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Clinical Trial Results:
A Phase II/III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study To Assess the Efficacy and Safety of Tocilizumab Versus Placebo In Patients With Systemic Sclerosis

Summary
EudraCT number	2011-001460-22
Trial protocol	GB DE
Global end of trial date	16 Jun 2015

Results information
Results version number	v2(current)
This version publication date	25 Jun 2016
First version publication date	06 Mar 2016
Other versions	v1
Version creation reason	New data added to full data set Interim results previously provided. Final result update required.

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

WA27788

ISRCTN number

US NCT number

NCT01532869

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

RocheTrial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

RocheTrial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, 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

Final

Date of interim/final analysis

05 Aug 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Jun 2015

Was the trial ended prematurely?

Main objective of the trial

The study was designed to evaluate the efficacy and safety of tocilizumab (TCZ) at a subcutaneous (SC) dose of 162 milligrams (mg) for 96 weeks (Week 0 to Week 48 of blinded-treatment period and Week 48 to Week 96 of open-label period) in participants with systemic sclerosis.

Protection of trial subjects

The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Mar 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 19

Country: Number of subjects enrolled

France: 8

Country: Number of subjects enrolled

Germany: 19

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

United States: 36

Worldwide total number of subjects

EEA total number of subjects

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

85 years and over

Subject disposition

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Recruitment details

Screening details

Randomization was stratified by joint involvement at baseline (>=4 or <4 tender joints of 28 tender joint count [TJC]). The study consisted of double-blind (Week 0 to Week 48) and open-label (Week 48 to Week 96) periods. Data analyzed up to Weeks 24 and 48 (data cut-off: 11 July 2014), and up to Week 96 (data cut-off: 05 August 2015) are reported.

Period 1 title

Blinded-Treatment Period (Up to Week 24)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo (Up to Week 24)

Arm description

Participants received TCZ matched placebo by SC injection every week (qw) for Week 0 to Week 48 (blinded-treatment period) and then received TCZ (162 mg) SC injection qw in the open-label period for Week 48 to Week 96

Arm type

Placebo

Investigational medicinal product name

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

TCZ matched placebo was administered SC qw for Week 0 to Week 48 (blinded-treatment period), followed by TCZ (162 mg) SC injection qw in the open-label period for Week 48 to Week 96.

Tocilizumab (Up to Week 24)

Arm description

Participants received TCZ (162 mg) by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then in the open-label period for Week 48 to Week 96.

Arm type

Experimental

Investigational medicinal product name

TCZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

TCZ was administered at a dose of 162 mg by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then in the open-label period for Week 48 to Week 96.

Number of subjects in period 1	Placebo (Up to Week 24)	Tocilizumab (Up to Week 24)
Started	44	43
Completed	36	35
Not completed	8	8
Adverse event, non-fatal	2	3
Death	-	1
Non-compliance	1	-
Lost to follow-up	-	1
Lack of efficacy	1	1
Withdrawal by subject	4	2

Period 2 title

Blinded-Treatment Period (Up to Week 48)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Placebo (Up to Week 48)

Arm description

Arm type

Placebo

Investigational medicinal product name

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

TCZ matched placebo was administered SC qw for Week 0 to Week 48 (blinded-treatment period) followed by TCZ (162 mg) SC injection qw in the open-label period for Week 48 to Week 96.

Tocilizumab (Up to Week 48)

Arm description

Participants received TCZ (162 mg) by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then in the open-label period for Week 48 to Week 96.

Arm type

Active comparator

Investigational medicinal product name

TCZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

TCZ was administered at a dose of 162 mg by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then in the open-label period for Week 48 to Week 96.

Number of subjects in period 2	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Started	44	43
Completed	33	30
Not completed	11	13
Physician decision	1	-
Adverse event, non-fatal	4	5
Death	-	3
Non-compliance	1	-
Lost to follow-up	-	1
Withdrawal by subject	5	3
Lack of efficacy	-	1

Period 3 title

Open-label Period (Week 48 to Week 96)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo to Tocilizumab (Up to Week 96)

Arm description

Arm type

Placebo

Investigational medicinal product name

TCZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

TCZ matched placebo was administered SC qw for Week 0 to Week 48 (blinded-treatment period), followed by TCZ (162 mg) SC injection qw in the open-label period for Week 48 to Week 96.

Tocilizumab to Tocilizumab (Up to Week 96)

Arm description

Participants received TCZ (162 mg) by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then in the open-label period for Week 48 to Week 96.

Arm type

Experimental

Investigational medicinal product name

TCZ

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

TCZ was administered at a dose of 162 mg by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then in the open-label period for Week 48 to Week 96.

Number of subjects in period 3	Placebo to Tocilizumab (Up to Week 96)	Tocilizumab to Tocilizumab (Up to Week 96)
Started	31	30
Completed	24	27
Not completed	7	3
Adverse event, non-fatal	4	1
Non-compliance	1	-
Lack of efficacy	1	1
Withdrawal by subject	1	1

Baseline characteristics

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Reporting group title

Placebo (Up to Week 24)

Reporting group description

Reporting group title

Tocilizumab (Up to Week 24)

Reporting group description

Participants received TCZ (162 mg) by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then in the open-label period for Week 48 to Week 96.

Reporting group values	Placebo (Up to Week 24)	Tocilizumab (Up to Week 24)	Total
Number of subjects	44	43	87
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	48.1 ± 12.9	51.2 ± 11.7	-
Gender categorical
Units: Subjects
Female	35	32	67
Male	9	11	20

End points

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Reporting group title

Placebo (Up to Week 24)

Reporting group description

Reporting group title

Tocilizumab (Up to Week 24)

Reporting group description

Participants received TCZ (162 mg) by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then in the open-label period for Week 48 to Week 96.

Reporting group title

Placebo (Up to Week 48)

Reporting group description

Reporting group title

Tocilizumab (Up to Week 48)

Reporting group description

Participants received TCZ (162 mg) by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then in the open-label period for Week 48 to Week 96.

Reporting group title

Placebo to Tocilizumab (Up to Week 96)

Reporting group description

Reporting group title

Tocilizumab to Tocilizumab (Up to Week 96)

Reporting group description

Participants received TCZ (162 mg) by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then in the open-label period for Week 48 to Week 96.

