Clinical trial NCT02745145
Conditions: Systemic Sclerosis-associated Interstitial Lung Disease
Keywords: Double-Blind Method Interstitial Lung Diseases Systemic Scleroderma Abituzumab Mycophenolate Efficacy, Safety
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2016-05-31; Completion date: 2018-05-30
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial was to compare two doses of abituzumab with placebo and determine whether abituzumab was more effective, safer, would be better tolerated and could provoke better immune response than placebo in the treatment of participants with SSc-ILD who already receive constant doses of mycophenolate.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Abituzumab 1500 mg intervention 2: Abituzumab 500 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Participants received Abituzumab 1500 mg administered as an intravenous infusion for 1 hour every 4 weeks up to Week 64. intervention 2: Participants received Abituzumab 500 mg administered as an intravenous infusion for 1 hour every 4 weeks up to Week 64. intervention 3: Participants received Placebo matched to Abituzumab administered as an intravenous infusion for 1 hour every 4 weeks up to Week 64.

Protocol documents:
Prot_000.pdf: 
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Clinical Trial Protocol
Clinical Trial Protocol Number
EMR200017-014
Title
A 
Phase 
II, 
randomized, 
double-blind, 
placebo-controlled, parallel-group, multicenter trial 
to evaluate the efficacy and safety of abituzumab in 
subjects 
with 
systemic 
sclerosis-associated 
interstitial lung disease (SSc-ILD)
Phase
II
IND Number
EudraCT Number
2015-005023-11
Coordinating Investigator
For all countries, except North America:
 
 
For sites in North America:
 
Sponsor
For all countries, except the USA:
Merck KGaA 
Frankfurter Strasse 250
64293 Darmstadt, Germany
For sites in the USA:
EMD Serono Research & Development Institute, 
Inc.
45A Middlesex Turnpike
Billerica, MA 01821, USA
Medical Responsible:
EMD Serono Research & Development Institute, 
Inc.
45A Middlesex Turnpike
Billerica, MA, 01821 USA
Telephone number: 
Fax number: 
Clinical Trial Protocol Version
26 July 2017/Version 5.0 including Amendments 1 
to 5
Replaces Version
14 September 2016/Version 4.0
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This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. 
It is intended for restricted use only and may not – in full or part – be passed on, reproduced, 
published, or used without express permission of Merck KGaA, Darmstadt, Germany, or its 
subsidiary. Copyright © 2017 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights 
reserved.
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Protocol Table of Contents
Protocol Table of Contents ..................................................................................................3
Table of In-Text Tables .......................................................................................................7
Table of In-Text Figures......................................................................................................7
List of Abbreviations ...........................................................................................................8
1
Synopsis..............................................................................................11
2
Sponsor, Investigators, and Trial Administrative Structure ...............25
3
Background Information.....................................................................26
3.1
Abituzumab.........................................................................................27
3.2
Trial Rationale ....................................................................................27
3.3
Risk-Benefit Analysis.........................................................................28
4
Trial Objectives ..................................................................................29
4.1
Primary Objective...............................................................................29
4.2
Secondary Objectives .........................................................................29
4.3
Other Objectives .................................................................................30
5
Investigational Plan ............................................................................30
5.1
Overall Trial Design and Plan ............................................................30
5.2
Discussion of Trial Design .................................................................32
5.2.1
Rationale for Trial Design ..................................................................32
5.2.2
Selection of Doses ..............................................................................33
5.2.3
Rationale for Inclusion and Exclusion Criteria ..................................34
5.2.4
Rationale for Primary Objective.........................................................34
5.2.5
Rationale for Secondary Objectives ...................................................35
5.2.6
Rationale for Exploratory Objectives .................................................38
5.2.7
Inclusion of Special Populations ........................................................38
5.3
Selection of Trial Population..............................................................38
5.3.1
Inclusion Criteria ................................................................................39
5.3.2
Exclusion Criteria...............................................................................40
5.4
Criteria for Initiation of Trial Treatment ............................................44
5.5
Criteria for Subject Withdrawal..........................................................44
5.5.1
Withdrawal from Trial Therapy..........................................................44
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5.5.2
Withdrawal from the Trial..................................................................45
5.6
Premature Termination of the Trial ....................................................45
5.7
Definition of End of Trial...................................................................45
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................46
6.1
Description of the Investigational Medicinal Product........................46
6.2
Dosage and Administration ................................................................46
6.3
Assignment to Treatment Groups.......................................................46
6.4
Noninvestigational Medicinal Products to be Used............................47
6.5
Concomitant Medications and Therapies ...........................................47
6.5.1
Permitted Medicines...........................................................................47
6.5.2
Prohibited Medicines..........................................................................48
6.5.3
Other Interventions.............................................................................48
6.5.4
Special Precautions.............................................................................48
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................50
6.6
Packaging and Labeling of the Investigational Medicinal Product....51
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................51
6.8
Investigational Medicinal Product Accountability.............................52
6.9
Assessment of Investigational Medicinal Product Compliance .........52
6.10
Blinding ..............................................................................................53
6.11
Emergency Unblinding.......................................................................54
6.12
Treatment of Overdose .......................................................................54
6.13
Medical Care of Subjects after End of Trial.......................................54
7
Trial Procedures and Assessments......................................................54
7.1
Schedule of Assessments....................................................................54
7.1.1
Screening Period.................................................................................55
7.1.2
Double-blind Treatment Period..........................................................55
7.1.3
Safety Follow-up Period.....................................................................56
7.1.4
Survival Follow-up .............................................................................56
7.2
Demographic and Other Baseline Characteristics ..............................56
7.3
Efficacy Assessments .........................................................................56
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7.4
Assessment of Safety..........................................................................57
7.4.1
Adverse Events ...................................................................................57
7.4.2
Pregnancy and In Utero Drug Exposure.............................................63
7.4.3
Clinical Laboratory Assessments .......................................................63
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............65
7.5
Pharmacokinetics................................................................................65
8
Statistics..............................................................................................66
8.1
Sample Size ........................................................................................66
8.2
Randomization....................................................................................66
8.3
Endpoints............................................................................................67
8.3.1
Primary Endpoint................................................................................67
8.3.2
Secondary Endpoints ..........................................................................67
8.3.3
Safety Endpoints.................................................................................68
8.3.4
Other Endpoints..................................................................................68
8.3.5
Pharmacokinetic 
ts ................................................................69
8.3.6
Other Exploratory Assessments..........................................................69
8.4
Analysis Sets.......................................................................................69
8.4.1
Modified Intent-to-Treat.....................................................................69
8.4.2
Intent-to-Treat.....................................................................................70
8.4.3
Per-Protocol ........................................................................................70
8.4.4
Safety..................................................................................................70
8.5
Description of Statistical Analyses.....................................................70
8.5.1
General Considerations.......................................................................70
8.5.2
Analysis of Primary Endpoints...........................................................71
8.5.3
Analysis of Secondary Endpoints.......................................................72
8.6
Interim and Additional Planned Analyses ..........................................74
9
Ethical and Regulatory Aspects..........................................................74
9.1
Responsibilities of the Investigator ....................................................74
9.2
Subject Information and Informed Consent .......................................75
9.3
Subject Identification and Privacy......................................................76
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9.4
Emergency Medical Support and Subject Card..................................76
9.5
Clinical Trial Insurance and Compensation to Subjects.....................77
9.6
Independent Ethics Committee or Institutional Review Board..........77
9.7
Health Authorities...............................................................................77
10
Trial Management...............................................................................77
10.1
Case Report Form Handling...............................................................77
10.2
Source Data and Subject Files............................................................78
10.3
Investigator Site File and Archiving...................................................79
10.4
Monitoring, Quality Assurance, and Inspection by Health 
Authorities ..........................................................................................79
10.5
Changes to the Clinical Trial Protocol................................................80
10.6
Clinical Trial Report and Publication Policy......................................80
10.6.1
Clinical Trial Report...........................................................................80
10.6.2
Publication..........................................................................................80
11
References Cited in the Text...............................................................80
12
Appendices .........................................................................................84
Appendix I:
Signature Pages and Responsible Persons for the Trial......................84
Signature Page – Protocol Lead.........................................................................................85
Signature Page –Coordinating Investigator .......................................................................86
Signature Page –Coordinating Investigator .......................................................................87
Signature Page – Principal Investigator.............................................................................88
Sponsor Responsible Persons not Named on the Cover Page ...........................................89
Appendix II:
Prednisone Equivalence Calculation ..................................................90
Appendix III:
New York Heart Association (NYHA) Criteria .................................91
Appendix IV:
Criteria for the Classification of Systemic Sclerosis..........................92
Appendix V:
Protocol Amendments and List of Changes .......................................94
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Table of In-Text Tables
Table 1
Schedule of Assessments – Screening through Week 52...................20
Table 2
Schedule of Assessments – Week 56 through Safety Follow-up .......23
Table 3
Predicted Pharmacokinetic and Target Inhibition ..............................33
Table 4
Clinical Laboratory Testing................................................................64
Table of In-Text Figures
Figure 1
Trial Design ........................................................................................32
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List of Abbreviations
ACR
American College of Rheumatology
ADA
Antidrug antibody
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANA
Antinuclear antibodies
ANCOVA
Analysis of covariance
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BDI
Baseline Dyspnea Index
BP
Blood pressure
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
CRISS
Combined Response Index for Systemic Sclerosis
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
dcSSc
Diffuse cutaneous systemic sclerosis
DLCO
Diffusion capacity of the lung for carbon monoxide
ECG
Electrocardiogram
eCRF
Electronic case report form
ERA
Endothelin receptor antagonist
EU
European Union
EULAR
European League Against Rheumatism
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
HBsAg
Hepatitis B surface antigen
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HIV
Human immunodeficiency virus
HRCT
High-resolution computed tomography
HRQoL
Health-related quality of life
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgG2
Immunoglobulin G2
IgM
Immunoglobulin M
ILD
Interstitial lung disease
IMP
Investigational medicinal product
INR
International normalized ratio
IPF
Idiopathic pulmonary fibrosis
IRB
Institutional Review Board
ITT
Intent-to-Treat
IUD
Intrauterine device
IUS
Intrauterine hormone releasing system
IVRS/IWRS
Interactive voice/web response system
KCO
Transfer coefficient of the lung for carbon monoxide
LTBI
Latent tuberculosis infection
MAR
Missing-at-random
mITT
Modified Intent-to-Treat
MMF
Mycophenolate mofetil
MPS
Sodium mycophenolate
mRNA
Messenger ribonucleic acid
mRSS
Modified Rodnan skin score
mSv
Millisieverts
NCI
National Cancer Institute
NT pro-BNP
N-terminal prohormone brain natriuretic peptide
NYHA
New York Heart Association
OMERACT
Outcome Measures in Rheumatology
PAH
Pulmonary arterial hypertension
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PD
Pharmacodynamic(s)
PEF
Peak expiratory flow
PK
Pharmacokinetic(s)
PP
Per-Protocol
PRO
Patient-reported outcome
PTT
Partial thromboplastin time
QLF
Quantitative lung fibrosis
QoL
Quality of life
RNA
Ribonucleic acid
SAE
Serious adverse event
SGRQ
St. George Respiratory Questionnaire
SHAQ
Scleroderma Health Assessment Questionnaire
SLS
Scleroderma Lung Study
SOC
System organ class
SSc
Systemic sclerosis
SSc-ILD
Systemic sclerosis-associated interstitial lung disease
SUSAR
Suspected unexpected serious adverse reaction
TB
Tuberculosis
TDI
Transition Dyspnea Index
TEAE
Treatment-emergent adverse event
TGF
Transforming growth factor
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
VAS
Visual analogue scale
WOCF
Worst observation carried forward
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1
Synopsis
Clinical Trial Protocol Number
EMR200017-014
Title
A 
Phase 
II, 
randomized, 
double-blind, 
placebo-controlled, parallel-group, multicenter 
trial to evaluate the efficacy and safety of 
abituzumab in subjects with systemic sclerosis-
associated interstitial lung disease (SSc-ILD)
Trial Phase
II
IND Number
FDA covered trial
Yes
EudraCT Number
2015-005023-11 
Coordinating Investigator
For all countries, except North America:
 
