Clinical trial NCT02453256
Conditions: Systemic Sclerosis
Sponsor: Hoffmann-La Roche
Start date: 2015-11-20; Completion date: 2019-02-04
Enrollment: 212 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the efficacy and safety of tocilizumab compared with placebo in participants with SSc across approximately 120 planned global study sites. The study will consist of a 48-week, double-blind, placebo-controlled period followed by a 48-week open-label treatment period. Participants will be assigned, in a 1:1 ratio, to double-blind treatment with active tocilizumab or matching placebo. In the open-label period, eligible participants from either arm may receive active tocilizumab.

Detailed description:

Arms: arm 1: Participants will receive double-blind matching placebo from Baseline to Week 47. Participants may then receive open-label tocilizumab from Weeks 48 to 96. arm 2: Participants will receive double-blind tocilizumab from Baseline to Week 47. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
Interventions: intervention 1: Placebo intervention 2: Tocilizumab
Intervention descriptions: intervention 1: Participants will receive matching placebo subcutaneous (SC) injections once weekly for 48 weeks of double-blind treatment. intervention 2: Participants will receive 162 mg SC tocilizumab once weekly for 48 weeks of double-blind treatment. The same regimen will be given to all eligible participants for 48 weeks of open-label treatment.

Protocol documents:
Prot_002.pdf: 
Official Title:  
A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Assess the Efficacy and Safety of Tocilizumab Versus 
Placebo in Patients With Systemic Sclerosis 
 
NCT Number:   
NCT02453256 
 
Document Dates:  
Protocol Amendment/Version 6: 05-May-17 


PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Tocilizumab—F. Hoffmann-La Roche Ltd 
Protocol WA29767, Version 6 
PROTOCOL 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP STUDY TO ASSESS THE 
EFFICACY AND SAFETY OF TOCILIZUMAB 
VERSUS PLACEBO IN PATIENTS WITH SYSTEMIC 
SCLEROSIS 
PROTOCOL NUMBER: WA29767 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2015-000424-28 
IND NUMBER: 
112406 
TEST PRODUCT: 
Tocilizumab (RO4877533) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  28 February 2015 
DATE AMENDED: 
Version 2:  02 April 2015 
Version 3:  12 July 2015 
Version 4:  17 December 2015 
Version 5:  06 September 2016 
Version 6: See electronic date stamp below. 
 
05-May-2017 23:47:30
Title
Approver's Name
Company Signatory (Clinical)
Date and Time (UTC)


 
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PROTOCOL AMENDMENT, VERSION 6: 
RATIONALE 
Protocol WA29767 has been amended to address the following changes.  These 
changes to the protocol, along with a rationale for each change, are summarized below: 
• 
The scheduling of treatment discontinuation and follow-up visits has been clarified in 
Section 3.1.1 and Appendices 1−3. 
• 
Language has been added to Section 3.1.2 to indicate that patients receiving 
escape therapy may continue to do so during the open-label period at the discretion 
of the investigator. 
• 
The criterion regarding washout times has been removed from Section 4.3.4 to 
allow patients who discontinue study drug during the double-blind period (prior to 
Week 48) to participate in the open label period without having to first undergo 
washout of other systemic sclerosis treatments. 
• 
Language has been added to clarify that patients who discontinue study drug prior 
to Week 48 and are eligible to receive open-label study drug at Week 48 must 
complete all Week 48 assessments per the Appendix 1 schedule of assessments 
(Section 4.3.4 and Appendix 3). 
• 
Section 4.3.4 has been modified to indicate that patients who start other 
medications for systemic sclerosis between treatment discontinuation and Week 48 
may remain on these medications during the open-label period at the discretion of 
the investigator. 
• 
Language has been added to Section 4.3.4 to clarify that patients who discontinue 
study drug prior to Week 48 and do not participate in the open-label period should 
complete only the Appendix 3 reduced schedule of assessments (Section 4.3.4 and 
Appendix 3) 
• 
Language regarding options for escape therapy during the open-label period has 
been added to Section 4.4.1.1. 
• 
Language has been added to Section 4.5.2 to emphasize that the same assessor 
should conduct the modified Rodnan Skin Score evaluations for a given patient at all 
study visits. 
• 
Section 4.5.12 has been updated to include information regarding repetition of 
pulmonary function tests in the event of over-reader rejection. 
• 
Language has been added regarding tuberculosis testing (Sections 4.5.14 and 
4.5.15 and Appendices 1− 2). 
• 
Section 4.5.14 has been updated to clarify the testing requirements for C-Reactive 
Protein.  
• 
The protocol has been revised to indicate that pregnancies will no longer be 
reported using the Pregnancy Report eCRF, but will be reported on the paper 
Clinical Trial Pregnancy Reporting Form and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form (Section 5.4.3.1). 


 
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• 
The protocol has been modified to reflect updates to the protocol template in the 
following sections: 
– 
The protocol has been modified to prohibit use of the term "sudden death" on 
the Adverse Event electronic Case Report Form (eCRF), unless it is combined 
with the presumed cause of death (e.g., "sudden cardiac death"), as use of the 
term "sudden death" will require the Sponsor to query the site for clarification on 
the cause of death (Section 5.3.5.8). 
– 
Section 5.3.5.11 has been modified to clarify the reporting of adverse events 
leading to hospitalization. 
– 
Language has been added to clarify that the Sponsor will review all protocol 
deviations, and prospective requests to deviate from the protocol are 
not allowed (Section 9.2). 
– 
The Web site URL for the "Roche Global Policy on Sharing of Clinical Trials 
Data" has been corrected (Section 9.5). 
• 
The schedules of assessments for the double-blind period and the open-label period 
have been modified to make the assessments of vital signs, body weight, and IL-6 
consistent (Appendix 1 and Appendix 2). 
• 
ANA samples taken subsequent to the sample taken at baseline have been 
removed from the schedules of assessments as they are no longer deemed 
necessary (Appendix 1 and Appendix 2). 
• 
Text was added to Appendix 2 to indicate that follow-up visits are not required for 
patients who transition to locally-provided tocilizumab at Week 96.  
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
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PROTOCOL AMENDMENT, VERSION 6: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 3.1.1:  Overview of Study 
This Phase III, multicenter, randomized, double-blind, placebo-controlled, two-arm, 
parallel-group study is designed to assess the efficacy and safety of TCZ in patients with 
SSc.  The study consists of two periods:  a 48-week, double-blind, placebo-controlled 
period, followed by a 48-week open-label treatment period.…Approximately 
212210 patients with dcSSc will be enrolled at approximately 75120 global sites.  The 
study design is presented schematically in Figure 1. 
All patients who discontinue study drug prematurely at any time during the study will 
undergo a treatment discontinuation (TD) visit as soon as possible after the decision to 
discontinue study drug.  These patients will also undergo follow-up assessments within 
4 weeks of study drug discontinuation and at 8 weeks after study drug discontinuation. 
Patients who discontinue study drug during the double-blind period will be encouraged 
to remain in the study and undergo safety monitoring and key efficacy assessments at 
all remaining scheduled visits through Week 48.  The schedule of assessments for 
patients who discontinue study drug is outlined in Appendix 3.  These patients will be 
eligible to enter the open-label treatment period of the study at Week 48 and receive 
TCZ (as per Appendix 2), beginning at Week 48, if they meet specified eligibility criteria 
(described in Section 4.3.4).  All patients will undergo follow up assessments within 
4 weeks and at 8 weeks after study drug discontinuation.  For patients who discontinue 
study drug prematurely, a but continue study assessments per Appendix 3, TD visits 
and/or follow-up visits may be combined with the next scheduled visit (as outlined in 
Appendix 3), provided that the timing of the scheduled visit coincides with the specified 
timing for the follow up visit.  In this caseTD or follow-up visit.  If a TD visit is being 
combined with another visit, only the TD visit assessments need to be completed. If a 
follow-up visit is being combined with the next scheduled visit in Appendix 3, the 
efficacy assessments required at the scheduled visit, as well as safety assessments 
from the follow-up visit will be performed. 
Patients who discontinue study drug prematurely in both the double-blind period and 
the open-label period will undergo two sets of TD and follow up visits. 
SECTION 3.1.2:  Escape Therapy and Other Concomitant Treatments 
for SSc 
Escape therapy will be available from Week 24 for patients with worsening of skin 
thickening, and from Week 16 for patients with decline in FVC (confirmed on 
two separate occasions within a 4-week period; see Section 4.4.1.1 for details).  The 


 
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decision to initiate escape therapy will be based on predefined criteria, investigator 
judgment, and discussion with the Medical Monitor.  Patients will continue to receive 
study drug in addition to escape therapy.  Upon completion of the 48-week double-blind 
treatment period, patients receiving escape therapy in addition to study drug can enter 
the open-label treatment period to receive TCZ.  These patients may remain on escape 
therapy during the open-label period at the discretion of the investigator. 
SECTION 4.3.4:  Open-Label Treatment for Patients Who Discontinue Study 
Drug in the Double-Blind Treatment Period 
If a patient discontinues study drug prematurely during the double-blind treatment period 
of the study (prior to Week 48), they may be eligible to participate in the open-label 
treatment period of the study and receive TCZ (as per Appendix 2), beginning at Week 
48, if they meet the following criteria: 
• 
Adhered to the study visits shown in Appendix 3 
• 
Did not receive any prohibited medication as described in Section 4.1.2 
• 
Adhered to appropriate washout times for other treatments as described in Section 
4.1.2 
• 
Did not develop a concurrent condition that would preclude participation as 
described in Section 4.1.2 
• 
Did not develop a safety issue that would preclude receipt of TCZ as determined by 
the Principal Investigator and Medical Monitor 
• 
Did not discontinue the study drug during the double-blind treatment period due to 
non-compliance  
Patients who are eligible and wish to receive open-label study drug at Week 48 must 
complete all Week 48 assessments (as per Appendix 1). If these patients discontinue 
after TCZ treatment in the open-label period, they should undergo a second TD visit 
and complete the 4 and 8 week follow-up visits. 
Patients who start other medications for systemic sclerosis (e.g., DMARDs) between 
treatment discontinuation and Week 48 may remain on these medications during the 
open-label period at the discretion of the investigator.  
Patients who do not participate in the open-label period should complete only the 
reduced schedule of assessments (as per Appendix 3). These patients are not required to 
undergo a second TD visit or complete Week 4 or Week 8 follow-up visits. 
SECTION 4.4.1.1:  Escape Therapy for Worsening mRSS or FVC 
Patients who initiate escape therapy during the double-blind period may remain on 
escape therapy during the open-label period, at the discretion of the investigator.  
Patients may initiate escape therapy during the open-label period if they meet the 
escape therapy criteria.  


 
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SECTION 4.5.2:  Dual Assessor Approach 
To prevent potential unblinding because of observed efficacy and laboratory changes, 
a dual-assessor approach will be used to evaluate these data.  To ensure consistency of 
assessments and limit inter-observer variability, it is essential that the same assessor 
conduct the mRSS evaluations for a given patient at all study visits.  Details regarding 
the dual-assessor approach are provided in a separate manual. 
SECTION 4.5.12:  Pulmonary Function Tests 
The acceptability of the FVC and DLco data, including the graphic representations of the 
maneuvers, will be determined centrally by over-readers blinded to treatment 
assignment.  Calculations for the reproducibility of the acceptable maneuvers will be 
performed and reviewed centrally by the blinded over-readers. 
The over-readers will state whether a session has been accepted or rejected.  If rejected, 
the following sessions should be repeated within 4 weeks: 
• 
FVC session from Week 8 onwards  
• 
DLCO session at Week 48 and/or Week 96  
• 
Session at any TD visit 
 
SECTION 4.5.14:  Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
TB testing at screening (see Section 4.5.15) 
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
• 
Chemistry panel:  (serum or plasma) BUN or urea, uric acid, creatinine, random 
glucose, potassium, sodium, chloride, calcium, phosphorus, total protein, albumin, 
creatine phosphokinase, C3, C4 
 
The following samples will be sent to the Sponsor or a designee for analysis: 
• 
Serum samples for analysis of the following PD biomarkers:  IL-6, sIL-6R, CRP 
Central CRP will be blinded to the site and Sponsor for all post-baseline visits 
until after the primary analysis.  Local CRP testing should only be performed 
if deemed clinically necessary by the investigator.  Local CRP results should 
not be shared with the Sponsor or entered into the eCRF until after the 
primary analysis. 
 
SECTION 4.5.15:  Tuberculosis Screening 
All patients will be evaluated for TB at screening. Testing must be repeated at Week 36, 
and the result confirmed, prior to initiation of open-label TCZ at Week 48 (except for 
patients who discontinued study drug prematurely who had a TB test performed at the 


 
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TD visit).  The test method (e.g. PPD or QuantiFERON test) is at the discretion of 
the investigator. 
Patients who test positive for TB at screening should be evaluated for evidence of active 
TB per local standard practice.  A patient with a positive TB test may be eligible for 
study inclusion only if diagnosed with latent TB and treated per local standard practice. 
Patients who test positive for TB at screening and were treated for latent TB must 
undergo repeat TB testing at the Week 36 visit.  However, since no applicable clinical 
practice guidelines currently exist regarding how to further evaluate patients who have 
had a positive TB test, a clinical evaluation at Week 36 and prompt local review of the 
Week 48 HRCT to evaluate for any evidence of active TB is required.  Investigators will 
be asked to confirm this assessment.   
Patients who test negative for TB at screening must undergo repeat TB testing at the 
Week 36 visit.  If the Week 36 visit TB test is positive, dosing of study drug must be 
interrupted and patients evaluated for evidence of active TB per local standard practice.  
If a patient is diagnosed with latent TB and has started TB treatment, the patient may 
recommence dosing with study drug. 
SECTION 5.3.5.8:  Deaths 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an abrupt 
and unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
replaced by the established cause of death.    The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
SECTION 5.3.5.11:  Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
• 
The following hospitalization scenarios are not considered to be adverse eventsAn 
event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 


 
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 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead:An event that leads to hospitalization 
under the following circumstances is not considered to be a serious adverse event, but 
should be reported as an adverse event instead. 
SECTION 5.4.3.1:  Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 8 weeks after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
A paper Clinical Trial Pregnancy Reporting Form should be completed and submitted 
to the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy) either by faxing or by scanning and emailing the form with use of the 
fax number or email address provided to investigators.and submitted via the EDC 
system.  A pregnancy report will automatically be generated and sent to Roche Safety 
Risk Management.  Pregnancy should not be recorded on the Adverse Event eCRF.  
The investigator should discontinue study drug and counsel the patient, discussing the 
risks of the pregnancy and the possible effects on the fetus.  Monitoring of the patient 
should continue until conclusion of the pregnancy.  Any serious adverse events 
associated with the pregnancy (e.g., an event in the fetus, an event in the mother during 
or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system. 
SECTION 9.2:  PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 


 
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reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
SECTION 9.5:  PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
APPENDIX 1:  Schedule of Assessments:  Screening, Baseline, and Double-
Blind Treatment Period 
The schedule of assessments for the screening, baseline, and double-blind treatment 
period has been revised to reflect the changes to the protocol. 
APPENDIX 2:  Schedule of Assessments:  Open-Label Treatment Period 
The schedule of assessments for the open-label treatment period has been revised to 
reflect the changes to the protocol. 
APPENDIX 3:  Schedule of Assessments:  Patients Who Have Discontinued 
Study Drug Prematurely 
The schedule of assessments for patients who have discontinued study drug 
prematurely has been revised to reflect the changes to the protocol. 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 18 
PROTOCOL SYNOPSIS .................................................................................... 19 
1. 
BACKGROUND .......................................................................................... 30 
1.1 
Background on Systemic Sclerosis ....................................... 30 
1.1.1 
Epidemiology ......................................................................... 30 
1.1.2 
Clinical Manifestations ........................................................... 30 
1.1.3 
Mortality ................................................................................. 31 
1.1.4 
Treatment for Systemic Sclerosis .......................................... 32 
1.2 
Interleukin-6 as Drug Target .................................................. 32 
1.3 
Background on Tocilizumab .................................................. 33 
1.3.1 
Clinical Safety and Immunogenicity of 
Tocilizumab in Patients with Rheumatoid Arthritis ................. 34 
1.3.1.1 
Intravenous Administration .................................................... 34 
1.3.1.2 
Subcutaneous versus Intravenous Administration ................. 34 
1.3.2 
Clinical Studies in Patients with Systemic 
Sclerosis ................................................................................ 35 
1.3.2.1 
Clinical Safety and Immunogenicity of 
Tocilizumab in Patients with Systemic Sclerosis ................... 35 
1.3.2.2 
Clinical Efficacy of Tocilizumab in Patients with 
Systemic Sclerosis ................................................................ 36 
1.4 
Study Rationale and Benefit−Risk Assessment ..................... 37 
2. 
OBJECTIVES .............................................................................................. 37 
2.1 
Efficacy Objectives ................................................................ 37 
2.2 
Safety Objectives ................................................................... 38 
2.3 
Immunogenicity Objectives .................................................... 38 
2.4 
Pharmacodynamic Objective ................................................. 38 
2.5 
Pharmacokinetic Objectives .................................................. 38 
2.6 
Exploratory Objectives ........................................................... 38 
3. 
STUDY DESIGN ......................................................................................... 39 
3.1 
Description of Study .............................................................. 39 
3.1.1 
Overview of Study ................................................................. 39 


 
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3.1.2 
Escape Therapy and Other Concomitant 
Treatments for SSc ................................................................ 40 
3.1.3 
Independent Data Monitoring Committee .............................. 41 
3.1.4 
Clinical Adjudication Committee ............................................ 41 
3.2 
End of Study and Length of Study ......................................... 42 
3.3 
Rationale for Study Design .................................................... 43 
3.3.1 
Rationale for Tocilizumab Dose and Schedule ...................... 43 
3.3.2 
Rationale for Patient Population ............................................ 44 
3.3.3 
Rationale for Control Group ................................................... 44 
3.3.4 
Rationale for Efficacy Endpoints ............................................ 44 
3.3.5 
Rationale for Biomarker Assessments ................................... 45 
3.4 
Outcome Measures ............................................................... 46 
3.4.1 
Efficacy Outcome Measures .................................................. 46 
3.4.2 
Safety Outcome Measures .................................................... 46 
3.4.3 
Immunogenicity Outcome Measures ..................................... 47 
3.4.4 
Pharmacodynamic Outcome Measure................................... 47 
3.4.5 
Pharmacokinetic Outcome Measures .................................... 47 
3.4.6 
Exploratory Outcome Measures ............................................ 47 
4. 
MATERIALS AND METHODS .................................................................... 48 
4.1 
Patients .................................................................................. 48 
4.1.1 
Inclusion Criteria .................................................................... 48 
4.1.2 
Exclusion Criteria ................................................................... 49 
4.2 
Method of Treatment Assignment and Blinding ..................... 52 
4.3 
Study Treatment .................................................................... 53 
4.3.1 
Formulation, Packaging, and Handling .................................. 53 
4.3.2 
Dosage, Administration, and Compliance .............................. 53 
4.3.3 
Investigational Medicinal Product Accountability ................... 54 
4.3.4 
Open-Label Treatment for Patients Who 
Discontinue Study Drug in the Double-Blind 
Treatment Period ................................................................... 55 
4.3.5 
Post-Trial Access to Tocilizumab ........................................... 55 
4.4 
Concomitant Therapy ............................................................ 56 
4.4.1 
Treatments for Systemic Sclerosis ........................................ 56 
4.4.1.1 
Escape Therapy for Worsening mRSS or FVC ...................... 57 


 
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4.4.1.2 
Treatments for Other Systemic Sclerosis 
Complications ........................................................................ 58 
4.4.1.3 
Medications Commonly Used in Systemic 
Sclerosis ................................................................................ 58 
4.4.2 
Drug-Drug Interactions .......................................................... 59 
4.5 
Study Assessments ............................................................... 59 
4.5.1 
Home Nursing Services ......................................................... 60 
4.5.2 
Dual Assessor Approach ....................................................... 60 
4.5.3 
Informed Consent Forms ....................................................... 60 
4.5.4 
Screening .............................................................................. 60 
4.5.4.1 
Re-Testing for Laboratory Eligibility Criteria .......................... 60 
4.5.4.2 
Re-Screening ......................................................................... 61 
4.5.5 
Medical History and Demographic Data ................................ 61 
4.5.6 
Physical Examinations ........................................................... 61 
4.5.7 
Vital Signs .............................................................................. 61 
4.5.8 
Digital Ulcer Count ................................................................. 62 
4.5.9 
Modified Rodnan Skin Score ................................................. 62 
4.5.10 
Physician's Global Assessment ............................................. 62 
4.5.11 
Combined Response Index for Systemic 
Sclerosis ................................................................................ 62 
4.5.12 
Pulmonary Function Tests ..................................................... 62 
4.5.13 
High-Resolution Computed Tomography Scans .................... 63 
4.5.14 
Laboratory, Biomarker, and Other Biological 
Samples ................................................................................. 64 
4.5.15 
Tuberculosis Screening ......................................................... 65 
4.5.16 
Electrocardiograms ................................................................ 66 
4.5.17 
Patient-Reported Outcomes .................................................. 66 
4.5.17.1 
Health Assessment Questionnaire Disability 
Index ...................................................................................... 66 
4.5.17.2 
Scleroderma Health Assessment Questionnaire ................... 67 
4.5.17.3 
Patient's Global Assessment ................................................. 67 
4.5.17.4 
Saint George’s Respiratory Questionnaire ............................ 67 
4.5.17.5 
FACIT-Fatigue ....................................................................... 67 
4.5.17.6 
SkinPRO Questionnaire......................................................... 67 


 
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4.5.17.7 
EuroQol 5-Dimension Questionnaire ..................................... 67 
4.5.17.8 
Work Productivity and Activity 
Impairment-General Health ................................................... 68 
4.5.18 
Samples for Roche Clinical Repository.................................. 68 
4.5.18.1 
Overview of the Roche Clinical Repository ............................ 68 
4.5.18.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 68 
4.5.18.3 
Sample Collection .................................................................. 69 
4.5.18.4 
Confidentiality ........................................................................ 69 
4.5.18.5 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 70 
4.5.18.6 
Withdrawal from the Roche Clinical Repository ..................... 71 
4.5.18.7 
Monitoring and Oversight ....................................................... 71 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 71 
4.6.1 
Patient Discontinuation .......................................................... 71 
4.6.2 
Study Drug Discontinuation ................................................... 72 
4.6.3 
Study and Site Discontinuation .............................................. 72 
5. 
ASSESSMENT OF SAFETY ....................................................................... 73 
5.1 
Safety Plan ............................................................................ 73 
5.1.1 
Opportunistic Infections and Serious Infections ..................... 73 
5.1.2 
Gastrointestinal Perforations ................................................. 74 
5.1.3 
Demyelinating Disorders ........................................................ 74 
5.1.4 
Hematologic Abnormalities .................................................... 74 
5.1.5 
Elevated Liver Enzymes ........................................................ 75 
5.1.6 
Elevated Lipids ...................................................................... 76 
5.1.7 
Malignancies .......................................................................... 77 
5.1.8 
Local Injection-Site Reactions ............................................... 77 
5.1.9 
Hypersensitivity and Anaphylaxis after TCZ 
Injection ................................................................................. 77 
5.2 
Safety Parameters and Definitions ........................................ 78 
5.2.1 
Adverse Events ..................................................................... 78 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 79 


 
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5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 79 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 80 
5.3.1 
Adverse Event Reporting Period ........................................... 80 
5.3.2 
Eliciting Adverse Event Information ....................................... 81 
5.3.3 
Assessment of Severity of Adverse Events ........................... 81 
5.3.4 
Assessment of Causality of Adverse Events ......................... 81 
5.3.5 
Procedures for Recording Adverse Events ............................ 82 
5.3.5.1 
Injection Reactions ................................................................ 82 
5.3.5.2 
Diagnosis versus Signs and Symptoms................................. 83 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 83 
5.3.5.4 
Persistent or Recurrent Adverse Events ................................ 83 
5.3.5.5 
Abnormal Laboratory Values ................................................. 84 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 84 
5.3.5.7 
Abnormal Liver Function Tests .............................................. 85 
5.3.5.8 
Deaths ................................................................................... 85 
5.3.5.9 
Preexisting Medical Conditions .............................................. 86 
5.3.5.10 
Lack of Efficacy or Worsening of Systemic 
Sclerosis ................................................................................ 86 
5.3.5.11 
Hospitalization or Prolonged Hospitalization .......................... 86 
5.3.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 87 
5.3.5.13 
Patient-Reported Outcome Data ........................................... 87 
5.3.5.14 
Adverse Events in Individuals Not Enrolled in the 
Study ..................................................................................... 87 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 88 
5.4.1 
Emergency Medical Contacts ................................................ 88 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ..................... 89 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 89 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 89 
5.4.3 
Reporting Requirements for Pregnancies .............................. 89 


 
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5.4.3.1 
Pregnancies in Female Patients ............................................ 89 
5.4.3.2 
Abortions ............................................................................... 90 
5.4.3.3 
Congenital Anomalies/Birth Defects ...................................... 90 
5.5 
Follow-Up of Patients after Adverse Events .......................... 90 
5.5.1 
Investigator Follow-Up ........................................................... 90 
5.5.2 
Sponsor Follow-Up ................................................................ 90 
5.6 
Post-Study Adverse Events ................................................... 90 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 91 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 91 
6.1 
Determination of Sample Size ............................................... 91 
6.2 
Summaries of Conduct of Study ............................................ 92 
6.3 
Summaries of Treatment Group Comparability ..................... 92 
6.4 
Efficacy Analyses .................................................................. 93 
6.4.1 
Primary Efficacy Endpoint ...................................................... 93 
6.4.2 
Secondary Efficacy Endpoints ............................................... 94 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 95 
6.5 
Safety Analyses ..................................................................... 95 
6.6 
Immunogenicity Analyses ...................................................... 96 
6.7 
Pharmacodynamic Analyses ................................................. 96 
6.8 
Pharmacokinetic Analyses ..................................................... 96 
6.9 
Interim Analysis ..................................................................... 96 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 97 
7.1 
Data Quality Assurance ......................................................... 97 
7.2 
Electronic Case Report Forms ............................................... 97 
7.3 
Electronic Patient-Reported Outcome Data ........................... 98 
7.4 
Source Data Documentation .................................................. 98 
7.5 
Use of Computerized Systems .............................................. 99 
7.6 
Retention of Records ............................................................. 99 
8. 
ETHICAL CONSIDERATIONS .................................................................... 99 
8.1 
Compliance with Laws and Regulations ................................ 99 
8.2 
Informed Consent .................................................................. 99 


 
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8.3 
Institutional Review Board or Ethics Committee .................. 101 
8.4 
Confidentiality ...................................................................... 101 
8.5 
Financial Disclosure ............................................................ 101 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 102 
9.1 
Study Documentation .......................................................... 102 
9.2 
Protocol Deviations .............................................................. 102 
9.3 
Site Inspections ................................................................... 102 
9.4 
Administrative Structure....................................................... 102 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 102 
9.6 
Protocol Amendments ......................................................... 103 
10. REFERENCES ......................................................................................... 104 


 
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LIST OF TABLES 
Table 1 
Risk Mitigation for Neutropenia ................................................... 75 
Table 2 
Risk Mitigation for Thrombocytopenia ......................................... 75 
Table 3 
Hepatic Enzyme Elevation Risk Mitigation .................................. 76 
Table 4 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 81 
Table 5 
Causal Attribution Guidance ....................................................... 82 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 42 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments:  Screening, 
Baseline, and Double-Blind Treatment 
Period ....................................................................... 109 
Appendix 2 
Schedule of Assessments:  Open-Label 
Treatment Period ..................................................... 115 
Appendix 3 
Schedule of Assessments:  Patients 
Who Have Discontinued Study Drug 
Prematurely .............................................................. 119 
Appendix 4 
Work Productivity and Activity 
ImpairmentGeneral Health 
Questionnaire (Version 2.0) ..................................... 121 
Appendix 5 
Clinician’s Global Assessment ................................. 123 
Appendix 6 
Health Assessment Questionnaire–
Disability Index 
and Scleroderma-Specific Visual 
Analog Score Scales for Scleroderma 
Health Assessment Questionnaire ........................... 124 
Appendix 7 
Patient’s Global Assessment ................................... 129 
Appendix 8 
Functional Assessment of Chronic 
Therapy–Fatigue ...................................................... 130 
Appendix 9 
EQ-5D™ .................................................................. 131 
Appendix 10 
Saint George’s Respiratory 
Questionnaire ........................................................... 134 
Appendix 11 
Scleroderma Skin Patient-Reported 
Outcome Questionnaire ........................................... 141 


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP STUDY TO ASSESS THE 
EFFICACY AND SAFETY OF TOCILIZUMAB 
VERSUS PLACEBO IN PATIENTS WITH SYSTEMIC 
SCLEROSIS 
PROTOCOL NUMBER: WA29767 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2015-000424-28 
IND NUMBER: 
112406 
TEST PRODUCT: 
Tocilizumab (RO4877533) 
MEDICAL MONITOR: 
 
SPONSOR: 
F.  Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by the Sponsor representative. 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF TOCILIZUMAB 
VERSUS PLACEBO IN PATIENTS WITH SYSTEMIC SCLEROSIS 
PROTOCOL NUMBER: 
WA29767 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2015-000424-28 
IND NUMBER: 
112406 
TEST PRODUCT: 
Tocilizumab (RO4877533) 
PHASE: 
III 
INDICATION: 
Systemic sclerosis 
SPONSOR: 
F.  Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To evaluate the efficacy of tocilizumab (TCZ) compared with placebo on skin sclerosis, as 
measured by modified Rodnan Skin Score (mRSS) at Week 48 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate the efficacy of TCZ compared with placebo on pulmonary function, as 
measured by forced vital capacity (FVC) at Week 48 
• 
To evaluate the efficacy of TCZ compared with placebo on patient-reported outcomes 
(PROs), as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI) 
and Patient's Global Assessment at Week 48 
• 
To evaluate the efficacy of TCZ compared with placebo as measured by the Physician's 
Global Assessment at Week 48 
• 
To evaluate the efficacy of TCZ compared with placebo by assessment of time to treatment 
failure (death, worsening of mRSS and/or FVC, or clinically significant systemic sclerosis 
[SSc] complication) up to Week 48 
Safety Objectives 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of TCZ compared with placebo, focusing on the nature, frequency, 
and severity of serious and non-serious adverse events, the frequency of SSc-related 
complications, and effects on vital signs, physical findings, and clinical laboratory results 
• 
To evaluate the safety of TCZ compared with placebo by assessing the number of digital 
ulcers 
• 
To assess the long-term safety of TCZ 


 
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Immunogenicity Objectives 
The immunogenicity objectives for this study are as follows: 
• 
To characterize the immunogenic potential of TCZ by measuring anti-TCZ antibodies 
• 
To assess the potential relationship between development of anti-TCZ antibodies and 
efficacy, safety, or pharmacokinetic (PK) outcome measures 
Pharmacodynamic Objectives 
The pharmacodynamic (PD) objectives for this study are as follows: 
• 
To compare changes in levels of PD biomarkers following treatment with TCZ versus 
placebo 
Pharmacokinetic Objectives 
The PK objectives for this study are as follows: 
• 
To characterize the pharmacokinetics of TCZ 
• 
To evaluate potential relationships between PK parameters for TCZ and efficacy, safety, or 
immunogenicity outcome measures 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate the efficacy of TCZ compared with placebo on skin sclerosis, as measured by 
mRSS at Week 24 
• 
To evaluate the efficacy of TCZ versus placebo measured by the proportion of responders 
as defined by the Combined Response Index for Systemic Sclerosis (CRISS) at Week 48 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by the visual analog 
scale (VAS) component of the Scleroderma Health Assessment Questionnaire (SHAQ) at 
Weeks 24 and 48 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by the Work 
Productivity and Activity ImpairmentGeneral Health (WPAI-GH) questionnaire at Weeks 
24 and 48 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by the EuroQol 
5-Dimension Questionnaire with three levels of severity (EQ-5D-3L) at Weeks 24 and 48 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by the Saint 
George’s Respiratory Questionnaire (SGRQ) at Week 48 
• 
To evaluate the effect of TCZ compared with placebo on fatigue as measured by Functional 
Assessment of Chronic Illness Therapy (FACIT)–Fatigue score at Week 48. 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by the Scleroderma 
Skin Patient-Reported Outcome (SkinPRO) questionnaire at Week 48 (for North America 
only) 
• 
To evaluate the efficacy of TCZ compared with placebo on the basis of change in 
pulmonary fibrosis, as determined using high-resolution computed tomography (HRCT) 
scans at Week 48 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by diffusion capacity 
of the lung for carbon monoxide (DLCO) at Week 48, and FVC at Week 24 
• 
To evaluate the maintenance of efficacy of TCZ, as measured by mRSS and FVC at 
Week 96 
• 
To assess whether non-inherited biomarkers are predictive of response to TCZ 
(i.e., predictive biomarkers), susceptibility to developing adverse events, or progression to a 
more severe disease state (i.e., prognostic biomarkers), can provide evidence of TCZ 
activity, or can increase the knowledge and understanding of disease biology 
Study Design 
Description of Study 
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, two-arm, 
parallel-group study designed to assess the efficacy and safety of TCZ in patients with SSc. 


 
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Number of Patients 
Approximately 212 patients with diffuse cutaneous systemic sclerosis (dcSSc) will be enrolled at 
approximately 75 global sites. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years at baseline (Day 1) 
• 
Able to comply with the study protocol, in the investigator’s judgment 
• 
Diagnosis of SSc, as defined using the American College of Rheumatology 
[ACR]/European League Against Rheumatism [EULAR] criteria  
• 
SSc disease duration of ≤ 60 months (defined as time from the first non−Raynaud 
phenomenon manifestation)  
• 
mRSS of ≥ 10 and ≤ 35 units at screening 
• 
Active disease that meets at least one of the following criteria at screening: 
− Disease duration of ≤ 18 months defined as time from the first non−Raynaud 
phenomenon manifestation 
− Increase in mRSS of ≥ 3 units compared with the most recent assessment performed 
within the previous 6 months 
− Involvement of one new body area and an increase in mRSS of ≥ 2 units compared 
with the most recent assessment performed within the previous 6 months 
− Involvement of two new body areas within the previous 6 months  
− Presence of at least one tendon friction rub 
• 
Presence of at least one of the following at screening: 
− C-reactive protein (CRP) ≥ 0.6 mg/dL (≥ 6 mg/L) 
− Erythrocyte sedimentation rate (ESR) ≥ 28 mm/hr 
− Platelet count ≥ 330 × 109/L (330,000/µL) 
• 
Uninvolved or mildly thickened skin at one of the following possible injection-site locations: 
− Front, middle region of the thigh 
− Abdomen, except for the 2-inch area directly around the navel 
− Outer area of the upper arm (if a patient caregiver is giving the injection) 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use single or combined contraceptive methods that result in a failure rate of < 1% per year 
during the treatment period and for up to 3 months after the last dose of study drug 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Examples of contraceptive methods with a failure rate of < 1% per year include tubal 
ligation, male sterilization, hormonal implants, established, proper use of combined oral 
or injected hormonal contraceptives, and certain intrauterine devices.   
Alternatively, it is acceptable to combine the use of two methods (e.g., two barrier 
methods such as a condom and a cervical cap).  Barrier methods must always be 
supplemented with the use of a spermicide. 


 
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• 
For men:  agreement to remain abstinent or use contraceptive measures and agreement to 
refrain from donating sperm, as defined below: 
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 8 weeks 
after the last dose of study drug. 
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Men must refrain from donating sperm during the treatment period and for at least 
8 weeks after the last dose of study drug. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating, or intending to become pregnant during the study 
• 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test at screening and a negative 
urine pregnancy test at baseline. 
• 
Major surgery (including joint surgery) within 8 weeks prior to screening or planned major 
surgery within 12 months following randomization 
• 
Skin thickening (scleroderma) limited to the face or areas distal to the elbows or knees at 
screening 
• 
Rheumatic autoimmune disease other than SSc, including but not limited to rheumatoid 
arthritis (RA) (diagnosed using ACR/EULAR criteria), systemic lupus erythematosus, mixed 
connective tissue disorder, polymyositis, dermatomyositis, eosinophilic fasciitis, primary 
Sjögren's syndrome, and eosinophilic myalgia syndrome, as determined by the investigator 
• 
Treatment with non-investigational or investigational cell-depleting therapies, including but 
not limited to alemtuzumab, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20 within 
18 months of baseline; or if treatment prior to 18 months from baseline, evidence of 
peripheral depletion of targeted lymphocyte subset at screening 
• 
Previous treatment with chlorambucil, bone marrow transplantation, or total lymphoid 
irradiation 
• 
Previous treatment with anti-IL6 therapy (including and not limited to TCZ)  
• 
Previous treatment with thalidomide, antithymocyte globulin, plasmapheresis, 
or extracorporeal photopheresis  
• 
Treatment with anakinra within 1 week prior to baseline 
• 
Treatment with etanercept within 2 weeks prior to baseline 
• 
Treatment with oral, intramuscular, or intravenous corticosteroids (> 10 mg/day of 
prednisone or equivalent) within 2 weeks prior to baseline 
• 
Treatment with methotrexate, hydroxychloroquine, cyclosporine A, azathioprine, 
mycophenolate mofetil, rapamycin, colchicine, or D-penicillamine, within 4 weeks prior to 
baseline 
• 
Immunization with a live or live attenuated vaccine within 4 weeks prior to baseline 
• 
Treatment with any investigational agent within 5 elimination half-lives of the investigational 
drug prior to baseline 
• 
Chronic treatment with any of the following within 5 elimination half-lives of the drug prior to 
baseline: 
− Pirfenidone 
− Nintedanib 
− Endothelin-receptor antagonists, terguride 
− Tyrosine-kinase inhibitors (e.g., imatinib, nilotinib, dasatinib)  
− Janus-kinase inhibitors 


 
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• 
Treatment with IV prostacyclin within 1 week prior to baseline 
• 
Treatment with ultraviolet phototherapy within 6 weeks prior to baseline 
• 
Treatment with infliximab, certolizumab, golimumab, abatacept, or adalimumab within 
8 weeks prior to baseline 
• 
Treatment with cyclophosphamide within 6 months prior to baseline 
• 
History of severe allergic or anaphylactic reactions to human, humanized, or murine 
monoclonal antibodies 
• 
Evidence of moderately severe concurrent nervous system, renal, endocrine, or 
gastrointestinal (GI) disease not related to SSc, as determined by the investigator 
• 
Pulmonary disease with FVC ≤ 55% of predicted (best of three acceptable and repeatable 
measurements as described in the site’s Pulmonary Function Testing Manual)   
OR 
DLCO ≤ 45% of predicted (corrected for hemoglobin, and the average of the 2 highest 
acceptable and repeatable measurements as described in the Pulmonary Function Testing 
Manual) 
• 
Class II or higher pulmonary arterial hypertension (PAH), as defined by the World Health 
Organization 
• 
Evidence of other moderately severe pulmonary disease (e.g., asthma, emphysema), as 
determined by the investigator 
• 
Cardiovascular disease with significant arrhythmia, congestive heart failure 
(New York Heart Association Class II−IV), unstable angina, uncontrolled hypertension, 
cor pulmonale, or symptomatic pericardial effusion 
• 
History of myocardial infarction in the last 6 months prior to screening 
• 
Current liver disease, as determined by the investigator 
• 
History of diverticulitis or chronic ulcerative lower GI disease, such as Crohn disease, 
ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient 
to perforations 
• 
Known active current or significant history of recurrent bacterial, viral, fungal, mycobacterial, 
or other infections, including but not limited to atypical mycobacterial disease, hepatitis B or 
C, herpes zoster, infected digital ulcers, and osteomyelitis 
• 
Any major episode of infection requiring hospitalization or treatment with IV antibiotics 
within 4 weeks prior to screening or oral antibiotics within 2 weeks prior to screening 
• 
Significant history of recurrent tuberculosis (TB), active TB requiring treatment within the 
previous 3 years, or untreated latent TB 
Patients should be screened for latent TB, and, if positive, will be eligible for the study 
after treatment per local standard practices. 
• 
History of or currently active primary or secondary immunodeficiency 
• 
Evidence of malignant disease, or malignancies diagnosed within the previous 5 years (with 
the exception of local basal or squamous cell carcinoma of the skin or carcinoma in situ of 
the cervix uteri that has been excised and cured) 
• 
History of alcohol, drug, or chemical abuse within 1 year prior to screening 
• 
Neuropathies or other conditions that might interfere with pain evaluation, as determined by 
the investigator 


 
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• 
At screening:  
Body weight > 150 kg 
Glomerular filtration rate < 45 mL/min 
Alanine transaminase (ALT) or Aspartate aminotransferase (AST) > 1.5 × the upper limit 
of normal (ULN) 
Total bilirubin > ULN 
Platelet count < 100 × 109/L (100,000/µL) 
Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L) 
White blood cell (WBC) count < 3.0 × 109/L (3000/µL) 
Absolute neutrophil count (ANC) < 2.0 × 109/L (2000/µL) 
Absolute lymphocyte count < 0.5 × 109/L (500/µL) 
Positive hepatitis B surface antigen or hepatitis C antibody 
Length of Study 
The length of the study, from screening of the first subject to the end of the study, is expected to 
be approximately 4 years. 
End of Study 
The end of the study will occur when the last participating patient completes the last scheduled 
visit of the follow-up period.  This is expected to occur 2 years after the last patient is enrolled. 
Outcome Measures 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is as follows: 
• 
Change in mRSS from baseline to Week 48 
The secondary efficacy outcome measures for this study are as follows: 
• 
Proportions of patients with ≥ 20%, ≥ 40%, and ≥ 60% improvement in mRSS at Week 48 
compared with baseline 
• 
Change in FVC from baseline to Week 48 
• 
Change in HAQ-DI from baseline to Week 48 
• 
Change in Patient's Global Assessment from baseline to Week 48 
• 
Change in Physician's Global Assessment from baseline to Week 48 
• 
Time to treatment failure, defined as the time from randomization to the time of one of the 
following events (whichever occurs first) during the 48-week double-blind treatment period: 
death,  
decline in percent-predicted FVC > 10% relative to baseline, 
> 20% increase in mRSS and an increase in mRSS of ≥ 5 points 
occurrence of a predefined SSc-related complication as adjudicated by the Clinical 
Adjudication Committee 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Frequency of deaths 
• 
Nature, frequency, and severity of adverse events 
• 
Incidence of specific laboratory abnormalities  
• 
Change from baseline in digital ulcer count 


 
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Immunogenicity Outcome Measures 
The immunogenicity outcome measures for this study are as follows: 
• 
Incidence of anti-TCZ antibodies during the study relative to the prevalence of anti-TCZ 
antibodies at baseline 
• 
Correlation between anti-TCZ−antibody status and efficacy, safety, or PK outcome 
measures 
Pharmacodynamic Outcome Measures 
The PD outcome measure for this study is as follows: 
• 
Predose ESR and serum IL-6, soluble IL-6 receptor (sIL-6R), and CRP levels at baseline 
and at subsequent timepoints after initiation of study drug 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Predose serum TCZ concentration at baseline and at specified timepoints thereafter 
• 
Correlation between PK parameters for TCZ and efficacy, safety, or immunogenicity 
outcome measures 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Proportions of patients who achieve a response, as determined by the investigator using 
CRISS, at Week 48 
• 
Change in the VAS component of the SHAQ from baseline to Week 24 and baseline to 
Week 48 
• 
Change in WPAI-GH score from baseline to Week 24 and baseline to Week 48 
• 
Change in EQ-5D-3L score from baseline to Week 24 and baseline to Week 48 
• 
Change in total score and subscores of the SGRQ from baseline to Week 48.   
• 
Change in total and domain scores of the SkinPRO questionnaire from baseline to Week 48 
(for North America only) 
• 
Change in FACIT-Fatigue score from baseline to Week 48. 
• 
Change in HRCT fibrosis score from baseline (based on HRCT scan performed within 
3 months prior to screening) to Week 48 
• 
Change in DLCO from baseline to Week 48 
• 
Proportion of patients with ≥ 15% decline in observed DLCO at Week 48 
• 
Proportion of patients with ≥ 15% decline in percentage of predicted DLCO at Week 48 
• 
Change in FVC from baseline to Week 24 
• 
Proportion of patients with ≥ 10% decline in observed FVC at Week 24 and at Week 48 
• 
Proportion of patients with ≥ 10% decline in percentage of predicted FVC at Week 24 and at 
Week 48 
• 
Change in mRSS from baseline to Week 24 and Week 96 
• 
Change in observed and percentage of predicted FVC from baseline to Week 96 
• 
Correlation between non-inherited biomarkers (serum levels of CCL18, sVCAM-1, COMP, 
and autotaxin; plasma levels of CXCL4; and whole blood gene signatures associated with 
plasmablasts and IFN) and efficacy, safety, PK, or immunogenicity outcome measures 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
Patients assigned to the TCZ group will receive a single subcutaneous (SC) injection of 
162 mg of TCZ once weekly (QW) for 48 weeks during the double-blind treatment period.  All 
patients will receive SC injections of 162 mg of TCZ QW for 48 weeks during the open-label 
treatment period. 