Primary: Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 24

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End point title

Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 24

End point description

Skin thickness was assessed by the mRSS. The mRSS was rated with scores ranging from 0 (normal) to 3 (severe skin thickening) across 17 different sites. The total score was the sum of the individual skin scores in the 17 body areas (e.g., face, hands, fingers; proximal area of the arms, distal area of the arms, thorax, abdomen; proximal area of the legs, and distal area of the legs, feet), giving a range of 0–51 units and had been validated for participants with systemic sclerosis (SSc). A negative change from baseline showed improvement. Intent-to-treat (ITT) population included all participants randomized who had received any study drug at the time of the Week 24 cutoff date (14 January 2014). Here, number of participants analyzed included only those participants who were evaluable for this outcome measure at any time point up to Week 24.

End point type

Primary

End point timeframe

Baseline, and Week 24

End point values	Placebo (Up to Week 24)	Tocilizumab (Up to Week 24)
Number of subjects analysed	43	41
Units: units on a scale
least squares mean (confidence interval 95%)	-1.22 (-3.42 to 0.98)	-3.92 (-6.17 to -1.67)

Change From Baseline in mRSS at Week 24

Comparison groups

Placebo (Up to Week 24) v Tocilizumab (Up to Week 24)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0915

Method

Mixed models analysis

Parameter type

Difference in Least Square (LS) mean

Point estimate

-2.7

Confidence interval

level

95%

sides

2-sided

lower limit

-5.85

upper limit

0.45

Primary: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) ^[1]

End point description

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to Week 8 after last dose that were absent before treatment or that worsened relative to pretreatment state. Safety population included all participants who received any study drug and provided at least one post-dose safety assessment (withdrawal, AE, death, laboratory assessment, vital signs).

End point type

Primary

End point timeframe

up to Week 48

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: Only descriptive data was planned to be reported.

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	44	43
Units: percentage of participants
number (not applicable)
Treatment-emergent AEs	90.9	97.7
Treatment-emergent SAEs	34.1	32.6

No statistical analyses for this end point

Secondary: Change From Baseline in Physical Function Assessed by Scleroderma Health Assessment Questionnaire Disability Index (SHAQ-DI)

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End point title

Change From Baseline in Physical Function Assessed by Scleroderma Health Assessment Questionnaire Disability Index (SHAQ-DI)

End point description

SHAQ-DI assessed five scleroderma-specific visual analogue scale (VAS) items to explore the impact of participant’s disease. These items were developed to measure the effect of scleroderma on five elements of disease that could have a great impact on a participant’s daily activities. Each VAS item was rated separately (0−100 millimeters [mm]), with higher scores indicating more severe disease. The five items were: 1) intestinal disease, 2) breathing problem, 3) Raynaud syndrome, 4) finger ulcers, and 5) overall disease. ITT population. Here, number of participants analyzed included only those participants who were evaluable for this outcome measure and “n” included those who were evaluable for the specific item at specified time point in specified timeframe.

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	42	41
Units: mm
least squares mean (confidence interval 95%)
Week 24: Intestinal VAS Score (n=42, 41)	5.81 (-1.43 to 13.06)	5.38 (-1.98 to 12.74)
Week 24: Breathing VAS Scores (n=42, 41)	8.54 (0.81 to 16.27)	4.42 (-3.47 to 12.31)
Week 24: Raynaud syndrome (n=42, 41)	2.41 (-6.96 to 11.78)	1.13 (-8.47 to 10.73)
Week 24: Finger ulcers VAS Score (n=42, 41)	9.2 (-0.22 to 18.61)	14.09 (4.45 to 23.73)
Week 24: Overall disease (n=42, 41)	1.89 (-4.99 to 8.77)	1.81 (-5.21 to 8.84)
Week 48: Intestinal VAS Score (n=41, 41)	7.91 (-0.37 to 16.18)	1.11 (-6.88 to 9.1)
Week 48: Breathing VAS Scores (n=41, 41)	0.55 (-7.09 to 8.19)	2.09 (-5.39 to 9.57)
Week 48: Raynaud syndrome (n=41, 41)	0.3 (-9.51 to 10.12)	-4.18 (-13.87 to 5.51)
Week 48: Finger ulcers VAS Score (n=41, 41)	4.97 (-3.15 to 13.1)	-0.83 (-8.83 to 7.17)
Week 48: Overall disease (n=41, 41)	3.46 (-4.5 to 11.41)	-4.36 (-12.27 to 3.55)

Physical Function Assessed by SHAQ-DI

Statistical analysis description

Change From Baseline in Intestinal VAS Score at Week 24. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9336

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-0.43

Confidence interval

level

95%

sides

2-sided

lower limit

-10.78

upper limit

9.91

Physical Function Assessed by SHAQ-DI

Statistical analysis description

Change From Baseline in Breathing VAS Score at Week 24. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4609

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-4.12

Confidence interval

level

95%

sides

2-sided

lower limit

-15.21

upper limit

6.96

Physical Function Assessed by SHAQ-DI

Statistical analysis description

Change From Baseline in Raynaud Syndrome Score at Week 24. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8493

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-1.28

Confidence interval

level

95%

sides

2-sided

lower limit

-14.7

upper limit

12.13

Physical Function Assessed by SHAQ-DI

Statistical analysis description

Change From Baseline in Finger Ulcers Score at Week 24. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4717

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

4.89

Confidence interval

level

95%

sides

2-sided

lower limit

-8.59

upper limit

18.37

Physical Function Assessed by SHAQ-DI

Statistical analysis description

Change From Baseline in Overall Disease Score at Week 24. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9876

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-9.93

upper limit

9.78

Physical Function Assessed by SHAQ-DI

Statistical analysis description

Change From Baseline in Intestinal VAS Score at Week 48. A total of 82 participants were included in analysis. One participant from placebo group, included at Week 24 analysis, was not included in Week 48 analysis because this participant had taken escape medication, and after censoring for Week 48 analyses, had no valid efficacy result for the endpoint.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.2407

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-6.8

Confidence interval

level

95%

sides

2-sided

lower limit

-18.3

upper limit

4.71

Notes
[2] - The analysis included fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at baseline visit, and treatment-by-visit interaction, as well as continuous covariates of baseline score and baseline score-by-visit interaction.