 
For sites in North America:
 
Sponsor
For all countries, except the USA:
Merck KGaA 
Frankfurter Strasse 250
64293 Darmstadt, Germany
For sites in the USA:
EMD Serono Research & Development Institute, 
Inc.
45A Middlesex Turnpike
Billerica, MA 01821, USA
Trial centers/countries
This trial will be conducted at approximately 
60 sites globally, including, but not limited to, 
North America and the European Union. 
Planned trial period
(first subject in-last subject out)
March 2016 to October 2020 
Trial Registry
ClinicalTrials.gov 
and 
other 
clinical 
trial 
registries
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Objectives: 
Primary Objective
The primary objective of the trial is to demonstrate efficacy of abituzumab in improving lung 
function of subjects with systemic sclerosis (SSc) associated interstitial lung disease 
(SSc-ILD).
Secondary Objectives
The secondary objectives of the trial are:
! To characterize further the effect of abituzumab on subjects with SSc-ILD who are treated 
with a stable mycophenolate regimen; 
! To characterize the safety, tolerability, and immunogenicity of abituzumab in subjects 
with SSc-ILD who are treated with a stable mycophenolate regimen;
! To evaluate the effect of abituzumab on SSc skin disease in subjects with diffuse skin 
involvement who are treated with a stable mycophenolate regimen;
! To evaluate health-related quality of life (HRQoL) outcomes of abituzumab in subjects 
with SSc-ILD who are treated with a stable mycophenolate regimen;
! To evaluate pharmacokinetic (PK) parameters of abituzumab in subjects with SSc-ILD 
who are treated with a stable mycophenolate regimen.
Exploratory Objectives
The exploratory objectives of the trial are:
!
 
 
 