 
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Comparator 
Patients assigned to the placebo group will receive SC injections of placebo QW for 48 weeks 
during the double-blind treatment period.   
Non-Investigational Medicinal Products 
From Week 24, escape therapy will be permitted for patients with worsening of skin thickening, 
and from Week 16, escape therapy will be permitted for patients with decline in FVC compared 
with baseline.  Patients may receive other concomitant treatments for SSc, including treatments 
for new and existing organ complications. 
Statistical Methods 
Primary Analysis 
The estimand of interest for the primary analysis is the difference between treatment arms in the 
mean change in the mRSS at Week 48 for the intent to treat (ITT) population.  The study has 
been designed to continue to capture efficacy data on patients who discontinue study drug 
prematurely or receive escape therapies during the double-blind treatment period.  These data 
will be included in the primary analysis.   
Determination of Sample Size   
A sample size of approximately 105 patients in the TCZ group and 105 patients in the placebo 
group (a total of 210 patients) will give power in the range of > 75% to 80%, (allowing for an 
estimated patient dropout rate of approximately 15% to 20%) to detect a between-group 
difference of 3.55 units (common standard deviation of 8.43) in mean change in mRSS from 
baseline to Week 48 using a two-group t-test, with a 5% two-sided significance level.  The 
minimal detectable difference in mRSS (smallest treatment difference that would give a 
statistically significant result) under these assumptions, and with a patient dropout rate of 20%, 
is approximately 2.6 units. 
Interim Analyses 
The Sponsor will define a futility analysis to which the Sponsor will remain blinded.  The futility 
analysis will be conducted by an external statistical group and reviewed by the iDMC.  The 
futility analysis will be based on the treatment difference for change from baseline in mRSS at 
Week 24; the stopping boundary will be determined by a beta spending function.  The study will 
be stopped for futility if the endpoint meets the futility criterion. 
The futility analysis will be conducted when approximately 76 patients have either reached the 
Week 24 visit or have withdrawn.  Since a repeated measures analysis will be used for the 
futility criterion, partial data from additional patients enrolled at (but not yet completed) Week 24 
will also be utilized in the analysis.  Thus, although only approximately one-third of the patients 
will have reached Week 24, the timing of the futility analysis approximates half of the final 
expected information (I) at Week 24, where I is the inverse of the expected variance of the 
treatment difference when all patients have reached Week 24. 
Full statistical details of the futility analysis, along with the rationale, and timing will be 
documented in the iDMC charter.  The iDMC charter will be made available to the relevant 
health authorities. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
CRP 
C-reactive protein 
CRISS 
Combined Response Index for Systemic Sclerosis 
CYP450 
cytochrome P450 
dcSSc 
diffuse cutaneous systemic sclerosis 
DLCO 
diffusion capacity of the lung for carbon monoxide 
DMARD 
disease-modifying anti-rheumatic drug 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ePRO 
electronic patient-reported outcome 
EQ-5D-3L 
EuroQol 5-Dimension Questionnaire with three levels of 
severity 
ERS 
European Respiratory Society 
ESR 
erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
EUSTAR 
Scleroderma Trials and Research 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FDA 
U.S. Food and Drug Administration 
FVC 
forced vital capacity 
GI 
gastrointestinal 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
HIPAA 
Health Insurance Portability and Accountability Act 
HN 
home nursing 
HRCT 
high-resolution computed tomography 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 
IL-6 
interleukin 6 
IL-6R 
interleukin 6 receptor 
ILD 
interstitial lung disease 
IM 
intramuscular 
IMP 
investigational medicinal product 


 
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Abbreviation 
Definition 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
IxRS 
interactive voice- or web-based response system 
lcSSc 
limited cutaneous systemic sclerosis 
LDL 
low-density lipoprotein 
∆LSM 
least-squares mean 
MCH 
mean corpuscular hemoglobin 
MCP 
metacarpal phalangeal 
mIL-6R 
membrane-bound interleukin 6 receptor 
mRSS 
modified Rodnan Skin Score 
NCEP 
National Cholesterol Education Program 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NHANES 
National Health and Nutrition Examination Survey 
PAH 
pulmonary arterial hypertension 
PD 
pharmacodynamic 
PFS 
prefilled syringe 
PIP 
proximal interphalangeal 
pcJIA 
polyarticular course juvenile idiopathic arthritis 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
PY 
patient-years 
QW 
once weekly 
RA 
rheumatoid arthritis 
RCR 
Roche Clinical Repository 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SGRQ 
Saint George’s Respiratory Questionnaire 
SHAQ 
Scleroderma Health Assessment Questionnaire 
sIL-6R 
soluble interleukin 6 receptor 
sJIA 
systemic juvenile idiopathic arthritis 
SkinPRO 
Scleroderma Skin Patient-Reported Outcome 
SSc 
systemic sclerosis 
TB 
tuberculosis 
TCZ 
tocilizumab 


 
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Abbreviation 
Definition 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WPAI-GH 
Work Productivity and Activity ImpairmentGeneral 
Health 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON SYSTEMIC SCLEROSIS 
Systemic sclerosis (SSc) is a rare connective tissue disease involving the skin, 
underlying tissues, blood vessels, and major organs.  It is characterized by 
microvascular damage and fibrosis of the skin and of various internal organs.  Although 
the pathogenesis of SSc is not yet fully understood, it is believed to result from increased 
systemic fibrosis, vasculopathy, and immune dysfunction. 
1.1.1 
Epidemiology 
SSc is most prevalent in adults aged 30−50 (Chifflot et al. 2008; 
National Institute of Arthritis and Musculoskeletal and Skin Diseases 2012).  SSc 
primarily affects women (Nikpour et al. 2014) and has an incidence and prevalence that 
varies by geographic region and ethnicity.  In the United States, the incidence is 
estimated to be 14−21 cases per 1,000,000 in 1 year (Steen et al. 1997; Mayes et al. 
2003; Barnes and Mayes 2012).  Multiple population-based studies estimate the 
prevalence of SSc in the United States at 105−300 cases per 1,000,000 
(Ranque and Mouthon 2010; Furst et al. 2012).  In a systematic literature review, 
Chifflot et al.  (2008) identified a north−south gradient of prevalence in Europe.  There 
were fewer cases in England and Iceland compared with France and Greece 
(England: 88 cases per 1,000,000 in 2000; Iceland: 71 cases per 1,000,000 in 1990; 
France: 158 cases per 1,000,000 in 2001; Greece: 154 cases per 1,000,000 in 2002). 
1.1.2 
Clinical Manifestations 
SSc is characterized by initial acral skin sclerosis of the hands, feet, and face that can 
progress to involve the entire body diffusely.  There are two major subsets of patients, 
divided according to the extent of skin involvement:  limited cutaneous system sclerosis 
(lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc).  dcSSc is associated with a 
greater extent of skin involvement, and often-rapid progression of internal organ 
manifestations.  Patients who have early onset of disease often have a more severe 
course (Gabrielli et al. 2009).  The extent and severity of skin sclerosis have been shown 
to be predictive of internal organ involvement and overall survival (Clements et al. 1995, 
2000; Steen and Medsger 2001).  In lcSSc, skin sclerosis is restricted to distal 
extremities; however, these patients also develop internal organ complications, most 
often interstitial lung disease and pulmonary hypertension.  These complications often 
occur later in the disease compared to patients with dcSSc.   
Raynaud phenomenon, one of the earliest and most common clinical symptoms, can 
result in digital pits, painful fingertip ulcers, and dry gangrene.  About 50% of all patients 
with SSc will experience a digital ulcer at some stage in their disease course (Ennis et al. 
2013).  Infections are common complications of digital ulcers. 
The gastrointestinal (GI) tract, heart, lungs, and kidneys are the internal organs with 
significant involvement in this disease.  Reflux disease, heartburn, dysphagia, and 


 
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odynophagia are typical GI symptoms, with cardiac findings including arrhythmia, heart 
block, and pericardial effusions.  Interstitial lung disease (ILD) and pulmonary arterial 
hypertension (PAH) are the two most common pulmonary manifestations of SSc.  ILD 
develops in up to 75% of patients with SSc overall (Bussone and Mouthon 2011).  
Clinical symptoms include tachypnea, exertional dyspnea, and dry cough.  PAH 
develops in approximately 20% of patients.  Symptoms include dyspnea, fatigue, 
atypical chest pain, lower extremity swelling, and syncope.  Renal crisis associated with 
SSc is characterized by sudden onset of arterial hypertension and rapidly progressive 
renal insufficiency.  Renal, cardiac, and pulmonary involvement and complications are 
known predictors of mortality (Ioannidis et al. 2005). 
Musculoskeletal involvement is more frequent than expected in patients with SSc and is 
a major cause of disability (Randone et al. 2008).  Symptoms include myalgia, muscle 
weakness, arthralgia, and generalized fatigue.  Approximately 20%−30% of patients 
have SSc-associated polyarthritis.  The proximal interphalangeal (PIP) and metacarpal 
phalangeal (MCP) joints, wrist joints, and ankle joints are affected the most often.  In 
contrast to other autoimmune diseases, joint effusions are not common, but thickening 
and fibrosis of the periarticular tissue may result in joint contractures.  Flexion 
contractures of the fingers can lead to severe impairment of hand function and muscle 
weakness.  Tendon friction rubs are palpable signs of overlying tendon sheath 
inflammation and/or fibrosis and occur most commonly at the fingers, wrists, elbows, 
knees, and ankles.  They have been associated with active disease and are predictive of 
further disease progression.  Friction rubs have been reported in approximately 20% of 
patients with diffuse cutaneous sclerosis and 40% of patients with disease duration 
of < 5 years (Avouac et al. 2010).   
Infections are a well-known disease complication in SSc.  Risk factors for infection may 
include skin and internal organ system involvement, such as esophageal and pulmonary 
involvement, severe Raynaud phenomenon, severe calcinosis, and immunosuppressive 
treatments used for disease management (Juárez et al. 2003).  In addition, infected ulcers 
and osteomyelitis were seen in patients in Study WA27788, an ongoing Phase II/III study 
of tocilizumab (TCZ) versus placebo in patients with SSc. 
1.1.3 
Mortality 
The life expectancy for patients with SSc is reduced (Fett and Werth 2011).  
The mortality rate for patients with SSc is higher than the rate for patients with other 
rheumatic diseases, with a 10-year survival of < 70% from the time of diagnosis 
(Steen and Medsger 2007).  The primary causes of SSc-related deaths are pulmonary 
fibrosis, PAH, heart failure, and cardiac arrhythmia.  Deaths not directly related to SSc 
are most frequently from infections, malignancies, and cardiovascular disease 
(Tyndall et al. 2010). 


 
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1.1.4 
Treatment for Systemic Sclerosis 
The treatment of patients with SSc can be challenging, given the heterogeneity of the 
disease.  To date, no therapy has been shown to modify disease progression.  However, 
recent advances have been made in the treatment of organ manifestations, and formal 
treatment guidelines have been published on the basis of both evidence from the literature 
and expert opinion (Kowal-Bielecka et al. 2009). 
Several lines of evidence support the role of interleukin 6 (IL-6) in the pathogenesis of 
SSc, as presented in Section 1.2.  Blockade of IL-6 may therefore be a treatment path 
for SSc.  This evidence, along with the unmet medical need in patients with SSc, builds 
the framework for this study. 
1.2 
INTERLEUKIN-6 AS DRUG TARGET 
The pro-inflammatory, multifunctional cytokine IL-6 is produced by a variety of cell types, 
including T cells, B cells, monocytes, fibroblasts, keratinocytes, and synovial and 
endothelial cells, leading to local production of IL-6 in joints affected by inflammatory 
processes such as rheumatoid arthritis (RA) and SSc.  It has been shown to be involved 
in diverse physiological processes, such as T-cell activation, B-cell differentiation, 
induction of immunoglobulin secretion, acute-phase protein production, stimulation of 
hematopoietic precursor cell growth and differentiation, osteoclast differentiation from 
precursor cells, proliferation of hepatic, dermal, and neural cells, and bone and lipid 
metabolism (Dayer and Choy 2010).  It exerts its effects through the IL-6 receptor 
(IL-6R), which is present both in soluble (sIL-6R) and membrane-bound (mIL-6R) forms. 
In vitro data from fibroblast cultures (Duncan and Berman 1991; Atamas 2002) and 
in vivo data from animal models of SSc (Hasegawa 2006; Kitaba et al. 2012) support a 
pathogenic role of IL-6 in the development of fibrosis, the histologic correlate of sclerosis.  
Kitaba et al. (2012) demonstrated the effectiveness of a murine anti-IL-6R antibody in 
preventing development of skin fibrosis in a mouse model of SSc.  The same antibody 
also showed efficacy for treatment of existing skin fibrosis in a bleomycin-induced mouse 
model for SSc. 
Increased levels of circulating IL-6, elevated levels of IL-6 in bronchoalveolar lavage 
fluid, and overexpression of IL-6 in endothelial cells and fibroblasts from involved skin 
have all been reported in patients with SSc (Koch et al. 1993).  Dermal fibroblasts from 
patients with SSc, compared with those from healthy controls, constitutively express 
higher levels of IL-6 (Kadono et al. 1998).  In addition, serum IL-6 levels correlate with 
the modified Rodnan skin score (mRSS; Ong and Denton 2010), a validated measure of 
the extent and severity of skin sclerosis (Furst et al. 1998).  Elevated serum IL-6 levels 
are also predictive of the extent and severity of skin involvement 3 years after disease 
onset (Ong and Denton 2010). 


 
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1.3 
BACKGROUND ON TOCILIZUMAB 
TCZ is a recombinant, humanized, anti-human monoclonal antibody of the IgG1 
subclass directed against the IL-6R.  Humanization was performed by grafting the 
complementary-determining region of the mouse anti-human IL-6R monoclonal antibody 
onto a human IgG1κ antibody framework, followed by transfection of both light- and 
heavy-chain genes into Chinese hamster ovary cells to produce a humanized antibody. 
TCZ binds specifically to sIL-6R and mIL-6R and has been shown to inhibit both 
membrane-bound and IL-6−mediated trans-signaling through the IL-6R.  As described 
previously, elevated tissue and serum levels of IL-6 have been implicated in the 
pathogenesis of SSc and are correlated with skin sclerosis, the hallmark of SSc disease.  
Thus, inhibition of the biological activity of IL-6 and/or its receptor represents a promising 
new approach for the treatment of SSc. 
Intravenous (IV) TCZ has been approved in more than 100 countries, including the 
United States, Japan, and the European Union, for the treatment of moderate to severe 
RA.  In several countries, including the United States and Canada, TCZ has been 
approved in combination with disease-modifying anti-rheumatic drugs (DMARDs) or as 
monotherapy at a recommended starting dose of 4 mg/kg followed by an increase to 
8 mg/kg on the basis of clinical response (Actemra [tocilizumab] Package Insert).  In all 
other countries, including the European Union, TCZ has been approved at a dose of 
8 mg/kg.  The dose can be reduced to 4 mg/kg if necessary.  IV TCZ has been approved 
in 3 regions so far, including the European Union, Switzerland, and Australia for the 
treatment of early RA.  IV TCZ has also been approved for the treatment of systemic 
juvenile idiopathic arthritis (sJIA) in the United States and the European Union, as well 
as for sJIA, polyarticular course juvenile idiopathic arthritis (pcJIA), and Castleman’s 
disease in India and Japan. 
Subcutaneous (SC) TCZ has been approved in more than 10 countries, including the 
United States, Japan, and European Union, for the treatment of moderate to severe RA.  
In several countries, including the United States and Canada, TCZ has been approved in 
combination with DMARDs or as monotherapy at a recommended starting dose of 
162 mg every 2 weeks (Q2W) followed by an increase to once weekly (QW) on the basis 
of clinical response.  In other regions, including the European Union, TCZ has been 
approved at a dose of 162 mg QW.  The dose can be reduced to Q2W if necessary.   
Information on the safety and efficacy of TCZ in clinical studies is provided below.  See 
the Tocilizumab Investigator's Brochure for information on nonclinical studies and 
additional details on clinical studies. 


 
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1.3.1 
Clinical Safety and Immunogenicity of Tocilizumab in Patients 
with Rheumatoid Arthritis 
1.3.1.1 
Intravenous Administration 
In patients with RA treated with IV TCZ, the most frequently reported adverse events by 
System Organ Class were infections and infestations, and GI disorders.  The most 
frequently reported serious adverse events by System Organ Class were infections and 
infestations, of which pneumonia and cellulitis were the most common. 
Clinically significant hypersensitivity events (defined as any adverse event within 
24 hours of infusion, not deemed “unrelated” to trial treatment, and leading to treatment 
discontinuation) have been reported in 60 patients leading to a rate of 0.38 (95% CI: 
0.29, 0.48) events per 100 PY.  Anaphylaxis occurred in 8 patients. 
1.3.1.2 
Subcutaneous versus Intravenous Administration 
In Study WA22762, patients received TCZ 162 mg SC QW plus placebo IV every 
4 weeks (Q4W), or TCZ 8 mg/kg IV Q4W plus placebo SC QW in a double-blind fashion 
for 24 weeks, in combination with non-biologic DMARDs.  All SC injections were given 
by prefilled syringe (PFS).  At Week 24, all patients were re-randomized to open-label 
TCZ 162 mg SC QW or TCZ 8 mg/kg IV Q4W for 72 weeks. 
The safety profiles of TCZ SC and TCZ IV were similar in Study WA22762, with the 
exception of injection-site reactions.  At Week 24, injection-site reactions were more 
common in the SC arm than in the IV arm (treated with SC placebo; 57.97 vs. 
32.59 events per 100 PY).  Clinically significant hypersensitivity reactions occurred at a 
rate of 4.16 per 100 patient-years (PY) in the IV arm and 2.07 per 100 PY in the SC arm.  
At Week 97, the rate of injection-site reactions per 100 PY was 26.05 in the SC arm, 
33.63 in the IV arm, 93.45 in the IV-to-SC arm, and 0 in the SC-to-IV arm.  The rate 
of clinically significant hypersensitivity reactions was comparable in the SC and IV arms 
at Week 97.  There were no events of anaphylaxis during the 2-year study. 
During the study, serious adverse events occurred at similar rates in the SC arm and the 
IV arm (14.61 vs.  15.43 per 100 PY), with the most common events being infections 
(3.95 vs.  3.92 per 100 PY).  The rate of deaths per 100 PY was 0.39 in the SC arm, 
0.49 in the IV arm, 0.78 in the IV-to-SC arm, and 0 in the SC-to-IV arm. 
Decreased mean platelet count and neutrophil count occurred in both the SC arm and 
IV arm, but mean levels remained within the normal range.  Decreases to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Grade 1 or 2 values were numerically greater in the SC arm than in the IV arm.  
At Week 97, analysis of laboratory parameters showed that cases of neutropenia, 
leukopenia, and thrombocytopenia were comparable across all four treatment arms.  
Shifts in laboratory parameters for alanine transaminase (ALT), aspartate 
aminotransferase (AST), total bilirubin, and alkaline phosphatase levels were similar in 
both the SC and IV treatment arms; although adverse shifts in total cholesterol, 


 
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low-density lipoprotein (LDL) cholesterol, and triglycerides were numerically more 
frequent in the SC arm compared with the IV arm. 
The proportion of patients who developed anti-TCZ antibodies through Week 97 was 
consistently low across all four treatment arms (range, 0%−1.6%).  Among the patients 
who developed anti-TCZ antibodies, only 1 patient in the IV arm had a clinically 
significant hypersensitivity reaction and 2 patients in the SC arm experienced 
injection-site reactions.  Among patients across all treatment arms who developed 
anti-TCZ antibodies with neutralizing potential (range, 0%−1.3%), none were classified 
as having loss of efficacy or withdrew because of lack of efficacy. 
1.3.2 
Clinical Studies in Patients with Systemic Sclerosis 
Efficacy and safety data are available from Study WA27788, an ongoing Phase II/III, 
randomized, double-blind study of 87 patients with SSc who were treated with SC 
injections of TCZ 162 mg or placebo. 
1.3.2.1 
Clinical Safety and Immunogenicity of Tocilizumab in Patients 
with Systemic Sclerosis 
The overall safety profile for TCZ in SSc, emerging after 48 weeks of treatment in 
Study WA27788, is consistent with the natural history of SSc and the known safety 
profile for TCZ.  Treatment with TCZ was generally well tolerated.  Except for a higher 
incidence of serious infections with TCZ, the observed adverse event profile was 
comparable between the placebo and active treatment arms.  No new or unexpected 
safety findings were observed.   
Adverse events and serious adverse events were reported in 90.9% and 34.1%, 
respectively, of placebo-treated patients compared with 97.7% and 32.6%, respectively, 
of TCZ-treated patients.  Four deaths were reported in the first 48 weeks 
of Study WA27788 (1 in the placebo arm and 3 in the TCZ arm).  The death in the 
placebo arm was attributed to cardiac failure, and the deaths in the TCZ arm were 
attributed to lung infection (considered to be related to TCZ), arrhythmia (considered to 
be unrelated to TCZ), and multi-organ failure (considered to be unrelated to TCZ). 
Injection-site reactions occurred in 4.5% of placebo-treated patients and 7.0% of 
TCZ-treated patients.  Injection-site reactions were reported in 2 placebo-treated 
patients (events of bruising and hematoma) and 3 TCZ-treated patients (2 patients with 
erythema and 1 with rash and contusion).   
Hypersensitivity events were defined as adverse events occurring immediately after or 
within 24 hours of the end of injection (excluding injection-site reaction events) that were 
not deemed to be unrelated to study drug.  According to this definition, over the 48-week 
treatment period, 3 patients (6.8%) in the placebo arm and 6 patients (14.0%) in the TCZ 
arm experienced a hypersensitivity event.  The reported events on TCZ were fatigue, 
pruritus, headache, somnolence, tension headache, hot flush, vertigo, and pollakiuria.  


 
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There were no clinically significant hypersensitivity events.  There were no events of 
anaphylaxis. 
Serious infections were more common in the TCZ arm (7 patients; 16.3%) than in the 
placebo arm (2 patients; 4.5%).  A total of 8 events of serious infections were considered 
to be related to study drug:  6 events in TCZ-treated patients (lung infection, infected 
skin ulcer [2 events in the same patient], osteomyelitis in 2 different patients, and sepsis) 
and 2 events in placebo-treated patients (lower respiratory tract infection and 
osteomyelitis).  None of the serious infections were associated with neutropenia.   
There were no events of GI perforation, demyelination, or malignancy. 
Four patients in the placebo arm and 5 patients in the TCZ arm discontinued because of 
adverse events. 
At Week 48, 1 TCZ-treated patient had tested positive for neutralizing anti-TCZ 
antibodies.  The patient completed 96 weeks of treatment with TCZ and did not 
experience obvious worsening of mRSS after developing anti-TCZ antibodies.  The 
patient did not experience any adverse events indicative of a hypersensitivity reaction. 
1.3.2.2 
Clinical Efficacy of Tocilizumab in Patients with Systemic 
Sclerosis 
The primary endpoint for Study WA27788 is change in the mRSS at Week 24.  The 
analysis at 24 weeks showed a numerically but not statistically significantly greater 
improvement in mRSS with TCZ versus placebo treatment (TCZ, −3.92; placebo, −1.22; 
adjusted difference in least-squares mean [∆LSM], −2.70 [95% confidence interval [CI]: 
−5.85, 0.45]; p = 0.0915).  Consistent with the Week 24 results, there was a numerically 
but not statistically significantly greater improvement in mRSS with TCZ versus placebo 
treatment at Week 48 (TCZ, −6.33; placebo, −2.77; ∆LSM, −3.55 [95% CI: −7.23, 0.12], 
p = 0.0579).  A greater proportion of patients on TCZ compared with placebo showed 
benefit on an individual patient level, because more TCZ-treated than placebo-treated 
patients showed at least a 20%, 40%, or 60% reduction in mRSS at Week 48:  in the 
TCZ arm, 17 (39.5%), 9 (20.9%), and 5 (11.6%) patients improved by at least 20%, 40%, 
or 60%, respectively, compared with 12 (27.3%), 3 (6.8%), and 0 (0%), respectively, in 
the placebo arm. 
Clinical improvements in most patient- and physician-reported outcomes were observed 
over the 48-week treatment period.  However, none of these results achieved statistical 
significance.  A worsening in the Health Assessment Questionnaire Disability Index 
(HAQ-DI) was noted in the placebo arm, whereas in the TCZ arm no change from 
baseline was apparent at Week 48 (TCZ, −0.002; placebo, 0.205, ∆LSM = −0.207 [95% 
CI: −0.471, 0.056]; p = 0.1212).  There was a greater improvement in Physician's Global 
Assessment (TCZ, −18.41; placebo, −9.39, ∆LSM = −9.02 [95% CI: −19.04, 1.00]; 
p = 0.0768) and in Patient’s Global Assessment (TCZ, −11.00; placebo, −2.70, 


 
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∆LSM = −8.30 [95% CI: −19.31, 2.71]; p = 0.1371) in the TCZ arm compared with the 
placebo arm at Week 48. 
Exploratory analyses of forced vital capacity (FVC) data from Study WA27788 showed 
that at Week 48 there was a decline of 6.6% (SD, 9.4%) from baseline in 
percent-predicted FVC in the placebo arm compared with a 2.1% (SD, 4.8 %) decline in 
the TCZ arm.  In addition, 28.1% of placebo-treated patients (9 of 32 patients) compared 
with 10.0% of TCZ-treated patients (3 of 30 patients) experienced a decline of ≥ 10 % in 
observed FVC at Week 48 compared with baseline.   
1.4 
STUDY RATIONALE AND BENEFIT−RISK ASSESSMENT 
SSc is a rare and devastating disease with no approved treatment options.  To date, no 
therapy has been shown to modify overall disease progression in SSc.  The data from 
Study WA27788, a double-blind, placebo-controlled study, demonstrated a clinically 
meaningful effect of TCZ on mRSS and FVC, as well as improvements in HAQ-DI, 
Physician's Global Assessment, and Patient's Global Assessment at Week 48.  This 
Phase III study is designed to confirm clinically and statistically the findings from 
Study WA27788.  Overall, no new or unexpected safety signals were observed in 
Study WA27788.  The benefit−risk profile for TCZ in SSc is considered to be positive on 
the basis of clinically meaningful, albeit not statistically significant, effects of TCZ on skin 
sclerosis and pulmonary function, the concordance of positive clinical and 
patient-reported outcomes (PROs), as well as the absence of safety findings that would 
be prohibitive of further development. 
2. 
OBJECTIVES 
This study will evaluate the efficacy and safety of TCZ compared with placebo in patients 
with SSc.  Specifically, 210 patients with dcSSc will be enrolled in this study.  Objectives 
and corresponding outcome measures for the study are outlined below. 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
• 
To evaluate the efficacy of TCZ compared with placebo on skin sclerosis, as 
measured by mRSS at Week 48 
 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate the efficacy of TCZ compared with placebo on pulmonary function, as 
measured by FVC at Week 48 
• 
To evaluate the efficacy of TCZ compared with placebo on PROs, as measured by 
the HAQ-DI and Patient's Global Assessment at Week 48 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by the 
Physician's Global Assessment at Week 48 


 
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• 
To evaluate the efficacy of TCZ compared with placebo by assessment of time to 
treatment failure (death, worsening of mRSS and/or FVC [see Section 4.4.1.1], or 
clinically significant SSc complication) up to Week 48 
 
2.2 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To evaluate the safety of TCZ compared with placebo, focusing on the nature, 
frequency, and severity of serious and non-serious adverse events, the frequency of 
SSc-related complications, and effects on vital signs, physical findings, and clinical 
laboratory results 
• 
To evaluate the safety of TCZ compared with placebo by assessing the number of 
digital ulcers 
• 
To assess the long-term safety of TCZ 
 
2.3 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objectives for this study are as follows: 
• 
To characterize the immunogenic potential of TCZ by measuring anti-TCZ 
antibodies 
• 
To assess the potential relationship between development of anti-TCZ antibodies 
and efficacy, safety, or pharmacokinetic (PK) outcome measures 
 
2.4 
PHARMACODYNAMIC OBJECTIVE 
The pharmacodynamic (PD) objective for this study is as follows: 
• 
To compare changes in levels of PD biomarkers following treatment with TCZ 
versus placebo 
 
2.5 
PHARMACOKINETIC OBJECTIVES 
The PK objectives for this study are as follows: 
• 
To characterize the pharmacokinetics of TCZ 
• 
To evaluate potential relationships between PK parameters for TCZ and efficacy, 
safety, or immunogenicity outcome measures 
 
2.6 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To evaluate the efficacy of TCZ compared with placebo on skin sclerosis, as 
measured by mRSS at Week 24 
• 
To evaluate the efficacy of TCZ versus placebo measured by the proportion of 
responders as defined by the Combined Response Index for Systemic Sclerosis 
(CRISS) at Week 48 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by the visual 
analog scale (VAS) component of the Scleroderma Health Assessment 
Questionnaire (SHAQ) at Weeks 24 and 48 


 
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• 
To evaluate the efficacy of TCZ compared with placebo, as measured by the Work 
Productivity and Activity ImpairmentGeneral Health (WPAI-GH) questionnaire at 
Weeks 24 and 48 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by the 
EuroQol 5-Dimension Questionnaire with three levels of severity (EQ-5D-3L) at 
Weeks 24 and 48 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by the Saint 
George’s Respiratory Questionnaire (SGRQ) at Week 48 
• 
To evaluate the effect of TCZ compared with placebo on fatigue as measured by 
Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score at Week 
48. 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by the 
Scleroderma Skin Patient-Reported Outcome (SkinPRO) questionnaire at Week 48 
(for North America only) 
• 
To evaluate the efficacy of TCZ compared with placebo on the basis of change in 
pulmonary fibrosis, as determined using high-resolution computed tomography 
(HRCT) scans at Week 48 
• 
To evaluate the efficacy of TCZ compared with placebo, as measured by diffusion 
capacity of the lung for carbon monoxide (DLCO) at Week 48 and FVC at Week 24 
• 
To evaluate the maintenance of efficacy of TCZ, as measured by mRSS and FVC at 
Week 96 
• 
To assess whether non-inherited biomarkers are predictive of response to TCZ 
(i.e., predictive biomarkers), susceptibility to developing adverse events, or 
progression to a more severe disease state (i.e., prognostic biomarkers), can 
provide evidence of TCZ activity, or can increase the knowledge and understanding 
of disease biology 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study 
This Phase III, multicenter, randomized, double-blind, placebo-controlled, two-arm, 
parallel-group study is designed to assess the efficacy and safety of TCZ in patients with 
SSc.  The study consists of two periods:  a 48-week, double-blind, placebo-controlled 
period, followed by a 48-week open-label treatment period.  Patients will be randomized 
in a 1:1 ratio to receive SC injections of 162 mg of TCZ QW or placebo QW for 48 weeks 
during the double-blind treatment period.  During the open-label treatment period, all 
patients will receive SC injections of 162 mg of TCZ QW for up to 48 weeks.  Patients 
receive their first dose of open-label treatment at Week 48.  Approximately 212 patients 
with dcSSc will be enrolled at approximately 75 global sites.  The study design is 
presented schematically in Figure 1. 


 
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The screening visit may occur up to 40 days prior to the baseline visit (Day 1).  Patients 
will be randomized at Day 1 through an interactive voice- or Web-based response 
system (IxRS).  Randomization will be centralized and stratified by IL-6 level 
(< 10; ≥ 10 pg/mL) at screening.   
Efficacy parameters will be assessed from baseline through Week 96, as described in 
the schedules of assessments (see Appendix 1−Appendix 3).  The primary analysis will 
occur after all patients have completed the Week 48 visit. 
All patients will be closely monitored for adverse events throughout the study and for at 
least 8 weeks after the last dose of study drug (see Section 5.3.1).  Adverse events will 
be graded according to the NCI CTCAE, Version 4.0. 
All patients who discontinue study drug prematurely at any time during the study will 
undergo a treatment discontinuation (TD) visit as soon as possible after the decision to 
discontinue study drug.  These patients will also undergo follow-up assessments within 
4 weeks of study drug discontinuation and at 8 weeks after study drug discontinuation. 
Patients who discontinue study drug during the double-blind period will be encouraged 
to remain in the study and undergo safety monitoring and key efficacy assessments at 
all remaining scheduled visits through Week 48.  The schedule of assessments for 
patients who discontinue study drug is outlined in Appendix 3.  These patients will be 
eligible to enter the open-label treatment period of the study at Week 48 and receive 
TCZ (as per Appendix 2), beginning at Week 48, if they meet specified eligibility criteria 
(described in Section 4.3.4).  For patients who discontinue study drug prematurely but 
continue study assessments per Appendix 3, TD visits and/or follow-up visits may be 
combined with the next scheduled visit (as outlined in Appendix 3), provided that the 
timing of the scheduled visit coincides with the specified timing for the TD or follow-up 
visit.  If a TD visit is being combined with another visit, only the TD visit assessments 
need to be completed. If a follow-up visit is being combined with the next scheduled 
visit in Appendix 3, the efficacy assessments required at the scheduled visit, as well as 
safety assessments from the follow-up visit will be performed. 
Patients who discontinue study drug prematurely in both the double-blind period and 
the open-label period will undergo two sets of TD and follow up visits. 
3.1.2 
Escape Therapy and Other Concomitant Treatments for SSc 
Escape therapy will be available from Week 24 for patients with worsening of skin 
thickening, and from Week 16 for patients with decline in FVC (confirmed on 
two separate occasions within a 4-week period; see Section 4.4.1.1 for details).  The 
decision to initiate escape therapy will be based on predefined criteria, investigator 
judgment, and discussion with the Medical Monitor.  Patients will continue to receive 
study drug in addition to escape therapy.  Upon completion of the 48-week double-blind 
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the open-label treatment period to receive TCZ.  These patients may remain on escape 
therapy during the open-label period at the discretion of the investigator. 
Patients may receive other concomitant treatments for SSc including treatments for new 
and existing organ complications as described in Section 4.4.1. 
3.1.3 
Independent Data Monitoring Committee 
An external independent Data Monitoring Committee (iDMC) will be established to 
perform regular review of the safety data at least two times per year to ensure the 
ongoing safety of participating patients until the last patient completes the double-blind 
treatment period.  Analyses required for the iDMC’s review will be performed by an 
independent data coordinating center/Contract Research Organization as described in 
the iDMC Charter.  The committee’s composition and a description of its responsibilities 
will be provided in the iDMC Charter. 
3.1.4 
Clinical Adjudication Committee 
A Clinical Adjudication Committee, an independent and blinded expert clinician panel, 
will adjudicate predefined serious adverse events with regard to their classification as 
SSc complications.  The definition of events for independent assessment and criteria for 
adjudication of the predefined SSc-related complications will be provided in a charter.  
The clinical expert panel's composition and a description of its responsibilities will also 
be provided in the charter. 




 
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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Tocilizumab Dose and Schedule 
Study WA27788 assessed the pharmacokinetics, pharmacodynamics, efficacy, and 
safety of TCZ 162 mg SC QW. 
Steady-state TCZ concentrations and PD responses (IL-6, sIL-6R, C-reactive protein 
[CRP], and erythrocyte sedimentation rate [ESR]) in patients with SSc were similar to 
those observed in patients with RA receiving the same dosing regimen, with saturation 
of the target (IL-6R) at steady-state concentrations. 
As described in Section 1.3.2.2, numerically favorable, albeit not statistically significant, 
improvements in mRSS, PROs, Physician's Global Assessment, and pulmonary function 
were demonstrated at Week 48 with TCZ 162 mg SC QW.  Although the study did not 
show statistically significant results, the difference in mean change from baseline in 
mRSS was 3.55 units in favor of TCZ over placebo.  More TCZ-treated patients than 
placebo-treated patients showed at least a 20%, 40%, or 60% reduction in mRSS at 
Week 48, indicating an effect of TCZ on skin sclerosis.  An important observation from 
the exploratory analysis indicated a possible beneficial effect of TCZ on pulmonary 
function and progression of lung disease:  at Week 48, the mean change in the 
percent-predicted FVC for placebo (n = 31) and TCZ (n = 30), respectively, was − 6.6% 
(SD = 9.4%, median = − 5.7%) and − 2.1% (SD = 4.8%, median = − 1.5%).  More 
placebo-treated than TCZ-treated patients had a ≥ 10% decline from baseline in the 
observed FVC at Week 48:  9 of 32 placebo-treated patients (28.1%) compared with 3 of 
30 TCZ-treated patients (10.0%).  Overall, these data indicate a consistent effect of TCZ 
162 mg SC QW across several endpoints in patients with SSc. 
Treatment with TCZ was generally well tolerated (see Section 1.3.2.1).  Except for a 
higher incidence of serious infections with TCZ, the observed adverse event profile was 
comparable between the placebo and active treatment arms.  No new or unexpected 
safety findings were observed.  Overall, the adverse events observed in patients 
receiving TCZ 162 mg SC QW in Study WA27788 were consistent with the natural 
history of SSc and the known safety profile for TCZ in other indications. 
The safety of SC TCZ was assessed in patients with RA in Studies WA22762 
and NA25520.  Overall, the safety profile of TCZ 162 mg SC QW was consistent with 
that of TCZ 162 mg SC Q2W, and the incidence of serious infections was low and 
comparable with both SC regimens. 
In summary, the use of TCZ 162 mg SC QW in this study is supported by the 
benefit−risk ratio demonstrated in Study WA27788 and the known safety profile of TCZ 
in patients with RA from the TCZ RA clinical trial program and the postmarketing setting.   