Physical Function Assessed by SHAQ-DI

Statistical analysis description

Change From Baseline in Breathing VAS Score at Week 48. A total of 82 participants were included in analysis. One participant from placebo group, included at Week 24 analysis, was not included in Week 48 analysis because this participant had taken escape medications, and after censoring for Week 48 analyses, had no valid efficacy result for the endpoint.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.7742

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

1.54

Confidence interval

level

95%

sides

2-sided

lower limit

-9.18

upper limit

12.26

Notes
[3] - The analysis included fixed, categorical effects of treatment, visit, stratification factor of joint involvement at baseline visit, and treatment-by-visit interaction, as well as continuous covariates of baseline score and baseline score-by-visit interaction.

Physical Function Assessed by SHAQ-DI

Statistical analysis description

Change From Baseline in Raynaud Syndrome Score at Week 48. A total of 82 participants were included in the analysis. One participant from placebo group, included at Week 24 analysis, was not included in Week 48 analysis because this participant had taken escape medication, and after censoring for Week 48 analyses, had no valid efficacy result for the endpoint.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.5182

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-4.48

Confidence interval

level

95%

sides

2-sided

lower limit

-18.28

upper limit

9.31

Notes
[4] - The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Physical Function Assessed by SHAQ-DI

Statistical analysis description

Change From Baseline in Finger Ulcers Score at Week 48. A total of 82 participants were included in the analysis. One participant from placebo group, included at Week 24 analysis, was not included in Week 48 analysis because this participant had taken escape medication, and after censoring for Week 48 analyses, had no valid efficacy result for the endpoint.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.3106

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-5.8

Confidence interval

level

95%

sides

2-sided

lower limit

-17.2

upper limit

5.59

Notes
[5] - The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Physical Function Assessed by SHAQ-DI

Statistical analysis description

Change From Baseline in Overall Disease Score at Week 48. A total of 82 participants were included in the analysis. One participant from placebo group, included at Week 24 analysis, was not included in Week 48 analysis because this participant had taken escape medication, and after censoring for Week 48 analyses, had no valid efficacy result for the endpoint.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.1717

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-7.82

Confidence interval

level

95%

sides

2-sided

lower limit

-19.11

upper limit

3.48

Notes
[6] - The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Secondary: Change From Baseline in HAQ-DI Score at Week 24 and Week 48

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End point title

Change From Baseline in HAQ-DI Score at Week 24 and Week 48

End point description

The HAQ-DI scale consisted of 20 questions referring to eight component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The total score indicated the participant’s self-assessed level of disability. There were four possible responses for each component: 0 = without any difficulty; 1 = with some difficulty; 2 = with much difficulty; 3 = unable to do. The HAQ-DI was the sum of the domain scores, divided by the number of domains that had a score (i.e. the average score), with total range of 0 to 3, higher scores showing larger functional limitation. ITT population. Here, number of participants analyzed included only those participants who were evaluable for this outcome measure and “n” included those who were evaluable for the specific item at specified time point in specified time frame.

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	42	41
Units: units on a scale
least squares mean (confidence interval 95%)
Week 24 (n=42, 41)	0.118 (-0.026 to 0.262)	0.137 (-0.01 to 0.285)
Week 48 (n=41, 41)	0.205 (0.017 to 0.393)	-0.002 (-0.188 to 0.183)

HAQ-DI Score at Week 24

Statistical analysis description

Change From Baseline in HAQ-DI Score at Week 24. A total of 82 participants were included in the analysis. One participant from placebo group, included at Week 24 analysis, was not included in Week 48 analysis because this participant had taken escape medication, and after censoring for Week 48 analyses, had no valid efficacy result for the endpoint.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.8503

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.186

upper limit

0.225

Notes
[7] - The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

HAQ-DI Score at Week 48

Statistical analysis description

Change From Baseline in HAQ-DI Score at Week 48. A total of 82 participants were included in the analysis. One participant from placebo group, included at Week 24 analysis, was not included in Week 48 analysis because this participant had taken escape medication, and after censoring for Week 48 analyses, had no valid efficacy result for the endpoint.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.1212

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-2.07

Confidence interval

level

95%

sides

2-sided

lower limit

-4.71

upper limit

0.056

Notes
[8] - The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Secondary: Change From Baseline in Clinician’s Global Assessment at Week 24 and Week 48

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End point title

Change From Baseline in Clinician’s Global Assessment at Week 24 and Week 48

End point description

The Clinician’s Global Assessment evaluated the overall impact of SSc on the participant as assessed by the physician on a VAS with scores ranging from 0 to 100 mm, with higher scores indicating worse disease in terms of severity, damage, or overall disease, but there was no standardization for the scale.ITT population. Here, number of participants analyzed included only those participants who were evaluable for this outcome measure and “n” included those who were evaluable for the specific item at specified time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	41	40
Units: mm
least squares mean (confidence interval 95%)
Week 24 (n=41, 39)	-7.25 (-12.99 to -1.51)	-8.24 (-14.06 to -2.41)
Week 48 (n=41, 40)	-9.39 (-16.66 to -2.12)	-18.41 (-25.3 to -11.52)

Clinician’s Global Assessment at Week 24 and 48

Statistical analysis description

Change From Baseline in Clinician’s Global Assessment at Week 24.The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8118

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-0.99

Confidence interval

level

95%

sides

2-sided

lower limit

-9.2

upper limit

7.23

Clinician’s Global Assessment at Week 24 and 48

Statistical analysis description

Change From Baseline in Clinician’s Global Assessment at Week 48. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0768

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-9.02

Confidence interval

level

95%

sides

2-sided

lower limit

-19.04

upper limit

Secondary: Change From Baseline in Patient’s Global Assessment at Week 24 and Week 48

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End point title

Change From Baseline in Patient’s Global Assessment at Week 24 and Week 48

End point description

The Patient’s Global Assessment was a patient’s reported outcome that represented the participant’s overall assessment of his or her current SSc on a 100 mm horizontal VAS scale (0 mm to 100 mm), with higher scores indicating worsening disease. ITT population. Here, number of participants analyzed included only those participants who were evaluable for this outcome measure and “n” included those who were evaluable for the specific item at specified time point in specified time frame.