Methodology: This is a Phase II, multicenter, double-blind, placebo-controlled, 
parallel-group trial to be conducted in adult subjects with SSc-ILD to evaluate the efficacy, 
safety, tolerability, and immunogenicity of multiple intravenous doses of abituzumab on top 
of background therapy. Subjects must be currently treated with the same mycophenolate 
regimen (stable dose) in a range of 1.5 to 3 g/day of mycophenolate mofetil (MMF) or 
1080 to 2160 mg/day of sodium mycophenolate (MPS) for at least 2 months prior to the 
Screening Visit and continued through Day 1 of the Treatment Period.
The trial is composed of a Screening Period, a Double-blind Treatment Period, a Safety 
Follow-up Period, and Survival Follow-up as follows:
! Screening Period: duration of up to 6 weeks; however, subjects should have the Day 1 visit 
as soon as possible after eligibility for the trial has been confirmed. 
! Double-blind Treatment Period: duration of 104 weeks (2 years) starting at randomization. 
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Subjects will be monitored at Weeks 2, 4, and every 4 weeks thereafter until Week 104. 
! Safety Follow-up Period: duration of 12 weeks. During the Safety Follow-up Period, 
monitoring for adverse events (AEs), assessment of disease progression, and an 
assessment for antidrug antibodies (ADA) will be carried out.
! Survival Follow-up:  each subject will be followed up by the site for survival status every 
12 weeks (∀1 week) after the subject’s last trial visit until death of the subject or end of 
the trial.
Approximately 175 subjects will be randomized in a 2:2:1 ratio to receive abituzumab 
1500 mg, placebo, or abituzumab 500 mg, respectively, given as an intravenous infusion over 
1 hour every 4 weeks with the last IMP administration at the Week 100 visit. 
Subjects are to continue their previous stable mycophenolate therapy. 
The effects of abituzumab on clinical status will be assessed through evaluations including 
pulmonary 
function 
tests, 
high-resolution 
computed 
tomography 
(HRCT), 
and 
patient-reported outcomes (PROs).
Subjects who meet the criteria for clinically meaningful progression during the Double-blind 
Treatment Period or Safety Follow-up Period should have a change in background therapy. 
With regard to progression of ILD, subjects taking less than the maximal specified dose of 
mycophenolate (3 g/day MMF or 2160 mg/day MPS) can have the mycophenolate dose 
increased while investigational medicinal product (IMP) is continued. Subjects taking the 
maximal specified dose of mycophenolate who have clinically meaningful progression should 
have the IMP discontinued and be treated according to local standard of care. If a nonbiologic
immunosuppressant (such as cyclophosphamide [oral or intravenous]) is initiated, then 
mycophenolate must be discontinued.
With regard to progression of manifestations not including ILD, subjects should be 
considered for change in therapy according to local standard of care, at the discretion of the 
Investigator.
Subjects meeting 1 or both of the below criteria will be considered as having clinically 
meaningful disease progression:
1. SSc-ILD: one of the following (in the absence of other causative intercurrent illness) on at 
least 2 occasions within approximately 4 weeks apart (as per OMERACT criteria): 
! Relative decrease from baseline in forced vital capacity (FVC) % predicted ≥10%;
! Relative decrease from baseline in FVC % predicted ≥5% to < 10% AND relative 
decrease from baseline in the diffusion capacity of the lung for carbon monoxide (DLCO) 
% predicted ≥15%.
2.  SSc progression other than interstitial lung disease (ILD): new onset of one or more of the 
following:
! Scleroderma renal crisis;
! Left ventricular failure (defined as ejection fraction ≤45%);
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! Pulmonary arterial hypertension requiring treatment.
If a subject discontinues IMP, then the subject should complete the early termination visit and 
then the remaining scheduled visits. At a minimum, the subject is expected to complete the 
trial visits at Weeks 12, 24, 36, 52, 64, 76, 88, and 104, as well as the Safety Follow-up 
period Week 12 visit. Subjects with discontinued IMP can come to the other scheduled visits 
during the trial period according to the Investigator's judgment. 
Subjects who withdraw from the treatment period would have an early termination visit 
followed by entrance into the Safety Follow-up Period. 
Subjects who withdraw from the trial (eg, withdraw consent, lost to follow up, or death) 
would not have any additional trial visits. 
All subjects will be followed up by the site for survival from the subject’s last trial visit until 
death or the end of the trial.
New onset or worsening of manifestations of scleroderma that are not captured by the 
pulmonary function tests, modified Rodnan skin score (mRSS), or digital ulcer count, should 
be reported as AEs.
If the ILD on HRCT worsens significantly according to the Investigator, then subjects can 
have the mycophenolate treatment increased to the protocol-specified maximal dose (ie, 
3 g/day MMF or 2160 mg/day MPS).
During the conduct of the trial, an Independent Data Monitoring Committee (IDMC) will 
monitor safety data on a regular basis (to be specified in the IDMC charter). The IDMC will 
also review the results of the interim futility analysis conducted by an independent statistical 
center. Based on the prespecified stopping boundary of futility, and the totality of the 
information at interim, the IDMC will make a recommendation to the Sponsor on continuing 
or stopping the trial for futility. An independent panel of dermatologists will provide 
guidance for further investigation and interpretation of cutaneous AEs that are serious, are 
Grade 3 or higher, or are not responding to treatment, and advise the IDMC whether any 
actions to modify clinical trial conduct should be considered.
Planned number of subjects: Approximately 175 subjects are planned for trial 
randomization.
Primary endpoint: The primary endpoint of this trial is the annual rate of absolute FVC 
change in volume (mL). 
Secondary efficacy endpoints: 
The key secondary endpoints include the following:
! Change in dyspnea from baseline as measured by the Mahler Transition Dyspnea Index 
(TDI) at Week 52;
! Absolute change from baseline in St. George Respiratory Questionnaire (SGRQ) total 
score at Week 52;
! Absolute change from baseline in mRSS at Week 52 in subjects with diffuse cutaneous 
skin involvement at baseline;
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! Absolute change from baseline in quantitative lung fibrosis (QLF) in the region of highest 
baseline severity at Week 52;
! Overall survival.
Other secondary efficacy endpoints include:
! Proportion of subjects with clinically meaningful progression of SSc by meeting clinically 
meaningful disease progression Criterion 1 (ILD) by Week 52 and by Week 104; 
! Proportions of subjects with clinically meaningful progression of SSc by meeting 
clinically meaningful disease progression Criterion 2 (SSc progression other than ILD) by 
Week 52 and by Week 104;
! Proportion of subjects with clinically meaningful progression by Week 52 and by 
Week 104;
! Proportion of subjects with absolute decrease from baseline of FVC % predicted ≥10% on 
2 or more consecutive occasions within approximately 4 weeks apart by Week 52 and by 
Week 104;
! Time to first clinically meaningful progression;
! Absolute change from baseline in FVC % predicted up to Week 104;
! Absolute change from baseline in DLCO % predicted up to Week 104;
! Absolute change from baseline in transfer coefficient of the lung for carbon monoxide 
(KCO) up to Week 104;
! Absolute change from baseline in QLF in the region of highest baseline severity at 
Week 104;
! Absolute change from baseline in quantitative HRCT analyses of extent of total ILD up to 
Week 104.
Safety endpoints:
! Nature, incidence, severity, relationship and outcome of AEs, serious AEs (SAEs), and 
AEs of special interest (AESIs) from screening up to Week 116;
! Number of subjects with treatment-emergent AEs, SAEs, and AESIs from baseline up to 
Week 116;
! Treatment-emergent changes in clinical laboratory measures, electrocardiogram (ECG) 
measures, and vital signs from baseline up to Week 116;
! Incidence of subjects with positive ADA titers from baseline up to Week 116.
Quality of life endpoints:
! Proportion of subjects with Mahler TDI worsening ≥2 up to Week 104;
! Proportion of subjects with Mahler TDI worsening ≥2 up to Week 104 for subjects with 
Mahler Baseline Dyspnea Index (BDI) ≥2;
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! Change in dyspnea from baseline as measured by the Mahler TDI up to Week 104;
! Change in dyspnea from baseline as measured by the Mahler TDI up to Week 104 for 
subjects with Mahler BDI ≥2;
! Absolute change from baseline for each of the following HRQoL questionnaires up to 
Week 104:
! Leicester Cough Index
! SGRQ
! Physician’s Global Assessment
! Patient’s Global Assessment
! Scleroderma Health Assessment Questionnaire (SHAQ)
! EQ-5D.
Skin fibrosis endpoints:
! In subjects with diffuse cutaneous SSc (dcSSc): 
! Absolute change from baseline in mRSS up to Week 104;
! Proportion of subjects with change from baseline in mRSS up to Week 104 according 
to the following categories: 
!
Worsened (absolute increase of ≥5 points and relative increase ≥25%), 
!
Improved (absolute decrease ≥5 points and relative decrease ≥25%), or 
!
Stable (do not meet either Worsened or Improved category).
! In subjects with digital ulcers at baseline: absolute change from baseline in digital ulcer 
count up to Week 104.
Combined response endpoint:
! Proportion of responders as defined by the Combined Response Index for Systemic 
Sclerosis (CRISS) up to Week 104.
Pharmacokinetic endpoints: 
Abituzumab concentrations and PK parameters (eg, Cmax and Cmin).
Other exploratory assessments: 
!
 
 
 
 
 
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!
 
