations
Erysipelas
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	0 / 51 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	2 / 51 (3.92%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Genital herpes zoster
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Herpes zoster
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	2 / 51 (3.92%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Cellulitis
subjects affected / exposed	1 / 100 (1.00%)	1 / 49 (2.04%)	0 / 50 (0.00%)	0 / 51 (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
Chronic sinusitis
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Pneumonia haemophilus
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Pyelonephritis
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Urinary tract infection
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Urosepsis
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	0 / 51 (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
Cholangitis infective
subjects affected / exposed	0 / 100 (0.00%)	1 / 49 (2.04%)	0 / 50 (0.00%)	0 / 51 (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
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	0 / 50 (0.00%)	1 / 51 (1.96%)
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
Hyponatraemia
subjects affected / exposed	0 / 100 (0.00%)	1 / 49 (2.04%)	0 / 50 (0.00%)	0 / 51 (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

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

Non-serious adverse events	Part 1: Tocilizumab qw + 26 weeks prednisone taper	Part 1: Tocilizumab q2w + 26 weeks prednisone taper	Part 1: Placebo + 26 weeks prednisone taper	Part 1: Placebo + 52 weeks prednisone taper
Total subjects affected by non serious adverse events
subjects affected / exposed	87 / 100 (87.00%)	44 / 49 (89.80%)	47 / 50 (94.00%)	44 / 51 (86.27%)
Vascular disorders
Haematoma
subjects affected / exposed	5 / 100 (5.00%)	3 / 49 (6.12%)	3 / 50 (6.00%)	1 / 51 (1.96%)
occurrences all number	5	3	3	1
Hypertension
subjects affected / exposed	12 / 100 (12.00%)	6 / 49 (12.24%)	4 / 50 (8.00%)	4 / 51 (7.84%)
occurrences all number	14	6	4	6
General disorders and administration site conditions
Asthenia
subjects affected / exposed	5 / 100 (5.00%)	3 / 49 (6.12%)	5 / 50 (10.00%)	0 / 51 (0.00%)
occurrences all number	8	3	5	0
Fatigue
subjects affected / exposed	8 / 100 (8.00%)	5 / 49 (10.20%)	8 / 50 (16.00%)	3 / 51 (5.88%)
occurrences all number	8	6	8	3
Non-cardiac chest pain
subjects affected / exposed	1 / 100 (1.00%)	2 / 49 (4.08%)	1 / 50 (2.00%)	3 / 51 (5.88%)
occurrences all number	2	2	1	3
Oedema peripheral
subjects affected / exposed	16 / 100 (16.00%)	12 / 49 (24.49%)	8 / 50 (16.00%)	6 / 51 (11.76%)
occurrences all number	17	16	10	9
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	6 / 100 (6.00%)	3 / 49 (6.12%)	7 / 50 (14.00%)	3 / 51 (5.88%)
occurrences all number	6	3	8	3
Dyspnoea
subjects affected / exposed	3 / 100 (3.00%)	3 / 49 (6.12%)	1 / 50 (2.00%)	3 / 51 (5.88%)
occurrences all number	3	3	1	3
Dyspnoea exertional
subjects affected / exposed	1 / 100 (1.00%)	0 / 49 (0.00%)	3 / 50 (6.00%)	0 / 51 (0.00%)
occurrences all number	1	0	3	0
Epistaxis
subjects affected / exposed	3 / 100 (3.00%)	1 / 49 (2.04%)	4 / 50 (8.00%)	0 / 51 (0.00%)
occurrences all number	3	1	4	0
Oropharyngeal pain