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	42	42
Units: mm
least squares mean (confidence interval 95%)
Week 24 (n=42, 42)	1.53 (-4.93 to 7.98)	-2.33 (-8.87 to 4.22)
Week 48 (n=41, 42)	-2.7 (-10.56 to 5.16)	-11 (-18.69 to -3.31)

Patient’s Global Assessment at Week 24 and 48

Statistical analysis description

Change From Baseline in Patient’s Global Assessment at Week 24. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4063

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-3.85

Confidence interval

level

95%

sides

2-sided

lower limit

-13.04

upper limit

5.34

Patient’s Global Assessment at Week 24 and 48

Statistical analysis description

Change From Baseline in Patient’s Global Assessment at Week 48. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1371

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-8.3

Confidence interval

level

95%

sides

2-sided

lower limit

-19.31

upper limit

2.71

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy−Fatigue (FACIT-Fatigue) Score at Week 24 and Week 48

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End point title

Change From Baseline in Functional Assessment of Chronic Illness Therapy−Fatigue (FACIT-Fatigue) Score at Week 24 and Week 48

End point description

This FACIT-Fatigue Scale was a 13-item measure with participants scoring each item on a 5-point scale (0 to 4) up to 52 points. The endpoint measured was fatigue. On this scale, a numerical increase indicated an improvement in the participant’s condition. ITT population. Here, number of participants analyzed included only those participants who were evaluable for this outcome measure and “n” included those who were evaluable for the specific item at specified time point in specified time frame.

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	41	42
Units: units on a scale
least squares mean (confidence interval 95%)
Week 24 (n=41, 42)	1.26 (-1.85 to 4.37)	2.68 (-0.41 to 5.77)
Week 48 (n=40, 42)	0.36 (-2.64 to 3.37)	3.11 (0.28 to 5.95)

FACIT-Fatigue Score at Week 24 and 48

Statistical analysis description

Change From Baseline in FACIT-Fatigue Score at Week 24. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5197

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

1.43

Confidence interval

level

95%

sides

2-sided

lower limit

-2.97

upper limit

5.82

FACIT-Fatigue Score at Week 24 and 48

Statistical analysis description

Change From Baseline in FACIT-Fatigue Score at Week 48. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1886

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

2.75

Confidence interval

level

95%

sides

2-sided

lower limit

-1.38

upper limit

6.88

Secondary: Change From Baseline in 5-D Itch Scale at Week 24 and Week 48

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End point title

Change From Baseline in 5-D Itch Scale at Week 24 and Week 48

End point description

The 5-D Itch Scale contained five domains of duration, degree, direction, disability, and distribution. The endpoint of the scale was pruritus. Each domain was scored on a 5-point scale, the scores of each of the five domains were achieved separately and then summed together to obtain a total 5-D score. 5-D scores ranged between 5 (no pruritus) and 25 (most severe pruritus). ITT population. Here, number of participants analyzed included only those participants who were evaluable for this outcome measure and “n” included those who were evaluable for the specific item at specified time point in specified time frame.

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	41	41
Units: units on a scale
least squares mean (confidence interval 95%)
Week 24 (n=41, 41)	-1.73 (-2.95 to -0.5)	-0.94 (-2.15 to 0.28)
Week 48 (n=40, 41)	-1.08 (-2.6 to 0.43)	-2.19 (-3.58 to -0.8)

5-D Itch Scale at Week 24 and Week 48

Statistical analysis description

Change From Baseline in 5-D Itch Scale at Week 24. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3651

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

-0.94

upper limit

2.51

5-D Itch Scale at Week 24 and Week 48

Statistical analysis description

Change From Baseline in 5-D Itch Scale at Week 48. The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2841

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-1.11

Confidence interval

level

95%

sides

2-sided

lower limit

-3.16

upper limit

0.94

Secondary: Change From Baseline in mRSS at Week 48

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End point title

Change From Baseline in mRSS at Week 48

End point description

End point type

Secondary

End point timeframe

Baseline, Week 48

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	43	41
Units: units on a scale
least squares mean (confidence interval 95%)	-2.77 (-5.44 to -0.11)	-6.33 (-8.86 to -3.79)

Change From Baseline in mRSS at Week 48

Statistical analysis description

The analysis included the fixed, categorical effects of treatment, visit, the stratification factor of joint involvement at the baseline visit, and treatment-by-visit interaction, as well as the continuous covariates of baseline score and baseline score-by-visit interaction.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0579

Method

Mixed models analysis

Parameter type

Difference in LS mean

Point estimate

-3.55

Confidence interval

level

95%

sides

2-sided

lower limit

-7.23

upper limit

0.12

Secondary: Percentage of Participants Who Maintained or Improved in mRSS From Week 24 to Week 48

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End point title

Percentage of Participants Who Maintained or Improved in mRSS From Week 24 to Week 48

End point description

Skin thickness was assessed by the mRSS. The mRSS was rated with scores ranging from 0 (normal) to 3 (severe skin thickening) across 17 different sites. The total score was the sum of the individual skin scores in the 17 body areas (e.g., face, hands, fingers; proximal area of the arms, distal area of the arms, thorax, abdomen; proximal area of the legs, and distal area of the legs, feet), giving a range of 0–51 units and had been validated for participants with SSc. A negative change from baseline showed improvement. Percentage of participants with an improvement in mRSS at Week 24 (change from baseline <0) that maintained or further improved at Week 48 were reported as “Yes” and “No” with Yes = improvers at Week 24 that had a change from baseline in MRSS at Week 48 <= change from baseline at Week 24. ITT population. Here number of participants analyzed included those with mRSS change from baseline <0 at Week 24 and with non-missing change from baseline in mRSS at Week 48.

End point type

Secondary

End point timeframe

Week 48

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	43	41
Units: percentage of participants
number (not applicable)	44.4	68.2

Improvement in mRSS From Week 24 to 48

Statistical analysis description

Percentage of Participants Who Maintained or Improved in mRSS From Week 24 to Week 48. The logistic regression model included the fixed categorical effects of treatment and the stratification factor of joint involvement at the baseline visit. The continuous covariate of baseline mRSS score was also included in the model.