 
 
Diagnosis and key inclusion and exclusion criteria: 
Male or female subjects between 18 and 75 years of age who provide written consent and 
fulfill the 2013 American College of Rheumatology/European League Against Rheumatism 
criteria for classification of SSc, have been taking the same mycophenolate regimen (stable 
dose) in a range of 1.5 to 3 g/day of MMF or 1080 to 2160 mg/day of MPS for at least 
2 months prior to the Screening Visit and continued through Day 1 of the Treatment Period, 
have at least 5% fibrosis of the lung on HRCT according to central reading, have a disease 
duration of < 7 years from the first non-Raynaud’s symptom, DLCO ≥30% predicted, FVC 
40% to 85% predicted, ratio of FVC to DLCO % predicted < 1.8, and agree to use a highly 
effective method of contraception for the duration of their participation in the trial meet the 
inclusion criteria. 
Subjects must not have underlying conditions that constitute an inappropriate risk or 
contraindication for trial participation including, but not limited to: significant renal 
impairment, obstructive lung disease/emphysema, pulmonary arterial hypertension, another 
inflammatory connective tissue disease (apart from scleroderma-associated myopathy,
fibromyalgia, and secondary Sjögren’s syndrome, which are allowed), and/or tuberculosis. 
The use of agents other than mycophenolate (MPS or MMF) considered by the Investigator to 
have immunomodulating, immunosuppressive, or potential scleroderma disease-modifying 
properties within 2 months of the Screening Visit is not allowed (or 5 months prior to the 
Screening Visit for cyclophosphamide).
Investigational medicinal product: dose/mode of administration/dosing schedule: 
Abituzumab 1500 or 500 mg will be administered as an intravenous infusion over 1 hour 
once every 4 weeks. Close observation of the subject is recommended for a period of at least 
1 hour after administration of the IMP. The last IMP administration is at the Week 100 visit
(2 years).
Reference therapy: dose/mode of administration/dosing schedule: Placebo (citrate 
buffered saline) will be administered as an intravenous infusion over 1 hour once every 
4 weeks. Close observation of the subject is recommended for a period of at least 1 hour after 
administration. The last administration of placebo is at the Week 100 visit (2 years).
Planned trial and treatment duration per subject: The planned total duration of the trial 
period with study visits is up to 122 weeks for each subject, including a 6-week Screening 
Period, a 104-week Double-blind Treatment Period, and a 12-week Safety Follow-up Period. 
All subjects will be followed up for survival from the last visit on trial until death or the end 
of trial.
Statistical methods: 
Sample size:
 
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Statistical analysis:
The interim futility analysis will be performed by an independent third party statistician when 
approximately 88 subjects have either completed 52 weeks of treatment or prematurely 
discontinued from the trial. The results of the interim analysis will be reviewed confidentially 
by the IDMC. The primary endpoint will be analyzed using all observed FVC data for these 
subjects by the interim analysis cut-off date and compared to the prespecified futility 
stopping boundary between the abituzumab 1500 mg arm and the placebo arm. The futility 
boundary is non-binding. Additional analysis of the primary and secondary endpoints is 
allowed at the IDMC’s discretion and supported by the independent third-party statistician. 
Based on the totality of the information at interim, the IDMC will make a recommendation to 
the Sponsor on continuing or stopping the trial for futility. 
The primary analysis will be performed by the Sponsor/Contract Research Organization staff 
when all subjects have either completed 52 weeks of treatment or prematurely discontinued 
from the trial. The primary endpoint and other efficacy endpoints will be analyzed using all 
observed data for all subjects by the primary analysis cut-off date. Results will be generated 
on the aggregate group level and reviewed by a restricted group to limit initial dissemination. 
The access of individual treatment information will be controlled to maintain the integrity of 
trial conduct. 
The sites and subjects remain blinded until the end of the trial. The trial will continue as 
planned and a final treatment analysis will be performed when all subjects have either 
completed 104 weeks of treatment or prematurely discontinued from the trial. 
The final database will be locked after all subjects have completed the 12 weeks of safety 
follow-up or prematurely discontinued from the trial. A final follow-up analysis will be 
performed to update the results with any remaining data collected from the Safety Follow-up 
Period.
The primary endpoint will be analyzed using a random coefficients linear regression model 
with absolute change from baseline in observed FVC volume (mL) as the outcome variable. 
The change in FVC volume is assumed to be linear within each subject over the course of the 
trial. The model will include random coefficients for intercept and time, fixed-effect terms for 
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treatment and time, treatment-by-time as the interaction term, and adjusting for baseline 
FVC, duration of prior mycophenolate use at baseline, age, sex, and height. Missing data will 
be assumed to be missing-at-random. The analysis of the primary endpoint and other efficacy 
endpoints will be conducted to include all the data collected during the trial for all subjects 
regardless of their adherence to treatment or use of rescue therapies. Sensitivity analysis will 
be performed to evaluate the potential effect of missing data on the robustness of the efficacy 
results, including tipping point analyses to assess the different assumptions about the missing 
outcomes and to explore the plausibility of missing data assumptions under which the 
conclusions change.
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Table 1
Schedule of Assessments – Screening through Week 52
Trial Period
Screening
Weeks During Double-blind Treatment Period (Visit Window ∀3 days)
Week
0
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
Trial Day
-42 to -1
1
3
5
15
22
29
57
85
113
141
169
197
225
253
281
309
337
365
Informed consent
X
Inclusion/exclusion 
criteria
X
Xa
Pharmacokinetic 
informed consent (Rich 
PK sampling only)
X
Demographic data
X
SSc-ILD and other 
medical history, 
medications, 
surgery/procedures
X
HRCT
X
X
X
12-lead ECG (locally 
read)
X
X
X
Tuberculosis 
assessment
X
Serum virology (HIV, 
HCV, HBV)
X
Serum pregnancy test c
X
PT, aPTT, TSH, and 
NT pro-BNP
X
Urine pregnancy test c,d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
Xe
X
Xe
Xe
Xe
Xe
X
Xe
Xe
Xe
Xe
Xe
Xe
X
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Trial Period
Screening
Weeks During Double-blind Treatment Period (Visit Window ∀3 days)
Week
0
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
Trial Day
-42 to -1
1
3
5
15
22
29
57
85
113
141
169
197
225
253
281
309
337
365
Vital signs, weight, 
height f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Mahler BDI/TDI and 
SGRQ g
X
X
X
X
X
Patient’s Global 
Assessment, Leicester 
Cough Index, SHAQ, 
EQ-5D, and Physician’s 
Global Assessment g
X
X
X
Randomization
X
IMP administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sampling h
X
X
X
X
Rich PK sampling i
X
X
X
X
Routine hematology, 
clinical chemistry, 
urinalysis dipstick j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary function 
tests (FVC, DLCO) k
X
X
X
X
X
X
mRSS
X
X
X
X
X
Digital ulcer counts l
X
X
X
X
X
Serum for ADA
X
X
X
 
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Trial Period
Screening
Weeks During Double-blind Treatment Period (Visit Window ∀3 days)
Week
0
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
Trial Day
-42 to -1
1
3
5
15
22
29
57
85
113
141
169
197
225
253
281
309
337
365
Concomitant 
medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA = antidrug antibodies; AE = adverse event; aPTT = activated partial thromboplastin time; BDI = Baseline Dyspnea Index; DLCO = diffusion capacity of the 
lung for carbon monoxide; ECG = electrocardiogram; FVC = forced vital capacity; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; HRCT = high-resolution computed tomography; IMP = investigational medicinal product; mRSS = modified Rodnan skin score; 
PK = pharmacokinetic; PT = prothrombin time; SGRQ = St. George Respiratory Questionnaire; SHAQ = Scleroderma Health Assessment Questionnaire; 
SSc-ILC = systemic sclerosis-associated interstitial lung disease; TDI = Transition Dyspnea Index; TSH = thyroid-stimulating hormone; VAS = visual analog scale.
a
Subject eligibility (based on screening assessments of the inclusion and exclusion criteria) must be checked again on Day 1 prior to randomization.
 