 
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3.3.2 
Rationale for Patient Population 
SSc is a heterogeneous disease, and clinical development has been affected by the 
variable course of the disease.  Patients with dcSSc have more rapidly progressive skin 
sclerosis compared with patients with lcSSc.  In general, peak skin scores of patients 
with dcSSc occur 24−40 months after onset, followed by regression of skin scores later 
in the course of the disease when skin atrophy may occur (Merkel et al. 2005).  In 
addition, a major loss of lung function occurs within the first 4−6 years after the onset of 
SSc (Steen and Medsger 2007).  In order to target patients with progressive skin 
disease and those who are at risk of developing internal organ complications, as well as 
exclude patients who may have spontaneous improvement of skin sclerosis, enrollment 
in this Phase III study will be restricted to patients with time ≤ 60 months since the onset 
of non-Raynaud symptoms and patients with active progressive skin disease. 
3.3.3 
Rationale for Control Group 
No drugs are approved for the treatment of SSc, and no adequate and well-controlled 
trials have demonstrated substantial evidence of a treatment effect in this disease.  
In the absence of approved drugs, evidence-based, consensus-derived 
recommendations to help guide treatment for patients with SSc have been developed by 
the European League Against Rheumatism (EULAR) and Scleroderma Trials and 
Research (EUSTAR) group, a group of experts from the United States and the European 
Union (Kowal-Bielecka et al. 2009).  The EUSTAR consensus statement includes 
14 recommendations for the treatment of organ-specific complications.  With respect to 
skin involvement, EUSTAR recommends that methotrexate may be considered for 
treatment of skin manifestations of early dcSSc, but notes that no positive effects on 
other organ manifestations have been established for methotrexate 
(Kowal-Bielecka et al. 2009).   
In the absence of treatment options that change the overall course of the disease or 
have a substantial effect on skin thickening, and based on the treatment effect of TCZ 
observed in Study WA27788, a placebo-controlled study design is proposed.  In the 
lessons-learned publication from the D-penicillamine study, Clements et al. (2004) 
concluded that definite answers are difficult to achieve when there is no placebo control, 
even in a randomized, controlled trial. 
3.3.4 
Rationale for Efficacy Endpoints 
The primary endpoint for this study (consistent with Study WA2788) is mean change in 
mRSS, a measure of skin thickness.  The extent and degree of skin thickness in patients 
with SSc have been shown to be predictive of SSc disease outcome.  Greater skin 
involvement is associated with internal organ complications and decreased survival 
(Bryan et al. 1999; Clements et al. 2000; Steen and Medsger 2000; Walker et al. 2007; 
Muangchan et al. 2012).  Improvement in skin thickness has been associated with 
increased survival, improvements in overall functioning, as well as improvement in 
Physician's Global Assessment of disease (Clements et al. 2000; 


 
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Steen and Medsger 2001).  Thus, skin thickness can be considered a measure that 
reflects overall disease severity.  The mRSS has been used as the primary endpoint in 
several clinical trials in dcSSc (Denton et al. 2007; Postlethwaite et al. 2008; 
Khanna et al. 2009) and has shown sensitivity to change.  The proportions of patients 
with ≥ 20%, ≥ 40%, and ≥ 60% improvement in mRSS at Week 48 compared with 
baseline will complement the primary endpoint of mean change in mRSS in the 
assessment of clinically meaningful changes in the progression of disease. 
Assessment of lung function is of clinical importance in patients with SSc because of 
high morbidity and mortality in patients with SSc-associated ILD.  Change in observed 
and percentage of predicted FVC from baseline to Week 48 will provide clinically 
important insight on the effect of TCZ on the development or progression of 
SSc-associated ILD in patients with SSc.  Change in HAQ-DI, Patient's Global 
Assessment, and Physician's Global Assessment from baseline to Week 48 will provide 
information on the patient- and physician-reported outcomes, reflecting physical 
functioning, emotional well-being, and general health status. 
3.3.5 
Rationale for Biomarker Assessments 
SSc is a rare and heterogeneous disease characterized by fibrosis of the skin and 
internal organs, vasculopathy, and dysregulated immune functions.  An increasing 
number of biomarkers have been associated with different features of SSc 
(Doran and Veale 2008; Castro and Jimenez 2010).  These biomarkers have provided 
new means to identify specific subsets of SSc patients, to predict the course of the 
disease and its complications, and to elucidate the underlying biological mechanisms of 
the disease.  Examples of SSc-related biomarkers are described below: 
• 
Plasma levels of the chemokine CXCL4 have been associated with the severity of 
disease (skin fibrosis, lung fibrosis, and PAH) and with the risk of progression of the 
disease (lung fibrosis and PAH; van Bon et al. 2014) 
• 
Serum levels of the chemokine CCL18 have been associated with higher risk of 
worsening of lung fibrosis in SSc patients (Tiev et al. 2011) 
• 
Serum soluble VCAM-1 levels have been associated with the severity of cardiac 
dysfunction in SSc patients (Shahin et al. 2000)  
• 
Serum COMP levels have been associated with the degree of skin fibrosis and with 
overall mortality in SSc patients (Hesselstrand et al. 2008, 2012) 
 


 
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In this study, the aim of the exploratory biomarker assessment is to assess whether 
non-inherited biomarkers: 
• 
can provide evidence of TCZ activity; 
• 
are predictive of response to TCZ (i.e., predictive biomarkers); 
• 
can increase the knowledge and understanding of disease biology; and 
• 
are predictive of progression to a more severe disease state (i.e., prognostic 
biomarkers). 
 
3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is as follows: 
• 
Change in mRSS from baseline to Week 48 
 
The secondary efficacy outcome measures for this study are as follows: 
• 
Proportions of patients with ≥ 20%, ≥ 40%, and ≥ 60% improvement in mRSS at 
Week 48 compared with baseline 
• 
Change in FVC from baseline to Week 48 
• 
Change in HAQ-DI from baseline to Week 48 
• 
Change in Patient's Global Assessment from baseline to Week 48 
• 
Change in Physician's Global Assessment from baseline to Week 48 
• 
Time to treatment failure, defined as the time from randomization to the time of one 
of the following events (whichever occurs first) during the 48-week double-blind 
treatment period: 
death,  
decline in percent-predicted FVC > 10% relative to baseline, 
> 20% increase in mRSS and an increase in mRSS of ≥ 5 points 
occurrence of a predefined SSc-related complication as adjudicated by the 
Clinical Adjudication Committee 
 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Frequency of deaths 
• 
Nature, frequency, and severity of adverse events 
• 
Incidence of specific laboratory abnormalities  
• 
Change from baseline in digital ulcer count 
 


 
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3.4.3 
Immunogenicity Outcome Measures 
The immunogenicity outcome measures for this study are as follows: 
• 
Incidence of anti-TCZ antibodies during the study relative to the prevalence of 
anti-TCZ antibodies at baseline 
• 
Correlation between anti-TCZ−antibody status and efficacy, safety, or PK outcome 
measures 
 
3.4.4 
Pharmacodynamic Outcome Measure 
The PD outcome measure for this study is as follows: 
• 
Predose ESR and serum IL-6, sIL-6R, and CRP levels at baseline and at 
subsequent timepoints after initiation of study drug 
3.4.5 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Predose serum TCZ concentration at baseline and at specified timepoints thereafter 
• 
Correlation between PK parameters for TCZ and efficacy, safety, or immunogenicity 
outcome measures 
 
3.4.6 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Proportions of patients who achieve a response, as determined by the investigator 
using CRISS, at Week 48 
• 
Change in the VAS component of the SHAQ from baseline to Week 24 and baseline 
to Week 48 
• 
Change in WPAI-GH score from baseline to Week 24 and baseline to Week 48 
• 
Change in EQ-5D-3L score from baseline to Week 24 and baseline to Week 48 
• 
Change in total score and subscores of the SGRQ from baseline to Week 48 
• 
Change in total and domain scores of the SkinPRO questionnaire from baseline to 
Week 48 (for North America only) 
• 
Change in FACIT-Fatigue score from baseline to Week 48. 
• 
Change in HRCT fibrosis score from baseline (based on HRCT scan performed 
within 3 months prior to screening) to Week 48 
• 
Change in DLCO from baseline to Week 48 
• 
Proportion of patients with ≥ 15% decline in observed DLCO at Week 48 
• 
Proportion of patients with ≥ 15% decline in percentage of predicted DLCO at 
Week 48 
• 
Change in FVC from baseline to Week 24 
• 
Proportion of patients with ≥ 10% decline in observed FVC at Week 24 and at 
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• 
Proportion of patients with ≥ 10% decline in percentage of predicted FVC at 
Week 24 and at Week 48 
• 
Change in mRSS from baseline to Week 24 and Week 96 
• 
Change in observed and percentage of predicted FVC from baseline to Week 96 
• 
Correlation between non-inherited biomarkers (serum levels of CCL18, sVCAM-1, 
COMP, and autotaxin; plasma levels of CXCL4; and whole blood gene signatures 
associated with plasmablasts and IFN) and efficacy, safety, PK, or immunogenicity 
outcome measures 
 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
This study will enroll approximately 210 patients with active progressive SSc. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed Informed Consent Form 
• 
Age ≥ 18 years at baseline (Day 1) 
• 
Able to comply with the study protocol, in the investigator’s judgment 
• 
Diagnosis of SSc, as defined using the American College of Rheumatology/EULAR 
criteria (van den Hoogen et al. 2013a; van den Hoogen et al. 2013b)  
• 
SSc disease duration of ≤ 60 months (defined as time from the first non−Raynaud 
phenomenon manifestation)  
• 
mRSS of ≥ 10 and ≤ 35 units at screening 
• 
Active disease that meets at least one of the following criteria at screening: 
− Disease duration of ≤ 18 months defined as time from the first non−Raynaud 
phenomenon manifestation 
− Increase in mRSS of ≥ 3 units compared with the most recent assessment 
performed within the previous 6 months 
− Involvement of one new body area and an increase in mRSS of ≥ 2 units 
compared with the most recent assessment performed within the previous 
6 months 
− Involvement of two new body areas within the previous 6 months  
− Presence of at least one tendon friction rub 
• 
Presence of at least one of the following at screening: 
− CRP ≥ 0.6 mg/dL (≥ 6 mg/L) 
− ESR ≥ 28 mm/hr 
− Platelet count ≥ 330 × 109/L (330,000/µL) 


 
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• 
Uninvolved or mildly thickened skin at one of the following possible injection-site 
locations: 
− Front, middle region of the thigh 
− Abdomen, except for the 2-inch area directly around the navel 
− Outer area of the upper arm (if a patient caregiver is giving the injection) 
• 
For women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 
remain abstinent or use single or combined contraceptive methods that result in a 
failure rate of < 1% per year during the treatment period and for up to 3 months after 
the last dose of study drug 
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Examples of contraceptive methods with a failure rate of < 1% per year include 
tubal ligation, male sterilization, hormonal implants, established, proper use of 
combined oral or injected hormonal contraceptives, and certain intrauterine 
devices.   
Alternatively, it is acceptable to combine the use of two methods (e.g., two 
barrier methods such as a condom and a cervical cap).  Barrier methods must 
always be supplemented with the use of a spermicide. 
• 
For men:  agreement to remain abstinent or use contraceptive measures and 
agreement to refrain from donating sperm, as defined below: 
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 8 weeks after the last dose of study drug. 
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Men must refrain from donating sperm during the treatment period and for at 
least 8 weeks after the last dose of study drug. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Pregnant or lactating, or intending to become pregnant during the study 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test at baseline. 
• 
Major surgery (including joint surgery) within 8 weeks prior to screening or planned 
major surgery within 12 months following randomization 


 
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• 
Skin thickening (scleroderma) limited to the face or areas distal to the elbows or 
knees at screening 
• 
Rheumatic autoimmune disease other than SSc, including but not limited to RA 
(diagnosed using ACR/EULAR criteria), systemic lupus erythematosus, mixed 
connective tissue disorder, polymyositis, dermatomyositis, eosinophilic fasciitis, 
primary Sjögren's syndrome, and eosinophilic myalgia syndrome, as determined by 
the investigator 
• 
Treatment with non-investigational or investigational cell-depleting therapies, 
including but not limited to alemtuzumab, anti-CD4, anti-CD5, anti-CD3, anti-CD19, 
and anti-CD20 within 18 months of baseline; or if treatment prior to 18 months from 
baseline, evidence of peripheral depletion of targeted lymphocyte subset at 
screening 
• 
Previous treatment with chlorambucil, bone marrow transplantation, or total 
lymphoid irradiation 
• 
Previous treatment with anti-IL6 therapy (including and not limited to TCZ)  
• 
Previous treatment with thalidomide, antithymocyte globulin, plasmapheresis, 
or extracorporeal photopheresis  
• 
Treatment with anakinra within 1 week prior to baseline 
• 
Treatment with etanercept within 2 weeks prior to baseline 
• 
Treatment with oral, intramuscular, or intravenous corticosteroids (> 10 mg/day of 
prednisone or equivalent) within 2 weeks prior to baseline 
• 
Treatment with methotrexate, hydroxychloroquine, cyclosporine A, azathioprine, 
mycophenolate mofetil, rapamycin, colchicine, or D-penicillamine, within 4 weeks 
prior to baseline 
• 
Immunization with a live or live attenuated vaccine within 4 weeks prior to baseline 
• 
Treatment with any investigational agent within 5 elimination half-lives of the 
investigational drug prior to baseline 
• 
Chronic treatment with any of the following within 5 elimination half-lives of the drug 
prior to baseline: 
− Pirfenidone 
− Nintedanib 
− Endothelin-receptor antagonists, terguride 
− Tyrosine-kinase inhibitors (e.g., imatinib, nilotinib, dasatinib)  
− Janus-kinase inhibitors 
• 
Treatment with IV prostacyclin within 1 week prior to baseline 
• 
Treatment with ultraviolet phototherapy within 6 weeks prior to baseline 
• 
Treatment with infliximab, certolizumab, golimumab, abatacept, or adalimumab 
within 8 weeks prior to baseline 
• 
Treatment with cyclophosphamide within 6 months prior to baseline 


 
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• 
History of severe allergic or anaphylactic reactions to human, humanized, or murine 
monoclonal antibodies 
• 
Evidence of moderately severe concurrent nervous system, renal, endocrine, or GI 
disease not related to SSc, as determined by the investigator 
• 
Pulmonary disease with FVC ≤ 55% of predicted (best of three acceptable and 
repeatable measurements as described in the site’s Pulmonary Function Testing 
Manual)  
OR 
DLCO ≤ 45% of predicted (corrected for hemoglobin, and the average of the 2 highest 
acceptable and repeatable measurements as described in the Pulmonary Function 
Testing Manual)  
• 
Class II or higher PAH, as defined by the World Health Organization (Galiè et al. 
2009) 
• 
Evidence of other moderately severe pulmonary disease (e.g., asthma, 
emphysema), as determined by the investigator 
• 
Cardiovascular disease with significant arrhythmia, congestive heart failure 
(New York Heart Association Class II−IV), unstable angina, uncontrolled 
hypertension, cor pulmonale, or symptomatic pericardial effusion 
• 
History of myocardial infarction in the last 6 months prior to screening 
• 
Current liver disease, as determined by the investigator 
• 
History of diverticulitis or chronic ulcerative lower GI disease, such as Crohn 
disease, ulcerative colitis, or other symptomatic lower GI conditions that might 
predispose a patient to perforations 
• 
Known active current or significant history of recurrent bacterial, viral, fungal, 
mycobacterial, or other infections, including but not limited to atypical mycobacterial 
disease, hepatitis B or C, herpes zoster, infected digital ulcers, and osteomyelitis 
• 
Any major episode of infection requiring hospitalization or treatment with IV 
antibiotics within 4 weeks prior to screening or oral antibiotics within 2 weeks prior to 
screening 
• 
Significant history of recurrent tuberculosis (TB), active TB requiring treatment within 
the previous 3 years, or untreated latent TB 
Patients should be screened for latent TB, and, if positive, will be eligible for the 
study after treatment per local standard practices. 
• 
History of or currently active primary or secondary immunodeficiency 
• 
Evidence of malignant disease, or malignancies diagnosed within the previous 
5 years (with the exception of local basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix uteri that has been excised and cured) 
• 
History of alcohol, drug, or chemical abuse within 1 year prior to screening 
• 
Neuropathies or other conditions that might interfere with pain evaluation, 
as determined by the investigator 


 
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• 
At screening:  
Body weight > 150 kg 
Glomerular filtration rate < 45 mL/min 
ALT or AST > 1.5 × the upper limit of normal (ULN) 
Total bilirubin > ULN 
Platelet count < 100 × 109/L (100,000/µL) 
Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L) 
WBC count < 3.0 × 109/L (3000/µL) 
Absolute neutrophil count (ANC) < 2.0 × 109/L (2000/µL) 
Absolute lymphocyte count < 0.5 × 109/L (500/µL) 
Positive hepatitis B surface antigen or hepatitis C antibody 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Prior to the Week 48 database lock, patients, investigators, other study site personnel, 
and Sponsor personnel (including monitors, project statisticians, and project team 
members) will remain blinded to treatment assignment.  To prevent potential unblinding 
because of observed efficacy and laboratory changes, a dual-assessor approach will be 
used to evaluate these data.  Details regarding the dual-assessor approach are provided 
in a separate manual.   
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IxRS.  Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study drug for any other reason, he or she 
should contact the Medical Monitor directly.  The investigator should document and 
provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a serious adverse event). 
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions (see Section 5.7) that are considered by the investigator or Sponsor to be 
related to study drug. 
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this trial.  Sponsor 
personnel responsible for performing PK assays will be unblinded to patients’ treatment 
assignments to identify appropriate PK samples to be analyzed.  Samples from patients 
assigned to the comparator arm will not be analyzed except by request (i.e., to evaluate 
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4.3 
STUDY TREATMENT  
Patients will be randomized in a 1:1 ratio to receive SC injections of TCZ 162 mg QW or 
placebo QW for 48 weeks during the double-blind treatment period.  Patients will receive 
their first dose of open-label TCZ at Week 48.  During the open-label treatment period, 
all patients will receive SC injections of TCZ 162 mg QW for up to 48 weeks. 
4.3.1 
Formulation, Packaging, and Handling 
TCZ or placebo will be supplied in 1-mL, ready-to-use, single-use PFSs (prefilled 
syringes), each delivering either 162 mg (0.9 mL) of TCZ solution or 0.9 mL of matching 
placebo when the plunger is fully depressed.  The placebo PFSs will resemble the active 
TCZ PFSs as closely as possible.  A patient will use one PFS for each dosing per week.   
The study drug must be stored according to the details on the product label.  The drug 
label indicates the storage temperature.  Local packaging in some countries may be 
different.  Upon arrival of investigational products at the site, site personnel should check 
for damage and verify proper identity, quantity, integrity of seals, and temperature 
conditions, and report any deviations or product complaints to the monitor upon 
discovery. 
All study drug PFS must be stored at a controlled temperature of 2°C–8°C.  PFS should 
be handled according to Good Manufacturing Practice and GCP procedures. 
Used PFS with study drug will be stored at room temperature in designated sharps 
containers and returned to the site for disposal per local schedule.  Under no 
circumstances is the investigator to allow study drug to be used other than as directed 
by the protocol. 
For information on the formulation and handling of TCZ, see the most recent 
Tocilizumab Investigator’s Brochure or local prescribing information for Actemra. 
4.3.2 
Dosage, Administration, and Compliance 
A single SC injection should be given to patients on the same day once weekly (QW), 
whenever possible.  If for any reason the weekly schedule cannot be kept (e.g., SC 
injections have to be postponed or moved forward to coincide with the next scheduled 
site visit), injections may be given a minimum of 5 days and a maximum of 11 days apart. 
The first SC injection in both study periods (double-blind and open-label) will be 
administered to patients at the site under close supervision.  Patients (and patient 
caregivers, if applicable) will be trained on how to perform SC injections at the Day 1 
visit.  After the patient or the patient’s caregiver has demonstrated competence in giving 
the injection correctly, SC injections may be administered by the patient or the patient’s 
caregiver at home.  If a patient is unable or does not wish to administer study drug at 
home, clinic staff may administer injections to the patient at the study site.  For patients 
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administered (or guidance provided) at Weeks 1 and 2 by a home nursing (HN) 
professional or (at sites with established teams) appropriately qualified site personnel at 
the patient's home or another suitable location (see Section 4.5.1 for details on HN 
services).  Provision of HN services is at the discretion of the investigator, and the 
patient must provide written informed consent to participate in HN services. 
The recommended injection sites are uninvolved (or mildly thickened) areas of skin at 
the front, middle region of the thigh, the abdomen except for the 2-inch area directly 
around the navel, and, if a caregiver is giving the injection, the outer area of the upper 
arm.  Injections should not be made into areas where the skin is not intact or is tender, 
bruised, red, or hard.  Injection sites will be inspected by site personnel or the HN 
professional, as applicable, at each visit and any injection-site reactions should be 
documented appropriately on the Adverse Event electronic Case Report From (eCRF). 
Patients will record details of their home-administered study drug injections in an 
electronic diary (e-diary).  Site personnel will monitor the medication records from the 
e-diary via an online portal.  Sharps containers will be provided for home usage, and 
patients will be instructed to place used PFSs immediately into the sharps container.  
The sharps containers should be returned to the clinic at each clinic visit and will be 
discarded by site staff per local practice.  Patients will be asked to return all unused 
PFSs in the provided boxes at each clinic visit.  Patients should also bring their e-diary to 
clinic visits.  Patient compliance will be assessed by maintaining adequate drug 
dispensing logs and return records (see Section 4.3.3), and by reviewing patient e-diary 
entries. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1. 
Any overdose or incorrect administration of study drug should be noted in the patient 
e-diary.  Adverse events associated with an overdose or incorrect administration of study 
drug should be recorded on the Adverse Event eCRF. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal product (IMP) required for completion of this study (i.e., TCZ) 
will be provided by the Sponsor where required by local health authority regulations.  
The study site will acknowledge receipt of IMP, using the IxRS to confirm the shipment 
condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
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Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Open-Label Treatment for Patients Who Discontinue Study 
Drug in the Double-Blind Treatment Period 
If a patient discontinues study drug prematurely during the double-blind treatment period 
of the study (prior to Week 48), they may be eligible to participate in the open-label 
treatment period of the study and receive TCZ (as per Appendix 2), beginning at Week 
48, if they meet the following criteria: 
• 
Adhered to the study visits shown in Appendix 3 
• 
Did not receive any prohibited medication as described in Section 4.1.2 
• 
Did not develop a concurrent condition that would preclude participation as 
described in Section 4.1.2 
• 
Did not develop a safety issue that would preclude receipt of TCZ as determined by 
the Principal Investigator and Medical Monitor 
• 
Did not discontinue the study drug during the double-blind treatment period due to 
non-compliance  
 
Patients who are eligible and wish to receive open-label study drug at Week 48 must 
complete all Week 48 assessments (as per Appendix 1). If these patients discontinue 
after TCZ treatment in the open-label period, they should undergo a second TD visit 
and complete the 4 and 8 week follow-up visits. 
Patients who start other medications for systemic sclerosis (e.g., DMARDs) between 
treatment discontinuation and Week 48 may remain on these medications during the 
open-label period at the discretion of the investigator.  
Patients who do not participate in the open-label period should complete only the 
reduced schedule of assessments (as per Appendix 3). These patients are not required to 
undergo a second TD visit or complete Week 4 or Week 8 follow-up visits. 
4.3.5 
Post-Trial Access to Tocilizumab 
The Sponsor will offer post-trial access to the study drug (TCZ) free of charge to eligible 
patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 


 
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A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for SSc 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for SSc 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, preventative 
vaccinations, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by a patient from 4 weeks prior to screening until 8 weeks after the 
last dose of study drug or until completion of the last scheduled visit, whichever occurs 
later.  In addition, all medications taken for SSc since diagnosis will be recorded at 
screening.  All such medications should be reported to the investigator and recorded on 
the Concomitant Medications eCRF. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
Use of lipid-lowering agents in patients with elevated lipids is strongly encouraged at any 
time during the study in conjunction with the investigator’s clinical judgment and based 
on guidelines such as the third report from the National Cholesterol Education Program 
(NCEP) Adult Treatment Panel III (NCEP 2001). 
4.4.1 
Treatments for Systemic Sclerosis 
Treatment with investigational agents, cell-depleting therapies, biologic agents 
(e.g., tumor necrosis factor antagonists), tyrosine-kinase inhibitors, endothelin receptor 
antagonists, terguride, alkylating agents such as chlorambucil, cyclophosphamide, bone 
marrow transplantation with total lymphoid irradiation, thalidomide, IV gamma globulin, 
antithymocyte globulin, plasmapheresis, or extracorporeal photopheresis is prohibited 
during the study. 
Patients will be allowed to receive escape treatment for worsening of skin thickening 
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treatment of other SSc complications and disease manifestations are permitted as 
described in Sections 4.4.1.2 and 4.4.1.3.  It is important that dose regimens of 
medications taken by patients during the double-blind treatment period (through Week 
48) remain stable if intended for chronic use.  However, dose adjustments for such 
medications will be allowed as required for patient safety, after discussion with the 
Medical Monitor. 
Concomitant treatments other than those described below (in Sections 4.4.1.1−4.4.1.3) 
may be initiated for management of SSc complications after discussion with the Medical 
Monitor. 
4.4.1.1 
Escape Therapy for Worsening mRSS or FVC 
At or after the Week 24 visit, escape therapy will be permitted in patients with worsening 
mRSS of a minimum of 5 points and at least 20% increase, relative to baseline. 
At or after the Week 16 visit, escape therapy will be permitted in patients with a 
decrease of > 10 relative percentage points in percentage of predicted FVC compared 
with baseline, with a decline from baseline confirmed on two separate occasions within a 
4-week period.   
Initiation of escape therapy for eligible patients will be based on investigator assessment 
but should be discussed with the Medical Monitor. 
Patients who initiate escape therapy during the double-blind treatment period should 
continue to receive blinded study drug and remain on escape therapy throughout the 
double-blind treatment period. 
Patients who initiate escape therapy during the double-blind period may remain on 
escape therapy during the open-label period, at the discretion of the investigator.  
Patients may initiate escape therapy during the open-label period if they meet the 
escape therapy criteria.  
The following are permitted escape therapies: 
Worsening in mRSS at or after Week 24: 
• 
Methotrexate 
After initial dose escalation, patients should remain on a stable dose of 
methotrexate (≤ 25 mg/wk by mouth or parenterally) throughout the study 
unless a dose reduction is required for safety reasons.  To minimize 
methotrexate toxicity, all patients treated with methotrexate must receive folic 
acid or equivalent at a dose of ≥ 5 mg/wk (refer to local package insert).   


 
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• 
Hydroxychloroquine 
Initial and maintenance doses of hydroxychloroquine should not exceed 
maximum recommended doses (refer to local package insert).   
 
In patients who are intolerant or inadequate responders to methotrexate or 
hydroxychloroquine, other DMARDs (such as mycophenolate mofetil) may be used as 
escape therapy after discussion with the Medical Monitor.   
Worsening in FVC at or after Week 16: 
• 
Treatment of SSc-associated ILD should be initiated as indicated per local treatment 
guidelines (excluding cyclophosphamide) 
• 
The choice of escape therapy for worsening of FVC should be discussed with the 
Medical Monitor prior to initiation of treatment. 
 
Only one escape therapy can be added to blinded study drug treatment.  A change in 
escape therapy is permitted after discussion with the Medical Monitor.   
4.4.1.2 
Treatments for Other Systemic Sclerosis Complications 
Initiation of treatments for SSc complications (except prohibited therapies, per 
Section 4.4.1) should be discussed with the Medical Monitor unless an urgent 
intervention is necessary as a result of the patient’s medical condition. 
Patients receiving IV prostacyclin at study entry for treatment of Raynaud phenomenon 
or digital ulcers may continue to receive such treatment.  Initiation of IV prostacyclin 
during the study is permitted for treatment of worsening Raynaud phenomenon or 
severe digital ulcers.  However, no IV prostacyclin therapy is to be administered at or 
within 1 week prior to the Day 1 or Week 48 visits. 
4.4.1.3 
Medications Commonly Used in Systemic Sclerosis 
NSAIDs and Analgesics 
Patients may be treated with NSAIDs, including cyclooxygenase-2 inhibitors, during the 
study.  The dose should remain stable through Week 48, unless dose reduction is 
required for patient safety.  The choice and doses of NSAIDs are at the discretion of the 
investigator.  For patients who receive corticosteroids and/or NSAIDs, prophylactic 
treatment with proton-pump inhibitors or H2-receptor blockers may be added at the 
investigator’s discretion, according to local standard of care.  Analgesics up to the 
maximum recommended dose may be used as required for pain.  However, patients 
should be discouraged from using analgesics, including NSAIDs, within 12 hours prior to 
performance of efficacy assessments at a clinic visit. 
Oral Corticosteroids 
Patients may receive corticosteroids at a stable dose of ≤ 10 mg/day of prednisone or 
equivalent during the study.  Increases in corticosteroid doses for chronic treatment of 
SSc are not allowed during the study.  To treat non−SSc-related conditions such as 


 
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asthma, doses of oral corticosteroids up to ≤ 40 mg/day of prednisone (or equivalent) are 
permitted for 2 weeks.  The dose of the corticosteroid should be tapered down to the 
previous level as rapidly as medically possible.  Decreases in corticosteroid doses for 
safety reasons are permitted.   
Intravenous or Intramuscular Corticosteroids 
IV or intramuscular (IM) corticosteroids are not permitted up to and including Week 48 of 
the study.  After the Week 48 visit, treatment with IV or IM corticosteroids is discouraged.  
However, if deemed medically necessary, IV or IM corticosteroids may be administered 
after discussion with the Medical Monitor. 
DMARDs 
All biologic or other conventional DMARDs must be discontinued with appropriate 
washout prior to the initiation of study drug as described in Section 4.1.2 and are 
prohibited during the study, except when given as escape therapy as described in 
Section 4.4.1.1 or after Week 24 for other significant systemic sclerosis complications as 
described in Section 4.4.1.2. 
4.4.2 
Drug-Drug Interactions 
The formation of cytochrome P450 (CYP450) enzymes may be suppressed by increased 
levels of cytokines (e.g., IL-6) during chronic inflammation.  Therefore, for molecules that 
antagonize cytokine activity, such as TCZ, it is expected that the formation of CYP450 
enzymes could be normalized.  When starting or stopping therapy with TCZ, patients 
taking medications that are individually dose adjusted and metabolized by means of 
CYP450, 3A4, 1A2, or 2C9 (e.g., atorvastatin, calcium-channel blockers, theophylline, 
warfarin, phenytoin, cyclosporine, or benzodiazepines) should be monitored, as doses 
may need to be adjusted to maintain their therapeutic effect.  Given its long elimination 
half-life, the effect of TCZ on CYP450 enzyme activity may persist for several weeks 
after stopping therapy. 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1−Appendix 3 for schedules of assessments performed during the 
study. 
Assessments and procedures should be performed in the sequence that is most 
practical for the site, as long as PROs are performed first and study drug administration 
is performed last.  The study visits should follow the schedule as much as possible and 
should occur on the same day of the week.  Study drug is also to be administered on the 
same day of the week; however, the timing of study drug administration can be altered to 
allow for an injection to be performed at a scheduled site visit, as long as the injection is 
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4.5.1 
Home Nursing Services 
At applicable sites, certain study assessments may be performed by an HN professional 
or (at sites with established teams) by appropriately qualified site personnel at the 
patient's home or another suitable location, to improve access and convenience for 
patients participating in the study.  The investigator at a participating site will determine if 
HN services are appropriate for a patient, and the patient must provide written informed 
consent to participate in HN services.  HN services will be scheduled on specified visit 
days, to allow for relevant assessments to be performed by the HN professional.  The 
schedules of assessments (see Appendix 1−Appendix 3) will specify the assessments 
that may be performed by an HN professional. 
For participating sites without established HN teams, the Sponsor will select a health 
care company that will be responsible for providing HN services for participating sites 
(the HN vendor).  The HN vendor is responsible for ensuring that all HN professionals 
are licensed, qualified, and in good standing, as per applicable regulations, and that 
appropriate background checks have been performed.  The HN network will 
communicate with the patient, the patient's caregiver (if applicable), and the patient’s site 
to coordinate HN services. 
4.5.2 
Dual Assessor Approach 
To prevent potential unblinding because of observed efficacy and laboratory changes, 
a dual-assessor approach will be used to evaluate these data.  To ensure consistency of 
assessments and limit inter-observer variability, it is essential that the same assessor 
conduct the mRSS evaluations for a given patient at all study visits.  Details regarding 
the dual-assessor approach are provided in a separate manual.   
4.5.3 
Informed Consent Forms 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
4.5.4 
Screening 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.4.1 
Re-Testing for Laboratory Eligibility Criteria 
Laboratory tests and pulmonary function tests (FVC and DLco) may be repeated twice 
during the screening period if they do not meet the eligibility criteria.  If a patient’s results 
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enter the study.  It will not be considered a re-testing if blood samples have to be re-
drawn because of sample handling problems. 
4.5.4.2 
Re-Screening 
Re-screening (i.e., repeating the entire screening process) is required if a patient has not 
met all of the eligibility criteria within 40 days of the original screening visit.  Patients are 
allowed to be re-screened once.  Each patient must be re-consented before re-screening 
can occur.  It will not be considered a re-screening if blood samples have to be re-drawn 
because of sample handling problems.  During the screening period, it will not be 
considered a re-screening if pulmonary function tests need to be repeated. 
4.5.5 
Medical History and Demographic Data 
Medical history includes clinically significant diseases (including SSc complications), 
reproductive status, smoking history, and use of alcohol and drugs of abuse.  In addition, 
all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 4 weeks prior to the 
screening visit and all SSc-related medications used by the patient since diagnosis will 
be recorded. 
Demographic data will include age, sex, and self-reported race and ethnicity. 
The National Health and Nutrition Examination Survey (NHANES) III reference values as 
described by Hankinson and colleagues (1999) will be used to calculate percentage of 
predicted FVC values.  The NHANES data sets have been standardized on the basis of 
key demographic information that includes race and ethnicity.  It is therefore necessary 
to record patient race and ethnicity to ensure that the most appropriate reference 
equation is used to establish the predicted values. 
4.5.6 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
GI, genitourinary, and neurological systems.  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened abnormalities after screening should be 
recorded as adverse events if appropriate. 
Physical examinations may be performed by an HN professional. 
4.5.7 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
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Additional measurements may be performed in the event of an adverse event, at the 
discretion of the investigator. 
Vital signs may be performed by an HN professional. 
4.5.8 
Digital Ulcer Count 
A digital ulcer is defined as an ulcer at or distal to the MCP joint on either the dorsal or 
volar surface, with loss of surface epithelialization.  This does not include fissures, 
cracks, or calcium extrusions from calcinosis cutis.  The number of fingers (0−10) with 
digital ulcers and the number of digital (or finger) ulcers will be counted and recorded by 
the investigator. 
Digital ulcers will be classified as active, indeterminate, or healed (Baron et al. 2014). 
Digital ulcer counts may be performed by an HN professional. 
4.5.9 
Modified Rodnan Skin Score 
Skin thickness will be assessed by palpation and rated using an mRSS that ranges from 
0 (normal) to 3 (severe skin thickening) across 17 different body sites.  The total score is 
the sum of the individual skin scores from all of these sites and ranges from 0 to 51 units.  
The instrument has been validated for patients with dcSSc.   
4.5.10 
Physician's Global Assessment  
The Physician's Global Assessment is to be completed on the basis of examination and 
overall assessment of the patient.  The physician’s assessment of the patient’s SSc 
status will be scored on a 100-mm horizontal VAS (see Appendix 5).  The extreme left 
end of the line represents “has no effect at all” (symptom free), and the extreme right 
end represents “worst possible effect.”  
4.5.11 
Combined Response Index for Systemic Sclerosis 
CRISS represents a composite measure of patient and physician reported outcomes, 
presence of SSc symptoms, and their severity.  The details on analysis of CRISS will be 
described in the Statistical Analysis Plan (SAP).   
4.5.12 
Pulmonary Function Tests 
Pulmonary function tests will include DLCO and FVC.  Pulmonary function tests will be 
conducted as per the study Pulmonary Function Manual, which is based on the 
American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus 
Statement.  The manual will include information on equipment, procedures, patient 
instructions, and precautions.  Spirometry tests will be performed on a centralized 
spirometry system (provided to all sites by a central spirometry vendor) configured to the 
requirements of the study and in accordance with ATS/ERS guidelines.  The DLco tests 
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and reports will be entered into the centralized spirometry system software as described 
in the Pulmonary Function Manual. 
The acceptability of the FVC and DLco data, including the graphic representations of the 
maneuvers, will be determined centrally by over-readers blinded to treatment 
assignment.  Calculations for the reproducibility of the acceptable maneuvers will be 
performed and reviewed centrally by the blinded over-readers.   
The over-readers will state whether a session has been accepted or rejected.  If rejected, 
the following sessions should be repeated within 4 weeks: 
• 
FVC session from Week 8 onwards  
• 
DLCO session at Week 48 and/or Week 96  
• 
Session at any TD visit 
 
The NHANES III reference values, standardized on the basis of key demographic 
information (including race and ethnicity), will be used to calculate percentage of 
predicted FVC values (Hankinson et al. 1999). 
The Miller et al. 1983, reference values will be used for the predicted DLco values. 
Percentage of predicted DLCO values will be calculated by visit.  Predicted DLCO values 
will be derived using height at screening, age at screening, and patient sex.  The 
predicted value is then adjusted for the hemoglobin level at each visit (Macintyre et al. 
2005). 
4.5.13 
High-Resolution Computed Tomography Scans 
HRCT scans will be obtained at baseline and at Week 48 to assess for pulmonary 
fibrosis (unless prohibited by local regulations).  Good-quality (as determined by the site 
radiologist and/or investigator) standard-of-care HRCT scans obtained within 3 months 
prior to screening and in accordance with study image acquisition guidelines can be 
used for baseline.  Existing scans should be sent to the vendor during the screening 
period so that acceptability can be assessed and scheduling of a new scan at the 
baseline visit can occur, if required, prior to study drug administration.  The HRCT films 
will be centrally reviewed and scored on the basis of texture-based analysis for changes 
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4.5.14 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Dipstick urinalysis:  pH, specific gravity, glucose, protein, ketones, blood 
Microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria), if indicated, will be performed at a central laboratory. 
• 
ESR (PD biomarker) 
• 
Pregnancy test during treatment 
All women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile will have urine pregnancy tests performed at 
specified visits during treatment.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
• 
TB testing at screening (see Section 4.5.15) 
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
• 
Hematology:  hemoglobin, hematocrit, mean corpuscular hemoglobin (MCH), MCH 
concentration, mean corpuscular volume, WBC count, RBC count, platelet count, 
absolute differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells) 
• 
Chemistry panel:  BUN or urea, uric acid, creatinine, random glucose, potassium, 
sodium, chloride, calcium, phosphorus, total protein, albumin, creatine 
phosphokinase, C3, C4 
• 
Liver profile:  AST, ALT, alkaline phosphatase, total bilirubin (direct and indirect will 
be performed if total bilirubin is greater than the ULN) 
• 
Serum lipids:  fasting total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides 
• 
Serology:  anti-nuclear antibodies, SSc-specific auto-antibodies (e.g., anti-PM/Scl, 
anti-topoisomerase, anti-RNA polymerase, anti-histone, anti-U1 snRP, and 
anti-centromere), hepatitis B surface antigen, and hepatitis C antibody 
Hepatitis B surface antigen and hepatitis C antibody serology will be performed 
at screening only, unless clinically indicated during the study. 
• 
Microscopic urinalysis (only if indicated after local dipstick urinalysis):  sediment, 
RBCs, WBCs, casts, crystals, epithelial cells, bacteria 
• 
Creatinine clearance 
• 
Pregnancy test at screening 
All women who are not postmenopausal (≥ 12 months of non-therapy-induced 
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The following samples will be sent to the Sponsor or a designee for analysis: 
• 
Serum samples for analysis of anti-TCZ antibodies 
• 
Serum samples for PK analysis 
• 
Serum samples for analysis of the following PD biomarkers:  IL-6, sIL-6R, CRP 
Central CRP will be blinded to the site and Sponsor for all post-baseline visits 
until after the primary analysis.  Local CRP testing should only be performed 
if deemed clinically necessary by the investigator.  Local CRP results should 
not be shared with the Sponsor or entered into the eCRF until after the 
primary analysis. 
• 
Serum samples for analysis of candidate biomarkers, including but not limited to 
CCL18, sVCAM-1, COMP, autotaxin, and other candidate biomarkers 
• 
Plasma (EDTA) samples for analysis of candidate biomarkers, including but not 
limited to CXCL4 
• 
Whole blood samples for RNA extraction for analysis of candidate biomarkers, 
including but not limited to gene signatures associated with plasmablasts and IFN 
 
Additional samples for PK analysis and analysis of anti-TCZ antibodies and sIL-6R will 
be collected prior to resuming study drug for patients who have missed at least three 
consecutive doses and at the time of anaphylaxis or a serious hypersensitivity reaction. 
Collection of blood and urine samples may be performed by an HN professional. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Samples will be destroyed when the final clinical study report has been completed, with 
the following exceptions: 
• 
Biomarker samples will be destroyed no later than 5 years after the date of final 
closure of the clinical database unless the patient gives specific consent for the 
remainder of the samples to be stored for optional exploratory research.  If the 
patient provides consent for optional exploratory research, the samples will be 
destroyed no later than 15 years after the date of final closure of the clinical 
database. 
 