Comparison groups

Placebo (Up to Week 48) v Tocilizumab (Up to Week 48)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2159

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.39

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

9.5

Variability estimate

Standard error of the mean

Dispersion value

0.704

Secondary: Change From Baseline in Tender Joint Count 28 (TJC28)

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End point title

Change From Baseline in Tender Joint Count 28 (TJC28)

End point description

Joint tenderness was evaluated as per assessment of 28 joints. Joints on both sides of the body, including shoulders, elbows, wrists, 10 metacarpal phalangeal (MCP) joints, 10 proximal interphalangeal joint (PIP) joints, and both knees, were assessed. Joints were classified as not tender = 0 or tender = 1. ITT population. Here n = evaluable for the specific item at specified time point in specified time frame.

End point type

Secondary

End point timeframe

Baseline, Weeks 3, 8, 16, 24, 32, 40, and 48

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	20	19
Units: joint count
arithmetic mean (standard deviation)
Week 3 (n=20, 19)	-2.75 ± 4.27	-2.32 ± 5.55
Week 8 (n=18, 19)	-3.06 ± 6.67	-4 ± 6.16
Week 16 (n=18, 17)	-3.5 ± 6	-3.65 ± 7.59
Week 24 (n=17, 16)	-2.06 ± 6.28	-4.31 ± 7.34
Week 32 (n=12, 11)	-3.33 ± 6.62	-3.18 ± 7.4
Week 40 (n=10, 10)	-3.8 ± 6.76	-4.3 ± 8.23
Week 48 (n=12, 10)	-2.92 ± 7.08	-5.1 ± 7.29

No statistical analyses for this end point

Secondary: Area Under the Concentration-Time Curve (AUC) From Time 0 to 168 Hour (AUC0-168)

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End point title

Area Under the Concentration-Time Curve (AUC) From Time 0 to 168 Hour (AUC0-168) ^[9]

End point description

AUC was a measure of the serum concentration of the drug over time which was measured in micrograms times (*) hour per milliliter (µg*hr/mL). It is used to characterize drug absorption. Pharmacokinetic (PK) population included all participants who received at least one TCZ injection and had at least one PK sample with detectable results. Here, “n” = participants evaluable for the specific item at specified time point in specified time frame.

End point type

Secondary

End point timeframe

Pre-dose, 24, 48, 72, 96, 120 or 144, and 168 hours post dose for Baseline and Week 16

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: No inter-group analysis was performed.

End point values	Tocilizumab (Up to Week 24)
Number of subjects analysed	7
Units: µg*hr/mL
arithmetic mean (standard deviation)
Baseline (n=7)	686 ± 455
Week 16 (n=4)	7508 ± 2369

No statistical analyses for this end point

Secondary: Mean Serum Concentrations of Interleukin (IL)-6 by Visit

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End point title

Mean Serum Concentrations of Interleukin (IL)-6 by Visit

End point description

Observed data was presented for this outcome measure. Safety population. Here, number of participants analyzed included only those participants who were evaluable for this outcome measure and “n” included those who were evaluable for the specific item at specified time point in specified time frame.

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 3, 8, 16, 24, and 48

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	43	43
Units: picograms per milliliters (pg/mL)
arithmetic mean (standard deviation)
Baseline (n=43, 42)	15.02 ± 18.19	13.57 ± 14.69
Week 1: Absolute values (n=43, 43)	17.24 ± 22.77	158.91 ± 326.42
Week 1: Change From Baseline (n=42, 42)	1.33 ± 27.29	147.37 ± 326.2
Week 2: Absolute values (n=43, 41)	12.6 ± 13.78	107.1 ± 73.75
Week 2: Change From Baseline (n=42, 40)	-3.07 ± 17.85	94.54 ± 67.99
Week 3: Absolute values (n=42, 40)	12.47 ± 10.72	116.58 ± 75.31
Week 3: Change From Baseline (n=41, 39)	-3.6 ± 15.28	104.44 ± 71.84
Week 8: Absolute values (n=42, 39)	15.39 ± 19.04	115.31 ± 66.39
Week 8: Change From Baseline(n=41,38)	0.15 ± 18.65	104.14 ± 62.95
Week 16: Absolute values (n=32,33)	12.51 ± 14.06	98.36 ± 61.65
Week 16: Change From Baseline (n=31,32)	-1.26 ± 11.34	88.86 ± 59.77
Week 24: Absolute values (n=36,34)	10.19 ± 10.55	84.67 ± 68.37
Week 24: Change From Baseline(n=35,33)	-2.74 ± 12.43	73.61 ± 68.07
Week 48: Absolute values (n=32,27)	10.5 ± 11.82	65.3 ± 35.95
Week 48: Change From Baseline (n=31,26)	-2.61 ± 14.92	55.6 ± 35.86

No statistical analyses for this end point

Secondary: Mean Serum Concentrations of Soluble IL-6 Receptor (R) by Visit

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End point title

Mean Serum Concentrations of Soluble IL-6 Receptor (R) by Visit

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 1, 2, 3, 8, 16, 24, and 48

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	44	43
Units: pg/mL
arithmetic mean (standard deviation)
Baseline (n=44, 42)	37.61 ± 11.12	39.39 ± 10.16
Week 1: Absolute values (n=44, 43)	51.03 ± 59.12	237.34 ± 71.38
Week 1: Change From Baseline (n=44, 42)	13.42 ± 57.91	198.39 ± 69.41
Week 2: Absolute values (n=43, 41)	44.07 ± 42.15	329.9 ± 81.93
Week 2: Change From Baseline (n=43, 40)	6.13 ± 41.6	291.38 ± 79.29
Week 3: Absolute values (n=44, 40)	41.64 ± 27.07	384.88 ± 99.41
Week 3: Change From Baseline (n=44, 39)	4.03 ± 26	346.68 ± 95.96
Week 8: Absolute values (n=42, 39)	38.66 ± 11.95	486.62 ± 116.41
Week 8: Change From Baseline (n=42, 38)	0.91 ± 5.07	447.77 ± 114.4
Week 16: Absolute values (n=32, 33)	37.71 ± 10.3	525.48 ± 164.9
Week 16: Change From Baseline (n=32, 32)	-0.08 ± 5.71	486.43 ± 163.32
Week 24: Absolute values (n=36, 34)	38.72 ± 13.06	520.18 ± 167.97
Week 24: Change From Baseline (n=36, 33)	1.11 ± 6.47	482.1 ± 168.44
Week 48: Absolute values (n=32, 27)	36.52 ± 9.93	491.44 ± 164.82
Week 48: Change From Baseline (n=32, 26)	-0.75 ± 5.2	454.19 ± 163.93