c
For women of childbearing potential or who are postmenopausal for less than 2 years. At Day 1, if the urine test is negative, the subject can be randomized and 
receive the first dose of IMP.
d
Performed locally per local constraints and regulations.
e
Focused physical examination only, according to standard of care.
f
Vital signs include 10-minute seated arterial blood pressure, pulse rate, and body temperature. Height will be measured at Day 1 only. Weight will be measured 
at Weeks 0, 24, 52, 76, and 104. Body weight will be measured with a balance beam scale, if possible.
g
Questionnaires should be completed before any other procedures are performed. Questionnaires should be performed in the following order: Patient’s Global 
Assessment, SHAQ, Mahler BDI (at Day 1) followed by Mahler TDI at the subsequent visits, SGRQ, Leicester Cough Index, and EQ-5D. The Mahler BDI/TDI 
administrator must be blinded to other assessments. The Physician’s Global Assessment (VAS) may be performed after other assessments at the visit are 
completed.
h
For all subjects, samples will be collected predose and immediately after the end of IMP infusion at Weeks 0 (Day 1), 4, 8, and 16.
i
For subjects who have provided informed consent for the rich PK sampling, additional samples will be collected on Days 3, 5, 15, and 22 (in addition to the pre-
and postdose samples at Weeks 0, 4, 8, and 16; see footnote h).
j
See Section 7.4.3 for list of routine laboratory assessments. Urine protein:creatinine ratio to be performed if dipstick urinalysis reveals at least 3+ protein. 
Microscopic urinalysis to be performed if blood is present.
k
The DLCO measurements will be corrected for hemoglobin level, and spirometry assessments will be centrally adjudicated.
l
Digital ulcers are those distal to the metacarpal phalangeal joints. New or worsening digital ulcers, or at any other site on the body, will be captured as AEs.
 
o
Adverse events should also be assessed for occurrence during the periods between trial visits.
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Table 2
Schedule of Assessments – Week 56 through Safety Follow-up
Trial Period
Weeks During Double-blind Treatment Period (Visit Window ∀5 days)
Safety 
Follow-up 
Number 
weeks post 
last visit 
(∀5 days)
Survival 
Follow-
up Post 
Last Trial 
Visit
Week
56
60
64
68
72
76
80
84
88
92
96
100
104
ETa
4
12
Every 12 
Weeks
Trial Day
393
421
449
477
505
533
561
589
617
645
673
701
729
HRCT
X
X
12-lead ECG (locally read)
X
X
X
X
Urine pregnancy test b,c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
Xd
Xd
Xd
Xd
Xd
X
Xd
Xd
Xd
Xd
Xd
Xd
X
X
Xd
X
Vital signs, weight e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Mahler TDI and SGRQ f
X
X
X
X
X
X
Patient’s Global Assessment, 
Leicester Cough Index, SHAQ, 
EQ-5D, and Physician’s Global 
Assessment f
X
X
X
IMP administration
X
X
X
X
X
X
X
X
X
X
X
X
Routine hematology, clinical 
chemistry, urinalysis g
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary function tests (FVC, 
DLCO) h
X
X
X
X
X
X
mRSS
X
X
X
X
X
X
Digital ulcer counts i
X
X
X
X
X
X
Serum for ADA
X
X
X
X
X
Concomitant 
medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Trial Period
Weeks During Double-blind Treatment Period (Visit Window ∀5 days)
Safety 
Follow-up 
Number 
weeks post 
last visit 
(∀5 days)
Survival 
Follow-
up Post 
Last Trial 
Visit
Week
56
60
64
68
72
76
80
84
88
92
96
100
104
ETa
4
12
Every 12 
Weeks
Trial Day
393
421
449
477
505
533
561
589
617
645
673
701
729
Adverse events j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital status k
X
ADA = antidrug antibodies; AE = adverse event; BDI = Baseline Dyspnea Index; DLCO = diffusion capacity of the lung for carbon monoxide; ECG = 
electrocardiogram; ET = early termination; FVC = forced vital capacity; HRCT = high resolution computed tomography; IMP = investigational medicinal product; 
mRSS = modified Rodnan skin score; SGRQ = St. George Respiratory Questionnaire; SHAQ = Scleroderma Health Assessment Questionnaire; TDI = Transition 
Dyspnea Index; VAS = visual analog scale.
a Subjects who discontinue IMP for any reason should complete the ET visit as soon as possible, but within 2 weeks of IMP discontinuation, and then the 
remaining scheduled trial visits. At a minimum, the subject is expected to complete the trial visits at Weeks 12, 24, 36, 52, 64, 76, 88, and 104, as well as the 
Safety Follow-up period Week 12 visit. Subjects with discontinued IMP can come to the other scheduled visits during the trial period according to the 
Investigator's judgment. Subjects who withdraw from the treatment period would have an early termination visit followed by entrance into the Safety Follow-up 
Period. Subjects who withdraw from the trial (eg, withdraw consent, lost to follow up, or death; see Section 5.5.2) would not have any additional trial visits. All 
subjects will be followed up by the site approximately every 12 weeks for survival from the subject’s last trial visit until death or the end of the trial.
b For women of childbearing potential or who are postmenopausal for less than 2 years. Positive urine pregnancy tests should be confirmed with a serum test. If 
the serum pregnancy test is subsequently positive, the subject will be withdrawn from IMP.
c Performed locally per local constraints and regulations.
d Focused physical examination only, according to standard of care.
e Vital signs include 10-minute seated arterial blood pressure, pulse rate, and body temperature. Weight will be measured at Weeks 0, 24, 52, 76, and 104. Body 
weight will be measured with a balance beam scale, if possible.
f Questionnaires should be completed before any other procedures are performed. Questionnaires should be performed in the following order: Patient’s Global 
Assessment, SHAQ, Mahler BDI (at Day 1) followed by Mahler TDI at the subsequent visits, SGRQ, Leicester Cough Index, and EQ-5D. The Mahler BDI/TDI 
administrator must be blinded to other assessments. The Physician’s Global Assessment (VAS) may be performed after other assessments at the visit are 
completed.
g See Section 7.4.3 for list of routine laboratory assessments. Urine protein:creatinine ratio to be performed if dipstick urinalysis reveals at least 3+ protein. 
Microscopic urinalysis to be performed if blood is present.
h The DLCO measurements will be corrected for hemoglobin level, and spirometry assessments will be centrally adjudicated.
I Digital ulcers are those distal to the metacarpal phalangeal joints. New or worsening digital ulcers, or at any other site on the body, will be captured as AEs. 
j Adverse events should also be assessed for occurrence during the periods between trial visits.
k Survival follow-up: All subjects will be assessed for survival every 12 weeks (∀1 week) from the last trial visit until death or end of the trial.
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2
Sponsor, Investigators, and Trial Administrative Structure
This clinical trial will be sponsored by: 
! EMD Serono Research & Development Institute, Inc., Billerica, Massachusetts, in the USA.
! Merck KGaA, Darmstadt, Germany in the countries outside the USA.
The trial will be conducted at approximately 60 sites globally, including, but not limited to, 
North America and the European Union (EU).  Approximately 15 sites are planned in the USA.
The Coordinating Investigators (for all countries, except in North America: 
 
; for sites in North America: 
 
), represent all Investigators for decisions and 
discussions regarding this trial, consistent with the International Council for Harmonisation 
(ICH) Topic E6 Good Clinical Practice (GCP; hereafter referred to as ICH GCP). The 
Coordinating Investigators will provide expert medical input and advice relating to trial design 
and execution and are responsible for the review and signoff of the clinical trial report. 
Signature pages for the Protocol Lead and the Coordinating Investigators as well as a list of 
Sponsor responsible persons are in Appendix I.
The trial will appear in clinicaltrials.gov and other clinical trial registries.
The Sponsor will enlist the support of 
, a contract research organization (CRO), to 
conduct the clinical part of the trial including trial set-up, coordination, monitoring, medical 
oversight, data capture, data management, statistical analysis, and clinical trial reporting. The 
Sponsor will also make use of the CRO’s central laboratory for sample analyses, storage, and 
shipment to specialized bioanalytical laboratories. The Sponsor will supervise all outsourced 
activities.
Investigational medicinal product (IMP) will be supplied by the Clinical Trial Supply 
Department at Merck and packaged and labeled by 
.
Spirometry data will be centrally read by 
 