4.5.15 
Tuberculosis Screening 
All patients will be evaluated for TB at screening. Testing must be repeated at Week 36, 
and the result confirmed, prior to initiation of open-label TCZ at Week 48 (except for 
patients who discontinued study drug prematurely who had a TB test performed at the 
TD visit).  The test method (e.g. PPD or QuantiFERON test) is at the discretion of 
the investigator. 


 
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Patients who test positive for TB at screening should be evaluated for evidence of active 
TB per local standard practice.  A patient with a positive TB test may be eligible for 
study inclusion only if diagnosed with latent TB and treated per local standard practice. 
Patients who test positive for TB at screening and were treated for latent TB must 
undergo repeat TB testing at the Week 36 visit.  However, since no applicable clinical 
practice guidelines currently exist regarding how to further evaluate patients who have 
had a positive TB test, a clinical evaluation at Week 36 and prompt local review of the 
Week 48 HRCT to evaluate for any evidence of active TB is required.  Investigators will 
be asked to confirm this assessment.   
Patients who test negative for TB at screening must undergo repeat TB testing at the 
Week 36 visit.  If the Week 36 visit TB test is positive, dosing of study drug must be 
interrupted and patients evaluated for evidence of active TB per local standard practice.  
If a patient is diagnosed with latent TB and has started TB treatment, the patient may 
recommence dosing with study drug. 
4.5.16 
Electrocardiograms 
Single ECG recordings will be obtained at screening and may be obtained at 
unscheduled timepoints if indicated.  ECG recordings should be performed after the 
patient has been resting in a supine position for at least 10 minutes. 
4.5.17 
Patient-Reported Outcomes 
Patients will use an electronic PRO (ePRO) device to capture PRO data.  The 
appropriate PRO assessments will be programmed to appear at specific visits, as noted 
in the schedule of assessments.  Not all assessments are included at every visit.  All 
assessments will be translated into the appropriate local language. 
The PRO assessments are to be completed by patients without assistance at the 
investigational site prior to the completion of other study assessments and the 
administration of study drug.  PRO assessments are completed in this manner to 
minimize any bias that may come from investigational site staff assessments.  However, 
site staff or patient caregivers may assist patients who are physically unable to complete 
the questionnaires by recording responses selected by patients.  Site staff (and patient 
caregivers, if applicable) will be trained on how to teach patients to use the ePRO device, 
as well as how to avoid providing interpretation of questions or selection of responses. 
4.5.17.1 
Health Assessment Questionnaire Disability Index 
The HAQ-DI consists of 20 questions referring to eight component sets:  
dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities 
(Wolfe 1989; see Appendix 6).  The total score indicates the patient’s self-assessed level 
of disability.  A negative change from baseline indicates improvement. 


 
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4.5.17.2 
Scleroderma Health Assessment Questionnaire 
The SHAQ is composed of the HAQ-DI scale with the addition of five 
scleroderma-specific VAS scales (Steen and Medsger 1997; see Appendix 6 for an 
example) to assess additional elements of SSc disease and the impact each element 
has on a patient’s daily life.  Each VAS item is rated separately, with higher scores 
indicating more severe disease.  The five VAS scales are: 1) intestinal disease, 
2) breathing problems, 3) Raynaud syndrome, 4) digital ulcers, and 5) overall disease.   
4.5.17.3 
Patient's Global Assessment 
The Patient's Global Assessment represents the patient’s overall assessment of his or 
her current SSc status on a 100-mm horizontal VAS (see Appendix 7).  The extreme left 
end of the scale indicates “has no effect at all” (symptom free), and the extreme right 
end indicates “worst possible effect.”  
4.5.17.4 
Saint George’s Respiratory Questionnaire 
The SGRQ (see Appendix 10) is a self-administered questionnaire that contains 50 
items distributed over three scales.  Symptom scale assesses the severity of respiratory 
symptoms; activity scale examines impairment in patient activity as a result of respiratory 
symptoms; and impact scale evaluates effects of respiratory symptoms on overall 
function and wellbeing.  Each scale can be scored from 0 to 100 and a total score 
represents the weighted average of these three subscores.  This questionnaire has been 
recently validated in early dcSSc (Wallace et al. 2015). 
4.5.17.5 
FACIT-Fatigue  
The FACIT-Fatigue is a 13-item measure of fatigue, with patients scoring each item on a 
5-point scale (see Appendix 8).  The assessment was originally developed for chronic 
illnesses and has been validated for patients with RA. 
4.5.17.6 
SkinPRO Questionnaire 
The SkinPRO is a 22-item, patient-completed questionnaire developed to measure skin 
health status as experienced by scleroderma patients with skin involvement.  There are 
4 separate domains:  skin symptoms, physical function, social function, and emotional 
response.  The recall period is “over the PAST 4 WEEKS,” and the response set for all 
items is a 7-point ordinal scale, ranging from “Not at all” to “Very much.”  The SkinPRO 
questionnaire is a new, exploratory measure developed specifically for scleroderma 
patients.  The SkinPRO questionnaire will be administered only in North America (see 
Appendix 1, Appendix 2, and Appendix 11).   
4.5.17.7 
EuroQol 5-Dimension Questionnaire 
The EQ-5D-3L is a generic, preference-based health utility measure with questions 
about mobility, self-care, usual activities, pain/discomfort, and anxiety/depression that 
are used to build a composite of the patient’s health status (see Appendix 9).  It is a 
concise scale that has performed well for patients with SSc (Gualtierotti et al. 2009).  
The EQ-5D-3L will be utilized in this study for economic modeling. 


 
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4.5.17.8 
Work Productivity and Activity Impairment−General Health 
The WPAI-GH questionnaire is a six-item scale, asking patients to estimate the amount 
of time that their work and daily activities were affected by their health over the previous 
7 days (Reilly et al. 1993).  The WPAI-GH assesses absenteeism as well as 
“presenteeism,” which accounts for the time when patients were present for work or 
activities but believed their health had a negative effect on their ability to perform at the 
usual level (see Appendix 4). 
4.5.18 
Samples for Roche Clinical Repository 
4.5.18.1 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future. 
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.18.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.5.17) will not be 
applicable at that site. 


 
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4.5.18.3 
Sample Collection 
The following RCR samples will be collected for research purposes, including but not 
limited to research on dynamic (non-inherited) biomarkers related to TCZ mode of action, 
IL-6 biology, SSc biology, or biology of related diseases (e.g., systemic lupus 
erythematosus, dermatomyositis): 
• 
Residual plasma and serum samples, including biomarker, PK, and anti-TCZ 
antibody samples 
• 
Residual whole blood for RNA extraction, including derivatives 
• 
Optional skin biopsy tissues:  Patients who consent to the RCR sampling will be 
asked to provide two 3-mm skin punch biopsies at the baseline and at the Week 48 
visits (see Appendix 1).  The first biopsy will be used to evaluate the gene 
expression in the skin of patients with SSc before and after treatment with TCZ.  
It has been shown that in skin biopsies, the expression of a four-gene signature, 
reflecting the activity of the TGFb and IFN pathways, correlates closely with the 
degree of skin fibrosis (Farina et al. 2010).  In addition, genome-wide gene 
expression analysis revealed that SSc patients can be categorized according to 
intrinsic gene signatures reflecting different biological mechanisms (Milano et al. 
2008).  The second biopsy will be used to evaluate protein biomarkers in the skin of 
SSc patients before and after treatment with TCZ.  It has been shown that, in skin 
biopsies, the detection of alpha smooth muscle actin-expressing cells is highly 
correlated with the development of skin fibrosis (Sappino et al. 1990) 
 
The following RCR samples will be collected for research purposes, including but not 
limited to research on genetic (inherited) biomarkers related to TCZ mode of action, 
IL-6 biology, SSc biology, or biology of related diseases (e.g., systemic lupus 
erythematosus, dermatomyositis): 
• 
Whole blood for DNA extraction 
 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.   
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.   
4.5.18.4 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 


 
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by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.18.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 


 
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4.5.18.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study WA29767 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study WA29767. 
4.5.18.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.  
A study retention plan will be put in place to minimize early discontinuation from the 
study and to encourage patients to follow the reduced schedule of assessments 
(see Appendix 3) even if study drug has been discontinued prematurely. 


 
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4.6.2 
Study Drug Discontinuation 
Patients must discontinue study drug if they experience any of the following: 
• 
Pregnancy 
• 
GI perforations (see Section 5.1.2) 
• 
Neutropenia < 500 cells/µL still present after repeat testing (see Section 5.1.4) 
• 
Thrombocytopenia < 50,000/µL still present after repeat testing (see Section 5.1.4) 
• 
ALT or AST > 5 × ULN or as specified in Section 5.1.5 
• 
Malignancies (with the exception of local basal or squamous cell carcinoma of the 
skin or carcinoma in situ of the cervix uteri that has been excised and cured; see 
Section 5.1.7) 
• 
Anaphylaxis or serious hypersensitivity (see Section 5.1.9) 
• 
Patient non-compliance, defined as missing multiple scheduled visits, not adhering 
to protocol requirements for permitted or prohibited concomitant therapy, or not 
adhering to safety risk mitigation strategies 
 
The primary reason for study drug discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study drug prematurely will not be replaced.  
A study retention plan will be put in place to minimize early discontinuation from the 
study and to encourage patients to follow the reduced schedule of assessments 
(see Appendix 3) even if study drug has been discontinued prematurely.  These patients 
will be eligible to enter the open-label treatment period of the study at Week 48 and 
receive TCZ (as per Appendix 2), beginning at Week 48, if they meet specified eligibility 
criteria (described in Section 4.3.4).   
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   


 
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The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Measures will be taken to ensure the safety of patients participating in this trial.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities 
(see Section 4.1.2).  In addition, patients will undergo safety monitoring during the study 
as described in Section 4.5, Section 5, and the schedules of assessments (see 
Appendix 1−Appendix 3). 
The following information is based on results from clinical studies.  Please refer to the 
Tocilizumab Investigator's Brochure for a complete summary of safety information.   
5.1.1 
Opportunistic Infections and Serious Infections 
Physicians should exercise caution when considering the use of TCZ in patients with a 
history of recurring infections or with underlying conditions (e.g., diabetes mellitus), 
which may predispose patients to infections.  TCZ should not be administered to patients 
with active infection.  The effects of TCZ on CRP and neutrophils, and the signs and 
symptoms of infection, should be considered when evaluating a patient for a potential 
infection.  Although rarely reported within the TCZ program because of the exclusion 
criteria at study entry, reactivation of viral and other serious infections 
(e.g., Epstein−Barr virus or TB) has been observed with biologic therapies for RA, 
including TCZ. 
Patients with SSc may be susceptible to certain serious infections and underlying 
conditions such as SSc-associated ILD and digital ulcers can increase this risk.  Patients 
enrolled in this study will be provided with a Patient Information Card, informing them 
and health care providers of the importance of recognition of early signs of infections, so 
that appropriate diagnostic and therapeutic measures can be introduced.   
Vigilance for timely detection of serious infection is recommended for patients receiving 
biologic agents, as signs and symptoms of acute inflammation may be lessened 
because of suppression of the acute-phase reaction.  Patients must be instructed to 


 
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contact their physician immediately when any symptoms suggesting infection appear, to 
ensure rapid evaluation and appropriate treatment.   
If a patient develops a serious infection, administration of TCZ is to be interrupted until 
the infection is controlled.  The clinician should consider the benefits and risks to the 
patient before resuming treatment with TCZ. 
5.1.2 
Gastrointestinal Perforations 
Symptomatic diverticulosis, diverticulitis, or chronic ulcerative lower GI disease, such as 
Crohn’s disease, ulcerative colitis, or other chronic lower GI conditions, might predispose 
patients to GI perforations.  Therefore, patients with these conditions are excluded from 
this study (see Section 4.1.2).  Timely diagnosis and appropriate treatment may reduce 
the potential for complications of diverticular disease and thus reduce the risk of 
GI perforations.  As a result, patients should be made aware of the symptomatology 
potentially indicative of diverticular disease and instructed to alert their health care 
provider as soon as possible if these symptoms arise.  Discontinuation of TCZ is 
required for patients who develop GI perforations. 
5.1.3 
Demyelinating Disorders 
The effect of treatment with TCZ on demyelinating disorders is not known; events have 
rarely been reported.  Patients should be closely monitored for signs and symptoms 
potentially indicative of central demyelinating disorders.  Physicians should exercise 
caution when considering the use of TCZ in patients with preexisting or recent-onset 
demyelinating disorders.  Treatment with TCZ should be interrupted during assessment 
of a potential demyelization event and be resumed only if the balance of benefits and 
risks of continuing study drug is favorable.   
5.1.4 
Hematologic Abnormalities 
Decreases in neutrophil and platelet counts have been observed following treatment with 
TCZ in combination with methotrexate.  In addition, there may be an increased risk of 
neutropenia for patients who have been previously treated with a tumor necrosis 
factor antagonist. 
Risk mitigation strategies for neutropenia and thrombocytopenia are summarized in 
Table 1 and Table 2, respectively.   


 
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Table 1 
Risk Mitigation for Neutropenia 
ANC 
Action 
> 1000 cells/µL 
• Maintain dose. 
500–1000 cells/µL 
• If neutropenia persists, interrupt TCZ dosing (or reduce TCZ dosing 
frequency to Q2W). 
• When ANC increases to > 1000 cells//µL, resume TCZ (or increase 
dosing frequency to QW), as clinically appropriate. 
< 500 cells/µL 
• If confirmed by repeat testing, discontinue TCZ. 
ANC = absolute neutrophil count; QW = once weekly; Q2W = every 2 weeks; TCZ = tocilizumab.   
Note:  Patients withdrawn from the study because of a reduced ANC must be followed 
closely for signs of infection, with treatment as deemed appropriate by the investigator, 
and must have a repeat WBC count with differential count performed weekly until the 
ANC is > 1000 cells/µL.  If the ANC does not return to > 1000 cells/µL within 2 months 
(or sooner if deemed necessary by the investigator), a hematology referral is recommended. 
 
Table 2 
Risk Mitigation for Thrombocytopenia 
Platelet count 
Action 
> 100,000/µL 
• Maintain dose. 
50,000−100,000/µL 
• If thrombocytopenia persists, interrupt TCZ dosing (or reduce 
TCZ dosing frequency to Q2W). 
• When platelet count increases to > 100,000/µL, resume TCZ 
(or increase dosing frequency to QW), as clinically 
appropriate. 
< 50,000/µL 
• If confirmed by repeat testing, discontinue TCZ. 
QW = once weekly; Q2W = every 2 weeks; TCZ = tocilizumab. 
Note:  Patients withdrawn from the study because of a reduced platelet count must repeat 
platelet tests weekly until the count is > 100,000/µL.  If platelets do not return to > 100,000/µL 
within 2 months (or sooner if deemed necessary by the investigator), a hematology referral is 
recommended. 
 
For patients receiving concomitant medications associated with hematologic toxicity, 
reduction or interruption of the suspected medication is recommended prior to modifying 
TCZ. 
5.1.5 
Elevated Liver Enzymes 
Risk mitigation strategies for patients with elevated ALT or AST are presented in Table 3.   


 
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Table 3 
Hepatic Enzyme Elevation Risk Mitigation 
ALT or AST Values 
Action 
ULN a to 3 × ULN 
• Reduce the dose of and, if necessary, interrupt treatment with 
concomitant DMARD and other hepatotoxic drugs.  If ALT/AST 
levels return to baseline, DMARD dosing may be resumed. 
• For persistent increases in this range, interrupt TCZ dosing (or 
reduce TCZ dosing frequency to Q2W). 
• When ALT/AST levels return to baseline, resume TCZ (or increase 
dosing frequency to QW), with or without the DMARD, as clinically 
appropriate.   
> 3 to 5 × ULN 
• Interrupt TCZ dosing until ≤ 3 × ULN (confirmed by repeat testing) 
and then follow the instructions above. 
• For persistent increases in this range, TCZ should be discontinued. 
> 5 × ULN 
• If confirmed by repeat testing, discontinue TCZ. 
DMARD = disease-modifying anti-rheumatic drug; QW = once weekly; Q2W = every 2 weeks; 
TCZ = tocilizumab; ULN = upper limit of normal. 
a ULN or the patient’s baseline value, whichever is higher. 
 
Discontinuation of study drug treatment is recommended with ALT or AST 
elevation > 3 × ULN combined with at least one of the following: 
• 
Total bilirubin > 2 × ULN 
• 
International normalized ratio > 1.5  
• 
Alkaline phosphatase > 2 × ULN 
• 
Presence of worsening fatigue, nausea, vomiting, fever, rash, or eosinophilia 
 
The Sponsor should be contacted for further discussion of the case. 
Patients withdrawn from the study because of elevated liver function tests must have 
repeat tests performed as clinically indicated until levels return to baseline.  If the 
patient’s liver function tests have not returned to normal or the patient’s baseline level 
within 6 months (or sooner if deemed necessary by the investigator), the investigator 
should consider referral to a specialist.  If the specialist deems a liver biopsy necessary, 
the prepared histologic slides will be requested by the Sponsor for central review by a 
third party and the biopsy report should be forwarded to the Sponsor. 
5.1.6 
Elevated Lipids 
For patients with LDL cholesterol levels of ≥ 160 mg/dL, it is strongly recommended that 
investigators advise therapeutic lifestyle changes that may include initiation of 
lipid-lowering agents.  Lipid-lowering agents should also be considered for patients with 
lower LDL cholesterol levels as part of their therapeutic lifestyle changes, depending on 
their overall risk as defined by the NCEP Adult Treatment Panel III (NCEP 2001) or other 
national guidelines. 


 
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5.1.7 
Malignancies 
The effect of IL-6R−signaling inhibition on the development of malignancies is not known.  
Although no imbalance of malignancies was observed in controlled clinical trials of TCZ 
in patients with RA, malignancies have been identified as a concern for other biologic 
agents.  It is recognized that identification of such events in TCZ-treated patients may 
require a longer period of surveillance.  TCZ administration should be discontinued for 
patients with malignancies (with the exception of local basal or squamous cell carcinoma 
of the skin or carcinoma in situ of the cervix uteri that has been excised and cured). 
5.1.8 
Local Injection-Site Reactions  
Local injection-site reactions, including but not limited to erythema, induration, pain, and 
SC emphysema, should be reported as described in Section 5.3.5.1.  If needed, 
injection-site reactions should be treated topically and the treatments should be reported 
on the eCRF. 
5.1.9 
Hypersensitivity and Anaphylaxis after TCZ Injection 
A systemic injection reaction is typically defined as an adverse event occurring during 
and within 24 hours after the SC injection of TCZ.  This may include hypersensitivity 
reactions or anaphylactic reactions.   
Signs of a possible hypersensitivity reaction include, but are not limited to, the following:  
• 
Fever, chills, pruritus, urticaria, angioedema, and skin rash 
• 
Cardiopulmonary reactions, including chest pain, dyspnea, hypotension, 
or hypertension 
 
Health care professionals administering TCZ injections should:  be trained in the 
appropriate procedures for TCZ administration, be able to recognize the symptoms 
associated with potential anaphylactic or hypersensitivity reactions, and have the 
appropriate medication available for immediate use in case of anaphylaxis or 
hypersensitivity reaction during or after administration of TCZ. 
If a patient has symptoms of anaphylaxis or serious hypersensitivity, or requires an 
interruption of the study drug because of symptoms of anaphylaxis or hypersensitivity, 
administration of TCZ must be discontinued permanently and the patient should be 
withdrawn from the study.  The patient should be treated according to the standard of 
care for management of the hypersensitivity reaction.  Blood samples for the presence of 
anti-TCZ antibodies and PK or PD assessment should be obtained at the time of the 
event and 8 weeks after the final dose, as outlined in Appendix 1 and Appendix 2. 
The first SC injection in both study periods (double-blind and open-label) will be 
administered to patients at the site under close supervision. 


 
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Study site personnel should educate patients about the signs and symptoms of 
hypersensitivity and anaphylaxis and instruct them to seek immediate medical attention 
if they experience such symptoms.  If anaphylaxis or serious hypersensitivity reaction 
occurs, injection of TCZ must be discontinued permanently and any remaining PFSs 
should be returned to the study site. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 


 
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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE 
criteria; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following: 
• 
Serious or medically significant hepatic events, including cases of potential 
drug-induced liver injury that include an elevated ALT or AST in combination with 
either an elevated bilirubin or clinical jaundice, as defined by Hy’s law (see 
Section 5.3.5.7) 


 
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• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
• 
Serious, opportunistic, or medically significant infections 
• 
Myocardial infarction or acute coronary syndrome 
• 
GI perforations 
• 
Malignancies 
• 
Anaphylaxis or hypersensitivity reactions (as defined in Section 5.1.9) 
• 
Demyelinating disorders 
• 
Stroke 
• 
Serious or medically significant bleeding events 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4−5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 8 weeks after the 
last dose of study drug or until completion of the last scheduled visit, whichever occurs 
later.  After this period, the investigator should report any serious adverse events that 
are believed to be related to prior study drug treatment (see Section 5.6). 


 
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5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 4 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 


 
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"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 5): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 5 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Injection Reactions 
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of injection reaction). 


 
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5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than injection reactions (see Section 5.3.5.1), a diagnosis (if 
known) should be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 


 
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A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level 
of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 


 
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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).  For management of study drug and abnormal liver function tests, please 
refer to Section 5.1.5. 
5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of SSc. 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 


 
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be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed to progression of SSc, "systemic sclerosis progression" should 
be recorded on the Adverse Event eCRF.   
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Systemic Sclerosis 
Medical occurrences or symptoms of deterioration that are anticipated as part of SSc 
should be recorded as an adverse event if judged by the investigator to have worsened 
in severity or frequency or changed in nature at any time during the study.  When 
recording a worsening of SSc on the Adverse Event eCRF, it is important to convey the 
concept that the condition has changed by describing a worsening of a symptom or 
syndrome (e.g., "worsening gastrointestinal reflux disease") instead of a general 
"worsening of systemic sclerosis." 
Worsening of skin thickening as measured by mRSS will be captured as efficacy 
assessment data only and should not be recorded as an adverse event.  Worsening of 
FVC, if not accompanied by clinical symptoms, will be captured as efficacy data only and 
should not be recorded as an adverse event.  Every effort should be made to document 
disease progression through use of objective criteria.  If there is any uncertainty as to 
whether an event is due to disease progression, it should be reported as an adverse 
event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   


 
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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
• 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available 
 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).   
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 
5.3.5.14 
Adverse Events in Individuals Not Enrolled in the Study 
If an adverse event inadvertently occurs in an individual not enrolled in the study 
(e.g., during administration of study drug), the Adverse Event Form provided to 
investigators should be completed and submitted to the Sponsor or its designee, either 
by faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators. 


 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for North America 
Medical Monitor: 
 
Telephone No.: 
+ 
 
Mobile Telephone No.: 
 
 
Medical Monitor Contact Information for Ex-North America 
Medical Monitor: 
 
Telephone No.: 
+ 
 
Mobile Telephone No.: 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators.   


 
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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event / Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 8 weeks after the last dose of study drug or until completion 
of the last scheduled visit, whichever occurs later.  Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Roche Safety Risk Management by the 
EDC system. 
In the event that the EDC system is unavailable, the Serious Adverse Event / Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 8 weeks after the last 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy) either by faxing or by scanning and emailing 
the form with use of the fax number or email address provided to investigators.  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial 


 
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Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available. 
5.4.3.2 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).   
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
8 weeks after the last dose of study drug or completion of the last scheduled visit, 
whichever occurs later), if the event is believed to be related to prior study drug 
treatment.   


 
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The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event / Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
• 
Tocilizumab Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Full details about all statistical issues and planned statistical analyses will be specified in 
a separate SAP.  A database lock will occur when the last patient has completed his or 
her Week 48 assessments or has been withdrawn from the study.  The original SAP will 
detail the reporting of data up to and including Week 48 and will be finalized prior to 
unblinding.  The SAP may be amended to describe analyses of data collected after 
Week 48, if deemed necessary.   
6.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 105 patients in the TCZ group and 105 patients in the 
placebo group (a total of 210 patients) will give power in the range of > 75% to 80%, 
(allowing for an estimated patient dropout rate of approximately 15% to 20%) to detect 
a between-group difference of 3.55 units (common standard deviation of 8.43) in mean 
change in mRSS from baseline to Week 48 using a two-group t-test, with a 
5% two-sided significance level.  The minimal detectable difference in mRSS (smallest 
treatment difference that would give a statistically significant result) under these 
assumptions, and with a patient dropout rate of 20%, is approximately 2.6 units. 


 
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6.2 
SUMMARIES OF CONDUCT OF STUDY 
Patient exclusions from the safety and intent-to-treat (ITT) populations, including the 
reason for exclusion, will be summarized by treatment group.  A summary of enrollment 
by country and investigator name will be produced. 
The number of patients that completed or discontinued from the study by Week 48, 
including a reason for discontinuation, will be summarized by treatment group.  A listing 
of withdrawals, including reason and study day of withdrawal, will be produced. 
The treatment duration within the study (defined as the time from the first dose of study 
drug to the last dose of study drug) will be summarized for the safety population at 
Week 48.  Compliance will be summarized by dose intensity (the number of doses 
actually received divided by the expected number of doses), cumulative dose, and 
number of patients with missed doses. 
The number and percentage of patients receiving escape therapy will be summarized by 
visit through Week 48. 
A listing of patients in each treatment group who were randomized according to an 
incorrect stratification value given at baseline will be produced for the Week 48 analysis 
(IxRS stratification data will be compared with data entered in the eCRF).   
A summary of all major protocol deviations will be produced. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
To descriptively assess the comparability of treatment arms (TCZ versus placebo) at 
baseline, clinically important baseline demographic and disease characteristics will be 
summarized for the safety population, with patients grouped according to the treatment 
actually received.  If it is found that there is a large difference in the number of patients in 
the safety population compared with the intent to treat (ITT) population, additional 
summaries will be produced with patients grouped according to the treatment assigned 
at randomization. 
These summary tables will include number of patients, mean, standard deviation, 
median, and range for continuous demographic/disease characteristics and number and 
percentage of patients for categorical characteristics. 
Baseline demographics will include, but not be limited to, the following variables:  sex, 
age, height, weight, race, ethnicity, country, reproductive status, and smoking history.  
Baseline disease characteristics will include, but are not be limited to, the following 
variables:  duration of SSc, mRSS, CRP level, ESR level, platelet level, HAQ-DI, 
percentage of predicted FVC, percentage of predicted DLCO (hemoglobin-corrected), 
auto-antibody status, and IL-6 status at Day 1. 


 
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Medical history data, including surgery and procedures and baseline conditions, will be 
summarized descriptively by treatment group using the safety population.  Previous and 
concomitant treatment will be summarized descriptively by treatment group.   
6.4 
EFFICACY ANALYSES 
The primary analysis population for efficacy will be the ITT population, which includes all 
patients who are randomized and who receive any study drug.  Patients in the ITT 
population will be grouped according to the treatment assigned at randomization. 
Statistical hypotheses will be tested at a nominal 5% significance level (allowing for 
adjustments for multiplicity as detailed in the SAP) against two-sided alternatives, 
and 95% CIs will be reported as appropriate.  Full details of adjustments for multiplicity 
and/or sequential order of analyses will be predefined in the SAP prior to unblinding of 
the treatment groups. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean change in mRSS from baseline to Week 48.  
The primary hypotheses to be tested are the following: 
• 
H0 (null hypothesis):  There is no difference between the TCZ group and the 
placebo group in mean change in mRSS from baseline to Week 48. 
• 
H1 (alternative hypothesis):  There is a difference between the TCZ group and the 
placebo group in mean change in mRSS from baseline to Week 48. 
 
Similar hypotheses will be tested for the secondary efficacy parameters. 
The mean change from baseline will be analyzed using a restricted maximum 
likelihood−based repeated-measures approach.  The analysis will include fixed, 
categorical effects for treatment, IL-6 stratification level (< 10; ≥ 10 pg/mL) at screening, 
visit, IL-6 level at screening−by-visit interaction, and treatment-by-visit interaction, as 
well as continuous covariates of baseline mRSS and baseline mRSS−by-visit interaction.  
An unstructured covariance structure will be used to model within-patient errors.    
The primary treatment comparison will be the contrast between treatment arms at 
Week 48.  Analyses will be implemented in SAS® using PROC MIXED and the 
Kenward-Roger approximation (Kenward and Roger 1997). 
The estimand of interest for the primary analysis is the difference between treatment 
arms in the mean change in the mRSS at Week 48 for the ITT population.  The study 
has been designed to continue to capture efficacy data on patients who discontinue 
study drug prematurely or receive escape therapies during the double-blind treatment 
period.  These data will be included in the primary analysis.  However, it is unrealistic to 
assume that complete data will be obtained from patients who discontinue study drug 
prematurely, and the primary analysis specified above assumes a missing-at-random 
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will tend to have similar efficacy to that of patients on TCZ who remained in the study.  
Sensitivity analyses using missing-not-at-random models will be implemented.  
Specifically, a pattern-mixture model will be implemented, using multiple imputations, 
whereby missing data in the placebo arm will be imputed using a missing-at-random 
assumption and missing data in the TCZ arm will be imputed in a stepwise fashion using 
multiple calls to PROC MI with a monotone regression statement using data from 
placebo-treated patients as the basis for the imputation (Ratitch and O'Kelly 2011).  This 
imputation method assumes that patients who are lost to follow-up in the TCZ arm will 
have a trajectory similar to that of patients in the placebo arm.  Other clinically plausible 
MNAR models may be implemented, and full details will be specified in the SAP. 
As appropriate, depending on the numbers of patients, analyses or summaries of the 
mean change in mRSS by clinically meaningful subgroups, including but not limited to 
disease duration and disease severity at baseline, will be carried out. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study are as follows: 
• 
Difference in proportions of patients with ≥ 20%, ≥ 40%, and ≥ 60% improvement in 
mRSS at Week 48 compared with baseline 
• 
Difference in mean change in FVC from baseline to Week 48 
• 
Difference in mean change in HAQ-DI from baseline to Week 48 
• 
Difference in mean change in Patient's Global Assessment from baseline to 
Week 48 
• 
Difference in mean change in Physician's Global Assessment from baseline to 
Week 48 
• 
Time to treatment failure, defined as the time from randomization to the time of one 
of the following events (whichever occurs first) during the 48-week double-blind 
treatment period: 
death,  
decline in percent-predicted FVC > 10% relative to baseline 
> 20% increase in mRSS and an increase in mRSS of ≥ 5 points 
occurrence of a predefined SSc-related complication as adjudicated by the 
Clinical Adjudication Committee 
 
For the secondary efficacy endpoints, the TCZ treatment group will be compared with 
the placebo group using the following methods, which will be specified further in the SAP: 
• 
Continuous variables, such as difference in mean change in observed FVC from 
baseline to Week 48, will be analyzed using the same methodology as specified for 
the primary analysis (see Section 6.4.1).  For the FVC, additional analyses using 
non-parametric methods will be used alongside cumulative density plots. 


 
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• 
For binary response variables, such as the proportion of patients with ≥ 20% 
improvement in mRSS at Week 48 compared with baseline, the weighted difference 
in proportion for the specified treatment group comparison will be presented, 
together with a 95% CI using the extended Mantel-Haenszel method and the 
p-value calculated using the Cochran-Mantel-Haenszel test, adjusting for the 
stratification factor, IL-6 level (< 10; ≥ 10 pg/mL) at screening.  Patients who receive 
escape therapy between baseline and Week 48 or have a missing Week 48 
assessment will be considered non-responders in the analysis. 
 
6.4.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are listed in Section 3.4.6 and will be analyzed as 
appropriate. 
6.5 
SAFETY ANALYSES 
The population for safety analyses will be the safety population.  The safety population is 
defined as all randomized patients who received at least one dose of study drug and 
provide data from at least one post dose safety assessment.  Patients will be grouped 
according to the treatment actually received. 
The safety outcome measures for this study are as follows: 
• 
Frequency of deaths 
• 
Nature, frequency, and severity of adverse events 
• 
Incidence of specific laboratory abnormalities  
• 
Change from baseline in digital ulcer count 
 
All data relating to safety will be summarized by treatment group for the 48-week 
double-blind treatment period.  The long-term safety will be summarized for the entire 
treatment period (i.e., through Week 96).   
Adverse events will be summarized by mapped term, appropriate thesaurus level, and 
toxicity grade.  All adverse events will be coded and tabulated by System Organ Class 
and Preferred Term for individual events within each body system and will be presented 
in descending frequency.  Adverse events will also be tabulated by severity and 
relationship to the study drug.  Serious adverse events will be summarized separately. 
Associated laboratory parameters, such as hepatic function, renal function, 
and hematologic values, will be grouped and presented together.  Marked abnormalities 
will be tabulated for each laboratory test by treatment group. 
The change from baseline for each vital sign variable will be computed and summarized 
using descriptive statistics.  Physical examination and ECG data will also be 
summarized descriptively. 


 
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6.6 
IMMUNOGENICITY ANALYSES 
The immunogenicity outcome measures for this study are the incidence of anti-TCZ 
antibodies during the study relative to the prevalence of anti-TCZ antibodies at baseline 
and the correlation between anti-TCZ−antibody status and efficacy, safety, or PK 
outcome measures. 
The immunogenicity analyses will include patients with at least one ATA assessment.  
The numbers and proportions of ATA-positive patients and ATA-negative patients during 
both the treatment and follow-up periods will be summarized by treatment group.  
Patients are considered to be ATA positive if they are ATA negative at baseline but 
develop an ATA response following study drug administration (treatment-induced ATA 
response), or if they are ATA positive at baseline and the titer of one or more 
postbaseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the 
baseline sample (treatment-enhanced ATA response).  Patients are considered to be 
ATA negative if they are ATA negative at baseline and all postbaseline samples are 
negative, or if they are ATA positive at baseline but do not have any postbaseline 
samples with a titer that is at least 4-fold greater than the titer of the baseline sample 
(treatment unaffected). 
The relationship between ATA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported descriptively via subgroup analyses. 
6.7 
PHARMACODYNAMIC ANALYSES 
The PD outcome measure for this study is predose ESR and serum IL-6, sIL-6R, and 
CRP levels at baseline and at subsequent timepoints after initiation of study drug. 
Data for all PD biomarkers will be presented using descriptive summary statistics, 
including mean, median, range, standard deviation, and coefficient of variation. 
6.8 
PHARMACOKINETIC ANALYSES 
The PK outcome measures for this study are predose serum TCZ concentration at 
baseline and at specified timepoints thereafter, and the correlation between PK 
parameters for TCZ and efficacy, safety, or immunogenicity outcome measures 
Predose concentrations of TCZ will be presented descriptively, including arithmetic 
means, median, range, standard deviations, and coefficients of variation. 
6.9 
INTERIM ANALYSIS 
The Sponsor will define a futility analysis to which the Sponsor will remain blinded.  The 
futility analysis will be conducted by an external statistical group and reviewed by the 
iDMC.  The futility analysis will be based on the treatment difference for change from 
baseline in mRSS at Week 24; the stopping boundary will be determined by a beta 


 
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spending function.  The study will be stopped for futility if the endpoint meets the futility 
criterion.   
The futility analysis will be conducted when approximately 76 patients have either 
reached the Week 24 visit or have withdrawn.  Since a repeated measures analysis will 
be used for the futility criterion, partial data from additional patients enrolled at (but not 
yet completed) Week 24 will also be utilized in the analysis.  Thus, although only 
approximately one-third of the patients will have reached Week 24, the timing of the 
futility analysis approximates half of the final expected information (I) at Week 24, where 
I is the inverse of the expected variance of the treatment difference when all patients 
have reached Week 24. 
Full statistical details of the futility analysis, along with the rationale and timing will be 
documented in the iDMC charter.  The iDMC charter will be made available to the 
relevant health authorities.   
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and other 
electronic data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 


 
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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
Patients will use an ePRO device to capture PRO data.  The data will be transmitted to a 
centralized database at the ePRO vendor. 
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required.  In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.   
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 


 
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7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union or European Economic Area will comply with the E.U.  
Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 


 
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or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/EC−approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S.  
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.   
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.   
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S.  FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., when the last 
participating patient completes the last scheduled visit). 


 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This study will be sponsored by Roche.  Approximately 210 patients are expected be 
enrolled in this study, at approximately 120 global sites.  Patients will be enrolled using 
an IxRS. 
Central facilities will be used for the majority of the laboratory assessments.  An iDMC 
will perform regular review of the safety data.  A Clinical Adjudication Committee will 
adjudicate predefined serious adverse events with regard to their classification as SSc 
complications. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 


 
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requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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104/Protocol WA29767, Version 6 
10. 
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Appendix 1  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period 
 
Screen. 
(up to  
40 d) 
Double-Blind Treatment Period (± 7 d, except Day 1) 
Unsch. 
Visit 
Treat. 
Discon. c 
Follow-Up a 
Assessment or Procedure 
Day 1, 
BL 
Wk  
4 b 
Wk 
8 b 
Wk  
16 b 
Wk  
24 b 
Wk  
36 b 
Wk  
48 b 
Wk  
4 
Wk  
8 a 
Informed consent 
x d 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical history e 
x 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion and exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
Electronic device training (PROs and study 
drug compliance) 
 
x 
 
 
 
 
 
 
 
 
 
 
PRO assessments f 
 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
Review study drug compliance 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Urinalysis g, h 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Pregnancy test g, i 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
HBsAg and HCV serology 
x 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis screening j 
x 
 
 
 
 
 
x 
 
 
x 
 
 
Serum sample for IL-6 for stratification 
purposes 
x 
 
 
 
 
 
 
 
 
 
 
 
Hematology g, k 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Chemistry panel (serum or plasma) and 
creatinine clearance g, l 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Liver profile g, m 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Lipid panel g,n 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
 
ANA sample  
 
x 
 
 
 
 
 
 
 
 
 
 


Appendix 1  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
110/Protocol WA29767, Version 6 
 
Screen. 
(up to  
40 d) 
Double-Blind Treatment Period (± 7 d, except Day 1) 
Unsch. 
Visit 
Treat. 
Discon. c 
Follow-Up a 
Assessment or Procedure 
Day 1, 
BL 
Wk  
4 b 
Wk 
8 b 
Wk  
16 b 
Wk  
24 b 
Wk  
36 b 
Wk  
48 b 
Wk  
4 
Wk  
8 a 
SSc-specific auto-antibody panel g, o 
 
x 
 
 
 
 
 
x 
x 
x 
 
 
Serum anti-TCZ antibody sample g, p 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
Serum sample for PK analysis g, p, q 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
IL-6 sample g, q 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
sIL-6R sample g,p,q 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
High-sensitivity CRP g 
x 
x 
x 
 
 
x 
 
x 
x 
x 
 
 
ESR g 
x 
x 
x 
 
 
x 
 
x 
x 
x 
 
 
Serum sample for candidate biomarkers g 
 
x 
 
 
 
x 
 
x 
 
 
 
 
Plasma (EDTA) sample for candidate 
biomarkers g 
 
x 
 
 
 
x 
 
x 
 
 
 
 
Whole blood sample for RNA extraction g 
 
x 
 
 
 
x 
 
x 
 
 
 
 
Skin biopsies (RCR sample, optional) r 
 
x 
 
 
 
 
 
x 
 
 
 
 
Whole blood RCR sample for DNA exaction 
(optional) 
 
x 
 
 
 
 
 
 
 
 
 
 
mRSS 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Forced vital capacity 
x  
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
DLCO 
x  
x 
 
 
 
x 
 
x 
x 
x 
 
 
Physician's Global Assessment s 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
High-resolution CT scan t 
 
x 
 
 
 
 
 
x 
 
 
 
 


Appendix 1  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
111/Protocol WA29767, Version 6 
 
Screen. 
(up to  
40 d) 
Double-Blind Treatment Period (± 7 d, except Day 1) 
Unsch. 
Visit 
Treat. 
Discon. c 
Follow-Up a 
Assessment or Procedure 
Day 1, 
BL 
Wk  
4 b 
Wk 
8 b 
Wk  
16 b 
Wk  
24 b 
Wk  
36 b 
Wk  
48 b 
Wk  
4 
Wk  
8 a 
Physical examination u 
x 
x 
 
 
 
 
 
 
x 
x 
 
 
Height 
x v 
 
 
 
 
 
 
 
 
 
 
 
Body weight g 
x 
x 
 
 
 
 
 
x 
x 
x 
 
 
Vital signs g, w 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Digital ulcer count g 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
ECG 
x 
 
 
 
 
 
 
 
x 
 
 
 
Echocardiogram 
x 
 
 
 
 
 
 
 
x 
x 
 
 
Adverse events g, x, y 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications g, z 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug distribution and administration g, 
aa 
 
x bb, cc 
x 
x 
x 
x 
x 
x bb 
 
 
 
 
ANA = anti-nuclear antibody; BL = baseline; CBC = complete blood count; CRP = C-reactive protein; CT = computed tomography; d = day; 
Discon.  = discontinuation; DLCO = diffusing capacity of the lung for carbon monoxide; eCRF = electronic Case Report Form; ESR = erythrocyte 
sedimentation rate; EQ-5D-3L = EuroQol 5-Dimension Questionnaire (three levels of severity); FVC = forced vital capacity; HAQ-DI = Health 
Assessment Questionnaire Disability Index; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HRCT = high-resolution computed 
tomography; IL = interleukin; mRSS = modified Rodnan Skin Score; PK = pharmacokinetic; PRO = patient-reported outcome; RCR = Roche Clinical 
Repository; Screen. = screening; SGRQ = Saint George’s Respiratory Questionnaire; SHAQ = Scleroderma Health Assessment Questionnaire; 
SkinPRO = Scleroderma Skin Patient-Reported Outcome; SSc = systemic sclerosis; TCZ = tocilizumab; Treat.  = treatment; Unsch.  = unscheduled; 
Wk = week; WPAI-GH = Work Productivity and Activity ImpairmentGeneral Health. 