No statistical analyses for this end point

Secondary: Percentage of Participants With Anti-Tocilizumab Antibody

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End point title

Percentage of Participants With Anti-Tocilizumab Antibody

End point description

Safety population. Here, number of participants analyzed included only those participants who were evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Baseline, and post-baseline (up to Week 48)

End point values	Placebo (Up to Week 48)	Tocilizumab (Up to Week 48)
Number of subjects analysed	43	42
Units: percentage of participants
number (not applicable)
Baseline	7	2.4
Post-Baseline	0	2.4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to Week 96 (reporting groups up to 24 Weeks and up to 48 Weeks present data as of the 11 July 2014 data cut-off date; reporting groups up to 96 weeks present data as of the 05 August 2015 data cut-off date).

Adverse event reporting additional description

MedDRA 17.0 was utilized up to Week 48; MedDRA 18.0 was utilized for Week 48 up to Week 96

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Placebo (up to 24 Weeks)

Reporting group description

Participants received TCZ matched placebo by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then received TCZ (162 mg) SC injection qw in the open-label period for Week 48 to Week 96. The data analyzed for placebo up to Week 24 was presented in this arm group.

Reporting group title

Tocilizumab (up to 24 Weeks)

Reporting group description

Participants received TCZ (162 mg) by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then in the open-label period for Week 48 to Week 96. The data analyzed for TCZ up to Week 24 was presented in this arm group.

Reporting group title

Placebo (up to 48 Weeks)

Reporting group description

Reporting group title

Tocilizumab (up to 48 Weeks)

Reporting group description

Reporting group title

Placebo to Tocilizumab (up to 96 Weeks)

Reporting group description

Participants received TCZ matched placebo by SC injection qw for Week 0 to Week 48 (blinded-treatment period) and then received TCZ (162 mg) SC injection qw in the open-label period for Week 48 to Week 96. The data analyzed for double-blind placebo to open-label tocilizumab up to Week 96 are presented in this reporting group.

Reporting group title

Tocilizumab to Tocilizumab (up to 96 Weeks)