.
Details of structures and associated procedures will be defined in the instructions and/or flow 
charts provided by each of the third-party vendors participating in the EMR200017-014 trial.
An independent data monitoring committee (IDMC) will be established to review available 
safety and tolerability data on a regular basis as well as the results of the interim futility analyses. 
Based on the prespecified stopping boundary of futility, and the totality of the information at 
interim, the IDMC will make a recommendation to the Sponsor on continuing or stopping the 
trial for futility. The IDMC will consist of an odd number of members appropriate to the type of 
trial and expertise needed, including at least 2 clinicians and a biostatistician. The membership is 
limited to individuals who are free of conflicts of interest and should not be employees of the 
Sponsor. The full list of IDMC members and IDMC responsibilities will be included in the 
IDMC charter.
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3
Background Information
Fibrosis is a key process involved in chronic organ injury and failure. It contributes to significant 
morbidity and mortality in lung, heart, liver, and kidney disease (Denton 2017). Although 
advances have been made in understanding the molecular pathogenesis of fibrosis, these 
conditions often progress and transplants remain the last and only option for patients with 
advanced fibrosis and organ failure.
In recent years, a number of emerging therapeutic approaches demonstrated clinical utility of 
slowing progression and functional decline in distinct fibrotic disorders such as idiopathic 
pulmonary fibrosis (IPF) by early intervention in patient groups at risk, although at best with 
modest success.
While most fibrotic disorders manifest predominantly in a single target organ, systemic sclerosis 
(SSc) is characterized by multiple tissue involvement with severely reduced quality of life (QoL) 
in patients (Friedman 2013, Balibar-Gurman 2012). In view of the pressing medical needs in SSc 
patients with lung involvement (mortality up to 50% by 10 years in patients with extensive 
disease), and the multiple tissues and organs that may be involved and thus assessed in an 
investigational drug trial, SSc-associated interstitial lung disease (SSc-ILD) was chosen as the 
first indication to study the antifibrotic effects of abituzumab.
Current therapies for SSc focus upon treatment of symptoms and of organ-based manifestations. 
Therapeutic advances include the use of angiotensin-converting enzyme inhibitors in 
scleroderma renal crisis, proton-pump inhibitors in gastrointestinal reflux, calcium channel 
blocker, and prostacyclin analogues in the treatment of Raynaud’s phenomenon, endothelin 
receptor antagonists (ERA) in ischemic digital ulcers prevention as well as prostacyclin analogs 
and ERA in associated pulmonary arterial
hypertension (PAH). Treatments targeting 
inflammation include corticosteroids and immunosuppressive agents (Bussone 2011). The 
duration of cyclophosphamide treatment is generally limited to 1 year because of toxicities, 
including the risk of bladder carcinoma. Mycophenolate is the preferred immunosuppressive 
agent of many physicians; however, because it has a more favorable safety profile than 
cyclophosphamide. Nevertheless, gastrointestinal symptoms may limit tolerability, especially at 
higher doses. Although immunosuppressive therapies may have disease-modifying activity, the 
effects observed in randomized, controlled trials have been limited (Tashkin 2006, 
Tashkin 2016).  
Despite advances in early diagnosis of disease and effective treatment for some complications, 
SSc still remains characterized by high morbidity and mortality. Five- and 10-year survival rates 
range between 78% to 84% and 55% to 65%, respectively. A recent report estimated lung 
involvement (PAH and interstitial lung disease [ILD]) mortality to be approximately 33% and 
ILD to account for 16% of SSc-related deaths. The 10-year survival rates of SSc-ILD is 
approximately 75% and 30% in limited versus extensive ILD, respectively.
With only limited treatment effects observed to date with candidate therapies, there remains a 
critical need for additional therapies.
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3.1
Abituzumab
Abituzumab, also known as EMD 525797 or DI17E6, is a humanized monoclonal 
immunoglobulin G2 (IgG2) antibody against the human αν-integrin subunit. Integrins are 
transmembrane proteins that exist as heterodimers of an alpha (α) and a beta (β) subunit. The 
binding of abituzumab to the αv subunit inhibits the binding of all αv integrins (ie, αvβx) to its 
extracellular matrix ligands (eg, latency associated protein of transforming growth factor 
[TGF]-β1, vitronectin, and fibronectin). This inhibition of αv integrin function is anticipated to 
lead to a reduction in the activation of TGF-β, a major mediator of fibrosis. Abituzumab thus has
potential to have antifibrotic activity.
Abituzumab drug product is currently formulated for administration via intravenous infusion. 
The target indication of the development program is SSc-ILD. For this trial in subjects with 
SSc-ILD, abituzumab will be administered at doses of 500 or 1500 mg at 4-week intervals on a 
background of stable mycophenolate.
Refer to the Investigator’s Brochure (IB) for further information about the nonclinical and 
clinical programs and Guidance for the Investigator.
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, and 
any additional applicable regulatory requirements.
3.2
Trial Rationale
This is a Phase II, multicenter, double-blind, placebo-controlled, parallel-group trial investigating 
the efficacy, safety, tolerability, and immunogenicity of abituzumab at 2 dose levels in subjects 
with SSc-ILD who are treated with a stable mycophenolate regimen. 
An interim futility analysis will be performed by an independent third party statistician when 
approximately 88 subjects have either completed 52 weeks of treatment or prematurely 
discontinued from the trial. The results of the interim futility analysis will be reviewed 
confidentially by the IDMC, who will make a recommendation to the Sponsor on continuing or 
stopping the trial for futility, based on predefined criteria in the IDMC charter. If the Sponsor 
follows an IDMC recommendation to stop the trial, then enrollment and treatment with IMP will 
be stopped and subjects will be required to complete the early termination visit and move into the 
Safety Follow-up Period. 
The trial design takes into consideration an emerging trend in the treatment of SSc-ILD for use 
of mycophenolate as an alternative to cyclophosphamide, given the recent data regarding similar 
effects on pulmonary function but more favorable safety profile of the former and thus its 
potential for long-term use (Tashkin 2016, Volkman 2015). The potential antifibrotic effects of 
abituzumab could have complementary effects on the disease process to the immunosuppressive 
effects of mycophenolate. Therefore, this trial will evaluate whether abituzumab is associated 
with benefit when added to stable mycophenolate treatment. 
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3.3
Risk-Benefit Analysis
Available data from preclinical studies with cynomolgus monkeys showed a favorable 
toxicological safety profile for abituzumab. No potential safety issues emerged from these 
studies other than antidrug antibody (ADA) formation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 the digital ulcer count will be also be assessed at 
scheduled visits (see Table 1 and Table 2). Only an increase in number or worsening of digital 
ulcers would be considered a safety issue since SSc itself can be associated with digital ulcer 
formation. Together, these data sets will provide monitoring for impaired wound healing or skin 
breakdown. All blistering or Grade ≥3 AEs in the skin and subcutaneous tissue disorders system 
organ class (SOC), will be designated as AEs of special interest (AESI). Any cutaneous reaction 
of Grade 1 or 2 that is not responding to specific treatment or is worsening will also be 
designated as an AESI. The occurrence of AESI or cutaneous serious AEs (SAEs) will be 
reviewed by an independent panel of dermatologists to provide guidance for further investigation 
and interpretation of these events, and advise the IDMC whether any actions to modify clinical 
trial conduct should be considered. An IDMC will review safety data to ensure safety of all 
subjects enrolled in the trial. If subjects have significant worsening of lung function, they may 
start rescue medication, as appropriate. No additional risk minimization measures are considered 
necessary at this time for studying the effects of abituzumab in subjects with SSc-ILD.
Based on the available nonclinical and clinical data to date, the conduct of the trial specified in 
this protocol is considered justifiable. 
4
Trial Objectives
4.1
Primary Objective
The primary objective of the trial is to demonstrate efficacy of abituzumab in improving lung 
function of subjects with SSc-ILD.
4.2
Secondary Objectives
The secondary objectives of the trial are:
! To characterize further the effect of abituzumab on subjects with SSc-ILD who are treated 
with a stable mycophenolate regimen; 
! To characterize the safety, tolerability, and immunogenicity of abituzumab in subjects with 
SSc-ILD who are treated with a stable mycophenolate regimen;
! To evaluate the effect of abituzumab on SSc skin disease in subjects with diffuse skin 
involvement who are treated with a stable mycophenolate regimen;
! To evaluate health-related quality of life (HRQoL) outcomes of abituzumab in subjects with 
SSc-ILD who are treated with a stable mycophenolate regimen;
! To evaluate pharmacokinetic (PK) parameters of abituzumab in subjects with SSc-ILD who 
are treated with a stable mycophenolate regimen.
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4.3
Other Objectives
The exploratory objectives of the trial are:
!
 