Appendix 1  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
112/Protocol WA29767, Version 6 
Note:  Assessments and procedures should be performed in the sequence that is most practical for the site, as long as PROs are performed first 
and study drug administration is performed last.   
a All patients will undergo follow-up assessments within 4 weeks of study drug discontinuation and at 8 weeks after study drug discontinuation.  
For patients who discontinue study drug prematurely, a follow-up visit can be combined with the next scheduled visit (as outlined in Appendix 3), 
provided that the timing of the scheduled visit coincides with the specified timing for the follow-up visit.  The follow-up visit at 4 weeks may be 
conducted by telephone. 
b For patients at participating sites who have provided written informed consent to participate in home nursing services, specified assessments at 
Weeks 4, 8, 16, 24, 36, and 48, as well as Week 8 of the Follow-up Period may be performed by a trained home nursing professional or (at sites 
with established teams) by appropriately qualified site personnel at the patient’s home or another suitable location. 
c Patients who discontinue study drug prematurely should undergo assessments as outlined in Appendix 3, with the timing of those visits being 
relative to baseline.  Assessments at the early treatment discontinuation visit should be performed as soon as possible after discontinuing study 
drug. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Medical history includes clinically significant diseases (including SSc complications) reproductive status, smoking history, and use of alcohol and 
drugs of abuse. 
f PRO questionnaires are to be completed prior to all other assessments during the study visit, with the exception of ECGs.  Patients will use an 
electronic PRO device to capture PRO data.  The appropriate PRO assessments will be programmed to appear at specific visits.  The HAQ-DI, 
will be completed at baseline and at Weeks 8, 16, 24, 36, and 48.  The Patient's Global Assessment, SHAQ, SGRQ, FACIT-Fatigue, and 
SkinPRO questionnaire will be completed at baseline and at Weeks 8, 16, 24, and 48.  The SkinPRO questionnaire will only be administered in 
North America.  The WPAI-GH and EQ-5D-3L will be completed at baseline and at Weeks 24 and 48. 
g For patients at participating sites who have provided written informed consent to participate in home nursing services, this assessment or 
procedure may be performed by a trained home nursing professional or (at sites with established teams) by appropriately qualified site personnel 
at the patient’s home or another suitable location. 
h Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, and bacteria).   
i All women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy test 
at screening.  Urine pregnancy tests will be performed at specified subsequent visits.  If a urine pregnancy test is positive, it must be confirmed 
by a serum pregnancy test. 
j Tuberculosis screening must be performed at screening and at Week 36.  The screening method (e.g. PPD or QuantiFERON test) is at the 
discretion of the investigator. 


Appendix 1  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
113/Protocol WA29767, Version 6 
k Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC count, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). 
l Chemistry panel includes total protein, serum albumin, creatine phosphokinase, sodium, potassium, calcium, BUN or urea, serum creatinine, C3, 
and C4.  Creatinine clearance will be calculated by a central laboratory. 
m Liver profile consists of AST, ALT, alkaline phosphatase, and total bilirubin (direct and indirect bilirubin will be performed if total bilirubin greater 
than the upper limit of normal). 
n Overnight fasting ( >  8 hours) is required.  An additional fasting lipid panel should be obtained 8 weeks after initiation of lipid-lowering therapy. 
o SSc-specific autoantibody panel includes anti-topoisomerase, anti-RNA polymerase, anti-PM/Scl, anti-histone, anti-U1 snRP, 
and anti-centromere antibodies. 
p Additional samples for PK analysis and analysis of anti-TCZ antibodies and sIL-6R will be collected prior to resuming study drug for patients who 
have missed at least three consecutive doses and at the time of anaphylaxis or a serious hypersensitivity reaction.   
q Samples for PK analysis and analysis of IL-6, sIL-6R, and candidate biomarkers will be obtained at a single blood draw and aliquoted according 
to the procedures in the Sample Handling and Logistics Manual. 
r Two 3-mm punch biopsies are to be obtained from clinically involved skin, preferably at the forearm (optional). 
s Physician's Global Assessment is to be completed by the investigator on the basis of examination and overall assessment of the patient. 
t As accepted by the local regulations.  Good-quality (as determined by the site radiologist and/or investigator), standard-of-care HRCT scans 
obtained within 3 months prior to screening and in accordance with study image acquisition guidelines can be used for baseline. 
u A physical examination will be performed but will not be recorded on the eCRF, if normal; any abnormality will be reported either on the 
Medical History eCRF (for screening examination) or Adverse Event eCRF (for examinations after the screening). 
v Height is required at screening only and will be recorded on the Vital Signs eCRF. 
w Vital signs will include measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated 
position, and temperature.  Additional measurements may be performed in the event of an adverse event, at the discretion of the investigator.  
Temperature readings (as part of vital signs) will be measured but will not be recorded on the eCRF, if normal; any abnormal body temperature 
will be reported on the Adverse Event eCRF. 
x After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 8 weeks after the last dose of study drug or 
until completion of the last scheduled visit, whichever occurs later.  However, for patients who discontinue study drug prematurely but continue 
scheduled visits, all adverse events will be reported until completion of the last scheduled visit or 8 weeks after the last dose of study drug, 
whichever occurs later.  After this period, the investigator should report any serious adverse events that are believed to be related to prior study 


Appendix 1  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
114/Protocol WA29767, Version 6 
drug treatment (see Section 5.6).  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the 
event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
y For all serious infectious adverse events, CBC, differentials, and platelets should be determined during the disease episode.  Every effort should 
be made to collect appropriate specimens for serology, polymerase chain reaction, or culture to identify the infectious organism.  The results of 
all laboratory assessments performed locally, except for CRP, should be reported on the eCRF. 
z Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by a patient from 4 weeks prior to screening until 8 weeks after the last dose of study drug or until completion of the last 
scheduled visit, whichever occurs later.  In addition, all medications taken for SSc since diagnosis will be recorded at screening. 
aa If for any reason the weekly schedule cannot be kept (e.g., SC injections have to be administered to patients during a site visit), injections may 
be given a minimum of 5 days and a maximum of 11 days apart. 
bb The first SC injection in both study periods (double-blind and open-label) will be administered to patients at the site under close supervision.  The 
Week 48 injection is the first dose for the open-label treatment period. 
cc Patients (and patient caregivers, if applicable) will be trained on how to perform SC injections at the Day 1 visit.  For patients and caregivers at 
applicable sites who require additional training, study drug may be administered (or guidance provided) at Weeks 1 and 2 by a home nursing 
professional or by appropriately qualified site personnel. 
 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
115/Protocol WA29767, Version 6 
Appendix 2  
Schedule of Assessments:  Open-Label Treatment Period 
 
Open-Label Treatment Period (± 7 d) 
Unsch.  
Visit 
Treat. 
Discon. b 
Follow-Up c 
Assessment or Procedure 
Wk 
52 a 
Wk 
60 a 
Wk  
72 a 
Wk  
84 a 
Wk  
96 a 
Wk  
4 
Wk 
8 a 
PRO assessments d 
 
 
x 
 
x 
 
 
 
 
Review study drug compliance 
x 
x 
x 
x 
x 
x 
x 
 
 
Urinalysis e,f 
 
x 
x 
x 
x 
x 
x 
 
 
Pregnancy test e,g 
x 
x 
x 
x 
x 
 
x 
 
 
Tuberculosis screening h 
 
 
 
 
 
 
x 
 
 
Hematology e,i 
x 
x 
x 
x 
x 
x 
x 
 
 
Chemistry panel (serum or plasma) and 
creatinine clearance e,j 
x 
x 
 
x 
 
x 
x 
 
 
Liver profile e,k 
x 
x 
x 
x 
x 
x 
x 
 
 
Lipid panel e,l 
 
x 
x 
 
x 
x 
x 
 
 
SSc-specific auto-antibody panel e,m 
 
 
 
 
x 
x 
x 
 
 
Serum anti-TCZ antibody sample e,n 
 
 
 
 
x 
x 
x 
 
x 
Serum sample for PK analysis e,n,o 
 
 
 
 
x 
x 
x 
 
x 
IL-6 sample e,o 
 
 
 
 
x 
 
x 
 
 
sIL-6R sample e,n,o 
 
 
 
 
x 
x 
x 
 
x 
High-sensitivity CRP e 
 
 
x 
 
x 
x 
x 
 
 
ESR e 
 
 
x 
 
x 
x 
x 
 
 
mRSS 
 
 
x 
 
x 
x 
x 
 
 
Forced vital capacity 
 
 
x 
 
x 
x 
x 
 
 
DLCO 
 
 
x 
 
x 
x 
x 
 
 


Appendix 2  
Schedule of Assessments:  Open-Label Treatment Period (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
116/Protocol WA29767, Version 6 
 
Open-Label Treatment Period (± 7 d) 
Unsch.  
Visit 
Treat. 
Discon. b 
Follow-Up c 
Assessment or Procedure 
Wk 
52 a 
Wk 
60 a 
Wk  
72 a 
Wk  
84 a 
Wk  
96 a 
Wk  
4 
Wk 
8 a 
Physician's Global Assessment p 
 
 
x 
 
x 
x 
x 
 
 
Physical examination q 
 
 
 
 
 
x 
x 
 
 
Body weight e 
 
 
 
 
x 
x 
x 
 
 
Vital signs e,r 
x 
x 
x 
x 
x 
x 
x 
 
 
Digital ulcer count e 
 
 
x 
 
x 
x 
x 
 
 
Echocardiogram 
 
 
 
 
 
x 
x 
 
 
Adverse events e,s,t 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications e,u 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug distribution and administration e,v 
xw 
x 
x 
x 
 
 
 
 
 
CBC = complete blood count; CRP = C-reactive protein; d = day; Discon.  = discontinuation; DLCO = diffusing capacity of the lung for carbon monoxide; 
eCRF = electronic Case Report Form; ESR = erythrocyte sedimentation rate; EQ-5D-3L = EuroQol 5-Dimension Questionnaire (three levels of 
severity); FVC = forced vital capacity; HAQ-DI = Health Assessment Questionnaire Disability Index; HBsAg = hepatitis B surface antigen; 
HCV = hepatitis C virus; HRCT = high-resolution computed tomography; IL = interleukin; mRSS = modified Rodnan Skin Score; PK = pharmacokinetic; 
PRO = patient-reported outcome; RCR = Roche Clinical Repository; SHAQ = Scleroderma Health Assessment Questionnaire; SGRQ = Saint 
George’s Respiratory Questionnaire; SkinPRO = Scleroderma Skin Patient-Reported Outcome; SSc = systemic sclerosis; TCZ = tocilizumab; 
Treat.  = treatment; Unsch.  = unscheduled; Wk = week; WPAI-GH = Work Productivity and Activity ImpairmentGeneral Health. 
Note:  Assessments and procedures should be performed in the sequence that is most practical for the site, as long as PROs are performed first 
and study drug administration is performed last.   
a For patients at participating sites who have provided written informed consent to participate in home nursing services, specified assessments at 
Weeks 52, 60, 72, 84, and 96, as well as Week 8 of the Follow-up Period may be performed by a trained home nursing professional or (at sites 
with established teams) by appropriately qualified site personnel at the patient’s home or another suitable location. 
b Discontinued patients should undergo a treatment discontinuation visit as soon as possible after discontinuing study drug. 


Appendix 2  
Schedule of Assessments:  Open-Label Treatment Period (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
117/Protocol WA29767, Version 6 
c All patients will undergo follow-up assessments within 4 weeks of study drug discontinuation and at 8 weeks after study drug discontinuation, 
except for patients who reach Week 96 but who transition onto locally provided TCZ prior to the follow up visit.  The follow-up visit at 4 
weeks may be conducted by telephone. 
d PRO questionnaires are to be completed prior to all other assessments during the study visit.  Patients will use an electronic PRO device to 
capture PRO data.  The appropriate PRO assessments will be programmed to appear at specific visits.  The HAQ-DI, Patient's Global 
Assessment, SHAQ, SGRQ, FACIT-Fatigue, and SkinPRO questionnaire will be completed at Weeks 72 and 96.  The SkinPRO questionnaire 
will only be administered in North America.  The WPAI-GH and EQ-5D-3L will be completed at Week 96. 
e For patients at participating sites who have provided written informed consent to participate in home nursing services, this assessment or 
procedure may be performed by a trained home nursing professional or (at sites with established teams) by appropriately qualified site personnel 
at the patient’s home or another suitable location. 
f Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, and bacteria).   
g Urine pregnancy tests will be conducted for all women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or 
surgically sterile.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
h Tuberculosis screening must be performed at screening and at Week 36.  The screening method (e.g. PPD or QuantiFERON test) is at the 
discretion of the investigator. 
i Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC count, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). 
j Chemistry panel includes total protein, serum albumin, creatine phosphokinase, sodium, potassium, calcium, BUN or urea, serum creatinine, C3, 
and C4.  Assessment of creatinine clearance is to be performed every 12 weeks and will be calculated by the central laboratory.  Creatinine 
clearance will be calculated by a central laboratory. 
k Liver profile consists of AST, ALT, alkaline phosphatase, and total bilirubin (direct and indirect bilirubin will be performed if total bilirubin greater 
than the upper limit of normal). 
l Overnight fasting (> 8 hours) is required.  An additional fasting lipid panel should be obtained 8 weeks after initiation of lipid-lowering therapy. 
m SSc-specific autoantibody panel includes anti-topoisomerase, anti-RNA polymerase, anti-PM/Scl, anti-histone, anti-U1 snRP, 
and anti-centromere antibodies. 
n Additional samples for PK analysis and analysis of anti-TCZ antibodies and sIL-6R will be collected prior to resuming study drug for patients who 
have missed at least three consecutive doses and at the time of anaphylaxis or a serious hypersensitivity reaction.   


Appendix 2  
Schedule of Assessments:  Open-Label Treatment Period (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
118/Protocol WA29767, Version 6 
o Samples for PK analysis and analysis of IL-6 and sIL-6R will be obtained at a single blood draw and aliquoted according to the procedures in the 
Sample Handling and Logistics Manual. 
p Physician's Global Assessment is to be completed by the investigator on the basis of examination and overall assessment of the patient. 
q A physical examination will be performed but will not be recorded on the eCRF, if normal; any abnormality will be reported on the Adverse Event 
eCRF. 
r Vital signs will include measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated 
position, and temperature.  Additional measurements may be performed in the event of an adverse event, at the discretion of the investigator.  
Temperature readings (as part of vital signs) will be measured but will not be recorded on the eCRF, if normal; any abnormal body temperature 
will be reported on the Adverse Event eCRF. 
s After initiation of study drug, all adverse events will be reported until 8 weeks after the last dose of study drug or until completion of the last 
scheduled visit, whichever occurs later.  However, for patients who discontinue study drug prematurely but continue scheduled visits, all adverse 
events will be reported until completion of the last scheduled visit or 8 weeks after the last dose of study drug, whichever occurs later.  After this 
period, the investigator should report any serious adverse events that are believed to be related to prior study drug treatment (see Section 5.6).  
The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the 
investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events 
considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
t For all serious infectious adverse events, CBC, differentials and platelets should be determined during the disease episode.  Every effort should 
be made to collect appropriate specimens for serology, polymerase chain reaction, or culture to identify the infectious organism.  The results of 
all laboratory assessments performed locally, except for CRP, should be reported on the eCRF. 
u Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by a patient from 4 weeks prior to screening until 8 weeks after the last dose of study drug or until completion of the last 
scheduled visit, whichever occurs later. 
v If for any reason the weekly schedule cannot be kept (e.g., SC injections have to be administered to patients during a site visit), injections may 
be given a minimum of 5 days and a maximum of 11 days apart. 
w Study drug administration only; no study drug distribution at this visit.   


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
119/Protocol WA29767, Version 6 
Appendix 3  
Schedule of Assessments:  Patients Who Have Discontinued 
Study Drug Prematurely 
 
Timing of Visit Relative to Baseline (Day 1) 
Assessment or  
Procedure 
Wk 8 a 
(± 7d) 
Wk 16 a 
(± 7d) 
Wk 24 a 
(± 7d) 
Wk 36 a 
(± 7d) 
Wk 48 a, e 
(± 7d) 
mRSS 
x 
x 
x 
x 
x 
Forced vital capacity 
x 
x 
x 
x 
x 
HAQ-DI 
x 
x 
x 
x 
x 
Adverse events a,b,c 
x 
x 
x 
x 
x 
Concomitant 
medications a,d 
x 
x 
x 
x 
x 


Appendix 3  
Schedule of Assessments:  Patients Who Have Discontinued 
Study Drug Prematurely (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
120/Protocol WA29767, Version 6 
CBC = complete blood count; CRP = C-reactive protein; d; eCRF = electronic Case Report Form; 
HAQ-DI = Health Assessment Questionnaire Disability Index; mrSS = modified Rodnan Skin 
Score; Wk = week. 
Note:  Patients who discontinue study drug prematurely but continue to attend scheduled study 
visits should follow a reduced assessment schedule as outlined above, starting with the first 
scheduled visit following discontinuation of study drug.  These patients should also undergo a 
treatment discontinuation (TD) visit as soon as possible after discontinuing study drug, and 
follow-up assessments within 4 weeks of study drug discontinuation and at 8 weeks after study 
drug discontinuation.  A TD and/or follow-up visit may be combined with the next scheduled 
visit (as outlined above in Appendix 3), provided that the timing of the scheduled visit 
coincides with the specified timing for the TD or follow-up visit. 
a For patients at participating sites who have provided written informed consent to participate in 
home nursing services, specified assessments at each visit may be performed by a trained 
home nursing professional or (at sites with established teams) by appropriately qualified site 
personnel at the patient’s home or another suitable location. 
b After initiation of study drug, all adverse events will be reported until 8 weeks after the last 
dose of study drug or until completion of the last scheduled visit, whichever occurs later.  
However, for patients who discontinue study drug prematurely but continue scheduled visits, 
all adverse events will be reported until completion of the last scheduled visit or 8 weeks after 
the last dose of study drug, whichever occurs later.  After this period, the investigator should 
report any serious adverse events that are believed to be related to prior study drug treatment 
(see Section 5.6).  The investigator should follow each adverse event until the event has 
resolved to baseline grade or better, the event is assessed as stable by the investigator, the 
patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
c For all serious infectious adverse events, CBC, differentials and platelets should be 
determined during the disease episode.  Every effort should be made to collect appropriate 
specimens for serology, polymerase chain reaction, or culture to identify the infectious 
organism.  The results of all laboratory assessments performed locally, except for CRP, should 
be reported on the eCRF. 
d Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, 
herbal or homeopathic remedies, nutritional supplements) used by a patient from 4 weeks prior 
to screening until 8 weeks after the last dose of study drug or until completion of the last 
scheduled visit, whichever occurs later.  Patients who start other medications for systemic 
sclerosis (e.g., DMARDs) between treatment discontinuation and Week 48 may remain on 
these medications during the open-label period at the discretion of the investigator.  
e Patients who enter the open-label period at Week 48 must complete the full Week 48 schedule 
of assessments in Appendix 1.  If these patients discontinue after TCZ treatment in the 
open-label period they should undergo a second TD visit and complete the 4 and 8 week 
follow-up visits. 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
121/Protocol WA29767, Version 6 
Appendix 4  
Work Productivity and Activity ImpairmentGeneral Health 
Questionnaire (Version 2.0) 
 
The following questions ask about the effect of your health problems on your 
ability to work and perform regular activities.  By health problems we mean any 
physical or emotional problem or symptom.  Please fill in the blanks or circle a 
number, as indicated. 
 
1. 
Are you currently employed (working for pay)?  
____  NO 
____  YES 
 
If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
 
2. 
During the past seven days, how many hours did you miss from work 
because of your health problems? Include hours you missed on sick days, 
times you went in late, left early, etc., because of your health problems.  Do 
not include time you missed to participate in this study. 
_____HOURS 
 
3. 
During the past seven days, how many hours did you miss from work 
because of any other reason, such as vacation, holidays, time off to 
participate in this study? 
_____HOURS 
 
4. 
During the past seven days, how many hours did you actually work? 
_____HOURS (If “0”, skip to question 6.) 


Appendix 4  
Work Productivity and Activity ImpairmentGeneral Health 
Questionnaire (Version 2.0) (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
122/Protocol WA29767, Version 6 
5. 
During the past seven days, how much did your health problems affect your 
productivity while you were working?  
 
Think about days you were limited in the amount or kind of work you could 
do, days you accomplished less than you would like, or days you could not 
do your work as carefully as usual.  If health problems affected your work 
only a little, choose a low number.  Choose a high number if health 
problems affected your work a great deal.   
 
Consider only how much health problems affected  
productivity while you were working. 
Health 
problems had 
no effect on my 
work 
 
 
 
 
 
 
 
 
 
 
 
Health 
problems 
completely 
prevented me 
from working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 
CIRCLE A NUMBER 
 
6. 
During the past seven days, how much did your health problems affect 
your ability to do your regular daily activities, other than work at a job?  
 
By regular activities, we mean the usual activities you do, such as work 
around the house, shopping, childcare, exercising, studying, etc.  Think 
about times you were limited in the amount or kind of activities you could do 
and times you accomplished less than you would like.  If health problems 
affected your activities only a little, choose a low number.  Choose a high 
number if health problems affected your activities a great deal.   
 
Consider only how much health problems affected your ability  
to do your regular daily activities, other than work at a job. 
Health problems 
had no effect on 
my daily 
activities 
 
 
 
 
 
 
 
 
 
 
 
Health problems 
completely 
prevented me 
from doing my 
daily activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
123/Protocol WA29767, Version 6 
Appendix 5  
Clinician’s Global Assessment 
On a scale of 0–100, where would you rate the overall effect systemic sclerosis has on 
your patient at this time? 
 
PLACE A VERTICALMARK ON THE LINE TO INDICATE YOUR ANSWER. 
 
 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
 
0 
100 
Has no effect at all 
 worst possible effect 
 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
124/Protocol WA29767, Version 6 
Appendix 6  
Health Assessment Questionnaire–Disability Index 
and Scleroderma-Specific Visual Analog Score Scales 
for Scleroderma Health Assessment Questionnaire 
HEALTH ASSESSMENT QUESTIONNAIRE 
 
In this section we are interested in learning how your illness affects your ability to 
function in daily life.   
 
Please check the response which best describes your usual abilities 
OVER THE PAST WEEK: 
DRESSING & 
GROOMING 
Are you able to: 
Without 
ANY 
Difficulty 
With 
SOME 
Difficulty 
With 
MUCH 
Difficulty 
UNABLE 
To Do 
- Dress yourself, 
including tying 
shoelaces and doing 
buttons? 
_____ 
_____ 
_____ 
_____ 
- Shampoo your hair? 
_____ 
_____ 
_____ 
_____ 
 
ARISING 
Are you able to: 
 
 
 
 
- Stand up from a 
straight chair? 
_____ 
_____ 
_____ 
_____ 
- Get in and out of bed? 
_____ 
_____ 
_____ 
_____ 
 
EATING 
Are you able to: 
 
 
 
 
- Cut your meat? 
_____ 
_____ 
_____ 
_____ 
- Lift a full cup or glass to 
your mouth? 
_____ 
_____ 
_____ 
_____ 
- Open a new milk 
carton? 
_____ 
_____ 
_____ 
_____ 
 
WALKING 
Are you able to: 
 
 
 
 
- Walk outdoors on flat 
ground? 
_____ 
_____ 
_____ 
_____ 
- Climb up five steps? 
_____ 
_____ 
_____ 
_____ 
 
 
 
 
 
 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
125/Protocol WA29767, Version 6 
Appendix 6  
Health Assessment Questionnaire–Disability Index 
and Scleroderma-specific Visual Analog Score scales 
for Scleroderma Health Assessment Questionnaire (cont.)  
 
Please check any AIDS OR DEVICES that you usually use for any of these 
activities: 
 
_____ Cane 
_____ Devices used for dressing 
(button hook, zipper pull, long-
handled shoe horn, etc.) 
 
_____ Walker 
_____ Built up or special utensils 
 
_____ Crutches 
_____ Special or built up chair 
 
_____ Wheelchair 
_____ Other 
(Specify:______________________) 
 
Please check any categories for which you usually need HELP FROM 
ANOTHER PERSON: 
 
_____ Dressing and Grooming 
_____ Eating 
 
_____ Arising 
_____ Walking 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
126/Protocol WA29767, Version 6 
Appendix 6  
Health Assessment Questionnaire–Disability Index 
and Scleroderma-Specific Visual Analog Score Scales 
for Scleroderma Health Assessment Questionnaire (cont.)  
Please check the response which best describes your usual abilities 
OVER THE PAST WEEK: 
HYGIENE 
Are you able to: 
Without 
ANY 
Difficulty 
With 
SOME 
Difficulty 
With 
MUCH 
Difficulty 
UNABLE 
To Do 
- Wash and dry your body? 
_____ 
_____ 
_____ 
_____ 
- Take a tub bath? 
_____ 
_____ 
_____ 
_____ 
- Get on and off the toilet? 
 
_____ 
_____ 
_____ 
_____ 
REACH 
Are you able to: 
 
 
 
 
- Reach and get down a 5 pound 
object (such as a bag of sugar) 
from just above your head? 
_____ 
_____ 
_____ 
_____ 
- Bend down to pick up clothing 
from the floor? 
_____ 
_____ 
_____ 
_____ 
 
 
 
 
 
GRIP 
Are you able to: 
 
 
 
 
- Open car doors? 
_____ 
_____ 
_____ 
_____ 
- Open jars which have been 
previously opened? 
_____ 
_____ 
_____ 
_____ 
- Turn faucets on and off? 
_____ 
_____ 
_____ 
_____ 
 
 
 
 
 
ACTIVITIES 
Are you able to: 
 
 
 
 
- Run errands and shop? 
_____ 
_____ 
_____ 
_____ 
- Get in and out of a car? 
_____ 
_____ 
_____ 
_____ 
- Do chores such as vacuuming or 
yardwork? 
_____ 
_____ 
_____ 
_____ 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
127/Protocol WA29767, Version 6 
Appendix 6  
Health Assessment Questionnaire–Disability Index 
and Scleroderma-Specific Visual Analog Score Scales 
for Scleroderma Health Assessment Questionnaire (cont.)  
 
Please check any AIDS OR DEVICES that you usually use for any of these 
activities: 
 
_____ Raised toilet seat 
_____ Bathtub bar 
 
_____ Bathtub seat 
_____ Long-handled appliances for 
reach 
 
_____ Jar opener (for jars 
_____ Long-handled appliances in bathroom 
  
 previously opened) 
_____ Other (Specify: ____________________) 
 
Please check any categories for which you usually need HELP FROM 
ANOTHER PERSON: 
 
_____ Hygiene  
_____ Gripping and opening things 
 
_____ Reach 
_____ Errands and chores 
 
 
We are also interested in learning whether or not you are affected by pain 
because of your illness. 
How much pain have you had because of your illness IN THE PAST WEEK: 
PLACE A VERTICAL (I) MARK ON THE LINE TO INDICATE THE SEVERITY OF THE PAIN. 
NO  
SEVERE 
PAIN 
PAIN 
 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
 
 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
128/Protocol WA29767, Version 6 
Appendix 6  
Health Assessment Questionnaire–Disability Index 
and Scleroderma-Specific Visual Analog Score Scales 
for Scleroderma Health Assessment Questionnaire (cont.) 
 
 
IN THE PAST WEEK, how much have your intestinal problems interfered with 
your daily activities? 
PLACE A VERTICAL (I) MARK ON THE LINE TO INDICATE THE LIMITATION OF ACTIVITY 
INTESTINAL PROBLEMS 
VERY SEVERE 
DO NOT LIMIT ACTIVITIES 
LIMITATION 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
 
IN THE PAST WEEK, how much have your breathing problems interfered with 
your daily activities? 
PLACE A VERTICAL (I) MARK ON THE LINE TO INDICATE THE LIMITATION OF ACTIVITY 
BREATHING PROBLEMS 
VERY SEVERE 
DO NOT LIMIT ACTIVITIES 
LIMITATION 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
 
IN THE PAST WEEK, how much has Raynaud’s interfered with your daily 
activities? 
PLACE A VERTICAL (I) MARK ON THE LINE TO INDICATE THE LIMITATION OF ACTIVITY 
RAYNAUD’S DOES 
VERY SEVERE 
NOT LIMIT ACTIVITIES 
LIMITATION 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
 
IN THE PAST WEEK, how much have your finger ulcers interfered with your 
daily activities? 
PLACE A VERTICAL (I) MARK ON THE LINE TO INDICATE THE LIMITATION OF ACTIVITY 
FINGER ULCERS 
VERY SEVERE 
DO NOT LIMIT ACTIVITIES 
LIMITATION 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
 
OVERALL, considering how much pain, discomfort, limitations in your daily life 
and other changes in your body and life, how severe would you rate your disease 
today? 
PLACE A VERTICAL (I) MARK ON THE LINE TO INDICATE THE LIMITATION OF ACTIVITY 
 
VERY SEVERE 
NO DISEASE 
LIMITATION 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
129/Protocol WA29767, Version 6 
Appendix 7  
Patient’s Global Assessment 
On a scale of 0–100 where would you rate the overall effect your systemic sclerosis has 
on you at this time?  
PLACE A VERTICAL MARK (I) ON THE LINE TO INDICATE YOUR ANSWER 
 
 
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 
 
0 
100 
Has no effect at all 
 worst possible effect 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
130/Protocol WA29767, Version 6 
Appendix 8  
Functional Assessment of Chronic Therapy–Fatigue 
 
 


 
 
Tocilizumab—F. Hoffmann-La Roche Ltd 
131/Protocol WA29767, Version 6 
Appendix 9  
EQ-5D™ 
 
 
 
 
 
 
EQ-5D Health Questionnaire 
(English version for the United States) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
© 1998 EuroQol Group.  EQ-5D™ is a trade mark of the EuroQol Group 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
132/Protocol WA29767, Version 6 
Appendix 9  
EQ-5D™ (cont.) 
By placing a checkmark in one box in each group below, please 
indicate which statements best describe your own health state today. 
 
Mobility 
I have no problems in walking about 
 
 
I have some problems in walking about 
 
 
I am confined to bed 
 
 
 
Self-Care 
I have no problems with self-care 
 
 
I have some problems washing or dressing myself 
 
 
I am unable to wash or dress myself 
 
 
 
Usual Activities (e.g.  work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities 
 
 
I have some problems with performing my usual activities 
 
 
I am unable to perform my usual activities 
 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
 
I have moderate pain or discomfort 
 
 
I have extreme pain or discomfort 
 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
 
I am moderately anxious or depressed 
 
 
I am extremely anxious or depressed 
 
 




 
Tocilizumab—F. Hoffmann-La Roche Ltd 
134/Protocol WA29767, Version 6 
Appendix 10  
Saint George’s Respiratory Questionnaire 
 


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1
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE
ORIGINAL ENGLISH VERSION
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ)
This questionnaire is designed to help us learn much more about how your
breathing is troubling you and how it affects your life. We are using it to find out
which aspects of your illness cause you most problems, rather than what the
doctors and nurses think your problems are.
Please read the instructions carefully and ask if you do not understand anything. Do
not spend too long deciding about your answers.
Before completing the rest of the questionnaire:
Please tick in one box to show how you describe
your current health:
Very good

Good

Fair

Poor

Very poor

Copyright reserved
P.W. Jones, PhD FRCP
Professor of Respiratory Medicine,
St. George’s University of London,
Jenner Wing,
Cranmer Terrace,
Tel. +44 (0) 20 8725 5371
London SW17 ORE, UK.
Fax +44 (0) 20 8725 5955
Tocilizumab—F. Hoffmann-La Roche Ltd 
135/Protocol WA29767, Version 6 


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2
St. George’s Respiratory Questionnaire
PART 1
Questions about how much chest trouble you have had over the past 3 months.
Please tick () one box for each question:
most
days
a week
several
days
a week
a few
days
a month
only with
chest
infections
not
at
all
1.
Over the past 3 months, I have coughed:





2.
Over the past 3 months, I have brought up
phlegm (sputum):





3.
Over the past 3 months, I have had shortness
of breath:





4.
Over the past 3 months, I have had attacks
of wheezing:





5.
During the past 3 months how many severe or very
unpleasant attacks of chest trouble have you had?
Please tick () one:
more than 3 attacks 
3 attacks 
2 attacks 
1 attack 
no attacks 
6.
How long did the worst attack of chest trouble last?
(Go to question 7 if you had no severe attacks)
Please tick () one:
a week or more 
3 or more days 
1 or 2 days 
less than a day 
7.
Over the past 3 months, in an average week, how many good days
(with little chest trouble) have you had?
Please tick () one:
No good days 
1 or 2 good days 
3 or 4 good days 
nearly every day is good 
every day is good 
8.
If you have a wheeze, is it worse in the morning?
Please tick () one:
No 
Yes 
Tocilizumab—F. Hoffmann-La Roche Ltd 
136/Protocol WA29767, Version 6 


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3
St. George’s Respiratory Questionnaire
PART 2
Section 1
How would you describe your chest condition?
Please tick () one:
The most important problem I have 
Causes me quite a lot of problems 
Causes me a few problems 
Causes no problem 
If you have ever had paid employment.
Please tick () one:
My chest trouble made me stop work altogether 
My chest trouble interferes with my work or made me change my work 
My chest trouble does not affect my work 
Section 2
Questions about what activities usually make you feel breathless these days.
Please tick () in each box that
applies to you these days:
True
False
Sitting or lying still 

Getting washed or dressed 

Walking around the home 

Walking outside on the level 

Walking up a flight of stairs 

Walking up hills 

Playing sports or games 

Tocilizumab—F. Hoffmann-La Roche Ltd 
137/Protocol WA29767, Version 6 


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4
St. George’s Respiratory Questionnaire
PART 2
Section 3
Some more questions about your cough and breathlessness these days.
Please tick () in each box that
applies to you these days:
True
False
My cough hurts 

My cough makes me tired 

I am breathless when I talk 

I am breathless when I bend over 

My cough or breathing disturbs my sleep 

I get exhausted easily 

Section 4
Questions about other effects that your chest trouble may have on you these days.
Please tick () in each box that
applies to you these days:
True
False
My cough or breathing is embarrassing in public


My chest trouble is a nuisance to my family, friends or neighbours


I get afraid or panic when I cannot get my breath


I feel that I am not in control of my chest problem


I do not expect my chest to get any better


I have become frail or an invalid because of my chest


Exercise is not safe for me


Everything seems too much of an effort


Section 5
Questions about your medication, if you are receiving no medication go straight to section 6.
Please tick () in each box that
applies to you these days:
True
False
My medication does not help me very much 

I get embarrassed using my medication in public 

I have unpleasant side effects from my medication 

My medication interferes with my life a lot 

Tocilizumab—F. Hoffmann-La Roche Ltd 
138/Protocol WA29767, Version 6 


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5
St. George’s Respiratory Questionnaire
PART 2
Section 6
These are questions about how your activities might be affected by your breathing.
Please tick () in each box that applies to
you because of your breathing:
True
False
I take a long time to get washed or dressed


I cannot take a bath or shower, or I take a long time


I walk slower than other people, or I stop for rests


Jobs such as housework take a long time, or I have to stop for rests


If I walk up one flight of stairs, I have to go slowly or stop


If I hurry or walk fast, I have to stop or slow down


My breathing makes it difficult to do things such as walk up hills, carrying things
up stairs, light gardening such as weeding, dance, play bowls or play golf
My breathing makes it difficult to do things such as carry heavy loads, dig the
garden or shovel snow, jog or walk at 5 miles per hour, play tennis or swim
My breathing makes it difficult to do things such as very heavy manual work,
run, cycle, swim fast or play competitive sports
Section 7
We would like to know how your chest usually affects your daily life.
Please tick () in each box that applies to
you because of your chest trouble:
True
False
I cannot play sports or games 

I cannot go out for entertainment or recreation 

I cannot go out of the house to do the shopping 

I cannot do housework 

I cannot move far from my bed or chair 

Tocilizumab—F. Hoffmann-La Roche Ltd 
139/Protocol WA29767, Version 6 


UK/ English (original) version
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6
St. George’s Respiratory Questionnaire
Here is a list of other activities that your chest trouble may prevent you doing. (You do not have
to tick these, they are just to remind you of ways in which your breathlessness may affect you):
Going for walks or wa king the dog
Doing things at home or in the garden
Sexual intercourse
Going out to church, pub, club or place of entertainment
Going out in bad weather or into smoky rooms
Visiting family or friends or playing with children
Please write in any other important activities that your chest trouble may stop you doing:
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Now would you tick in the box (one only) which you think best describes how your chest affects you:
It does not stop me doing anything I would like to do 
It stops me doing one or two things I would like to do 
It stops me doing most of the things I would like to do 
It stops me doing everything I would like to do 
Thank you for filling in this questionnaire. Before you finish would you please check to see that you have
answered all the questions.
Tocilizumab—F. Hoffmann-La Roche Ltd
140/Protocol WA29767, Version 6 


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
141/Protocol WA29767, Version 6 
Appendix 11  
Scleroderma Skin Patient-Reported Outcome Questionnaire 
 
 
 


Date Prepared: 18-Jun-2014
We would like to know how scleroderma affects your SKIN and how these skin problems has affected 
the way you feel and do things. Please try to think back to your SKIN as you answer these questions. 
questionnaire, as they are more related to how scleroderma affects the blood vessels. 
Note that ulcers on your hands or fingers or Raynaud’s symptoms are NOT the focus of this 
Some questions may have different meanings for different people, please answer according to whatever 
you feel the question means for you. 
1.  How tight has your skin felt?
0
1
2
3
4
5
6
13. How frustrated have you been about your skin? 
0
1
2
3
4
5
6
2.  How swollen have your hands been? 
10. How worried have you been about your skin? 
14. How much have you felt like you lack control over your 
skin’s condition? 
0
1
2
3
4
5
6
3.  How dry has your skin been?
0
1
2
3
4
5
6
4.  How much has your skin been tingling or burning?
0
1
2
3
4
5
6
0
1
2
3
4
5
6
6.  How hard has your skin felt? 
0
1
2
3
4
5
6
7.  How discolored has your skin been?
0
1
2
3
4
5
6
8.  How itchy has your skin felt? 
0
1
2
3
4
5
6
9.  How self-conscious have you been because of your skin? 
0
1
2
3
4
5
6
0
1
2
3
4
5
6
11. How depressed have you been about your skin?
0
1
2
3
4
5
6
12. How much have you not felt like your true self because of 
the way your skin is? 
0
1
2
3
4
5
6
0
1
2
3
4
5
6
5.  How painful has your skin been? 
Over the PAST 4 WEEKS: 
Not at all                        Very Much 
Tocilizumab—F. Hoffmann-La Roche Ltd 
142/Protocol WA29767, Version 6 


Date Prepared: 18-Jun-2014
21. How much has your skin affected the clothes you wear? 
22. How much has your skin interfered with your sex life?
(please answer "Not at all" if this does not apply to you) 
16. How much difficulty have you had with opening or closing 
your mouth because of skin tightness? 
17. How much difficulty have you had with moving parts of 
your body because of skin tightness?
18. How much has your skin’s condition interfered with your daily
activities (examples: work, study, leisure activities)? 
20. How much has your skin interfered with your interactions
with people?
15. How much difficulty have you had doing things with your 
hands because of skin tightness? 
Over the PAST 4 WEEKS: 
Not at all                        Very Much 
0
1
2
3
4
5
6
0
1
2
3
4
5
6
0
1
2
3
4
5
6
0
1
2
3
4
5
6
0
1
2
3
4
5
6
19. How much has your skin prevented you from going out to 
socialize?
0
1
2
3
4
5
6
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Tocilizumab—F. Hoffmann-La Roche Ltd 
143/Protocol WA29767, Version 6 

SAP_001.pdf: 
Official Title:  
A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Assess the Efficacy and Safety of Tocilizumab Versus 
Placebo in Patients With Systemic Sclerosis 
 
NCT Number:   
NCT02453256 
 
Document Dates:  
SAP version 2: 23-Jan-2018 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Tocilizumab—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan WA29767
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP STUDY TO ASSESS THE 
EFFICACY AND SAFETY OF TOCILIZUMAB 
VERSUS PLACEBO IN PATIENTS WITH 
SYSTEMIC SCLEROSIS
PROTOCOL NUMBER:
WA29767
STUDY DRUG:
Tocilizumab (RO4877533)
VERSION NUMBER:
2
IND NUMBER:
112406
EUDRACT NUMBER:
2015-000424-28
SPONSOR
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
DATE FINAL:
Version 1:  8 August 2017
DATE(S) AMENDED:
Version 2:  See electronic date stamp below.
Name                                                             Reason for Signing                              Date and Time
(UTC)
23-Jan-2018 09:28:29
Company Signatory


Tocilizumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan WA29767
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE
The Statistical Analysis Plan WA29767 Version 2 was amended as follows:

Section 2.2.2 (Secondary Efficacy Outcome Measures):  Change from baseline in 
mRSS and FVC at Week 24 were listed as exploratory endpoints in the protocol.  
However, the analysis of these endpoints is part of the multiplicity testing procedure 
and the resulting P-values will not be considered exploratory.  The mRSS and FVC 
at Week 48 are key endpoints, and showing a treatment effect following 24 weeks of 
treatment is considered important.