subjects affected / exposed	7 / 100 (7.00%)	4 / 49 (8.16%)	4 / 50 (8.00%)	8 / 51 (15.69%)
occurrences all number	9	4	5	12
Psychiatric disorders
Anxiety
subjects affected / exposed	2 / 100 (2.00%)	1 / 49 (2.04%)	6 / 50 (12.00%)	1 / 51 (1.96%)
occurrences all number	2	2	6	1
Depression
subjects affected / exposed	3 / 100 (3.00%)	2 / 49 (4.08%)	3 / 50 (6.00%)	1 / 51 (1.96%)
occurrences all number	3	2	3	1
Insomnia
subjects affected / exposed	4 / 100 (4.00%)	1 / 49 (2.04%)	4 / 50 (8.00%)	4 / 51 (7.84%)
occurrences all number	4	1	4	4
Sleep disorder
subjects affected / exposed	1 / 100 (1.00%)	3 / 49 (6.12%)	1 / 50 (2.00%)	1 / 51 (1.96%)
occurrences all number	1	4	1	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	5 / 100 (5.00%)	2 / 49 (4.08%)	2 / 50 (4.00%)	0 / 51 (0.00%)
occurrences all number	5	2	2	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	7 / 100 (7.00%)	2 / 49 (4.08%)	2 / 50 (4.00%)	2 / 51 (3.92%)
occurrences all number	11	2	2	3
Cardiac disorders
Palpitations
subjects affected / exposed	2 / 100 (2.00%)	2 / 49 (4.08%)	4 / 50 (8.00%)	2 / 51 (3.92%)
occurrences all number	2	2	6	2
Nervous system disorders
Dizziness
subjects affected / exposed	6 / 100 (6.00%)	10 / 49 (20.41%)	6 / 50 (12.00%)	8 / 51 (15.69%)
occurrences all number	9	11	9	9
Headache
subjects affected / exposed	27 / 100 (27.00%)	10 / 49 (20.41%)	16 / 50 (32.00%)	12 / 51 (23.53%)
occurrences all number	40	20	24	26
Paraesthesia
subjects affected / exposed	4 / 100 (4.00%)	2 / 49 (4.08%)	4 / 50 (8.00%)	4 / 51 (7.84%)
occurrences all number	4	2	4	4
Tremor
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	3 / 50 (6.00%)	3 / 51 (5.88%)
occurrences all number	0	0	3	3
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	2 / 100 (2.00%)	1 / 49 (2.04%)	3 / 50 (6.00%)	1 / 51 (1.96%)
occurrences all number	2	1	3	1
Eye disorders
Cataract
subjects affected / exposed	5 / 100 (5.00%)	1 / 49 (2.04%)	3 / 50 (6.00%)	4 / 51 (7.84%)
occurrences all number	5	1	3	5
Dry eye
subjects affected / exposed	1 / 100 (1.00%)	3 / 49 (6.12%)	1 / 50 (2.00%)	1 / 51 (1.96%)
occurrences all number	1	3	1	1
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	3 / 100 (3.00%)	3 / 49 (6.12%)	3 / 50 (6.00%)	4 / 51 (7.84%)
occurrences all number	3	3	3	4
Constipation
subjects affected / exposed	0 / 100 (0.00%)	1 / 49 (2.04%)	3 / 50 (6.00%)	4 / 51 (7.84%)
occurrences all number	0	1	6	4
Diarrhoea
subjects affected / exposed	12 / 100 (12.00%)	3 / 49 (6.12%)	8 / 50 (16.00%)	5 / 51 (9.80%)
occurrences all number	13	3	12	6
Dyspepsia
subjects affected / exposed	0 / 100 (0.00%)	0 / 49 (0.00%)	4 / 50 (8.00%)	1 / 51 (1.96%)
occurrences all number	0	0	5	1
Nausea
subjects affected / exposed	8 / 100 (8.00%)	2 / 49 (4.08%)	5 / 50 (10.00%)	4 / 51 (7.84%)
occurrences all number	11	2	7	5
Vomiting
subjects affected / exposed	2 / 100 (2.00%)	2 / 49 (4.08%)	2 / 50 (4.00%)	3 / 51 (5.88%)
occurrences all number	2	2	3	3
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	5 / 100 (5.00%)	7 / 49 (14.29%)	3 / 50 (6.00%)	5 / 51 (9.80%)
occurrences all number	5	7	3	5
Dry skin
subjects affected / exposed	2 / 100 (2.00%)	3 / 49 (6.12%)	0 / 50 (0.00%)	0 / 51 (0.00%)
occurrences all number	2	4	0	0
Ecchymosis
subjects affected / exposed	0 / 100 (0.00%)	2 / 49 (4.08%)	1 / 50 (2.00%)	3 / 51 (5.88%)
occurrences all number	0	2	1	4
Night sweats
subjects affected / exposed	1 / 100 (1.00%)	3 / 49 (6.12%)	1 / 50 (2.00%)	1 / 51 (1.96%)