 
 
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is a Phase II, multicenter, double-blind, placebo-controlled, parallel-group trial to be 
conducted in adult male and female subjects with SSc-ILD who are treated with stable 
mycophenolate to explore the efficacy, safety, tolerability, and immunogenicity of multiple 
intravenous doses of abituzumab. Subjects must have received the same mycophenolate 
treatment (ie, stable dose) in a range of 1.5 to 3 g/day of mycophenolate mofetil (MMF) or 
1080 to 2160 mg/day of sodium mycophenolate (MPS) for at least 2 months prior to the 
Screening Visit and continued through Day 1 of the Treatment Period. The trial will be 
conducted at approximately 60 sites globally.
The planned total duration of the trial is up to 122 weeks and is composed of a Screening Period, 
a Double-blind Treatment Period, and a Safety Follow-up Period. In addition, there is a Survival 
Follow-up Period. The trial periods are as follows:
! Screening Period: duration of up to 6 weeks; however, subjects should have the Day 1 visit as 
soon as possible after the eligibility for the trial has been confirmed. 
! Double-blind Treatment Period: duration of 104 weeks (2 years) starting at randomization. 
Subjects will be monitored at Weeks 2, 4, and every 4 weeks thereafter until Week 104. 
! Safety Follow-up Period: duration of 12 weeks. During the Safety Follow-up Period, 
monitoring for AEs, disease progression, and an assessment for ADA will be carried out.
! Survival Follow-up: Each subject will be followed up by the site for survival status every 
12 weeks (∀1 week) after the last trial visit, until death of the subject or end of the trial.
Approximately 175 subjects will be randomized in a 2:2:1 ratio to receive abituzumab 1500 mg, 
placebo, or abituzumab 500 mg, respectively, given by intravenous infusion over 1 hour every 
4 weeks with the last IMP administration at the Week 100 visit. 
Subjects are to continue their previous stable mycophenolate regimen. 
The effects of abituzumab on clinical status will be assessed through evaluations including 
pulmonary function tests, high-resolution computed tomography (HRCT), and patient-reported 
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outcomes (PROs). The diffusion capacity of the lung for carbon monoxide (DLCO) 
measurements will be corrected for hemoglobin level and spirometry assessments will be 
centrally adjudicated.
Subjects who meet the criteria for clinically meaningful progression of SSc-ILD (see 
Section 6.5.5) during the Double-blind Treatment Period or Follow-up Period should have a 
change in background therapy. Subjects taking less than the maximal specified dose of 
mycophenolate (3 g/day MMF or 2160 mg/day MPS) can have the mycophenolate dose 
increased while IMP is continued. Subjects taking the maximal specified dose of mycophenolate 
who have clinically meaningful progression should have the IMP discontinued and be treated 
according to the local standard of care. If a nonbiologic immunosuppressant (such as 
cyclophosphamide [oral or intravenous]) is initiated, then mycophenolate must be discontinued. 
If a subject discontinues IMP, then the subject should complete the early termination visit and 
then the remaining scheduled visits. At a minimum, the subject is expected to complete the trial 
visits at Weeks 12, 24, 36, 52, 64, 76, 88, and 104, as well as the Safety Follow-up period Week 
12 visit. Subjects with discontinued IMP can come to the other scheduled visits during the trial 
period according to the Investigator's judgment. 
Subjects who withdraw from the treatment period would have an early termination visit followed 
by entrance into the Safety Follow-up Period. 
Subjects who withdraw from the trial (eg, withdraw consent, lost to follow-up, or death; see 
Section 5.5.2) would not have any additional trial visits. 
Regardless of treatment completion or not, all subjects will be followed up by the site for 
survival from the subject’s last visit on the trial until death or end of the trial. Subjects who have 
clinically meaningful progression of SSc other than ILD should be treated according to the local 
standard of care.
During the Double-blind Treatment Period, efficacy assessments will include evaluations of 
pulmonary function (forced vital capacity [FVC] and DLCO), HRCT, and PRO questionnaires. 
Routine safety, HRQoL, 
, and PK assessments will be performed as described in the 
Schedule of Assessments (Table 1 and Table 2).
 
 
The trial design is displayed in Figure 1.
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Figure 1
Trial Design
IV = intravenous; EOT = end of trial; pts = patients; Q4 weeks = every 4 weeks; SSc-ILD = systemic sclerosis-
associated interstitial lung disease.
An interim futility analysis will be performed when approximately 88 subjects have either 
completed 52 weeks of treatment or prematurely discontinued from the trial. The primary 
analysis will be conducted when all subjects have either completed 52 weeks of treatment or 
prematurely discontinued from the trial. The primary analysis will use all the cumulative data at 
the time of the primary analysis cut-off date. The final treatment analysis will be conducted when 
all subjects have completed the 104-week treatment or prematurely discontinued from the trial. 
The final follow-up analysis will be conducted after all subjects have completed the 12-week 
Safety Follow-up Period or prematurely discontinued from the trial. All subjects will be followed 
up for survival until this point.
During the conduct of the trial, an IDMC will convene to monitor unblinded safety data on a 
regular basis, as specified in the IDMC charter, to ensure the safety of subjects in this trial. The 
IDMC will also review the results of the interim futility analysis and make a recommendation to 
the Sponsor on continuing or stopping the trial for futility, based on the criteria in the IDMC 
charter.
5.2
Discussion of Trial Design
5.2.1
Rationale for Trial Design
Given the expected rate of progression of SSc-ILD, a trial of 1-year duration is likely to be able 
to evaluate changes in FVC and other pulmonary function tests associated with the IMP. 
However, a 2-year treatment period is preferred because it will be important to evaluate the 
durability of the treatment effect, long-term safety, and whether treatment effect size increases 
during the second year of treatment (for instance, in case there is some lag time between 
initiation of IMP and significant changes in FVC). In the Scleroderma Lung Study (SLS) I trial 
(Tashkin 2006), in which the patients were treated for with oral cyclophosphamide/placebo for 
1 year and then followed for an additional year without treatment, a benefit of cyclophosphamide 
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treatment as compared with placebo was observed up until approximately 18 months of 
treatment, but there was no notable benefit by 24 months of treatment. 
Use of a placebo comparator arm is considered appropriate because subjects in this trial will 
continue to take their previous mycophenolate therapy, while placebo or abituzumab is added. In 
addition, there are clearly-defined criteria for clinically meaningful progression. Subjects who 
meet these criteria should have a change in therapy as outlined (either increase in mycophenolate 
dose or switch to local standard of care, such as cyclophosphamide, with discontinuation of 
mycophenolate and IMP).
Subjects with disease progression who are withdrawn from IMP will be encouraged to continue 
treatment period assessments through the Safety Follow-up Period to evaluate the clinical course 
after cessation of IMP and initiation of treatment under local standard care (eg, 
cyclophosphamide).
5.2.2
Selection of Doses
The relationship between target inhibition and clinical response remains to be determined in 
clinical trials. Two doses will be used to establish an exposure-response relationship. 
 