Section 3.2.1 (Definition of SSc-related Complications):  For SSc-related 
complications clarified that these are adverse events that are adjudicated 
independently by committee before the study is unblinded.

Section 4.6.1 (Controlling for Type 1 Error):  Changed the order of secondary 
endpoints in the multiplicity hierarchy 

Section: 4.6.3.2 (Time to Treatment Failure):  Clarified that time to an event will be 
relative to first dose of study drug, rather than date of randomisation as specified in 
the protocol since only treatment emergent adverse events are being adjudicated.  
Defined censoring for the analysis (previously omitted).

For events deemed SSc-related complications only serious events will be included 
in the time to treatment failure endpoint.  Although non serious Grade 3 and 4 
events are also being adjudicated, the information made available on these events 
to the adjudication committee is limited to eCRF data as detailed patient narratives 
are not available for non-serious events.

Included time to event analysis of the components of time to treatment failure.

Defined a sensitivity analysis of time to treatment failure where discontinuation from 
study for the following reasons will also be classed as a treatment failure: death, 
lack of efficacy, lost to follow up, withdrawal by subject, physician decision (whereas 
withdrawal from study for the following reasons will not be counted as an event: 
adverse event, pregnancy, protocol violation, non-compliance, study terminated by 
Sponsor, other).

Clarified that Serious SSc-related complications will be summarised by system 
organ class (SOC), and will be further subcategorised descriptively for assessment 
of internal organ involvement (including, but not limited to, cardiac disease, renal 
disease, and GI disease).

Section 4.6.3.3 (Binary Endpoints):  For the binary endpoints of ≥20%, 40%, and 
60% improvement in mRSS at Week 48, there will be an additional analysis 
whereby data from patients post initiation of immuno-modulation therapy (e.g., 
DMARDs and/or Biologics) will be censored so that these patients will become non 
responders in the analysis.


Tocilizumab—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan WA29767

Section 4.6.5.1(Sensitivity to Primary Estimand):  Added details of a tipping point 
analysis for the primary estimand, and expanded on details of the pattern mixture 
model to allow programming of this analysis to be clear from the SAP text. As a 
sensitivity to the primary estimand, a linear regression analysis (with HuberWhite 
sandwich errors) of change from baseline in mRSS at Week 48 is added.

Section 4.6.5.3 (Sensitivity to Secondary Endpoints):  Added tipping point analyses 
and pattern mixture models to the secondary endpoints included in the multiplicity 
testing procedure.

Section 4.6.5.3.2 (Subgroup Analyses):  Added further subgroup analyses for 
additional disease characteristics and baseline demography; namely baseline 
mRSS, sex, age, race, and region.

Removed Appendix 3: Details of date imputations will be included in the 
programming documentation

Appendix 10:  Added details of the CochranMantelHaenszel test for difference in 
proportions.
Additional minor changes have been made to improve clarity and consistency.


Tocilizumab—F. Hoffmann-La Roche Ltd
4/Statistical Analysis Plan WA29767
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 7
2.
STUDY DESIGN........................................................................................... 7
2.1
Protocol Synopsis.................................................................... 8
2.2
Outcome Measures ................................................................. 8
2.2.1
Primary Efficacy Outcome Measures ...................................... 8
2.2.2
Secondary Efficacy Outcome Measures.................................. 8
2.2.3
Exploratory Efficacy Outcome Measures................................. 9
2.2.4
Pharmacokinetic Outcome Measures.................................... 10
2.2.5
Pharmacodynamic Outcome Measures................................. 10
2.2.6
Immunogenicity Outcome Measures ..................................... 10
2.2.7
Safety Outcome Measures .................................................... 10
2.3
Determination of Sample Size ............................................... 10
2.4
Analysis Timing ..................................................................... 11
3.
STUDY CONDUCT..................................................................................... 11
3.1
Randomization Issues ........................................................... 11
3.2
Data Monitoring ..................................................................... 12
3.2.1
Definition of SSc-Related Complications ............................... 12
4.
STATISTICAL METHODS .......................................................................... 12
4.1
Analysis Populations ............................................................. 12
4.1.1
All Patients............................................................................. 12
4.1.2
Intent-to-Treat Population...................................................... 12
4.1.3
Pharmacokinetic-Evaluable Population ................................. 13
4.1.4
Safety Population .................................................................. 13
4.2
Analysis of Study Conduct..................................................... 13
4.3
Analysis of Treatment Group Comparability .......................... 14
4.3.1
Demographics ....................................................................... 14
4.3.2
Disease Characteristics......................................................... 14
4.4
Data Cut for Analyses............................................................ 15
4.5
Visit Windows ........................................................................ 15


Tocilizumab—F. Hoffmann-La Roche Ltd
5/Statistical Analysis Plan WA29767
4.6
Efficacy Analysis.................................................................... 17
4.6.1
Controlling for Type 1 Error ................................................... 17
4.6.2
Primary Efficacy Endpoint...................................................... 18
4.6.2.1
Definition of Modified Rodnan Skin Score ............................. 18
4.6.2.2
Statistical Analysis................................................................. 18
4.6.2.3
Stratification Factors.............................................................. 19
4.6.3
Secondary Efficacy Endpoints............................................... 19
4.6.3.1
Continuous Endpoints ........................................................... 19
4.6.3.2
Time to Treatment Failure ..................................................... 21
4.6.3.3
Binary Endpoints ................................................................... 22
4.6.4
Exploratory Efficacy Endpoints.............................................. 22
4.6.5
Sensitivity Analyses............................................................... 25
4.6.5.1
Sensitivity to Primary Estimand ............................................. 25
4.6.5.2
Alternative Estimand.............................................................. 27
4.6.5.3
Sensitivity to Secondary Endpoints ....................................... 27
4.6.5.4
Immuno-Modulating Treatments............................................ 27
4.6.5.5
Subgroup Analyses ............................................................... 28
4.7
Pharmacokinetic Analyses..................................................... 29
4.8
Exposure Effect Analyses ...................................................... 29
4.9
Pharmacodynamic Analyses ................................................. 29
4.10
Safety Analyses..................................................................... 30
4.10.1
Adverse Events ..................................................................... 30
4.10.2
Deaths ................................................................................... 32
4.10.3
Laboratory Data..................................................................... 32
4.10.4
Lipid Data .............................................................................. 32
4.10.5
Vital Signs.............................................................................. 33
4.10.6
Immunogenicity ..................................................................... 33
4.10.7
Digital Ulcers ......................................................................... 34
4.11
SSc-Specific Autoantibody Panel .......................................... 34
4.12
Missing Data.......................................................................... 34
4.13
Interim Analyses .................................................................... 34
5.
REFERENCES ........................................................................................... 35


Tocilizumab—F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan WA29767
LIST OF TABLES
Table 1
Time Windows for Assigning Assessment Study Days to 
Study Visits (Weeks) for Efficacy (mRSS and FVC) ................... 16
Table 2
National Cholesterol Education Program (ATPIII) Thresholds .... 33
Table 3
Blood Pressure JNC 7 Category Criteria .................................... 33
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 8
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 37
Appendix 2
Schedule of Assessments:  Screening, Baseline, and 
Double-Blind Treatment Period................................................... 46
Appendix 3
Schedule of Assessments:  Open-Label Treatment Period ........ 52
Appendix 4
Schedule of Assessments:  Patients Who Have Discontinued 
Study Drug Prematurely.............................................................. 56
Appendix 5
HAQ-DI ....................................................................................... 58
Appendix 6
St. George’s Respiratory Questionnaire ..................................... 59
Appendix 7
FACIT-FATIGUE......................................................................... 61
Appendix 8
SkinPRO ..................................................................................... 62
Appendix 9
EQ-5D-3L.................................................................................... 63
Appendix 10
WPAI-GH .................................................................................... 64
Appendix 11
Cochran-Mantel-Haenszel Test .................................................. 65


Tocilizumab—F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan WA29767
1.
BACKGROUND
This document describes the statistical methods to be used for the analysis of the 
clinical efficacy, clinical safety, pharmacokinetic (PK), and pharmacodynamic (PD) data 
from the Phase III Study WA29767 (FocuSSced).  The study drug tocilizumab 
(TCZ, RO4877533) is a recombinant humanized monoclonal antibody directed against 
the human interleukin 6 (IL-6) receptor.  Rheumatoid arthritis (RA) and systemic 
sclerosis (SSc) have been linked to the effects of IL-6 on cell proliferation.
Study WA29767 is a multicenter, randomized, double-blind, placebo-controlled, two-arm, 
parallel-group trial in patients with SSc.  There is a 48-week blinded period followed by a 
48-week open-label period.
The primary endpoint is the difference in the change in modified Rodnan skin score 
(mRSS) from baseline at Week 48.
This document only describes the statistical methods and analyses used in the reporting 
of the double-blind phase of the study, up to Week 48.  The analysis of biomarkers, 
including skin biopsies, will be covered in a separate document.  The exploratory data 
analysis up to Week 96 will be described in a separate analysis plan.
2.
STUDY DESIGN
This Phase III, multicenter, randomized, double-blind, placebo-controlled, two-arm, 
parallel-group study is designed to assess the efficacy and safety of TCZ in patients with 
SSc.  The study consists of two periods:  a 48-week, double-blind, placebo-controlled 
period, followed by a 48-week open-label treatment period.  Patients will be randomized 
in a 1:1 ratio to receive SC injections of 162 mg of TCZ QW (once weekly) or placebo 
QW for 48 weeks during the double-blind treatment period.  During the open-label 
treatment period, all patients will receive SC injections of 162 mg of TCZ QW for up to 
48 weeks.  Patients receive their first dose of open-label treatment at Week 48.  
Approximately 210 patients will be enrolled at approximately 75 global sites.  The study 
design is presented schematically in Figure 1.


Tocilizumab—F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan WA29767
Figure 1
Study Schema
Adult patients 
with systemic 
sclerosis 
(n = 210) 
TCZ 162 mg SC QW
(n =105)
Placebo SC QW
(n = 105)
Week 48
Escape Therapy 
from Week 16 (for 
FVC) or from 
Week 24 (for 
mRSS) a
Randomization (1:1 ratio)
Day 1
Screening (40 days)
Double-Blind Treatment Period 
(48 weeks)
Open-Label Treatment Period 
(48 weeks)
TCZ 162 mg 
SC QW
Week 96
Primary Endpoint:  
mRSS at Week 48
Baseline
FVCforced vital capacity; mRSSmodified Rodnan Skin Score; nnumber; QWonce 
weekly; SCsubcutaneous; TCZtocilizumab.
aAlso includes escape therapy for worsening of systemic sclerosis.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1 and includes the study objectives, inclusion and 
exclusion criteria, outcome measures, and statistical methods as stated in the Protocol.
2.2
OUTCOME MEASURES
All assessments and procedures are detailed in the Protocol.
2.2.1
Primary Efficacy Outcome Measures
Change in mRSS from baseline at Week 48.
2.2.2
Secondary Efficacy Outcome Measures

Proportions of patients with 20%, 40%, and 60% improvement in mRSS at 
Week 48 compared with baseline

Change in forced vital capacity (FVC) from baseline to Week 48

Change in Health Assessment Questionnaire Disability Index (HAQ-DI) from 
baseline to Week 48

Change in Patient’s Global Assessment from baseline to Week 48


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
Change in Physician’s Global Assessment from baseline to Week 48

Time to treatment failure at Week 48
Analyses of the following endpoints, which were listed as exploratory endpoints in the 
protocol, have been included in the multiplicity testing procedure and the resulting p-
values will not be considered exploratory (Section 4.6.1):

Change in FVC (forced vital capacity) from baseline to Week 24

Change in mRSS from baseline to Week 24
2.2.3
Exploratory Efficacy Outcome Measures

Proportions of patients who achieve a response, as determined by the investigator 
using Combined Response Index for Systemic Sclerosis (CRISS), at Week 48

Change in the Visual Analogue Scale (VAS) component of the Scleroderma Health 
Assessment Questionnaire (SHAQ) from baseline to Week 24 and baseline to 
Week 48

Change in Work Productivity and Activity Impairment Questionnaire: General Health 
(WPAI-GH) score from baseline to Week 24 and baseline to Week 48

Change in EuroQol 5-Dimension Questionnaire with three levels of severity 
(EQ-5D-3L) score from baseline to Week 24 and baseline to Week 48

Change in total score and subscores of Saint George’s Respiratory Questionnaire 
(SGRQ) from baseline to Week 48

Change in total and domain scores of the Scleroderma Skin Patient-Reported
Outcome (SkinPRO) questionnaire from baseline to Week 48 (administered to 
patients in North America only)

Change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score 
from baseline to Week 48.

Change in high-resolution computed tomography (HRCT) fibrosis score from 
baseline (based on HRCT scan performed within 12 months prior to screening) to 
Week 48

Change in diffusion capacity of the lung for carbon monoxide (DLco) from baseline to 
Week 48

Proportion of patients with 15% decline in observed DLCO at Week 48 relative to 
baseline

Proportion of patients with 15% decline in percentage of predicted DLCO at 
Week 48 relative to baseline

Proportion of patients with 10% decline in observed FVC at both Week 24 and 
Week 48 relative to baseline

Proportion of patients with 10% decline in percentage of predicted FVC at Week 24 
and at Week 48 relative to baseline


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
Proportion of patients achieving MCID (change 0.22 in the HAQ-DI ) in the HAQ-DI 
at Week 48
2.2.4
Pharmacokinetic Outcome Measures
The PK and exposure-effect outcome measures for this study are as follows:

Predose observed serum TCZ concentration at baseline and at specified timepoints 
thereafter (Ctrough).

Correlation between PK parameters (e.g., Ctrough) for TCZ and efficacy (e.g., mRSS 
or any positively trending efficacy outcome noted in Sections 2.2.1 and 2.2.2, safety 
(CTC grades for neutrophils, platelets, ALT, and AST, or any negatively trending 
safety outcome noted in Section 2.2.7), or immunogenicity outcome measures, as 
relevant.  Ctrough may be categorized into exposure bins (e.g., high, medium, and low) 
to assist in identifying trends.
2.2.5
Pharmacodynamic Outcome Measures
The PD outcome measures for this study are as follows:

Serum sIL-6R, IL-6, erythrocyte sedimentation rate (ESR) and C reactive protein 
(CRP) levels predose at baseline and at subsequent time points after initiation of 
study drug.
2.2.6
Immunogenicity Outcome Measures
The immunogenicity outcome measures for this study are as follows:

Incidence of anti-drug (TCZ) antibodies (ADA) during the study relative to the 
prevalence of anti-TCZ antibodies at baseline

Correlation between ADA status and efficacy, safety or PK measures
2.2.7
Safety Outcome Measures
The safety evaluations will consist of the following:

Nature, frequency, and severity of adverse events (AEs) and serious AEs

Frequency of deaths

Incidence of specific laboratory abnormalities

Change from baseline in digital ulcer count

Frequency of SSc-related complications as determined by the Clinical Adjudication 
Committee
2.3
DETERMINATION OF SAMPLE SIZE
A sample size of approximately 105 patients in the TCZ group and 105 patients in the 
placebo group (a total of 210 patients) will give power in the range of 75% to 80%, 
(allowing for an estimated patient dropout rate of approximately 15% to 20%) to detect 
a between-group difference of 3.55 units (common standard deviation of 8.43) in mean 
change in mRSS from baseline to Week 48 using a two-group t-test, with a
5% two-sided significance level.  The minimal detectable difference (smallest treatment 


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difference that would give a statistically significant result) under these assumptions, and 
with a patient dropout rate of 20%, is approximately 2.6.
The loss of power at Week 48 due to performing a futility analysis based on mRSS at 
Week 24 (see Section 4.12) on a subset of patients was minimal, at approximately 3% 
based on simulations.
The following power calculations for key secondary endpoints use the maximum 
available alpha according to the multiplicity procedure (Section 4.6.1).
The required sample size of 210 patients based on the primary endpoint, gives 94% 
power for change from baseline in percent predicted FVC at week 48 at the 4% two-
sided significance level, assuming 15% dropout (mean difference 0.043, common 
standard deviation 0.075, WilcoxonMannWhitney two sample test).
Assuming 70% of patients on TCZ are event free at 48 weeks of follow up, 50% of 
patients event free on placebo (hazard ratio [HR] 0.52) gives a power of 80% at the 
two-sided 4.5% significance level for the time to treatment failure endpoint based on 
210 patients with 15% dropout at 48 weeks.
Under the same assumptions for number of patients and dropouts the power for the 
change from baseline in HAQ-DI at Week 48 is 65% using a two-group t-test at the 
two-sided 5% significance level (mean difference 0.181, common standard deviation 
0.517).
2.4
ANALYSIS TIMING
The primary study analysis will occur when the last patient has either withdrawn or 
completed his or her Week 48 visit, and will be based on cleaned data for all patients up 
to and inclusive of their Week 48 assessment date, as well as safety follow-up data for 
patients that withdrew prior to Week 48.  A Week 48 Clinical Study Report (CSR) based 
on these analyses will be produced.
There will be a final analysis and CSR when all patients have reached the end of the 
open-label period (Week 96) of the study and/or have completed their safety follow-up
visits.  The analyses for Week 96 data will be covered in a separate Statistical Analysis 
Plan.
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
At baseline, patients will be randomized (stratified by IL-6 level (10; 10 pg/mL) at 
screening) to study drug assignment and assigned randomization and study drug 
assignment numbers through an interactive voice/web response system (IxRS).  
Patients will be randomized in a 1:1 ratio to receive either 162 mg of subcutaneous (SC) 


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TCZ weekly (QW) (Group A) or SC placebo QW (Group B) for 48 weeks.  To ensure 
randomization is carried out correctly, Roche Internal User Acceptance Testing of the 
IxRS system will be conducted prior to the first patient being enrolled into the study.  In 
addition, the independent data coordinating center (iDCC) will review IxRS data as part 
of the independent data monitoring committee (iDMC) preparation.
3.2
DATA MONITORING
An external iDMC will review unblinded safety data and will convene at least two times 
per year.  Analyses required for the iDMC’s data review will be performed as described 
in the iDMC Charter.
A review for safety will be performed at the same time as the futility analysis when 
approximately 76 patients have completed 24 weeks of treatment (see Protocol 
Section 6.9).
3.2.1
Definition of SSc-Related Complications
A Clinical Adjudication Committee (AC), an independent and blinded expert clinician 
panel, adjudicated serious AEs and Grade 3 and 4 AEs with regard to their classification 
as SSc-related complications. Serious AEs only (not Grade 3 and 4 events that are 
without patient narratives) positively adjudicated as SSC-related complications will be 
used for the analysis of time to treatment failure.
These adjudication decisions are captured in the electronic Case Report Form (eCRF), 
and the review of these adverse events will be completed before study unblinding. Full
details of the adjudication committee process have been documented in a charter which 
will be made available.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
Disposition summaries will be based on the All Patients population. Analysis of safety 
data will be based on the safety population. The primary analysis population for efficacy 
will be the intention to treat (ITT) population.
4.1.1
All Patients
The All Patients population will include all subjects randomized in the study.
4.1.2
Intent-to-Treat Population
The ITT (intent-to-treat) population will be a modified ITT and include all subjects 
randomized in the study who received any study drug. The treatment group for this 
population will be defined according to the treatment assigned at randomization by IxRS.


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4.1.3
Pharmacokinetic-Evaluable Population
The PK population will include all patients who received at least one TCZ injection and 
had at least one PK sample with detectable results.
4.1.4
Safety Population
The safety population will include all patients who received any study drug and provided 
at least one post-dose safety assessment (withdrawal, AE, death, laboratory 
assessment, vital signs). Patients will be included in the treatment arm for the treatment 
most frequently received at the time of the analysis.
4.2
ANALYSIS OF STUDY CONDUCT
The patients excluded from the safety and ITT populations will be summarized, including 
the reason for exclusion, by treatment group.  A summary of enrolment by country and 
investigator name will be produced.
The number of patients that completed or discontinued from the study by Week 48, 
including a reason for discontinuation, will be summarized by treatment group.  A listing 
of withdrawals for the Week 48 analysis will be produced.
Total duration of patient participation in the study will be summarized for the safety 
population at Week 48.  Total duration on study will be calculated as the date of the last 
safety assessment (including study drug exposure) up to and including the Week 48 cut 
date, minus the date of first injection of study drug, plus 1 day.
Duration of study treatment will be summarized for the safety population at Week 48,
calculated as the date of the last injection up to and including the Week 48 cut date, 
minus the date of first injection of study drug, plus 1 day.
Compliance will be summarized by dose intensity (the number of doses actually received 
divided by the expected number of doses), the cumulative dose, and the number of 
patients with missed doses.
The number and frequency of patients first receiving immuno-modulating treatments 
(e.g., disease-modifying anti-rheumatic drugs [DMARDS]) will be summarized by visit up 
to Week 48 (refer to Section 4.6.5.3).
A listing of the number of patients in each treatment group that were randomized 
according to an incorrect stratification value given at baseline will be produced at 
Week 48 (IxRS data will be compared to the clinical database).
A listing of patients with major protocol deviations including those that entered the study 
without meeting all inclusion/exclusion entry criteria will be produced.


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4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
To descriptively assess the comparability of treatment arms (placebo versus TCZ 
162 mg SC) at baseline, summary tables will be produced for the safety population for 
clinically important baseline demographic and disease characteristics by treatment 
received.  If it is found that there is a large difference in the number of patients in the 
safety population compared to the ITT population, additional summaries will be produced 
as randomized.
These summary tables will include number of patients, mean, standard deviation, and 
median for continuous demographic/disease characteristics and number and percentage 
of patients for categorical characteristics.
Demographic and baseline disease characteristics will be summarized as described in 
the following sections.
4.3.1
Demographics

Sex

Age

Height

Weight

Race 

Ethnicity

Country

Reproductive status

Smoking history
4.3.2
Disease Characteristics

IL-6

IL-6 level (10; 10 pg/mL)

Duration of SSc

mRSS

CRP

ESR

Platelets

HAQ-DI

Physician’s Global VAS

Patient’s Global VAS

% predicted FVC


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
% predicted DLCO (hemoglobin corrected)

Anti-topoisomerase (positive 20 U/mL)

Anti-RNA polymerase (positive 20 U/mL) 

Anti-centromere (positive 1:40 dilution)

Anti-nuclear antibodies (ANA) (positive 1:40 dilution).
The number of patients positive for hepatitis B surface antigen (HBsAg) and hepatitis C 
antibody (anti-HCV) at screening will be summarized for the safety population.
Medical history data, including surgery and procedures and baseline conditions, will be 
summarized descriptively by treatment group using the safety population. Descriptive 
summaries of any previous and concomitant treatment will be produced by treatment 
group. A glossary showing the mapping of investigator verbatim terms to diseases will 
be produced for the medical history data included in the analysis for Week 48.
4.4
DATA CUT FOR ANALYSES
For each patient, the day of first injection of study treatment will be designated study 
day 1.  Each subsequent assessment point will be assigned a study day calculated as 
(date of assessmentdate of first injection of study treatment) 1.
Efficacy datasets will be cut at the Week 48 exposure date plus 28 days. The exposure 
date will be the date of the Week 48 study drug injection, identified as the injection that 
occurs within the protocol time window of 337 (/7 days). Typically, this will be the first 
open label dose. If more than one injection occurs in the time window then the study 
day of the earliest open label drug will be used, or, if there is no open label dose in the 
time window, the day of the latest injection in the window will be used. If the Week 48 
study drug injection is missing the data sets will be cut at study day 337 plus 28 days.
The efficacy data within the cut datasets that is included for analysis, in particular for the 
Week 48 visit, is described in Section 4.5.
For safety, the data will be cut at the day prior to the Week 48 exposure date or the day 
prior to the first dose of open label treatment, whichever is later. If the Week 48 
exposure date is missing, the data will be cut at study day 337. All data including data 
collected in safety follow-up visits or spontaneously reported AEs will be included in 
safety summaries.
There will also be a final analysis of all available data including all visits up to Week 96 
and the 8 weeks of safety follow-up, which will be described in a separate analysis plan.
4.5
VISIT WINDOWS
All patient assessments within the cut efficacy datasets that are collected by scheduled 
visits will be assigned to a study week using the actual study day of the assessment; this 


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includes withdrawal visits and any unscheduled visits. Time windows will be continuous 
from the midpoint between two consecutive study visits to the next midpoint, and will be 
dependent on the schedule of assessments (as given in Appendix 2, Appendix 3, and 
Appendix 4) for each variable independently. An example table of time windowing for 
the mRSS and FVC is shown below (Table 1). Mapping of other variables will similarly 
be based on the scheduled visits. Data will never be mapped to visits for which the 
assessment was not scheduled in the Protocol.
Table 1
Time Windows for Assigning Assessment Study Days to Study 
Visits (Weeks) for Efficacy (mRSS and FVC)
Study Visit
Scheduled 
Study Day 
7days
Efficacy Time Window
Baseline
0
1
Week 8
56
1 to84
Week 16
112
84 to140
Week 24
168
140 to210
Week 36
252
210 to294
Week 48
336
294 *to study day of first OL dose
*Except for FVC, HRCT and DLco, where the upper bound of week 48 is the cut date, 
i.e. week 48 exposure + 28 days regardless of open label dosing.
For FVC assessments of insufficient quality, repeats were requested during study 
conduct within 4 weeks of the initial assessment, therefore for FVC (and HRCT, DLco) 
all data within the cut (Week 48 exposure plus 28 days) will be mapped to Week 48. 
Any efficacy assessments that occurred after the study day of first open label dose that 
is used in the analysis or summary tables will be flagged in the relevant listing.
For all efficacy assessments except for mRSS, if more than one particular efficacy 
assessment occurs within the same time window, then the nearest non-missing 
assessment to the nominal time point will be assigned to that visit.  If there are two (or
more) efficacy assessments that occur the same time away from the nominal time point, 
then the latest assessment will be assigned to that visit.  For multiple mRSS 
assessments that occur within the same time window, in order to account for repeated 
assessments to allow assessor consistency the latest assessment within a time window 
will be used.
For calculations of percent predicted DLCO, the hemoglobin value nearest to the DLCO
assessment will be used.
If more than one particular safety assessment (e.g., laboratory result or vital sign) occurs 
within the same time window then the worst value will be assigned to the visit. The last 


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value from screening will be used for baseline assessments of safety if there is no 
baseline (study day 1) value.
For summaries of data not collected by visit, such as AEs, medical history, and 
concomitant medications, all data in the Week 48 safety data cut will be included.
4.6
EFFICACY ANALYSIS
4.6.1
Controlling for Type 1 Error
The following diagram shows the order and weighting applied to the testing of the key 
clinical endpoints, including primary, secondary and some exploratory endpoints.  This 
roll-back approach will preserve the overall type I error of 5%.  Please note that no 
adjustment to the alpha level for mRSS at Week 24 will be made to account for the 
futility analysis (Section 4.12).
Assuming the primary efficacy endpoint is significant at the 5% level, then percent 
predicted FVC (ppFVC) will be weighted at 0.8 and will hence be tested at a 4% alpha.  
Both time to treatment failure and HAQ-DI will be weighted at 0.1 so that if ppFVC fails 
to meet significance at the 4% level, each can still be tested at a minimum of 0.5% 
significance level (0.005).  If ppFVC is significant, then the alpha will be transferred to 
the time to treatment failure endpoint which can then be tested at a 4.5% alpha.  If 
ppFVC and time to treatment failure are significant at the 4% and 4.5% alpha 
respectively, then the alpha will be passed to the HAQ-DI hypothesis and HAQ-DI will be 
tested at an alpha of 5%.  If ppFVC is not significant, but time to treatment failure is, the 
0.5% alpha can be transferred to HAQ-DI which can then be tested at the 1% level.  If 
the time to treatment failure endpoint is not significant then HAQ-DI will be tested at an 
alpha level of 0.5%.


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If HAQ-DI is significant at the acquired significance level then the other secondary 
endpoints listed below HAQ-DI will be tested in order at the alpha level passed down by 
HAQ-DI. If the endpoint being tested is non-significant at the acquired significance level 
then that end point and those below in the hierarchy will be non-significant, although 
p-values will still be produced. If HAQ-DI is non-significant, none of the subsequent 
secondary endpoints will be claimed for statistical significance and instead descriptive 
p-values will be presented.
If the primary endpoint is not significant at the 5% level the testing will stop.
4.6.2
Primary Efficacy Endpoint
The estimand of interest for the primary analysis is the difference between treatment
arms in the mean change in the mRSS at Week 48 for the ITT population in the 
regimens as actually taken. The study has been designed to continue to capture 
efficacy data on patients who discontinue study drug prematurely and may receive 
additional immuno-modulating treatments (e.g., DMARDs) and in patients who receive 
escape therapies (i.e., immuno-modulating treatment in addition to study drug) during 
the double-blind treatment period.  All data will be included in the primary analysis. The 
primary analysis specified above assumes a missing-at-random missing-data
mechanism whereby patients who are lost to follow-up from the TCZ arm will tend to 
have similar efficacy to that of patients on TCZ who remained in the study.
4.6.2.1
Definition of Modified Rodnan Skin Score
The mRSS is a measure of skin thickness across 17 different body sites and has a 
range of 0 to 51 in whole units (see Protocol Section 4.5.9 for further details). There will 
be no imputation of missing data prior to the analysis detailed in Section 4.6.2.2 and the 
total scores as collected in the site electronic device will be used, rather than derived 
total scores. All missing assessments will be adjusted for within the model fitting 
process.
4.6.2.2
Statistical Analysis
The primary efficacy endpoint is the change in mRSS from baseline at Week 48.  The 
mean change from baseline will be analyzed using a restricted maximum 
likelihood-based repeated measures approach.  The analysis will include the fixed, 
categorical effects for treatment, visit, the stratification factor IL-6 level (10; ≥10 pg/mL) 
at screening, IL-6 level at screening-by-visit interaction, and treatment-by-visit 
interaction, as well as the continuous covariates of baseline mRSS score and baseline 
mRSS score–by–visit interaction.  Analyses will be implemented in SASusing 
PROC MIXED.  An unstructured covariance structure will be used to model the within-
patient errors.  The Kenward–Roger approximation (Kenward and Roger 1997) will be 
used to estimate the denominator degrees of freedom.
The primary treatment comparison will be the contrast between treatments at the 
Week 48 timepoint.  Least square means, along with a difference in means, a 95% CI for 


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the difference in means, and the p-value will be reported.  The significance test will be 
based on a two-sided 0.05.
4.6.2.3
Stratification Factors
Efficacy analyses will adjust for the stratification factor at randomization, which is the 
categorical variable IL-6 level (10; 10 pg/mL) at screening.  Data from the IxRS used 
for the randomization, not the actual value of IL-6 at screening, will be used.
4.6.3
Secondary Efficacy Endpoints
Further details on the definition of secondary endpoints are provided in Section 6.4.2 of 
the Protocol.
4.6.3.1
Continuous Endpoints
For all continuous secondary endpoints, except for FVC, the primary method of analysis 
for change from baseline will be a repeated measures model to compare the treatment 
effect at Week 48, as described above in Section 4.6.2.2.
Least square means, along with a difference in means, a 95% CI for the difference in 
means, and the p-value will be reported at Week 48.
The least square means of the change from baseline by treatment group in all primary 
and secondary continuous endpoints, along with 95% CIs will be plotted and tabulated 
by visit up to Week 48.
No imputation will be made for missing assessments prior to analyses.  All missing data 
will be adjusted for within the model fitting process where applicable.
The primary method of analysis for change from baseline in FVC endpoints will be a 
non-parametric analysis method based on the expectation that the distribution of data 
will be non-normal.  Change from baseline to Week 48 in percent predicted 
FVC (ppFVC) will be analyzed using a Van Elteren test stratified by screening IL-6 level 
(10; 10 pg/mL).  The median change from baseline for each treatment group and the 
corresponding 95% CI for the median will be presented for ppFVC, along with the Van 
Elteren p-value.  A cumulative distribution plot will be produced for both FVC endpoints 
(absolute and percent predicted).
The median change from baseline, along with 95% CIs will be summarized and plotted 
by visit up to Week 48.
Additional parametric analyses consistent with the method used for other secondary 
endpoints will also be conducted for the FVC.
Forced Vital Capacity (FVC):
Percent predicted FVC and change from baseline in percent predicted FVC will be 
calculated by visit. The predicted FVC is derived using height (ht) in (cm) at screening, 


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age at screening, sex, and race (Caucasian, Mexican American, and African American). 
An example calculation is given below (Hankinson et al. 1999).
(Caucasian men, 20 years of age)
FVC0.1933(0.00064 age)(0.000269 age age)(0.00018642 ht ht)
(Caucasian women, 18 years of age)
FVC0.3560(0.01870 age)(0.000382 age age)(0.00014815 ht ht)
For Asian and Asian-American patients, a correction factor of 0.88 is applied (Hankinson 
et al. 2010).  A plot of the mean change from baseline by treatment group by visit for the 
percent predicted FVC will be produced up to Week 48.
HAQ-DI:
The HAQ-DI is a 20-item, validated questionnaire used to assess difficulty in performing 
activities of daily living.  The HAQ-DI assesses eight domains of physical functioning: 
Dressing and Grooming (2 items), Hygiene (3 items), Arising (2 items), Reach (2 items), 
Eating (3 items), Grip (3 items), Walking (2 items), Common Daily Activities (3 items). 
The questions assess usual abilities ranging from 0 “without any difficulty” to 3 “unable to 
do.”  A negative change from baseline indicates improvement.  The Minimal Clinically 
Important Difference (MCID) for improvement ranges from 0.140.22 (Khanna et 
al. 2006; Pope 2011).
The total HAQ-DI score will be calculated according to the developer’s scoring algorithm 
(see Appendix 5 for details).
Patients in Japan were administered the Japanese version of the HAQ-DI, known at the 
J-HAQ.  The two questionnaires contain the same evaluation components and are 
comparable.  The pain VAS aspect of the HAQ-DI (which is not part of J-HAQ) was not 
implemented for this study and therefore HAQ-DI and J-HAQ will be combined for 
analysis.
HAQ-DI will also be summarized descriptively as a binary endpoint based on the 
proportion of patients achieving an improvement from baseline0.22.
Patient Global Assessment:
The Patient’s Global Assessment represents the patient’s overall assessment of his or 
her current SSc status on a 100 mm horizontal VAS.  The extreme left end of the scale 
indicates “has no effect at all” (symptom free), and the extreme right end indicates “worst 
possible effect”.  A negative change from baseline indicates improvement. The MCID 
has been reported by Sekhon and Pope 2010 to be 6.70.
Physician Global Assessment: 
The Physician Global Assessment represents the clinician’s overall assessment of the 
patient’s current SSc status on a 100 mm horizontal VAS. The extreme left end of the 
scale indicates “has no effect at all” (symptom free), and the extreme right end indicates 


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“worst possible effect”.  Higher scores indicate worse disease in terms of severity, 
damage, or overall disease, but there is no standardization for the scale (Pope 2011).  
A negative change from baseline indicates improvement.  Expert consensus has 
suggested a range of 813 units for the MCID (Gazi et al. 2007).
4.6.3.2
Time to Treatment Failure
Time to treatment failure was previously defined in the protocol as the time from 
randomization to the time of first: 

death

decline in percent predicted FVC >10% relative to baseline

increase in mRSS 20% and an increase in mRSS of 5 points relative to baseline

occurrence of a predefined SSc-related complication as adjudicated by the Clinical 
Adjudication Committee
Whichever occurs first, during the Week 48 double-blind treatment period.
However, specifically, time to an event will be relative to first dose of study drug, rather 
than date of randomisation as only treatment emergent AEs were adjudicated, and as 
described in Section 3.2.1, for events deemed SSc-related complications only serious 
events will be included in the time to treatment failure endpoint.
Time to treatment failure will be summarized descriptively by Kaplan-Meier curves and 
the median, 25th, and 75th percentiles (where possible) and 95% CI for the median.  
The treatment groups will be compared using a Cox proportional hazards model 
adjusting for the stratification factor applied at randomization. A 95% CI for the HR and 
a p-value will be produced. Data from patients who discontinue from the study prior to 
Week 48 will be censored from the study day after the discontinuation date. Data post 
initiation of immuno-modulation therapy (e.g., DMARDs and/or Biologics) and/or data 
collected after stopping study drug will not be censored.
These analyses will be repeated, where appropriate, for the individual components of 
time to treatment failure; namely death, decline in percent predicted FVC 10% relative 
to baseline, relative increase in mRSS 20%, and an increase in mRSS of 5 points, or 
occurrence of a predefined serious SSc-related complication.
An analysis of time to treatment failure excluding serious infections from the adjudicated 
serious SScrelated complications will also be conducted.
A sensitivity analysis of time to treatment failure will be performed where discontinuation 
from study for the following reasons will also be classed as a treatment failure: death, 
lack of efficacy, lost to follow-up, withdrawal by subject, physician decision (whereas 
withdrawal from study for the following reasons will not be counted as an event: AE, 
pregnancy, protocol violation, non-compliance, study terminated by sponsor, other).