occurrences all number	1	3	1	1
Pruritus
subjects affected / exposed	2 / 100 (2.00%)	4 / 49 (8.16%)	1 / 50 (2.00%)	1 / 51 (1.96%)
occurrences all number	2	4	1	1
Rash
subjects affected / exposed	7 / 100 (7.00%)	5 / 49 (10.20%)	4 / 50 (8.00%)	2 / 51 (3.92%)
occurrences all number	7	5	7	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	13 / 100 (13.00%)	8 / 49 (16.33%)	10 / 50 (20.00%)	8 / 51 (15.69%)
occurrences all number	13	10	11	11
Back pain
subjects affected / exposed	14 / 100 (14.00%)	7 / 49 (14.29%)	7 / 50 (14.00%)	10 / 51 (19.61%)
occurrences all number	16	14	8	12
Bursitis
subjects affected / exposed	1 / 100 (1.00%)	4 / 49 (8.16%)	2 / 50 (4.00%)	1 / 51 (1.96%)
occurrences all number	1	4	2	1
Muscle spasms
subjects affected / exposed	4 / 100 (4.00%)	6 / 49 (12.24%)	6 / 50 (12.00%)	4 / 51 (7.84%)
occurrences all number	4	9	6	6
Musculoskeletal pain
subjects affected / exposed	12 / 100 (12.00%)	6 / 49 (12.24%)	5 / 50 (10.00%)	2 / 51 (3.92%)
occurrences all number	13	7	7	2
Myalgia
subjects affected / exposed	9 / 100 (9.00%)	4 / 49 (8.16%)	4 / 50 (8.00%)	4 / 51 (7.84%)
occurrences all number	9	4	5	5
Neck pain
subjects affected / exposed	6 / 100 (6.00%)	1 / 49 (2.04%)	2 / 50 (4.00%)	4 / 51 (7.84%)
occurrences all number	7	1	3	4
Osteoarthritis
subjects affected / exposed	7 / 100 (7.00%)	2 / 49 (4.08%)	3 / 50 (6.00%)	3 / 51 (5.88%)
occurrences all number	7	3	3	3
Pain in extremity
subjects affected / exposed	8 / 100 (8.00%)	5 / 49 (10.20%)	5 / 50 (10.00%)	5 / 51 (9.80%)
occurrences all number	8	7	5	7
Infections and infestations
Bronchitis
subjects affected / exposed	8 / 100 (8.00%)	4 / 49 (8.16%)	5 / 50 (10.00%)	5 / 51 (9.80%)
occurrences all number	9	4	5	5
Conjunctivitis
subjects affected / exposed	4 / 100 (4.00%)	1 / 49 (2.04%)	4 / 50 (8.00%)	1 / 51 (1.96%)
occurrences all number	5	1	4	1
Cystitis
subjects affected / exposed	7 / 100 (7.00%)	0 / 49 (0.00%)	2 / 50 (4.00%)	3 / 51 (5.88%)
occurrences all number	13	0	4	8
Gastroenteritis
subjects affected / exposed	3 / 100 (3.00%)	4 / 49 (8.16%)	4 / 50 (8.00%)	3 / 51 (5.88%)
occurrences all number	3	4	4	4
Nasopharyngitis
subjects affected / exposed	29 / 100 (29.00%)	12 / 49 (24.49%)	9 / 50 (18.00%)	13 / 51 (25.49%)
occurrences all number	39	15	12	17
Oral herpes
subjects affected / exposed	4 / 100 (4.00%)	5 / 49 (10.20%)	3 / 50 (6.00%)	2 / 51 (3.92%)
occurrences all number	4	5	3	2
Pharyngitis
subjects affected / exposed	4 / 100 (4.00%)	0 / 49 (0.00%)	1 / 50 (2.00%)	3 / 51 (5.88%)
occurrences all number	4	0	1	3
Rhinitis
subjects affected / exposed	6 / 100 (6.00%)	4 / 49 (8.16%)	2 / 50 (4.00%)	3 / 51 (5.88%)
occurrences all number	6	4	2	3
Sinusitis
subjects affected / exposed	3 / 100 (3.00%)	4 / 49 (8.16%)	1 / 50 (2.00%)	2 / 51 (3.92%)
occurrences all number	4	4	1	2
Upper respiratory tract infection
subjects affected / exposed	10 / 100 (10.00%)	6 / 49 (12.24%)	5 / 50 (10.00%)	7 / 51 (13.73%)
occurrences all number	10	7	5	9
Urinary tract infection
subjects affected / exposed	10 / 100 (10.00%)	4 / 49 (8.16%)	2 / 50 (4.00%)	4 / 51 (7.84%)
occurrences all number	15	5	4	7
Metabolism and nutrition disorders
Hypercholesterolaemia
subjects affected / exposed	2 / 100 (2.00%)	3 / 49 (6.12%)	0 / 50 (0.00%)	1 / 51 (1.96%)
occurrences all number	2	3	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