Reporting group description

Serious adverse events	Placebo (up to 24 Weeks)	Tocilizumab (up to 24 Weeks)	Placebo (up to 48 Weeks)	Tocilizumab (up to 48 Weeks)	Placebo to Tocilizumab (up to 96 Weeks)	Tocilizumab to Tocilizumab (up to 96 Weeks)
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 44 (25.00%)	9 / 43 (20.93%)	15 / 44 (34.09%)	14 / 43 (32.56%)	22 / 44 (50.00%)	17 / 43 (39.53%)
number of deaths (all causes)	1	1	1	2	1	2
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer metastatic
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Raynaud's phenomenon
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Impaired healing
subjects affected / exposed	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Reproductive system and breast disorders
Uterine haemorrhage
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Status asthmaticus
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Psychotic disorder
subjects affected / exposed	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Cyanosis
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Atrioventricular block
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congestive cardiomyopathy
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Haemolytic uraemic syndrome
subjects affected / exposed	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eosinophilia
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colonic pseudo-obstruction
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric antral vascular ectasia
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal fibrosis
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin ulcer
subjects affected / exposed	0 / 44 (0.00%)	1 / 43 (2.33%)	1 / 44 (2.27%)	2 / 43 (4.65%)	1 / 44 (2.27%)	2 / 43 (4.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin necrosis
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure acute
Additional description: The previous event Renal failure acute at Week 48 was updated to Acute kidney injury at Week 96
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Scleroderma renal crisis
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	2 / 44 (4.55%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Autoimmune thyroiditis
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Scleroderma
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Systemic sclerosis
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	1 / 43 (2.33%)	1 / 44 (2.27%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Osteomyelitis
subjects affected / exposed	0 / 44 (0.00%)	2 / 43 (4.65%)	1 / 44 (2.27%)	2 / 43 (4.65%)	2 / 44 (4.55%)	2 / 43 (4.65%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1	2 / 2	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)	2 / 44 (4.55%)	2 / 43 (4.65%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	2 / 2	0 / 3	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1
Oesophageal candidiasis
subjects affected / exposed	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)	1 / 44 (2.27%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural cellulitis
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo (up to 24 Weeks)	Tocilizumab (up to 24 Weeks)	Placebo (up to 48 Weeks)	Tocilizumab (up to 48 Weeks)	Placebo to Tocilizumab (up to 96 Weeks)	Tocilizumab to Tocilizumab (up to 96 Weeks)
Total subjects affected by non serious adverse events
subjects affected / exposed	26 / 44 (59.09%)	28 / 43 (65.12%)	32 / 44 (72.73%)	34 / 43 (79.07%)	39 / 44 (88.64%)	38 / 43 (88.37%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	3 / 43 (6.98%)
occurrences all number	0	0	0	0	0	3
Vascular disorders
Raynaud's phenomenon
subjects affected / exposed	1 / 44 (2.27%)	3 / 43 (6.98%)	2 / 44 (4.55%)	5 / 43 (11.63%)	2 / 44 (4.55%)	6 / 43 (13.95%)
occurrences all number	1	3	2	5	2	6
Hypertension
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	3 / 44 (6.82%)	2 / 43 (4.65%)	4 / 44 (9.09%)	3 / 43 (6.98%)
occurrences all number	0	0	3	2	4	3
Nervous system disorders
Dizziness
subjects affected / exposed	2 / 44 (4.55%)	3 / 43 (6.98%)	2 / 44 (4.55%)	3 / 43 (6.98%)	2 / 44 (4.55%)	5 / 43 (11.63%)
occurrences all number	2	3	2	3	2	5
Headache
subjects affected / exposed	2 / 44 (4.55%)	3 / 43 (6.98%)	3 / 44 (6.82%)	5 / 43 (11.63%)	5 / 44 (11.36%)	8 / 43 (18.60%)
occurrences all number	2	5	3	7	6	12
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 44 (6.82%)	0 / 43 (0.00%)	3 / 44 (6.82%)	0 / 43 (0.00%)	3 / 44 (6.82%)	0 / 43 (0.00%)
occurrences all number	3	0	3	0	3	0
Fatigue
subjects affected / exposed	2 / 44 (4.55%)	4 / 43 (9.30%)	2 / 44 (4.55%)	5 / 43 (11.63%)	3 / 44 (6.82%)	6 / 43 (13.95%)
occurrences all number	2	7	2	9	3	10
Oedema peripheral
subjects affected / exposed	1 / 44 (2.27%)	3 / 43 (6.98%)	1 / 44 (2.27%)	3 / 43 (6.98%)	3 / 44 (6.82%)	4 / 43 (9.30%)
occurrences all number	1	3	1	3	3	4
Injection site erythemia
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	2 / 44 (4.55%)	3 / 43 (6.98%)
occurrences all number	0	0	0	0	3	3
Gastrointestinal disorders
Abdominal Pain
Additional description: One case of abdominal pain was updated between Week 24 and 48 to diverticulum. The remaining 2 cases at week 48 fall below the 5% threshold and are therefore not presented.
subjects affected / exposed	0 / 44 (0.00%)	3 / 43 (6.98%)	0 / 44 (0.00%)	0 / 43 (0.00%)	2 / 44 (4.55%)	4 / 43 (9.30%)
occurrences all number	0	3	0	0	2	4
Diarrhoea
subjects affected / exposed	4 / 44 (9.09%)	6 / 43 (13.95%)	4 / 44 (9.09%)	7 / 43 (16.28%)	5 / 44 (11.36%)	12 / 43 (27.91%)
occurrences all number	4	7	4	9	5	16
Gastrooesophageal reflux disease
subjects affected / exposed	4 / 44 (9.09%)	4 / 43 (9.30%)	5 / 44 (11.36%)	5 / 43 (11.63%)	7 / 44 (15.91%)	5 / 43 (11.63%)
occurrences all number	4	4	5	5	7	5
Vomiting
subjects affected / exposed	0 / 44 (0.00%)	3 / 43 (6.98%)	1 / 44 (2.27%)	3 / 43 (6.98%)	2 / 44 (4.55%)	3 / 43 (6.98%)
occurrences all number	0	3	1	4	4	5
Dyspepsia
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	3 / 44 (6.82%)	3 / 43 (6.98%)	3 / 44 (6.82%)	3 / 43 (6.98%)
occurrences all number	0	0	3	3	3	3
Nausea
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	3 / 44 (6.82%)	2 / 43 (4.65%)	5 / 44 (11.36%)	3 / 43 (6.98%)
occurrences all number	0	0	5	2	7	3
Constipation
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	4 / 44 (9.09%)	2 / 43 (4.65%)
occurrences all number	0	0	0	0	4	2
Mouth ulceration
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	3 / 44 (6.82%)	2 / 43 (4.65%)
occurrences all number	0	0	0	0	3	2
Respiratory, thoracic and mediastinal disorders
Dyspnoea
Additional description: The Investigator removed an adverse event of dyspnoea between Week 24 and Week 48 reporting events.
subjects affected / exposed	4 / 44 (9.09%)	2 / 43 (4.65%)	3 / 44 (6.82%)	4 / 43 (9.30%)	3 / 44 (6.82%)	5 / 43 (11.63%)
occurrences all number	4	2	3	4	3	5
Cough
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	4 / 43 (9.30%)
occurrences all number	0	0	0	0	1	4
Oropharyngeal pain
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	3 / 43 (6.98%)
occurrences all number	0	0	0	0	0	3
Pulmonary hypertension
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	1 / 44 (2.27%)	3 / 43 (6.98%)
occurrences all number	0	0	0	0	1	3
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	3 / 44 (6.82%)	7 / 43 (16.28%)	4 / 44 (9.09%)	8 / 43 (18.60%)	9 / 44 (20.45%)	12 / 43 (27.91%)
occurrences all number	3	8	4	9	9	13
Skin ulcer
subjects affected / exposed	6 / 44 (13.64%)	6 / 43 (13.95%)	7 / 44 (15.91%)	7 / 43 (16.28%)	9 / 44 (20.45%)	8 / 43 (18.60%)
occurrences all number	7	15	11	17	15	22
Erythema
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	3 / 44 (6.82%)	1 / 43 (2.33%)
occurrences all number	0	0	0	0	5	2
Pruritus generalised
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	3 / 43 (6.98%)
occurrences all number	0	0	0	0	0	3
Psychiatric disorders
Sleep disorder
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	3 / 44 (6.82%)	1 / 43 (2.33%)	3 / 44 (6.82%)	1 / 43 (2.33%)
occurrences all number	0	0	3	1	3	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	6 / 44 (13.64%)	6 / 43 (13.95%)	8 / 44 (18.18%)	6 / 43 (13.95%)	10 / 44 (22.73%)	6 / 43 (13.95%)
occurrences all number	7	6	11	6	13	8
Back pain
subjects affected / exposed	3 / 44 (6.82%)	5 / 43 (11.63%)	3 / 44 (6.82%)	6 / 43 (13.95%)	3 / 44 (6.82%)	8 / 43 (18.60%)
occurrences all number	4	5	4	6	5	8
Pain in extremity
subjects affected / exposed	1 / 44 (2.27%)	5 / 43 (11.63%)	2 / 44 (4.55%)	5 / 43 (11.63%)	2 / 44 (4.55%)	7 / 43 (16.28%)
occurrences all number	1	5	2	7	2	11
Musculoskeletal pain
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	3 / 44 (6.82%)	2 / 43 (4.65%)
occurrences all number	0	0	0	0	3	2
Infections and infestations
Infected skin ulcer
subjects affected / exposed	5 / 44 (11.36%)	0 / 43 (0.00%)	5 / 44 (11.36%)	1 / 43 (2.33%)	7 / 44 (15.91%)	3 / 43 (6.98%)
occurrences all number	6	0	7	1	11	3
Nasopharyngitis
subjects affected / exposed	2 / 44 (4.55%)	3 / 43 (6.98%)	4 / 44 (9.09%)	5 / 43 (11.63%)	5 / 44 (11.36%)	8 / 43 (18.60%)
occurrences all number	3	3	5	6	6	9
Urinary tract infection
subjects affected / exposed	3 / 44 (6.82%)	2 / 43 (4.65%)	3 / 44 (6.82%)	3 / 43 (6.98%)	5 / 44 (11.36%)	6 / 43 (13.95%)
occurrences all number	3	2	3	3	5	9
Herpes zoster
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	2 / 44 (4.55%)	3 / 43 (6.98%)	2 / 44 (4.55%)	4 / 43 (9.30%)
occurrences all number	0	0	2	3	2	4
Upper respiratory tract infection
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	6 / 44 (13.64%)	1 / 43 (2.33%)	8 / 44 (18.18%)	3 / 43 (6.98%)
occurrences all number	0	0	8	1	10	5
Cellulitis
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	3 / 44 (6.82%)	0 / 43 (0.00%)
occurrences all number	0	0	0	0	3	0
Lower respiratory tract infection
subjects affected / exposed	0 / 44 (0.00%)	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 43 (0.00%)	3 / 44 (6.82%)	0 / 43 (0.00%)
occurrences all number	0	0	0	0	3	0