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The proportion of patients with each of the components of time to treatment failure will 
be summarized descriptively. Serious SSc-related complications will be summarised by 
system organ class (SOC), and will be further subcategorised descriptively for 
assessment of internal organ involvement (including, but not limited to, cardiac disease, 
renal disease, and GI disease). All SSc-related complications (including adjudicated 
non-serious CTC grade 3 and 4 AEs) will be listed.
4.6.3.3
Binary Endpoints
For binary secondary endpoints, such as proportion of patients with 40% improvement 
in mRSS at Week 48 compared to baseline, the weighted difference in proportion will be 
presented, together with the 95% CI using the extended Mantel-Haenszel method and 
the p-value calculated using the CochranMantelHaenszel test, adjusting for the 
stratification factor, IL-6 level (10; 10 pg/mL) at screening (see Appendix 11 for
statistical formulas) (Koch et al. 1989).  Patients who have a missing Week 48 
assessment will be considered non-responders in the analysis.
For mRSS binary endpoints only there will be an additional analysis whereby data from 
patients post initiation of immuno-modulation therapy (e.g., DMARDs and/or Biologics) 
will be censored so that these patients will become non-responders in the analysis.
4.6.4
Exploratory Efficacy Endpoints
All exploratory endpoints will be summarized and where applicable exploratory p-values
will be produced using the same methodology as specified for the secondary endpoints 
in Section 4.6.3 unless stated otherwise.
Combined Response Index for Systemic Sclerosis
The Combined Response Index for Systemic Sclerosis (CRISS) will be summarized as 
both a binary and continuous endpoint.  There will be no imputation of missing data.  
The calculation for the CRISS score is a two-step process and is as follows (Khanna et 
al. 2016):
Step 1: if a patient develops any of the following they will be assigned a probability of 
improving equal to 0.0

new scleroderma renal crisis

decline in ppFVC 15% relative to baseline confirmed by a second FVC within one 
month, HRCT to confirm ILD (if previous HRCT did not show ILD) and FVC 80% of 
predicted attributable to systemic sclerosis

new onset of left ventricular failure (defined as left ventricular ejection fraction 45%) 
requiring treatment, attributable to systemic sclerosis

new onset of pulmonary arterial hypertension on right–sided heart catheterization 
requiring treatment, attributable to systemic sclerosis


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Step 2: for the remaining patients, compute the predicted probability of improving for 
each subject using the following equation (equation to derive predicted probabilities from 
a logistic regression model):
−5.54 −0.81 ∗∆ + 0.21 ∗∆% −0.40 ∗∆ −0.44 ∗∆! −3.41 ∗∆#$%!&'
1 + −5.54 −0.81 ∗∆ + 0.21 ∗∆% −0.40 ∗∆ −0.44 ∗∆! −3.41 ∗∆#$%!&'
where, MRSS indicates the change in MRSS from baseline to follow-up, FVC denotes the 
change in ppFVC from baseline to follow-up, Pt-glob indicates the change in patient 
global assessment, MD-glob denotes the change in physician global assessment, and 
HAQ-DI is the change in HAQ-DI. All changes are absolute change (Time2-Timebaseline).
Subjects for which the predicted probability is greater or equal to 0.60 are considered 
improved, while subjects for which the predicted probability is below 0.60 are considered 
non-improved.  Continuous analysis will be performed using non-parametric methods.
Scleroderma Health Assessment Questionnaire
The SHAQ is composed of the HAQ-DI scale (or J-HAQ scale for Japanese patients) 
with the addition of five scleroderma-specific VAS scales to assess additional elements
of SSc disease.  Each VAS item is rated separately, with higher scores indicating more 
severe disease (range 0100 mm).  The five VAS scales are: 1) intestinal disease, 
2) breathing problems, 3) Raynaud syndrome, 4) digital ulcers, and 5) overall disease.  
These VAS scales will all be analyzed independently.  A negative change from baseline 
indicates improvement.
Saint George’s Respiratory Questionnaire
Saint George’s Respiratory Questionnaire contains 50 items distributed over three 
scales: respiratory symptom severity (symptoms); impairment in patient activity as a 
result of respiratory symptoms (activity); and impact of respiratory symptoms on overall 
function and wellbeing (impact).  Each scale is scored from 0 to 100, with the total score 
representing the weighted average of these three subscores.
Each item in the SGRQ has specific weight (lowest possible weight0, highest100).  
Scores for the three scales and total are calculated using the assigned weights.  The 
numerator and denominator for the total and each scale are comprised of individual item 
weights, minus specific scale weights.  Additional details pertaining to missing data and 
scoring are described in Appendix 6.
FACIT Fatigue Scale
The FACIT fatigue scale is a 13-item measure of fatigue, with patients scoring each item 
on a 5-point scale.  A positive change from baseline indicates improvement.  
FACIT-Fatigue total score will be calculated according to developer’s algorithm 
(Appendix 7)


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SkinPRO Questionnaire
The SkinPRO is a 22-item, patient-completed questionnaire developed to measure skin 
health status as experienced by scleroderma patients with skin involvement.  There are 
4 separate domains: skin symptoms, physical function, social function, and emotional 
response. Although the 22-item was administered, it will be scored in accordance with 
the most recent validation work from the literature, which uses 18 items as described in
Appendix 8 (Man A et al. 2017). There are 4 separate sub-scales: physical effects, 
physical limitations, emotional effects, and social effects. The response set for all items 
is a 7-point ordinal scale, ranging from “Not at all” to “Very much”.  Total and subscale 
scores will be calculated as described in Appendix 8. The questionnaire was only 
administered in patients in North America so results will be summarized for that 
subgroup only.
EuroQol 5-Dimension Questionnaire
The EQ-5D-3L is a generic, preference-based health utility measure with questions 
about mobility, self-care, usual activities, pain/discomfort, and anxiety/depression that 
are used to build a composite of the patient’s health status.  It is a concise scale that has 
performed well for patients with SSc (Gualtierotti et al. 2016).  The EQ-5D-3L will be 
utilized in this study for economic modeling.  A positive change from baseline indicates 
improvement.  The EQ-5D will be scored according to the developer’s guidelines 
(EQ-5D-3L User Guide) using UK utility values.  For further details of EQ-5D see 
Appendix 9.
Work Productivity and Activity ImpairmentGeneral Health
The WPAI-GH questionnaire is a six-item scale, asking patients to estimate the amount 
of time that their work and daily activities were affected by their health over the previous 
7 days.  The WPAI yields four types of scores:
1.
Absenteeism (work time missed)
2.
Presenteesism (impairment at work / reduced on-the-job effectiveness)
3.
Work productivity loss (overall work impairment / absenteeism plus presenteeism)
4.
Activity Impairment
WPAI scores will be calculated according to developer’s algorithm described in
Appendix 10.
DLCO
Predicted DLCO values are derived using height (ht) at screening (inches), age at 
screening, and patient sex.  The formula for predicted values for females and males are 
presented below (Pesola et al. 2004):
Females: 2.2382(0.111 age)(0.4068 ht)
Males: 12.9113(0.229 age)(0.418 ht)


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The predicted value is then adjusted for the hemoglobin level (g/dL) at each visit using 
the following formula to give predicted hemoglobin adjusted values
(MacIntyre et al. 2005):
Females: DL,CO,predicted for HbDL,CO,predicted(1.7 Hb/(9.38Hb))
Males: DL,CO,predicted for HbDL,CO,predicted(1.7 Hb/(10.22Hb))
A plot and summary of the median change from baseline by treatment group by visit for 
the percent predicted DLCO will be produced up to Week 48.
HRCT
Change from baseline to Week 48 in Quantitative Lung Fibrosis Score of the lobe of 
most involvement (QLF-LM) as determined by HRCT scans will be summarized for the 
exploratory endpoint of change in HRCT.
The lobe of most involvement is determined as the lobe with the worst (highest) score at 
baseline out of the 5 lobes (left lower, left upper, right lower, right middle, right upper) for 
the specified parameter of interest (QLF in this case).
Other parameters collected from HRCT readings may also be summarized and change 
from baseline of QLF-LM and other HRCT parameters may be summarised separately 
by patients with and without ILD at baseline.
HRCT scans that were done prior to baseline may be permitted in place of a baseline 
scan in some cases.
4.6.5
Sensitivity Analyses
4.6.5.1
Sensitivity to Primary Estimand
If found to be statistically significant (p0.05), the primary endpoint will be re-analyzed 
assuming that missing data is missing not at random (MNAR), rather than MAR, via 
tipping-point sensitivity analyses implemented using multiple imputation.
The PROC MI procedure in SAS using the Markov chain Monte Carlo method will be 
used to partially impute data and convert the dataset into a monotone missing data 
pattern.  One thousand monotone datasets will be imputed using the seed 1689, by 
treatment group, including the stratification factor as an indicator variable.
After imputing non-monotone data, the missing values remaining will be imputed using 
the PROC MI monotone regression procedure in SAS.  This regression based approach 
imputes missing data in a sequential manner with the use of univariate models; for each 
time point, a regression model based on all patients who have observations (imputed or 
observed) available at this time point is fitted and used to impute observations for 
patients with missing values at this time point. The variables included in the imputation 
model will be treatment group, the stratification factor, IL-6 level (10; 10 pg/mL) at 
screening, and the mRSS scores by visit. The seed that will be used is 13820647. Only 


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one complete dataset will be imputed per monotone dataset, resulting in one thousand 
complete datasets. 
Tipping-point analysis will be implemented by adding (or subtracting) a constant delta to 
the MAR imputed values at the Week 48 analysis time point in the direction of lack of 
efficacy for TCZ and in the direction of improvement for placebo. A range of evenly 
spaced deltas will be used to adjust imputed values in the TCZ and placebo arms 
independently in order to produce a grid of delta adjustments to missing values in both 
arms. The size of the deltas will be chosen pragmatically based on the primary analysis, 
so that adjustments that lead to non-significance are encompassed in the grid. In 
particular, assuming MAR on placebo, i.e., no delta adjustment, an adjustment on the 
TCZ arm that just tips the analysis into non-significance will be included.
For each pair of delta adjustments (TCZ and placebo) each dataset will be analyzed 
separately using the same analysis model specified for the primary endpoint and the 
results combined using the PROC MIANALYZE procedure in SAS. The resulting point 
estimates of treatment effect, 95% CIs and corresponding p-values under each pair of 
deltas will be tabulated.
As an additional sensitivity analysis to the primary estimand a pattern-mixture model will 
be implemented, using multiple imputations, whereby missing data in the placebo arm 
will be imputed using a missing-at-random assumption and missing data in the TCZ arm 
will be imputed in a stepwise fashion using multiple calls to PROC MI with a monotone 
regression statement using data from placebo-treated patients as the basis for the 
imputation (Ratitch and O'Kelly 2011).  This imputation method assumes that patients 
who are lost to follow-up in the TCZ arm, that stop study drug and may revert to 
standard of care, will have a trajectory similar to that of patients in the placebo arm.  This 
is a reasonable assumption as there is a lack of proven effective treatment for patients to 
transition to. It also assumes that these patients will not have an immediate worsening 
of outcome upon study drug discontinuation.  Conservatively, missing data on the 
placebo arm is assumed missing at random, since withdrawals on placebo in the Phase 
II Fasscinate Study on average had worse outcomes at the point of withdrawal than 
patients that continued in the study.
Firstly, the data will be imputed to be monotone exactly as described for the tipping point 
analysis. Successive calls to PROC MI will then be made, using seed 298 for all calls, 
starting with TCZ patients with missing data for the first post-baseline visit. As a first 
step these patients will be selected out and pooled with the placebo patients. A 
regression model based on all placebo patients who have observations available at this 
time point will be fitted and used to impute observations for TCZ patients with missing 
values at this time point. The imputation model will include the stratification factor, IL-6 
level (10; 10 pg/mL) at screening, in addition to the baseline mRSS score, and first 
post baseline mRSS score. In step two, TCZ patients with the second post-baseline 
time point missing will be selected out and pooled with the placebo group. As well as 


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the stratification factor, the model will include the second post-baseline visit mRSS 
scores, as well as prior observed or imputed mRSS scores from the previous step. Data 
across all the visits will be imputed in this way, to result in a thousand imputed datasets 
(there will only be one imputation per monotone dataset). Each dataset will be analyzed 
separately using the same analysis model specified for the primary endpoint and the 
results combined using the PROC MIANALYZE procedure in SAS. The resulting point 
estimate of treatment effect, 95% CI and corresponding p-value will be presented
(Ratitch and O'Kelly 2011).
A linear regression analysis (with HuberWhite sandwich errors) of change from 
baseline in mRSS at week 48 will be performed. The model will include the stratification 
factor, baseline mRSS score, and treatment group.
4.6.5.2
Alternative Estimand
A second estimand for the difference in change from baseline in mRSS will also be 
determined. Data post initiation of immuno-modulation therapy (e.g., DMARDs and/or 
Biologics) and/or data collected after stopping study drug will be censored and the mixed 
model repeated measurement (MMRM) model described in Section 4.6.2.2 will be 
implemented.  The estimand of interest for this analysis is the difference between 
treatment arms in the mean change in the mRSS at Week 48 for the ITT population if the 
randomized treatments were taken as directed.
4.6.5.3
Sensitivity to Secondary Endpoints
Similarly, tipping point analyses and pattern mixture models, using the same seeds and 
number of imputations will be performed for all the continuous variables in the multiplicity 
testing procedure shown in Section 4.6.1 with the exception of the time to treatment 
failure endpoint. For each endpoint the analysis method of the imputed datasets will be 
the same method as specified for the multiplicity testing procedure.
For the binary endpoints of the difference in proportions of patients with 20%, 40%, 
and 60% improvement in mRSS at Week 48 compared with baseline, a tipping point 
analysis will also be performed. Patients with missing change from baseline in mRSS at 
Week 48 are non-responders for the primary analysis method. These patients will be 
incrementally set to responders independently for each treatment arm. The number of 
patients with missing data set to responders per treatment arm will be presented in a 
grid, and the resulting difference in proportions, 95% CI and p-value will be tabulated.
4.6.5.4
Immuno-Modulating Treatments
Introduction of an immuno-modulating treatment such as a DMARD or Biologic will be 
identified using preferred terms (e.g., mycophenolate mofetil).
A summary and listing of immuno-modulating treatments will be produced.


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The number and percent of patients that initiated at least one additional 
immuno-modulating therapy will be summarized by the following categories (not mutually 
exclusive) and further sensitivity analyses may be performed on these subgroups as 
appropriate:

Discontinued study drug

Continued study drug

Met mRSS protocol escape criterion

Met FVC protocol escape criterion

Met mRSS and FVC protocol escape criteria

Did not meet either mRSS or FVC protocol escape criteria
4.6.5.5
Subgroup Analyses
The analysis of the change from baseline in the mRSS will be conducted using a 
repeated measures model to compare the treatment effect at Week 48 for the subgroups
IL-6 at screening (10 pg/ml and 10 pg/ml) which will include the treatment-by-IL-6 at 
screening interaction in addition to the fixed and random effects specified for the primary 
analysis.
In addition, separate analyses of the change from baseline in mRSS will be conducted
using a repeated measures model to compare the treatment effect at Week 48 for the 
subgroups listed below.  For each subgroup analysis, the same model as used for the 
primary analysis will be used but will also include the parameter of interest as a class 
variable at baseline, as well as the baseline parameter of interest-by-treatment 
interaction. The treatment difference for each subgroup and a 95% CI will be presented.

baseline CRP (0.6, 0.6 mg/dL)

baseline ESR (28, 28 mm/hr)

baseline platelets (330, 330109/L)

baseline disease duration (2, 2 years)

baseline mRSS score (25, 25)

Sex (Male, Female)

baseline Age (<65,65)

An observed data summary of mean change from baseline in mRSS at Week 48 by 
treatment group for the following categories of race will be produced (American 
Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other 
Pacific Islander, White, Other)

An observed data summary of mean change from baseline in mRSS at Week 48 by 
treatment group for the following regions will be produced (North America, Western 
Europe, Central Europe, Latin America, Japan)


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Specific safety and efficacy endpoints described in the PK section below will be 
produced by TCZ serum concentration quartiles.  Other subgroup analyses may be 
performed as appropriate.
4.7
PHARMACOKINETIC ANALYSES
For the Week 48 analysis, TCZ serum concentrations (Ctrough) will be summarized by visit 
using descriptive statistics, means, medians, standard deviations, minimum, maximum, 
and coefficients of variation (standard deviation/mean)*100).  Plots of mean and 
standard deviation of TCZ (Ctrough) by visit will also be presented.  Tocilizumab 
concentration at Week 48 will be summarized based on tertiles of the values.  Effect of 
ADA positivity on serum TCZ concentrations will be assessed by comparing the 
individual concentration-time profiles of ADA positive patients (definition in 
Section 4.10.6) with the individual profiles of the remainder of the population.  Nonlinear 
mixed-effect modelling (NONMEM) will be used to estimate population and individual 
PK parameters and the influence of various covariates on these parameters will be 
investigated. Major baseline covariates will be identified and the dependence of 
PK parameters on each covariate will be described. Secondary PK parameters, such as 
AUC, Cmax, and Ctrough at steady state, will be listed and summarized.  Results of the 
popPK analysis will be reported separately from the CSR.
4.8
EXPOSURE EFFECT ANALYSES
In order to characterize exposure-efficacy relationships, continuous responses (e.g., 
mRSS and all positively trending secondary efficacy endpoints as noted in Section 2.2) 
will be summarized based on exposure tertiles (high, medium, and low exposures) in the 
active treatment group and compared to placebo patients.  In addition, for binary 
secondary endpoints (e.g., patients who show a 20% improvement in mRSS at 
Week 48) a comparison of observed TCZ Ctrough at Week 48 grouped in tertiles, in 
responders will be compared to non-responders.
In order to characterize exposure-safety relationships, summary tables of AEs by tertiles 
of observed TCZ Ctrough at Week 48 will be produced.  The proportion of patients by 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) grade (categorization based on worst post-baseline value) (NCI 2003) will be 
summarized by tertiles of observed TCZ Ctrough for neutrophils, platelets, ALT (alanine 
transaminase), and AST (aspartate aminotransferase) at Week 48.
An evaluation of exposure-response (PD, safety, efficacy) endpoints, where relevant, will 
additionally be conducted as part of the population based analysis and summarized in 
the popPK report.
4.9
PHARMACODYNAMIC ANALYSES
For the Week 48 analysis, sIL-6R, IL-6, CRP, and ESR levels and change from baseline 
will be summarized by visit using descriptive summary statistics, including the means, 


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medians, ranges, and standard deviations. For these PD parameters, plots of mean and 
standard deviation or standard errors by visit will also be presented.
4.10
SAFETY ANALYSES
Safety data will be summarized using descriptive statistics under the treatment received 
most frequently; no statistical analyses comparing safety data between two groups will 
be conducted.  All safety data in the Week 48 safety data cut will be included for the 
primary analysis.  
Since data entry for the study is ongoing, safety data that are not associated with a 
specific visit may be updated after the analysis time point for an individual patient.  For 
example, an adverse event (AE) that starts on or prior to the Week 48 visit for a specific 
patient will be included in the Week 48 analysis.  It is possible that the AE may be 
updated beyond Week 48 for the patient (e.g., an AE that was ongoing could be given 
an end date).  Such updates would be reported in the Week 96 final CSR.
4.10.1
Adverse Events
Medical Dictionary for Regulatory Activities (MedDRA) will be used as the thesaurus for 
AEs and disease codes, and the GNE drug dictionary will be used for treatments.  A 
glossary of these codes will be produced.  Because all outputs produced for the 
Week 48 and Week 96, reporting will be produced using the latest versions of MedDRA 
and the GNE drug dictionary; there may be discrepancies between the different reporting 
events for the same AE/medication.
Only treatment-emergent AEs will be summarized.  Treatment-emergent events are 
defined as those AEs with observed or imputed onset date on or after the start date of 
trial treatment.  Only where the most extreme intensity is greater than the initial intensity 
(or if most extreme intensity is not missing and initial intensity is missing) will events with 
an onset date prior to the start of trial treatment be considered treatment-emergent.  An 
AE with a completely missing start date will be assumed to be treatment-emergent 
unless the AE has a complete non-imputed end date that is prior to study day 1.
Adverse events will be coded and tabulated by system organ class (SOC) and/or 
preferred term.  In tabulations, preferred terms and their associated SOC will be 
presented in order of descending frequency summed across the treatment arms.  
Adverse events will also be tabulated by severity and relationship to study medication as 
indicated by the investigator.  Adverse events leading to withdrawal, AEs leading to 
death, and AEs leading to a dose modification or interruption will be summarized.
Adverse event rates per 100 patientyears exposure (defined as the number of 
events/total duration in the study multiplied by 100) will be calculated for each AE 
preferred term and SOC, along with the corresponding 95% CIs for the rates of the SOC 
(exact based on the χ2 distribution [Ulm et al. 1990]).


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The following will also be summarized, and listings produced where required:

Serious AEs

AEs leading to withdrawal

AEs leading to death

AEs leading to a dose modification or interruption

Non-serious AEs occurring in 5% of patients in at least one treatment group

Injection-site reactions (ISRs) by severity

Hypersensitivity AEs (AEs occurring immediately after or within 24 hours of the 
end of an injection that are not deemed “unrelated” to study treatment) 

Clinically significant Hypersensitivity AEs (AEs occurring immediately after or 
within 24 hours of the end of an injection that are not deemed “unrelated” to 
study treatment and that led to study treatment discontinuation)
Adverse events of special interest will be defined using published Standard MedDRA 
Queries (SMQs) or AE Grouped Terms (AEGTs) defined by Roche Drug Safety.  The 
groupings of AEs will include but may not be limited to the following:

All and Serious Infections (Infections and Infestations SOC)

Opportunistic infections [OI] (Roche Standard AEGT Basket)

Malignancies (Malignant or Unspecified tumors SMQ Narrow) confirmed by medical 
review

Malignancies excluding NMSC (confirmed by medical review)

All and/or Serious Hepatic events (Hepatic failure, Fibrosis, and Cirrhosis and Other 
Liver Damage-related Conditions SMQ Wide or Hepatitis, non-infectious SMQ Wide)

Stroke (Ischemic Cerebrovascular Conditions SMQ Narrow or Hemorrhagic 
Cerebrovascular SMQ Narrow)

Myocardial infarction [MI] (MI SMQ Narrow)

Anaphylactic reaction events occurring immediately after or within 24 hours of 
injection of tocilizumab, summarized separately according to the following:
–
Roche Standard AEGT Basket according to Sampson’s criteria (Sampson et al. 
2006)
–
Anaphylactic Reaction SMQ Narrow 

Gastrointestinal perforations (Gastrointestinal perforation SMQ Wide) confirmed by 
medical review

All and/or Serious Bleeding events (Hemorrhage terms [excluding laboratory terms] 
SMQ Wide)

Demyelinating events (Demyelination SMQ Narrow)
A glossary showing the mapping of investigator verbatim terms to preferred terms will be 
produced for all AEs included in the analysis for Week 48. For each AE of special 


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interest table based on SMQs/AEGTs, a corresponding listing of the preferred terms that 
comprise the SMQ will be produced.  A listing of deaths and SAEs that occur during the 
Week 48 double-blind period will be produced at Week 48.
The time to first non-infectious SAE (SAEs excluding infections), and time to first 
infection SAE will be presented as KM plots.
4.10.2
Deaths
Details of any deaths will be presented in the form of an individual patient listing and 
descriptive summaries, including a summary of the death rate per 100 patient-years of 
exposure (defined as the number of deaths/total duration in the study multiplied by 100) 
based on the safety population.
4.10.3
Laboratory Data
All laboratory data will be converted to SI units.  The International Standard for the 
Handling and Reporting of Laboratory Data COG 3007 (Version 3.0) will be used to 
implement reference ranges and marked abnormalities for laboratory data where 
possible.  Summary tables will detail the actual values and changes from baseline of the 
laboratory parameters over visits up to Week 48.  Summaries of the number of patients 
by CTC grade for hematology and hepatic laboratory parameters will be produced (for 
summaries referring to NCI CTCAE (National Cancer Institute Common Terminology 
Criteria for Adverse Events) grading ([NCI 2003], Version 4.0 will be used) by Week 48.  
For liver laboratory tests, the number of patients will be summarized by category for 
baseline and worst post baseline result by Week 48.
The number of patients with marked abnormalities will be summarized by Week 48.
4.10.4
Lipid Data
Fasting lipids consist of total cholesterol, triglycerides, HDL, and LDL, and these will be 
summarized separately from the other laboratory parameters when referencing gradings 
or shifts.
Threshold for the presentation of lipid data are defined by the National Cholesterol 
Education Program Adult Treatment Panel III (NCEP 2001), and are shown in Table 2.


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Table 2
National Cholesterol Education Program (ATPIII) Thresholds
LDL (mg/dL)
100
(optimal)
100129
(normal)
130159
(borderline high)
160
(high)
HDL (mg/dL)
40
(low)
4059
(normal)
60
(high)
Total cholesterol 
(mg/dL)
200
(desirable)
200239
(borderline high)
240
(high)
Triglycerides 
(mg/dL)
150
(normal)
150499
(high)
500
(very high)
ATPIIIAdult Treatment Panel III; HDLhigh density lipoprotein; LDLlow density lipoprotein.
4.10.5
Vital Signs
Summary tables will detail the actual values and changes from baseline of the laboratory 
parameters over visits up to Week 48 for pulse rate, systolic blood pressure, and 
diastolic blood pressure (after patient is supine for at least 5 minutes).
Blood pressure will also be summarized by visit using the following JNC 7 categories (as 
presented in Table 3):
Table 3
Blood Pressure JNC 7 Category Criteria
Blood Pressure Category
Criteria
Normal
SBP120 mmHg and DBP80 mm Hg
Pre-hypertension
120SBP140 mmHg or 80DBP90 mmHg
Stage I hypertension
140SBP160 mmHg or 90DBP100 mmHg
Stage II hypertension
SBP160 mmHg or DBP100 mmHg
SBPsystolic blood pressure
4.10.6
Immunogenicity
Samples for the detection of anti-TCZ antibodies (ADA, anti-drug antibodies, here refers 
to anti-TCZ antibodies) and analysis of immunogenicity will be taken at baseline and at 
Weeks 1, 8, 16, 24, 36, and 48 (or study withdrawal/completion).  For patients 
experiencing anaphylaxis or hypersensitivity reactions that result in withdrawal from the 
study, a sample for detection of ADA will be taken at the time of the event and also at 
least 8 weeks after the last dose of TCZ/placebo.
Blood samples will be analyzed for the evaluation of immunogenicity of TCZ by a 
number of different assays.  Samples that are positive for ADA in the screening assay 
will be further analyzed by a confirmation assay to confirm specificity.  If the confirmation 
assay is positive, two additional tests will be performed:  a neutralizing assay for the 
ability to inhibit the activity of TCZ and a test for ADA of the IgE isotype.
The immunogenicity analyses will include patients with at least one sample analyzed 
using immunogenicity assay.  The numbers and proportions of ADA positive patients 
after TCZ exposure during the study (including both the treatment and follow-up periods) 


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will be summarized by treatment group.  Patients are considered to be ADA positive if 
they are ADA negative at baseline but develop an ADA response following study drug 
administration (treatment-induced ADA response).
The relationship between ADA status and safety, efficacy, and PK (Section 4.7) 
endpoints will be analyzed and reported descriptively via subgroup analyses.
4.10.7
Digital Ulcers
The digital ulcer count at baseline and the change in digital ulcer category by visit will be 
summarized by treatment group.  A shift table of the number of digital ulcers by visit from 
the previous visit by treatment arm will be produced.
4.11
SSC-SPECIFIC AUTOANTIBODY PANEL
The SSc-specific autoantibody panel will include tests for the following antibodies:  anti-
topoisomerase (positive 20 U/mL), anti-RNA polymerase (positive 20 U/mL),
anti-PM/Scl (positive 20 U/mL), anti-U1 snRP (positive 20 U/mL), anti-histone (positive
1 U/mL), and anti-centromere (positive 1:40 dilution).  Shift tables of the number of 
patients positive for each antibody at screening and Week 48 will be summarized for the 
safety population.
4.12
MISSING DATA
Methods for handling missing data for key efficacy variables are presented in 
Section 4.6.  Partial dates for AEs, concomitant medications, laboratory assessments,
and medical history will be imputed.
4.13
INTERIM ANALYSES
A futility analysis was conducted to which the sponsor remained blinded. The analysis 
was conducted after the first 76 patients reached the Week 24 visit or withdrew and was 
based on the change from baseline in mRSS at Week 24. The futility analysis was 
conducted by an external statistical group, iDCC (independent Data Co-ordinating 
Centre) and was reviewed by the iDMC. Details of the futility analysis, along with the 
rationale and timing are documented in the study iDMC charter. The beta spending 
function used and all other details of the futility analysis were exactly as specified in the 
charter; however the maximum information of the planned design was altered in the 
SEQ DESIGN procedure in SAS from the assumed 1.064 that had been specified in the 
charter upon instructions to the iDCC from the blinded Sponsor. The amount of 
information about an unknown parameter available from the data can be measured by 
the Fisher information. For a maximum likelihood statistic, the information level is the 
inverse of its variance. The maximum information is the information level at the final 
analysis stage of the group sequential trial, if the trial continued as planned.  When 
designing the interim the predicted maximum information can be estimated from the 
sample size and an assumed standard deviation. The boundary and operating 


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characteristics of the interim were based on the information fraction at the interim being 
approximately 0.5.
The original design of this interim was based on the Phase II study data assuming a 
common standard deviation of 6.76 at Week 24. However the standard deviation of the 
pooled blinded week 24 data at the time of the interim snapshot was 5.43, much smaller 
than that originally assumed when designing the interim; thus the variability was lower in 
the Phase III study than had been expected. Assuming a standard deviation in both 
treatment arms of 5.43 and 98 patients per arm completing to Week 24 the standard 
error assumed for the final analysis at Week 24 was re-evaluated by the Sponsor; giving 
an expected maximum information of 1.66. This adjustment was made in order that the 
interim fraction would be approximately 0.5, in accordance with the planned boundary. 
The interim was conducted in December 2016, with a “continue” decision made by the 
iDMC on 16 December 2016. The Sponsor remained blinded throughout, with only a 
continue decision communicated. All documentation, including the closed meeting 
minutes and recommendations from the iDMC, will be made available after study 
unblinding.
5.
REFERENCES
[NCEP] National Cholesterol Education Program (NCEP).  Executive summary of the 
third report of the National Cholesterol Education Program (NCEP) Expert Panel 
on detection, evaluation, and treatment of high blood cholesterol in adults (Adult 
Treatment Panel III).  JAMA 2001;285:248697.
Common Terminology Criteria, Version 3.0, National Cancer Institute, USA, Published 
December 12, 2003.
EQ-5D-3L User Guide: Basic information on how to use the EQ-5D-3L instrument. 
(https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-3L_UserGuide_2015.pdf)
Gazi H, Pope JE, Clements P, et al. Outcome measurements in scleroderma: results 
from a Delphi exercise. J Rheumatol 2007;34:501–9.
Gualtierotti R, Ingegnoli F, Scalone L, et al., Feasibility, acceptability and construct 
validity of EQ-5D in systemic sclerosis. Swiss Med Wkly 2016;146: w14394.
Guideline on multiplicity issues in clinical trials EMA/CHMP/44762/2017.
Hankinson JL, Kawut SM, Shahar E, et al. Performance of American Thoracic Society-
recommended spirometry reference values in a multiethnic sample of adults: the 
multi-ethnic study of atherosclerosis (MESA) lung study. Chest 
2010;137(1):138-45.
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample 
of the general U.S. population. Am J Respir Crit Care Med 1999;159:179–87.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 1997;53:983–97.


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Khanna D, Beroccal VJ, Giannini EH, et al. The American College of Rheumatology 
Provisional Composite Response Index for Clinical Trials in Early Diffuse 
Cutaneous Systemic Sclerosis. Arthritis and Rheumatology 2016;68(2):299311.
Khanna D, Furst DE, Hays RD, et al. Minimally important difference in diffuse systemic 
sclerosis:  results from the D-penicillamine study. Ann Rheum Dis 
2006;65(10):1325-9.
Koch GG, Car GJ, Amara A, et.al. Categorical data analysis. In StateBerry, D., A., 
Statistical Methodology in the Pharmaceutical Sciences, New York:Marcel Dekker, 
1989:389-473.
MacIntyre N, Crapo R, Viegi G, et al. Standardisation of the single-breath determination 
of carbon monoxide uptake in the lung. Eur Respir J 2005;26:720–35.
Man A, Correa JK, Ziemek J, et al. Development and Validation of a Patient-reported 
Outcome instrumen t for skin involvement in patients with systemic sclerosis. Ann 
Rheum Dis 2017.
Pesola GR, Sunmonu Y, Huggins G, et al. Measured diffusion capacity versus prediction 
equation estimates in blacks without lung disease. Respiration 2004;71:484–92.
Pope J. Measures of systemic sclerosis (scleroderma). Arthritis Care Res 
2011;63(Suppl 11):S98111.
Ratitch B, O'Kelly M.  Implementation of pattern-mixture models using standard 
SAS/STAT procedures.  Proceedings of the PharmaSUG conference: 
2011 May 811.
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis:  summary report – Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol 2006;117:391-7.
Sekhon S, Pope J. The minimally important difference in clinical practice for 
patient-centered outcomes including Health Assessment Questionnaire, fatigue, 
pain, sleep, Global Visual Analog Scale, and SF-36 in scleroderma. J Rheumatol 
2010;37:5918.
Ulm K. A simple method to calculate the confidence interval of a standardized mortality 
ratio (SMR). Am J Epidemiol 1990;131:373−5.


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Appendix 1
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF TOCILIZUMAB 
VERSUS PLACEBO IN PATIENTS WITH SYSTEMIC SCLEROSIS
PROTOCOL NUMBER:
WA29767
VERSION NUMBER:
6
EUDRACT NUMBER:
2015-000424-28
IND NUMBER:
112406
TEST PRODUCT:
Tocilizumab (RO4877533)
PHASE:
III
INDICATION:
Systemic sclerosis
SPONSOR:
F.  Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
The primary efficacy objective for this study is as follows:

To evaluate the efficacy of tocilizumab (TCZ) compared with placebo on skin sclerosis, as 
measured by modified Rodnan Skin Score (mRSS) at Week 48
The secondary efficacy objectives for this study are as follows:

To evaluate the efficacy of TCZ compared with placebo on pulmonary function, as 
measured by forced vital capacity (FVC) at Week 48

To evaluate the efficacy of TCZ compared with placebo on patient-reported outcomes 
(PROs), as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI) 
and Patient's Global Assessment at Week 48

To evaluate the efficacy of TCZ compared with placebo as measured by the Physician's 
Global Assessment at Week 48

To evaluate the efficacy of TCZ compared with placebo by assessment of time to treatment 
failure (death, worsening of mRSS and/or FVC, or clinically significant systemic sclerosis 
[SSc] complication) up to Week 48
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the safety of TCZ compared with placebo, focusing on the nature, frequency, 
and severity of serious and non-serious adverse events, the frequency of SSc-related 
complications, and effects on vital signs, physical findings, and clinical laboratory results

To evaluate the safety of TCZ compared with placebo by assessing the number of digital 
ulcers

To assess the long-term safety of TCZ


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Appendix 1
PROTOCOL SYNOPSIS (cont.)
Immunogenicity Objectives
The immunogenicity objectives for this study are as follows:

To characterize the immunogenic potential of TCZ by measuring anti-TCZ antibodies

To assess the potential relationship between development of anti-TCZ antibodies and 
efficacy, safety, or pharmacokinetic (PK) outcome measures
Pharmacodynamic Objectives
The pharmacodynamic (PD) objectives for this study are as follows:

To compare changes in levels of PD biomarkers following treatment with TCZ versus 
placebo
Pharmacokinetic Objectives
The PK objectives for this study are as follows:

To characterize the pharmacokinetics of TCZ

To evaluate potential relationships between PK parameters for TCZ and efficacy, safety, or 
immunogenicity outcome measures
Exploratory Objectives
The exploratory objectives for this study are as follows:

To evaluate the efficacy of TCZ compared with placebo on skin sclerosis, as measured by 
mRSS at Week 24

To evaluate the efficacy of TCZ versus placebo measured by the proportion of responders 
as defined by the Combined Response Index for Systemic Sclerosis (CRISS) at Week 48

To evaluate the efficacy of TCZ compared with placebo, as measured by the visual analog 
scale (VAS) component of the Scleroderma Health Assessment Questionnaire (SHAQ) at 
Weeks 24 and 48

To evaluate the efficacy of TCZ compared with placebo, as measured by the Work 
Productivity and Activity ImpairmentGeneral Health (WPAI-GH) questionnaire at Weeks 
24 and 48

To evaluate the efficacy of TCZ compared with placebo, as measured by the EuroQol 
5-Dimension Questionnaire with three levels of severity (EQ-5D-3L) at Weeks 24 and 48

To evaluate the efficacy of TCZ compared with placebo, as measured by the Saint 
George’s Respiratory Questionnaire (SGRQ) at Week 48

To evaluate the effect of TCZ compared with placebo on fatigue as measured by Functional 
Assessment of Chronic Illness Therapy (FACIT)–Fatigue score at Week 48.

To evaluate the efficacy of TCZ compared with placebo, as measured by the Scleroderma 
Skin Patient-Reported Outcome (SkinPRO) questionnaire at Week 48 (for North America 
only)

To evaluate the efficacy of TCZ compared with placebo on the basis of change in 
pulmonary fibrosis, as determined using high-resolution computed tomography (HRCT) 
scans at Week 48

To evaluate the efficacy of TCZ compared with placebo, as measured by diffusion capacity 
of the lung for carbon monoxide (DLCO) at Week 48, and FVC at Week 24

To evaluate the maintenance of efficacy of TCZ, as measured by mRSS and FVC at 
Week 96

To assess whether non-inherited biomarkers are predictive of response to TCZ 
(i.e., predictive biomarkers), susceptibility to developing adverse events, or progression to a 
more severe disease state (i.e., prognostic biomarkers), can provide evidence of TCZ 
activity, or can increase the knowledge and understanding of disease biology


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Appendix 1
PROTOCOL SYNOPSIS (cont.)
Study Design
Description of Study
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, two-arm, 
parallel-group study designed to assess the efficacy and safety of TCZ in patients with SSc.
Number of Patients
Approximately 212 patients with diffuse cutaneous systemic sclerosis (dcSSc) will be enrolled at 
approximately 75 global sites.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at baseline (Day 1)

Able to comply with the study protocol, in the investigator’s judgment

Diagnosis of SSc, as defined using the American College of Rheumatology 
[ACR]/European League Against Rheumatism [EULAR] criteria 

SSc disease duration of 60 months (defined as time from the first nonRaynaud 
phenomenon manifestation) 

mRSS of 10 and 35 units at screening

Active disease that meets at least one of the following criteria at screening:

Disease duration of 18 months defined as time from the first nonRaynaud 
phenomenon manifestation

Increase in mRSS of 3 units compared with the most recent assessment performed 
within the previous 6 months

Involvement of one new body area and an increase in mRSS of 2 units compared 
with the most recent assessment performed within the previous 6 months

Involvement of two new body areas within the previous 6 months 

Presence of at least one tendon friction rub

Presence of at least one of the following at screening:

C-reactive protein (CRP) 0.6 mg/dL (6 mg/L)

Erythrocyte sedimentation rate (ESR) 28 mm/hr

Platelet count 330 109/L (330,000/L)

Uninvolved or mildly thickened skin at one of the following possible injection-site locations:

Front, middle region of the thigh

Abdomen, except for the 2-inch area directly around the navel

Outer area of the upper arm (if a patient caregiver is giving the injection)


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Appendix 1
PROTOCOL SYNOPSIS (cont.)

For women who are not postmenopausal (12 months of non-therapy-induced amenorrhea) 
or surgically sterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use single or combined contraceptive methods that result in a failure rate of 1% per year 
during the treatment period and for up to 3 months after the last dose of study drug
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
Examples of contraceptive methods with a failure rate of 1% per year include tubal 
ligation, male sterilization, hormonal implants, established, proper use of combined oral 
or injected hormonal contraceptives, and certain intrauterine devices.  
Alternatively, it is acceptable to combine the use of two methods (e.g., two barrier 
methods such as a condom and a cervical cap).  Barrier methods must always be 
supplemented with the use of a spermicide.

For men:  agreement to remain abstinent or use contraceptive measures and agreement to 
refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 8 weeks 
after the last dose of study drug.
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
Men must refrain from donating sperm during the treatment period and for at least 
8 weeks after the last dose of study drug.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or lactating, or intending to become pregnant during the study

Women who are not postmenopausal (12 months of non-therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test at screening and a negative 
urine pregnancy test at baseline.

Major surgery (including joint surgery) within 8 weeks prior to screening or planned major 
surgery within 12 months following randomization

Skin thickening (scleroderma) limited to the face or areas distal to the elbows or knees at 
screening

Rheumatic autoimmune disease other than SSc, including but not limited to rheumatoid 
arthritis (RA) (diagnosed using ACR/EULAR criteria), systemic lupus erythematosus, mixed 
connective tissue disorder, polymyositis, dermatomyositis, eosinophilic fasciitis, primary 
Sjögren's syndrome, and eosinophilic myalgia syndrome, as determined by the investigator

Treatment with non-investigational or investigational cell-depleting therapies, including but 
not limited to alemtuzumab, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20 within 
18 months of baseline; or if treatment prior to 18 months from baseline, evidence of 
peripheral depletion of targeted lymphocyte subset at screening

Previous treatment with chlorambucil, bone marrow transplantation, or total lymphoid 
irradiation

Previous treatment with anti-IL6 therapy (including and not limited to TCZ) 

Previous treatment with thalidomide, antithymocyte globulin, plasmapheresis, 
or extracorporeal photopheresis 

Treatment with anakinra within 1 week prior to baseline

Treatment with etanercept within 2 weeks prior to baseline


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Appendix 1
PROTOCOL SYNOPSIS (cont.)

Treatment with oral, intramuscular, or intravenous corticosteroids (10 mg/day of 
prednisone or equivalent) within 2 weeks prior to baseline

Treatment with methotrexate, hydroxychloroquine, cyclosporine A, azathioprine, 
mycophenolate mofetil, rapamycin, colchicine, or D-penicillamine, within 4 weeks prior to 
baseline

Immunization with a live or live attenuated vaccine within 4 weeks prior to baseline

Treatment with any investigational agent within 5 elimination half-lives of the investigational 
drug prior to baseline

Chronic treatment with any of the following within 5 elimination half-lives of the drug prior to 
baseline:

Pirfenidone

Nintedanib

Endothelin-receptor antagonists, terguride

Tyrosine-kinase inhibitors (e.g., imatinib, nilotinib, dasatinib) 

Janus-kinase inhibitors

Treatment with IV prostacyclin within 1 week prior to baseline

Treatment with ultraviolet phototherapy within 6 weeks prior to baseline

Treatment with infliximab, certolizumab, golimumab, abatacept, or adalimumab within 
8 weeks prior to baseline

Treatment with cyclophosphamide within 6 months prior to baseline

History of severe allergic or anaphylactic reactions to human, humanized, or murine 
monoclonal antibodies

Evidence of moderately severe concurrent nervous system, renal, endocrine, or 
gastrointestinal (GI) disease not related to SSc, as determined by the investigator

Pulmonary disease with FVC 55% of predicted (best of three acceptable and repeatable 
measurements as described in the site’s Pulmonary Function Testing Manual)  
OR
DLCO 45% of predicted (corrected for hemoglobin, and the average of the 2 highest 
acceptable and repeatable measurements as described in the Pulmonary Function Testing 
Manual)

Class II or higher pulmonary arterial hypertension (PAH), as defined by the World Health 
Organization

Evidence of other moderately severe pulmonary disease (e.g., asthma, emphysema), as 
determined by the investigator

Cardiovascular disease with significant arrhythmia, congestive heart failure 
(New York Heart Association Class IIIV), unstable angina, uncontrolled hypertension, 
cor pulmonale, or symptomatic pericardial effusion

History of myocardial infarction in the last 6 months prior to screening

Current liver disease, as determined by the investigator

History of diverticulitis or chronic ulcerative lower GI disease, such as Crohn disease, 
ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient 
to perforations

Known active current or significant history of recurrent bacterial, viral, fungal, mycobacterial, 
or other infections, including but not limited to atypical mycobacterial disease, hepatitis B or 
C, herpes zoster, infected digital ulcers, and osteomyelitis


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Appendix 1
PROTOCOL SYNOPSIS (cont.)

Any major episode of infection requiring hospitalization or treatment with IV antibiotics 
within 4 weeks prior to screening or oral antibiotics within 2 weeks prior to screening

Significant history of recurrent tuberculosis (TB), active TB requiring treatment within the 
previous 3 years, or untreated latent TB
Patients should be screened for latent TB, and, if positive, will be eligible for the study 
after treatment per local standard practices.

History of or currently active primary or secondary immunodeficiency

Evidence of malignant disease, or malignancies diagnosed within the previous 5 years (with 
the exception of local basal or squamous cell carcinoma of the skin or carcinoma in situ of 
the cervix uteri that has been excised and cured)

History of alcohol, drug, or chemical abuse within 1 year prior to screening

Neuropathies or other conditions that might interfere with pain evaluation, as determined by 
the investigator

At screening: 
Body weight 150 kg
Glomerular filtration rate 45 mL/min
Alanine transaminase (ALT) or Aspartate aminotransferase (AST) 1.5 the upper limit 
of normal (ULN)
Total bilirubin ULN
Platelet count 100 109/L (100,000/L)
Hemoglobin 85 g/L (8.5 g/dL; 5.3 mmol/L)
White blood cell (WBC) count 3.0 109/L (3000/L)
Absolute neutrophil count (ANC) 2.0 109/L (2000/L)
Absolute lymphocyte count 0.5 109/L (500/L)
Positive hepatitis B surface antigen or hepatitis C antibody
Length of Study
The length of the study, from screening of the first subject to the end of the study, is expected to 
be approximately 4 years.
End of Study
The end of the study will occur when the last participating patient completes the last scheduled 
visit of the follow-up period.  This is expected to occur 2 years after the last patient is enrolled.
Outcome Measures
Efficacy Outcome Measures
The primary efficacy outcome measure for this study is as follows:

Change in mRSS from baseline to Week 48
The secondary efficacy outcome measures for this study are as follows:

Proportions of patients with 20%, 40%, and 60% improvement in mRSS at Week 48 
compared with baseline

Change in FVC from baseline to Week 48

Change in HAQ-DI from baseline to Week 48

Change in Patient's Global Assessment from baseline to Week 48

Change in Physician's Global Assessment from baseline to Week 48


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Appendix 1
PROTOCOL SYNOPSIS (cont.)