19 Oct 2012

The inclusion criteria related to the requirement for a history of ESR >/=50 mm/hr and active disease according to an ESR >/=30 mm/hr were clarified; The exclusion criteria were revised to exclude only major ischemic events unrelated to GCA and a new exclusion criterion added to exclude participants who received pulsed methylprednisolone within 6 weeks of baseline; The criteria concerning re-screening and retesting for laboratory inclusion/exclusion criteria were outlined; The definition of remission was clarified; All participants were made eligible for transition from Part 1 to Part 2 of the study; The status of prednisone as an investigational medicinal product (IMP) during Part 1 of the study was clarified; The protocol was aligned with the Sponsor’s memorandum on “Implementing immunoglobulin (Ig)E Assay for tocilizumab Immunogenicity Testing” and immunogenicity testing for participants who discontinued treatment with tocilizumab was added; Collection of information on prior medications and electrocardiograms (ECGs) was simplified; Visit windows were revised to increase flexibility and participant retention; Collection of laboratory assessments was clarified; Information on tocilizumab syringe labels was standardized with that of drug supply; Lipid-lowering agents were added to the list of permitted concomitant non-investigational medicinal products (NIMPs).

08 Feb 2013

Following Food and Drug Administration (FDA) feedback the definition of relapsing participants was updated to include those with active disease despite at least 2 consecutive weeks of treatment with >/=40 mg/day prednisone (or equivalent) at any time; Following FDA feedback the key secondary endpoint defining a comparison of the proportion of participants in sustained remission at Week 52 in the tocilizumab groups versus the placebo group with 52-week prednisone taper was added; The terminology of the dual assessors was changed; Addition of a ribonucleic acid (RNA) blood sample and serum sample for biomarkers at unscheduled visit; Addition of an exclusion criterion specifying that previous treatment with tofacitinib was not permitted; Timing of the collection of the immunogenicity samples was amended.

22 Jan 2014

To better reflect clinical practice where CRP is replacing ESR in several health centers, the requirement for a CRP >/=2.45 mg/dL for participants where a historical ESR value was unavailable was added; Removal of the requirement of ESR >/=30 mm/hr or CRP >/=1 mg/dL to confirm active disease in participants with a positive temporal artery biopsy within 6 weeks of baseline; Definition of flare was modified to allow the clinical assessor to consider an elevated ESR as disease flare in the absence of GCA signs and symptoms if, in their opinion, it was attributable to GCA; Further clarification of the definition of new-onset GCA was made; Clarification to the concomitant therapy section on the use of intra-arterial (IA), intravenous (IV) and intramuscular (IM) glucocorticoids; The time window required for a latent tuberculosis test to be performed prior to initiation of study drug treatment was increased form 3 weeks to 6 weeks.

Were there any global interruptions to the trial? No

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 Phase III, Multicenter, Randomized, Double-Blind Placebo-Controlled Study to Assess the Efficacy and Safety of Tocilizumab in Subjects With Giant Cell Arteritis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 26 weeks prednisone taper)

Primary: Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 26 weeks prednisone taper)

Secondary: Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 52 weeks prednisone taper)

Secondary: Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 weeks prednisone taper versus Placebo + 52 weeks prednisone taper)

Secondary: Time to First GCA Disease Flare

Secondary: Time to First GCA Disease Flare

Secondary: Total Cumulative Prednisone Dose

Secondary: Total Cumulative Prednisone Dose

Secondary: Change From Baseline in Short Form (SF)-36 Questionnaire Score at Week 52

Secondary: Change From Baseline in Short Form (SF)-36 Questionnaire Score at Week 52

Secondary: Change From Baseline in Patient Global Assessment (PGA) of Disease Activity Assessed Using Visual Analogue Scale (VAS) at Week 52

Secondary: Change From Baseline in Patient Global Assessment (PGA) of Disease Activity Assessed Using Visual Analogue Scale (VAS) at Week 52

Secondary: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State of Tocilizumab

Secondary: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State of Tocilizumab

Secondary: Maximum Serum Concentration at Steady State (Cmax,ss) of Tocilizumab

Secondary: Maximum Serum Concentration at Steady State (Cmax,ss) of Tocilizumab

Secondary: Minimum Serum Concentration at Steady State (Cmin,ss) of Tocilizumab

Secondary: Minimum Serum Concentration at Steady State (Cmin,ss) of Tocilizumab

Secondary: Minimum Observed Serum Concentration (Ctrough) of Tocilizumab

Secondary: Minimum Observed Serum Concentration (Ctrough) of Tocilizumab

Secondary: Serum Interleukin-6 (IL-6) Level

Secondary: Serum Interleukin-6 (IL-6) Level

Secondary: Serum Soluble IL-6 Receptor (sIL-6R) Level

Secondary: Serum Soluble IL-6 Receptor (sIL-6R) Level

Secondary: Erythrocyte Sedimentation Rate (ESR)

Secondary: Erythrocyte Sedimentation Rate (ESR)

Secondary: C-Reactive Protein (CRP) Level

Secondary: C-Reactive Protein (CRP) Level

Secondary: Percentage of Participants With Anti-Tocilizumab Antibodies

Secondary: Percentage of Participants With Anti-Tocilizumab Antibodies

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase III, Multicenter, Randomized, Double-Blind Placebo-Controlled Study to Assess the Efficacy and Safety of Tocilizumab in Subjects With Giant Cell Arteritis