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Were there any global substantial amendments to the protocol? Yes

09 Mar 2012

- To clarify that participants were required to have uninvolved skin at at least one of 3 locations to ensure application of SC study drug in uninvolved skin. The area for SC injection had been expanded in one area from the lower abdomen to the entire abdomen except for the 2-inch area directly around the navel. - To add a lipid panel at Week 8. - To clarify that investigators must draw immunogenicity labs in participants with hypersensitivity reactions leading to withdrawal from study drug, not just in the case of serious hypersensitivity leading to withdrawal from study drug. - To clarify that Sponsor company requested a review of liver biopsy slides and report if the investigator deemed a liver biopsy necessary but Sponsor company did not request a liver biopsy. The investigators might have deemed a liver biopsy necessary in the management of persistently elevated liver enzymes. In that case, Sponsor company was requesting a biopsy report and slides of the biopsied tissue.

02 Nov 2012

- To remove recruitment barriers to allow for completion and closeout of recruiting for this study. - To provide clarification on the use of SSc medications, including those initiated after baseline, specifically allowing modification of the dose regimen after Week 24 if clinically warranted. - To provide clarification that after the baseline visit, per the Principal Investigator’s clinical judgment, if angiotensin-converting enzyme inhibitors, calcium-channel blockers, proton-pump inhibitors, and/or vasodilators need to be initiated for chronic use, the dose regimen should remain stable up to and including Week 24, unless dose adjustments are required for safety reasons or cytochrome P450 (CYP450) interactions. - To allow safety assessments to be done before efficacy assessments if necessary due to clinical assessor availability since this does not compromise data quality and subsequent analysis. - To replace the reporting time frame for serious adverse events, AEs of special interest, and pregnancies from within “1 working day” to “24 hours.” - To update safety information from Actemra SC studies as of October 2012.

20 Nov 2012

- To add back in the Schedule of Sampling from the PK Substudy, which was inadvertently removed from the protocol during the previous amendment.

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 II/III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study To Assess the Efficacy and Safety of Tocilizumab Versus Placebo In Patients With Systemic Sclerosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 24

Primary: Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 24

Primary: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Change From Baseline in Physical Function Assessed by Scleroderma Health Assessment Questionnaire Disability Index (SHAQ-DI)

Secondary: Change From Baseline in Physical Function Assessed by Scleroderma Health Assessment Questionnaire Disability Index (SHAQ-DI)

Secondary: Change From Baseline in HAQ-DI Score at Week 24 and Week 48

Secondary: Change From Baseline in HAQ-DI Score at Week 24 and Week 48

Secondary: Change From Baseline in Clinician’s Global Assessment at Week 24 and Week 48

Secondary: Change From Baseline in Clinician’s Global Assessment at Week 24 and Week 48

Secondary: Change From Baseline in Patient’s Global Assessment at Week 24 and Week 48

Secondary: Change From Baseline in Patient’s Global Assessment at Week 24 and Week 48

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy−Fatigue (FACIT-Fatigue) Score at Week 24 and Week 48

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy−Fatigue (FACIT-Fatigue) Score at Week 24 and Week 48

Secondary: Change From Baseline in 5-D Itch Scale at Week 24 and Week 48

Secondary: Change From Baseline in 5-D Itch Scale at Week 24 and Week 48

Secondary: Change From Baseline in mRSS at Week 48

Secondary: Change From Baseline in mRSS at Week 48

Secondary: Percentage of Participants Who Maintained or Improved in mRSS From Week 24 to Week 48

Secondary: Percentage of Participants Who Maintained or Improved in mRSS From Week 24 to Week 48

Secondary: Change From Baseline in Tender Joint Count 28 (TJC28)

Secondary: Change From Baseline in Tender Joint Count 28 (TJC28)

Secondary: Area Under the Concentration-Time Curve (AUC) From Time 0 to 168 Hour (AUC0-168)

Secondary: Area Under the Concentration-Time Curve (AUC) From Time 0 to 168 Hour (AUC0-168)

Secondary: Mean Serum Concentrations of Interleukin (IL)-6 by Visit

Secondary: Mean Serum Concentrations of Interleukin (IL)-6 by Visit

Secondary: Mean Serum Concentrations of Soluble IL-6 Receptor (R) by Visit

Secondary: Mean Serum Concentrations of Soluble IL-6 Receptor (R) by Visit

Secondary: Percentage of Participants With Anti-Tocilizumab Antibody

Secondary: Percentage of Participants With Anti-Tocilizumab Antibody

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase II/III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study To Assess the Efficacy and Safety of Tocilizumab Versus Placebo In Patients With Systemic Sclerosis