Time to treatment failure, defined as the time from randomization to the time of one of the 
following events (whichever occurs first) during the 48-week double-blind treatment period:
death, 
decline in percent-predicted FVC 10% relative to baseline,
20% increase in mRSS and an increase in mRSS of 5 points
occurrence of a predefined SSc-related complication as adjudicated by the Clinical 
Adjudication Committee
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Frequency of deaths

Nature, frequency, and severity of adverse events

Incidence of specific laboratory abnormalities 

Change from baseline in digital ulcer count
Immunogenicity Outcome Measures
The immunogenicity outcome measures for this study are as follows:

Incidence of anti-TCZ antibodies during the study relative to the prevalence of anti-TCZ 
antibodies at baseline

Correlation between anti-TCZantibody status and efficacy, safety, or PK outcome 
measures
Pharmacodynamic Outcome Measures
The PD outcome measure for this study is as follows:

Predose ESR and serum IL-6, soluble IL-6 receptor (sIL-6R), and CRP levels at baseline
and at subsequent timepoints after initiation of study drug
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Predose serum TCZ concentration at baseline and at specified timepoints thereafter

Correlation between PK parameters for TCZ and efficacy, safety, or immunogenicity 
outcome measures
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Proportions of patients who achieve a response, as determined by the investigator using 
CRISS, at Week 48

Change in the VAS component of the SHAQ from baseline to Week 24 and baseline to 
Week 48

Change in WPAI-GH score from baseline to Week 24 and baseline to Week 48

Change in EQ-5D-3L score from baseline to Week 24 and baseline to Week 48

Change in total score and subscores of the SGRQ from baseline to Week 48.  

Change in total and domain scores of the SkinPRO questionnaire from baseline to Week 48 
(for North America only)

Change in FACIT-Fatigue score from baseline to Week 48.

Change in HRCT fibrosis score from baseline (based on HRCT scan performed within 
3 months prior to screening) to Week 48

Change in DLCO from baseline to Week 48

Proportion of patients with 15% decline in observed DLCO at Week 48

Proportion of patients with 15% decline in percentage of predicted DLCO at Week 48


Tocilizumab—F. Hoffmann-La Roche Ltd
44/Statistical Analysis Plan WA29767
Appendix 1
PROTOCOL SYNOPSIS (cont.)

Change in FVC from baseline to Week 24

Proportion of patients with 10% decline in observed FVC at Week 24 and at Week 48

Proportion of patients with 10% decline in percentage of predicted FVC at Week 24 and at 
Week 48

Change in mRSS from baseline to Week 24 and Week 96

Change in observed and percentage of predicted FVC from baseline to Week 96

Correlation between non-inherited biomarkers (serum levels of CCL18, sVCAM-1, COMP, 
and autotaxin; plasma levels of CXCL4; and whole blood gene signatures associated with 
plasmablasts and IFN) and efficacy, safety, PK, or immunogenicity outcome measures
Investigational Medicinal Products
Test Product (Investigational Drug)
Patients assigned to the TCZ group will receive a single subcutaneous (SC) injection of 
162 mg of TCZ once weekly (QW) for 48 weeks during the double-blind treatment period.  All 
patients will receive SC injections of 162 mg of TCZ QW for 48 weeks during the open-label 
treatment period.
Comparator
Patients assigned to the placebo group will receive SC injections of placebo QW for 48 weeks 
during the double-blind treatment period.  
Non-Investigational Medicinal Products
From Week 24, escape therapy will be permitted for patients with worsening of skin thickening, 
and from Week 16, escape therapy will be permitted for patients with decline in FVC compared 
with baseline.  Patients may receive other concomitant treatments for SSc, including treatments 
for new and existing organ complications.
Statistical Methods
Primary Analysis
The estimand of interest for the primary analysis is the difference between treatment arms in the 
mean change in the mRSS at Week 48 for the intent to treat (ITT) population.  The study has 
been designed to continue to capture efficacy data on patients who discontinue study drug 
prematurely or receive escape therapies during the double-blind treatment period.  These data 
will be included in the primary analysis.  
Determination of Sample Size  
A sample size of approximately 105 patients in the TCZ group and 105 patients in the placebo 
group (a total of 210 patients) will give power in the range of 75% to 80%, (allowing for an 
estimated patient dropout rate of approximately 15% to 20%) to detect a between-group 
difference of 3.55 units (common standard deviation of 8.43) in mean change in mRSS from 
baseline to Week 48 using a two-group t-test, with a 5% two-sided significance level.  The 
minimal detectable difference in mRSS (smallest treatment difference that would give a 
statistically significant result) under these assumptions, and with a patient dropout rate of 20%, 
is approximately 2.6 units.


Tocilizumab—F. Hoffmann-La Roche Ltd
45/Statistical Analysis Plan WA29767
Appendix 1
PROTOCOL SYNOPSIS (cont.)
Interim Analyses
The Sponsor will define a futility analysis to which the Sponsor will remain blinded.  The futility 
analysis will be conducted by an external statistical group and reviewed by the iDMC.  The 
futility analysis will be based on the treatment difference for change from baseline in mRSS at 
Week 24; the stopping boundary will be determined by a beta spending function.  The study will 
be stopped for futility if the endpoint meets the futility criterion.
The futility analysis will be conducted when approximately 76 patients have either reached the 
Week 24 visit or have withdrawn.  Since a repeated measures analysis will be used for the 
futility criterion, partial data from additional patients enrolled at (but not yet completed) Week 24 
will also be utilized in the analysis.  Thus, although only approximately one-third of the patients 
will have reached Week 24, the timing of the futility analysis approximates half of the final 
expected information (I) at Week 24, where I is the inverse of the expected variance of the 
treatment difference when all patients have reached Week 24.
Full statistical details of the futility analysis, along with the rationale, and timing will be 
documented in the iDMC charter.  The iDMC charter will be made available to the relevant 
health authorities


Tocilizumab—F. Hoffmann-La Roche Ltd 
46/Statistical Analysis Plan WA29767 
Appendix 2  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period 
 
Screen.
(up to 
40 d) 
Double-Blind Treatment Period ( 7 d, except Day 1) 
Unsch.
Visit 
Treat. 
Discon. c 
Follow-Up a
Assessment or Procedure 
Day 1,
BL 
Wk 
4 b 
Wk 
8 b 
Wk  
16 b 
Wk 
24 b 
Wk 
36 b 
Wk 
48 b 
Wk 
4 
Wk 
8 a 
Informed consent 
x d 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical history e 
x 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion and exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
Electronic device training (PROs and study 
drug compliance) 
 
x 
 
 
 
 
 
 
 
 
 
 
PRO assessments f 
 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
Review study drug compliance 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Urinalysis g, h 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Pregnancy test g, i 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
HBsAg and HCV serology 
x 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis screening j 
x 
 
 
 
 
 
x 
 
 
x 
 
 
Serum sample for IL-6 for stratification 
purposes 
x 
 
 
 
 
 
 
 
 
 
 
 
Hematology g, k 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Chemistry panel (serum or plasma) and 
creatinine clearance g, l 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Liver profile g, m 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Lipid panel g,n 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
 
ANA sample  
 
x 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
Appendix 2  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period (cont.) 
 
Tocilizumab—F. Hoffmann-La Roche Ltd 
47/Statistical Analysis Plan WA29767 
 
Screen.
(up to 
40 d) 
Double-Blind Treatment Period ( 7 d, except Day 1) 
Unsch.
Visit 
Treat. 
Discon. c 
Follow-Up a
Assessment or Procedure 
Day 1,
BL 
Wk 
4 b 
Wk 
8 b 
Wk  
16 b 
Wk 
24 b 
Wk 
36 b 
Wk 
48 b 
Wk 
4 
Wk 
8 a 
SSc-specific auto-antibody panel g, o 
 
x 
 
 
 
 
 
x 
x 
x 
 
 
Serum anti-TCZ antibody sample g, p 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
Serum sample for PK analysis g, p, q 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
IL-6 sample g, q 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
sIL-6R sample g,p,q 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
High-sensitivity CRP g 
x 
x 
x 
 
 
x 
 
x 
x 
x 
 
 
ESR g 
x 
x 
x 
 
 
x 
 
x 
x 
x 
 
 
Serum sample for candidate biomarkers g 
 
x 
 
 
 
x 
 
x 
 
 
 
 
Plasma (EDTA) sample for candidate 
biomarkers g 
 
x 
 
 
 
x 
 
x 
 
 
 
 
Whole blood sample for RNA extraction g 
 
x 
 
 
 
x 
 
x 
 
 
 
 
Skin biopsies (RCR sample, optional) r 
 
x 
 
 
 
 
 
x 
 
 
 
 
Whole blood RCR sample for DNA exaction 
(optional) 
 
x 
 
 
 
 
 
 
 
 
 
 
mRSS 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Forced vital capacity 
x  
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
DLCO 
x  
x 
 
 
 
x 
 
x 
x 
x 
 
 
Physician's Global Assessment s 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
High-resolution CT scan t 
 
x 
 
 
 
 
 
x 
 
 
 
 
Physical examination u 
x 
x 
 
 
 
 
 
 
x 
x 
 
 


 
 
 
 
 
 
Appendix 2  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period (cont.) 
 
Tocilizumab—F. Hoffmann-La Roche Ltd 
48/Statistical Analysis Plan WA29767 
 
Screen.
(up to 
40 d) 
Double-Blind Treatment Period ( 7 d, except Day 1) 
Unsch.
Visit 
Treat. 
Discon. c 
Follow-Up a
Assessment or Procedure 
Day 1,
BL 
Wk 
4 b 
Wk 
8 b 
Wk  
16 b 
Wk 
24 b 
Wk 
36 b 
Wk 
48 b 
Wk 
4 
Wk 
8 a 
Height 
x v 
 
 
 
 
 
 
 
 
 
 
 
Body weight g 
x 
x 
 
 
 
 
 
x 
x 
x 
 
 
Vital signs g, w 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Digital ulcer count g 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
ECG 
x 
 
 
 
 
 
 
 
x 
 
 
 
Echocardiogram 
x 
 
 
 
 
 
 
 
x 
x 
 
 
Adverse events g, x, y 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications g, z 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug distribution and administration g, 
aa 
 
x bb, cc 
x 
x 
x 
x 
x 
x bb 
 
 
 
 
ANA  anti-nuclear antibody; BL  baseline; CBC  complete blood count; CRP  C-reactive protein; CT  computed tomography; d  day; 
Discon.   discontinuation; DLCO  diffusing capacity of the lung for carbon monoxide; eCRF  electronic Case Report Form; ESR  erythrocyte 
sedimentation rate; EQ-5D-3L  EuroQol 5-Dimension Questionnaire (three levels of severity); FVC  forced vital capacity; HAQ-DI  Health 
Assessment Questionnaire Disability Index; HBsAg  hepatitis B surface antigen; HCV  hepatitis C virus; HRCT  high-resolution computed 
tomography; IL  interleukin; mRSS  modified Rodnan Skin Score; PK  pharmacokinetic; PRO  patient-reported outcome; RCR  Roche Clinical 
Repository; Screen.  screening; SGRQ  Saint George’s Respiratory Questionnaire; SHAQ  Scleroderma Health Assessment Questionnaire; 
SkinPRO  Scleroderma Skin Patient-Reported Outcome; SSc  systemic sclerosis; TCZ  tocilizumab; Treat.   treatment; Unsch.   unscheduled; 
Wk  week; WPAI-GH  Work Productivity and Activity ImpairmentGeneral Health. 


 
 
 
 
 
 
Appendix 2  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period (cont.) 
 
Tocilizumab—F. Hoffmann-La Roche Ltd 
49/Statistical Analysis Plan WA29767 
Note:  Assessments and procedures should be performed in the sequence that is most practical for the site, as long as PROs are performed first 
and study drug administration is performed last.   
a All patients will undergo follow-up assessments within 4 weeks of study drug discontinuation and at 8 weeks after study drug discontinuation.  
For patients who discontinue study drug prematurely, a follow-up visit can be combined with the next scheduled visit (as outlined in Appendix 3 
provided that the timing of the scheduled visit coincides with the specified timing for the follow-up visit.  The follow-up visit at 4 weeks may be 
conducted by telephone. 
b For patients at participating sites who have provided written informed consent to participate in home nursing services, specified assessments at 
Weeks 4, 8, 16, 24, 36, and 48, as well as Week 8 of the Follow-up Period may be performed by a trained home nursing professional or (at sites 
with established teams) by appropriately qualified site personnel at the patient’s home or another suitable location. 
c Patients who discontinue study drug prematurely should undergo assessments as outlined in Appendix 3, with the timing of those visits being 
relative to baseline.  Assessments at the early treatment discontinuation visit should be performed as soon as possible after discontinuing study 
drug. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e Medical history includes clinically significant diseases (including SSc complications) reproductive status, smoking history, and use of alcohol and 
drugs of abuse. 
f PRO questionnaires are to be completed prior to all other assessments during the study visit, with the exception of ECGs.  Patients will use an 
electronic PRO device to capture PRO data.  The appropriate PRO assessments will be programmed to appear at specific visits.  The HAQ-DI, 
will be completed at baseline and at Weeks 8, 16, 24, 36, and 48.  The Patient's Global Assessment, SHAQ, SGRQ, FACIT-Fatigue, and 
SkinPRO questionnaire will be completed at baseline and at Weeks 8, 16, 24, and 48.  The SkinPRO questionnaire will only be administered in 
North America.  The WPAI-GH and EQ-5D-3L will be completed at baseline and at Weeks 24 and 48. 
g For patients at participating sites who have provided written informed consent to participate in home nursing services, this assessment or 
procedure may be performed by a trained home nursing professional or (at sites with established teams) by appropriately qualified site personnel 
at the patient’s home or another suitable location. 
h Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, and bacteria).   
i All women who are not postmenopausal ( 12 months of non-therapy-induced amenorrhea) or surgically sterile will have a serum pregnancy test 
at screening.  Urine pregnancy tests will be performed at specified subsequent visits.  If a urine pregnancy test is positive, it must be confirmed 
by a serum pregnancy test. 
j Tuberculosis screening must be performed at screening and at Week 36.  The screening method (e.g. PPD or QuantiFERON test) is at the 
discretion of the investigator. 


 
 
 
 
 
 
Appendix 2  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period (cont.) 
 
Tocilizumab—F. Hoffmann-La Roche Ltd 
50/Statistical Analysis Plan WA29767 
k Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC count, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). 
l Chemistry panel includes total protein, serum albumin, creatine phosphokinase, sodium, potassium, calcium, BUN or urea, serum creatinine, C3, 
and C4.  Creatinine clearance will be calculated by a central laboratory. 
m Liver profile consists of AST, ALT, alkaline phosphatase, and total bilirubin (direct and indirect bilirubin will be performed if total bilirubin greater 
than the upper limit of normal). 
n Overnight fasting (   8 hours) is required.  An additional fasting lipid panel should be obtained 8 weeks after initiation of lipid-lowering therapy. 
o SSc-specific autoantibody panel includes anti-topoisomerase, anti-RNA polymerase, anti-PM/Scl, anti-histone, anti-U1 snRP, 
and anti-centromere antibodies. 
p Additional samples for PK analysis and analysis of anti-TCZ antibodies and sIL-6R will be collected prior to resuming study drug for patients who 
have missed at least three consecutive doses and at the time of anaphylaxis or a serious hypersensitivity reaction.   
q Samples for PK analysis and analysis of IL-6, sIL-6R, and candidate biomarkers will be obtained at a single blood draw and aliquoted according 
to the procedures in the Sample Handling and Logistics Manual. 
r Two 3-mm punch biopsies are to be obtained from clinically involved skin, preferably at the forearm (optional). 
s Physician's Global Assessment is to be completed by the investigator on the basis of examination and overall assessment of the patient. 
t As accepted by the local regulations.  Good-quality (as determined by the site radiologist and/or investigator), standard-of-care HRCT scans 
obtained within 3 months prior to screening and in accordance with study image acquisition guidelines can be used for baseline. 
u A physical examination will be performed but will not be recorded on the eCRF, if normal; any abnormality will be reported either on the 
Medical History eCRF (for screening examination) or Adverse Event eCRF (for examinations after the screening). 
v Height is required at screening only and will be recorded on the Vital Signs eCRF. 
w Vital signs will include measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated 
position, and temperature.  Additional measurements may be performed in the event of an adverse event, at the discretion of the investigator.  
Temperature readings (as part of vital signs) will be measured but will not be recorded on the eCRF, if normal; any abnormal body temperature 
will be reported on the Adverse Event eCRF. 


 
 
 
 
 
 
Appendix 2  
Schedule of Assessments:  Screening, Baseline, and Double-Blind Treatment Period (cont.) 
 
Tocilizumab—F. Hoffmann-La Roche Ltd 
51/Statistical Analysis Plan WA29767 
x After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 8 weeks after the last dose of study drug or 
until completion of the last scheduled visit, whichever occurs later.  However, for patients who discontinue study drug prematurely but continue 
scheduled visits, all adverse events will be reported until completion of the last scheduled visit or 8 weeks after the last dose of study drug, 
whichever occurs later.  After this period, the investigator should report any serious adverse events that are believed to be related to prior study 
drug treatment (see Section 5.6).  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the 
event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
y For all serious infectious adverse events, CBC, differentials, and platelets should be determined during the disease episode.  Every effort should 
be made to collect appropriate specimens for serology, polymerase chain reaction, or culture to identify the infectious organism.  The results of 
all laboratory assessments performed locally, except for CRP, should be reported on the eCRF. 
z Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by a patient from 4 weeks prior to screening until 8 weeks after the last dose of study drug or until completion of the last 
scheduled visit, whichever occurs later.  In addition, all medications taken for SSc since diagnosis will be recorded at screening. 
aa If for any reason the weekly schedule cannot be kept (e.g., SC injections have to be administered to patients during a site visit), injections may 
be given a minimum of 5 days and a maximum of 11 days apart. 
bb The first SC injection in both study periods (double-blind and open-label) will be administered to patients at the site under close supervision.  The 
Week 48 injection is the first dose for the open-label treatment period. 
cc Patients (and patient caregivers, if applicable) will be trained on how to perform SC injections at the Day 1 visit.  For patients and caregivers 
at applicable sites who require additional training, study drug may be administered (or guidance provided) at Weeks 1 and 2 by a home nursing 
professional or by appropriately qualified site personnel.


 
Tocilizumab—F. Hoffmann-La Roche Ltd 
52/Statistical Analysis Plan WA29767 
Appendix 3  
Schedule of Assessments:  Open-Label Treatment Period 
 
Open-Label Treatment Period ( 7 d) 
Unsch.  
Visit 
Treat. 
Discon. b 
Follow-Up c 
Assessment or Procedure 
Wk 
52 a 
Wk 
60 a 
Wk  
72 a 
Wk  
84 a 
Wk  
96 a 
Wk 
4 
Wk 
8 a 
PRO assessments d 
 
 
x 
 
x 
 
 
 
 
Review study drug compliance 
x 
x 
x 
x 
x 
x 
x 
 
 
Urinalysis e,f 
 
x 
x 
x 
x 
x 
x 
 
 
Pregnancy test e,g 
x 
x 
x 
x 
x 
 
x 
 
 
Tuberculosis screening h 
 
 
 
 
 
 
x 
 
 
Hematology e,i 
x 
x 
x 
x 
x 
x 
x 
 
 
Chemistry panel (serum or plasma) and 
creatinine clearance e,j 
x 
x 
 
x 
 
x 
x 
 
 
Liver profile e,k 
x 
x 
x 
x 
x 
x 
x 
 
 
Lipid panel e,l 
 
x 
x 
 
x 
x 
x 
 
 
SSc-specific auto-antibody panel e,m 
 
 
 
 
x 
x 
x 
 
 
Serum anti-TCZ antibody sample e,n 
 
 
 
 
x 
x 
x 
 
x 
Serum sample for PK analysis e,n,o 
 
 
 
 
x 
x 
x 
 
x 
IL-6 sample e,o 
 
 
 
 
x 
 
x 
 
 
sIL-6R sample e,n,o 
 
 
 
 
x 
x 
x 
 
x 
High-sensitivity CRP e 
 
 
x 
 
x 
x 
x 
 
 
ESR e 
 
 
x 
 
x 
x 
x 
 
 
mRSS 
 
 
x 
 
x 
x 
x 
 
 
Forced vital capacity 
 
 
x 
 
x 
x 
x 
 
 
DLCO 
 
 
x 
 
x 
x 
x 
 
 


 
 
 
 
 
 
Appendix 3  
Schedule of Assessments:  Open-Label Treatment Period (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
53/Statistical Analysis Plan WA29767 
 
 
Open-Label Treatment Period ( 7 d) 
Unsch.  
Visit 
Treat. 
Discon. b 
Follow-Up c 
Assessment or Procedure 
Wk 
52 a 
Wk 
60 a 
Wk  
72 a 
Wk  
84 a 
Wk  
96 a 
Wk 
4 
Wk 
8 a 
Physician's Global Assessment p 
 
 
x 
 
x 
x 
x 
 
 
Physical examination q 
 
 
 
 
 
x 
x 
 
 
Body weight e 
 
 
 
 
x 
x 
x 
 
 
Vital signs e,r 
x 
x 
x 
x 
x 
x 
x 
 
 
Digital ulcer count e 
 
 
x 
 
x 
x 
x 
 
 
Echocardiogram 
 
 
 
 
 
x 
x 
 
 
Adverse events e,s,t 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications e,u 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug distribution and administration e,v 
xw 
x 
x 
x 
 
 
 
 
 
CBC  complete blood count; CRP  C-reactive protein; d  day; Discon.   discontinuation; DLCO  diffusing capacity of the lung for carbon monoxide; 
eCRF  electronic Case Report Form; ESR  erythrocyte sedimentation rate; EQ-5D-3L  EuroQol 5-Dimension Questionnaire (three levels of 
severity); FVC  forced vital capacity; HAQ-DI  Health Assessment Questionnaire Disability Index; HBsAg  hepatitis B surface antigen; 
HCV  hepatitis C virus; HRCT  high-resolution computed tomography; IL  interleukin; mRSS  modified Rodnan Skin Score; PK  pharmacokinetic; 
PRO  patient-reported outcome; RCR  Roche Clinical Repository; SHAQ  Scleroderma Health Assessment Questionnaire; SGRQ  Saint 
George’s Respiratory Questionnaire; SkinPRO  Scleroderma Skin Patient-Reported Outcome; SSc  systemic sclerosis; TCZ  tocilizumab; 
Treat.   treatment; Unsch.   unscheduled; Wk  week; WPAI-GH  Work Productivity and Activity ImpairmentGeneral Health. 
Note:  Assessments and procedures should be performed in the sequence that is most practical for the site, as long as PROs are performed first 
and study drug administration is performed last.   
a For patients at participating sites who have provided written informed consent to participate in home nursing services, specified assessments at 
Weeks 52, 60, 72, 84, and 96, as well as Week 8 of the Follow-up Period may be performed by a trained home nursing professional or (at sites 
with established teams) by appropriately qualified site personnel at the patient’s home or another suitable location. 
b Discontinued patients should undergo a treatment discontinuation visit as soon as possible after discontinuing study drug. 


 
 
 
 
 
 
Appendix 3  
Schedule of Assessments:  Open-Label Treatment Period (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
54/Statistical Analysis Plan WA29767 
c All patients will undergo follow-up assessments within 4 weeks of study drug discontinuation and at 8 weeks after study drug discontinuation, 
except for patients who reach Week 96 but who transition onto locally provided TCZ prior to the follow up visit.  The follow-up visit at 4 
weeks may be conducted by telephone. 
d PRO questionnaires are to be completed prior to all other assessments during the study visit.  Patients will use an electronic PRO device to 
capture PRO data.  The appropriate PRO assessments will be programmed to appear at specific visits.  The HAQ-DI, Patient's Global 
Assessment, SHAQ, SGRQ, FACIT-Fatigue, and SkinPRO questionnaire will be completed at Weeks 72 and 96.  The SkinPRO questionnaire 
will only be administered in North America.  The WPAI-GH and EQ-5D-3L will be completed at Week 96. 
e For patients at participating sites who have provided written informed consent to participate in home nursing services, this assessment or 
procedure may be performed by a trained home nursing professional or (at sites with established teams) by appropriately qualified site personnel 
at the patient’s home or another suitable location. 
f Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, and bacteria).   
g Urine pregnancy tests will be conducted for all women who are not postmenopausal ( 12 months of non-therapy-induced amenorrhea) or 
surgically sterile.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
h Tuberculosis screening must be performed at screening and at Week 36.  The screening method (e.g. PPD or QuantiFERON test) is at the 
discretion of the investigator. 
i Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC count, platelet count, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). 
j Chemistry panel includes total protein, serum albumin, creatine phosphokinase, sodium, potassium, calcium, BUN or urea, serum creatinine, C3, 
and C4.  Assessment of creatinine clearance is to be performed every 12 weeks and will be calculated by the central laboratory.  Creatinine 
clearance will be calculated by a central laboratory. 
k Liver profile consists of AST, ALT, alkaline phosphatase, and total bilirubin (direct and indirect bilirubin will be performed if total bilirubin greater 
than the upper limit of normal). 
l Overnight fasting ( 8 hours) is required.  An additional fasting lipid panel should be obtained 8 weeks after initiation of lipid-lowering therapy. 
m SSc-specific autoantibody panel includes anti-topoisomerase, anti-RNA polymerase, anti-PM/Scl, anti-histone, anti-U1 snRP, 
and anti-centromere antibodies. 
n Additional samples for PK analysis and analysis of anti-TCZ antibodies and sIL-6R will be collected prior to resuming study drug for patients who 
have missed at least three consecutive doses and at the time of anaphylaxis or a serious hypersensitivity reaction.   
o Samples for PK analysis and analysis of IL-6 and sIL-6R will be obtained at a single blood draw and aliquoted according to the procedures in the 
Sample Handling and Logistics Manual. 


 
 
 
 
 
 
Appendix 3  
Schedule of Assessments:  Open-Label Treatment Period (cont.) 
Tocilizumab—F. Hoffmann-La Roche Ltd 
55/Statistical Analysis Plan WA29767 
p Physician's Global Assessment is to be completed by the investigator on the basis of examination and overall assessment of the patient. 
q A physical examination will be performed but will not be recorded on the eCRF, if normal; any abnormality will be reported on the Adverse Event 
eCRF. 
r Vital signs will include measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated 
position, and temperature.  Additional measurements may be performed in the event of an adverse event, at the discretion of the investigator.  
Temperature readings (as part of vital signs) will be measured but will not be recorded on the eCRF, if normal; any abnormal body temperature 
will be reported on the Adverse Event eCRF. 
s After initiation of study drug, all adverse events will be reported until 8 weeks after the last dose of study drug or until completion of the last 
scheduled visit, whichever occurs later.  However, for patients who discontinue study drug prematurely but continue scheduled visits, all adverse 
events will be reported until completion of the last scheduled visit or 8 weeks after the last dose of study drug, whichever occurs later.  After this 
period, the investigator should report any serious adverse events that are believed to be related to prior study drug treatment (see Section 5.6).  
The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the 
investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events 
considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
t For all serious infectious adverse events, CBC, differentials and platelets should be determined during the disease episode.  Every effort should 
be made to collect appropriate specimens for serology, polymerase chain reaction, or culture to identify the infectious organism.  The results of 
all laboratory assessments performed locally, except for CRP, should be reported on the eCRF. 
u Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by a patient from 4 weeks prior to screening until 8 weeks after the last dose of study drug or until completion of the last 
scheduled visit, whichever occurs later. 
v If for any reason the weekly schedule cannot be kept (e.g., SC injections have to be administered to patients during a site visit), injections may 
be given a minimum of 5 days and a maximum of 11 days apart. 
w 
Study drug administration only; no study drug distribution at this visit. 


 
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Appendix 4  
Schedule of Assessments:  Patients Who Have Discontinued Study Drug Prematurely 
 
Timing of Visit Relative to Baseline (Day 1) 
Assessment or  
Procedure 
Wk 8 a 
( 7d) 
Wk 16 a 
( 7d) 
Wk 24 a 
( 7d) 
Wk 36 a 
( 7d) 
Wk 48 a, e 
( 7d) 
mRSS 
x 
x 
x 
x 
x 
Forced vital capacity 
x 
x 
x 
x 
x 
HAQ-DI 
x 
x 
x 
x 
x 
Adverse events a,b,c 
x 
x 
x 
x 
x 
Concomitant medications a,d 
x 
x 
x 
x 
x 


 
 
 
 
 
Appendix 4  
Schedule of Assessments:  Patients Who Have Discontinued Study Drug Prematurely (cont.) 
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CBC  complete blood count; CRP  C-reactive protein; d; eCRF  electronic Case Report Form; HAQ-DI  Health Assessment Questionnaire 
Disability Index; mrSS  modified Rodnan Skin Score; Wk  week. 
Note:  Patients who discontinue study drug prematurely but continue to attend scheduled study visits should follow a reduced assessment schedule 
as outlined above, starting with the first scheduled visit following discontinuation of study drug.  These patients should also undergo a treatment 
discontinuation (TD) visit as soon as possible after discontinuing study drug, and follow-up assessments within 4 weeks of study drug 
discontinuation and at 8 weeks after study drug discontinuation.  A TD and/or follow-up visit may be combined with the next scheduled visit 
(as outlined above in Appendix 3), provided that the timing of the scheduled visit coincides with the specified timing for the TD or follow-up 
visit. 
a For patients at participating sites who have provided written informed consent to participate in home nursing services, specified assessments at 
each visit may be performed by a trained home nursing professional or (at sites with established teams) by appropriately qualified site personnel 
at the patient’s home or another suitable location. 
b After initiation of study drug, all adverse events will be reported until 8 weeks after the last dose of study drug or until completion of the last 
scheduled visit, whichever occurs later.  However, for patients who discontinue study drug prematurely but continue scheduled visits, all adverse 
events will be reported until completion of the last scheduled visit or 8 weeks after the last dose of study drug, whichever occurs later.  After this 
period, the investigator should report any serious adverse events that are believed to be related to prior study drug treatment (see Section 5.6).  
The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the 
investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events 
considered to be related to study drug or trial-related procedures until a final outcome can be reported. 
c For all serious infectious adverse events, CBC, differentials and platelets should be determined during the disease episode.  Every effort should 
be made to collect appropriate specimens for serology, polymerase chain reaction, or culture to identify the infectious organism.  The results of 
all laboratory assessments performed locally, except for CRP, should be reported on the eCRF. 
d Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by a patient from 4 weeks prior to screening until 8 weeks after the last dose of study drug or until completion of the last 
scheduled visit, whichever occurs later.  Patients who start other medications for systemic sclerosis (e.g., DMARDs) between treatment 
discontinuation and Week 48 may remain on these medications during the open-label period at the discretion of the investigator.  
e Patients who enter the open-label period at Week 48 must complete the full Week 48 schedule of assessments in Appendix 1.  If these patients 
discontinue after TCZ treatment in the open-label period they should undergo a second TD visit and complete the 4 and 8 week follow-up 
visits. 


 
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Appendix 5  
HAQ-DI 
The HAQ-DI is a self-completed patient questionnaire specific for RA.  It consists of 
20 questions referring to eight domains: dressing/grooming, arising, eating, walking, 
hygiene, reach, grip, and common daily activities.  There are four possible responses for 
each component: 
0without any difficulty 
1with some difficulty 
2with much difficulty 
3unable to do 
 
A domain score is determined from the highest score of the components in that domain 
(except when aids and devices are taken into account; see below).  For example, if there 
are three components in a domain and the responses were 1, 2 and 0 to the 
components in the domain, then the score for the domain would be 2. 
If a domain consists of only two questions and has one missing response, then the 
non-missing response will be used as the value for the domain.  If a domain consists of 
three questions and has one missing response, then the domain score will be the higher 
of the two responses.  If a domain consists of three questions and has two missing 
responses, then the domain will be considered missing. 
To calculate the HAQ-DI, the patient must have a domain score for at least six of the 
eight domains.  The HAQ-DI is the sum of the domain scores, divided by the number of 
domains that have a score. 
The HAQ-DI takes into account the patient’s use of aids or devices in the scoring for a 
domain.  For each of the eight domains, there is an aids or devices companion 
variable(s) that is used to record any assistance the patient uses.  Where aids or devices 
are indicated by a patient for a domain or help from another person is required for a 
domain, if the maximum score for the domain is 2, the domain score is increased to 2 
to reflect the use of an aid or device, or help.  If the maximum value is 2, the score is 
not modified.  In the event that a domain score is missing but a corresponding aid or 
device is listed, then the score for that domain will reflect the use of the aid or device 
(i.e., it will be scored as 2). 
Where “other” is ticked for use of aids or devices, the use of the aid or device will not be 
assigned to a domain and will therefore not be reflected in the domain scoring. 
HAQ-DI scores can range from 0 to 3. 


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Appendix 6
St. George’s Respiratory Questionnaire
OUTLINE OF SCORING ALGORITHM
Three component scores are calculated: Symptoms; Activity; Impacts. One Total score 
is also calculated.
PRINCIPLE OF CALCULATION
Each questionnaire response has a unique empirically derived 'weight'. The lowest 
possible weight is zero and the highest is 100. Each component of the questionnaire is 
scored separately in three steps: 
1.
The weights for all items with a positive response are summed. 
2.
The weights for missed items are deducted from the maximum possible weight for 
each component. The weights for all missed items are deducted from the maximum 
possible weight for the Total score. 
3.
The score is calculated by dividing the summed weights by the adjusted maximum 
possible weight for that component and expressing the result as a percentage: 
Total and scale scores will be calculated as follows:
Total Score100*((Σ item weights)/(maximum total weight))
Symptom Score100*((Σ item 1, 2, 3, 4, 5, 6, 7, 8 weights)/(maximum symptom total 
weight))
Activity Score100*((Σ item 11, 15 weights)/(maximum activity total weight))
Impact Score100*((Σ item 9, 10, 12, 13, 14, 16, 17 weights)/(maximum impact total 
weight)
Sum of maximum possible weights for each component and Total: 

Symptoms: 662.5 

Activity: 1209.1 

Impacts: 2117.8 

Total: 3989.4 
(Note: these are the maximum possible weights that could be obtained for the worst 
possible state of the patient). 
It will be noted that the questionnaire requests a single response to questions 1-7, 9-10 
and 17. If multiple responses are given to one of these questions then the weights for all 
positive responses for that question will be averaged.


 
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Appendix 6  
St. George’s Respiratory Questionnaire (cont.) 
 
For information regarding question weights, please refer to the St George’s Respiratory 
Questionnaire Manual, Version 2.3. 
Missing individual items for the scoring of the SGRQ will be handled as follows: The 
symptoms component will be considered missing if more than 2 of the items are missing.  
The activity component will be considered missing if more than 4 of the items are 
missing.  The impacts component will be considered missing if more than 6 of the items 
are missing.  The total score will be considered missing if any component is missing.  
For a valid component questionnaire with unanswered questions, the predefined weight 
and score for a particular missing question will be used to calculate the aggregated 
score for the component (St George’s Respiratory Questionnaire Manual, Version 2.3).  
Missing data will not be imputed. 
 
 


 
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Appendix 7  
FACIT-FATIGUE 
The FACIT-Fatigue questionnaire consists of 13 statements designed to measure the 
degree of fatigue experienced by the patient in the previous 7 days.  For each question 
there are five possible responses: 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a 
bit), 4 (very much).  Statements 1 to 6 and 9 to 13 are worded so that higher scores 
correspond to greater fatigue, while statements 7 and 8 are worded so that higher 
scores correspond to less fatigue.  All scores except those for statements 7 and 8 will 
therefore be “reversed” on the 0 to 4 scale (i.e., a response of 0 will receive a score of 4, 
a response of 1 will receive a score of 3, etc.), so that for all questions higher scores will 
reflect improvement. 
For each questionnaire, if there are less than 7 responses recorded, then the total 
fatigue score will be considered missing.  If there are 7 or more responses recorded, 
then the total fatigue score for that questionnaire will be calculated as the average of the 
non-missing scores multiplied by 13.  FACIT-Fatigue scores range from 0 to 52. 
 
 


 
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Appendix 8  
SkinPRO 
The SkinPRO is a patient-reported outcome instrument developed to assess the skin-
related quality of life in patients with Ssc.  Initially, the SkinPRO contained 22 items, but 
following further validation work, 4 items from the SkinPRO were dropped (2, 4, 6, 22) 
resulting in an 18 item final version referred to as the SSPRO (Man A et al. 2017).  The 
SSPRO has 4 subscales: physical effects, physical limitations, emotional effects, and 
social effects.  Each item is scored on a 7-point Likert scale (06) with verbal anchors at 
0 (Not at all) and 6 (very much). 
For the version of the SSPRO in protocol WA29767, items 1, 3, 5, 721 contribute to the 
total score.  This has a range of 0 to 108, which is then transformed to a 0100 scale 
(the score is divided by 108 and then multiplied by 100).  Higher scores indicate greater 
severity of symptoms/impacts.  For the subscales, the items included are as follows: 
physical effects (Items 1, 3, 5, 7, 8), physical limitations (Items 9-14), emotional effects 
(items 1518), and social effects (items 1921).  The subscale scores are also 
transformed to a 0-100 scale for ease of comparison. 
 
 


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Appendix 9
EQ-5D-3L
The EQ VAS records the respondents self-rated health status on a vertical graduated 
(0-100) visual analogue scale.  Participants draw a line from a box to the point on the 
thermometer-like scale corresponding to their health state (100Best health state).  
Scores for the visual analogue scale reflect the position where participant's line crosses 
the thermometer-like scale.
The EQ-5D-3L descriptive system comprises 5 dimensions of health:
1.
mobility
2.
self-care
3.
usual activities
4.
pain/discomfort
5.
anxiety/depression
Each dimension comprises three levels (no problems, some problems, and extreme 
problems).  Participants are asked to indicate their level of health by checking one of the 
three responses for each domain. 


 
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Appendix 10  
WPAI-GH 
WPAI outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity, i.e., worse outcomes, as follows:  
Questions: 
1. currently employed 
2. hours missed due to health problems 
3. hours missed other reasons 
4. hours actually worked 
5. degree health affected productivity while working 
6. degree health affected regular activities 
 
Scores: 
Multiply scores by 100 to express in percentages 
Percent work time missed due to health: Q2/(Q2Q4) 
Percent impairment while working due to health: Q5/10 
Percent overall work impairment due to health: 
Q2/(Q2Q4)[(1  (Q2/(Q2Q4)))(Q5/10)] 
Percent activity impairment due to health: Q6/10  


 
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Appendix 11  
Cochran-Mantel-Haenszel Test 
 
The weighted difference in proportions is the difference in the response rates in the 
experimental treatment group compared with the co ntrol treatment group, adjusted 
for any stratification factors.  With two stratification factors, the number of patients in 
each strata is defined as nijk where i is the level of the first stratification factor and j 
is the level of the second stratification factor and k is treatment group (experimental 
or control).  The number of events in each strata is denoted by xijk, where i, j and k 
are as above.  The proportion of responders in each strata will be calculated by: 
ijk
ijk
ijk
n
x
p

 where i, j and k are as above 
 
The difference in proportions for each strata will then be calculated as the proportion 
of patients in each strata in the experimental treatment group (EXP) minus the 
proportion of patients in each strata in the control treatment group (CON) and 
denoted  
ijCON
ijEXP
ij
p
p
d


, for i and j as above. 
 
The weights for each strata (i, j) will be calculated as follows: 
ijCON
ijEXP
ijCON
ijEXP
ij
n
n
n
n
w


*
 
 
Within each strata, the weighted differences in the proportions in each of the 
treatment groups will be calculated as follows: 
ij
ij
ij
d
w
wd 
 
 
and then summed: 


i
j
ij
wd
WD
 
 
After calculation of the weighted difference in proportions, the calculation of the 95% 
confidence interval is as follows; 
 
Continuity-corrected Proportions 
1
5.0
#



ijk
ijk
ijk
n
x
p
 
 
Variances 
















ijCON
ijCON
ijCON
ijEXP
ijEXP
ijEXP
ij
ij
n
p
p
n
p
p
w
Up
#
#
#
#
2
1
1
var
 


 
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Appendix 11  
Cochran-Mantel-Haenszel Test (cont.)  
 
To calculate the sum of the weights and variances over all strata: 
Sum over Strata 


i
j
ij
w
W
 (sum of weights) 


i
j
ij
Up
Var
var
 (sum of variances) 
Point Estimate and Standard Error 
W
WD
d 
; 
2
W
Var
se 
 
Stratified 95% Confidence Intervals 
Lower Limit
se
d
96
.1


 
Upper Limit
se
d
96
.1