 
 
 
 
 
 
 
 
 
 
 
EOI = end of infusion; IV = intravenous.
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5.2.3
Rationale for Inclusion and Exclusion Criteria
The 2013 American College of Rheumatology (ACR)/European League Against Rheumatism 
(EULAR) criteria are standard for use in clinical trials of subjects with SSc. 
Subjects will have disease duration of less than 7 years from first non-Raynaud’s sign or 
symptom in order to decrease the risk of recruiting subjects with disease that may be too far 
advanced, and thus associated with low likelihood to be able to demonstrate trial drug effect and 
increased safety risks (and thus drug treatment effect might not be shown).
Similarly, subjects will be required to have DLCO ≥30% predicted and FVC predicted 40% to 
85%. The upper boundary specified for FVC selects subjects with clinically significant 
impairment for use of an interventional therapy. The lower boundaries for FVC and DLCO 
reduce risk of recruiting subjects with disease that is too far advanced to respond to medical 
intervention, and may also represent subjects at significantly increased risk of AEs. The 
inclusion of subjects with FVC/DLCO ratio < 1.8 decreases the likelihood of enrolling subjects 
with significant pulmonary hypertension (which is associated with poor prognosis and may 
confound interpretation of effects of abituzumab).
Fibrosis on HRCT (≥5% as defined in Inclusion Criterion 4) will be required in order to confirm 
that subjects have ILD, select for a population considered appropriate for treatment with a 
potentially antifibrotic therapy such as abituzumab, and possible improvement in fibrosis among 
all trial subjects. Computed tomography will only be done in subjects who meet the criteria for 
DLCO and FVC in order to reduce HRCT exposure in those subjects who would not be eligible 
for the trial. 
In order to decrease confounding of trial results, subjects with concurrent conditions that may 
significantly impact safety and efficacy analyses will be excluded. Likewise, background 
mycophenolate should be stable in order to evaluate the effect of the addition of abituzumab 
compared with placebo (rather than the effect of changing mycophenolate dose). 
Immunosuppressant and other potentially disease-modifying treatment use within 2 months of 
the Screening Visit (or cyclophosphamide use within 5 months of the Screening Visit) is likewise 
excluded in order to decrease confounding trial results. Mycophenolate is chosen as the 
background medication for this trial as experience in the community has led to its increased use, 
and the results of the SLS II trial are expected to increase its use further.
5.2.4
Rationale for Primary Objective 
Forced vital capacity is a clinically relevant surrogate endpoint for clinical benefit, as decreased 
FVC is associated with mortality (Steen 2000, Assassi 2009) and a decrease to < 70% FVC was 
associated with higher mortality than a decrease in which FVC remained ≥70% in SSc-ILD 
(Goh 2008, Moore 2013).
The primary endpoint of the trial is the annual rate of absolute FVC change in volume (mL). 
Forced vital capacity is robust, validated, sensitive to change, and doable in a setting of a clinical 
trial as shown in IPF (du Bois 2012). Decrease in FVC reflects decrease in lung function and has 
been associated with increased mortality. This measure was successfully used in SSc-ILD where 
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a significant difference between cyclophosphamide and placebo in FVC was observed in the SLS 
I trial (Tashkin 2006). The SLS I trial for cyclophosphamide versus placebo (without background 
immunosuppressive) showed a mean absolute improvement of FVC decline of 2.5% at 1 year 
and was considered clinically significant in the community. In addition, FVC is also the primary 
endpoint of the SLS II National Institutes of Health-sponsored trial.
A change of 2% to 6% in FVC % predicted is the minimally clinically important difference in 
IPF patients (du Bois 2011).
Change in FVC was the basis for the approvals of nintedanib and pirfenidone in IPF during 
2014. These programs had primary endpoints of annual rate of decline in FVC (measured in 
milliliters per year) and change from baseline to Week 52 in the percentage of the predicted 
FVC, respectively (Richeldi 2014, King 2014). From 6 large independent placebo-controlled 
trials of pirfenidone and nintedanib in IPF, analysis showed an improvement of at least 100 mL 
in the annual rate of observed FVC decline in volume, equivalent to approximately 3% 
improvement in FVC % predicted at 1 year serving as the basis for approvals. The association 
between significant difference in FVC decline and numerical trend toward improvement in 
mortality in these IPF trials was also highlighted by FDA reviewers (Karimi-Shah 2015).
Pulmonary function tests will be performed according to the American Thoracic Society and 
European Respiratory Society recommendations. Detailed procedures for performing pulmonary 
function assessments are included in the Instructions for Use 
 and Procedural 
Manual for DLCO testing provided by 
.
5.2.5
Rationale for Secondary Objectives 
Efficacy
In addition to the primary efficacy endpoint, key secondary endpoints will include change in 
dyspnea as assessed by Mahler index, change in St. George Respiratory Questionnaire (SGRQ) 
total score, quantitative lung fibrosis (QLF), and overall survival. Effects on skin will be 
assessed using a standard index, the modified Rodnan skin score (mRSS). In addition to 
improving quality of life, including how patients with SSc-ILD feel and function, a critical goal 
of therapy is to prolong life. Overall survival will be evaluated as a key secondary endpoint. In 
addition, survival status will be followed for all subjects until the end of the trial in order to raise 
the potential to observe effects on survival.
The QLF change has been found to be a sensitive marker of change and can precede change in 
FVC (Kim 2010, Kim 2011, Tashkin 2014). Since QLF directly measures the treatment effect on 
lung fibrosis, the results are complementary to clinical data such as FVC and PROs. Quantitative 
lung fibrosis assessments will also be centrally read.
Forced vital capacity will also be assessed using categorical measures to define potential 
responders.
The DLCO is another standard measurement of lung function (MacIntyre 2005); it measures the 
diffusing capacity of the lung, reflecting vascular bed size/perfusion as well as the extent of 
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interstitial lung disease. However, it shows higher measurement variability compared to FVC. 
Measurements will be corrected for hemoglobin level and DLCO assessments will be centrally 
adjudicated with the other spirometry assessments.
An analysis of the proportion of subjects with clinically meaningful progression as defined by 
Outcome Measures in Rheumatology (OMERACT) for patients with ILD (Khanna 2015) will be 
performed. Abituzumab is expected to reduce the number of subjects with such progression of 
disease.
Several HRQoL parameters will be assessed in this trial. These will be administered based on 
availability of the respective validated questionnaires in local language. 
The measures endorsed by the OMERACT working group as the ‘inner core’ measures for ILD 
(Khanna 2015) and included in this trial are the following: Leicester Cough Index, Patient’s 
Global Assessment, and SGRQ, as well as ‘functional status’ (this will be assessed by the 
Scleroderma Health Assessment Questionnaire [SHAQ]), overall ILD on HRCT, FVC % 
predicted, and all-cause mortality. The assessments in this trial that are not part of the inner core 
include the Mahler index and the Physician’s Global Assessment. The Mahler Dyspnea Index is 
advised to be included as this has been shown in the SLS I trial to show a statistically significant 
difference between the cyclophosphamide and placebo groups (p < 0.001). The Physician’s 
Global Assessment is done rapidly via a visual analogue scale (VAS) and is standard in many 
trials for overall assessment of subjects. 
The SHAQ is an adaptation of the HAQ-DI and has been validated in SSc (Steen 1997). In 
addition to the 8 domains of activity in the HAQ (dressing, arising, eating, walking, hygiene, 
reach, grip, and common daily activities), the SHAQ includes 5 additional scleroderma-specific 
VAS encompassing the domains of overall disease activity, Raynaud’s phenomenon, finger 
ulcers, breathing, and intestinal problems. For each item in the HAQ, patients report the amount 
of difficulty experienced performing the activity. The 5 additional VAS in the SHAQ ask 
patients how much symptoms interfere with daily activities and are scored similarly to other 
VAS.
As dyspnea is a central feature of SSc-ILD and is an independent predictor of function and 
HRQoL, it will be assessed using 2 indices: the Mahler index and the SGRQ (Baron 2008). The 
Mahler Transition Dyspnea Index (TDI) fulfills OMERACT criteria for feasibility, reliability, 
and validity, and in moderate ILD, subject changes in Mahler TDI score were observed 
(Khanna 2009). The TDI is sensitive to change. The Baseline Dyspnea Index (BDI)-TDI 
measures changes in dyspnea severity from the baseline as established by the BDI. The 
computerized version appears to have eliminated earlier concerns regarding the role of the 
interviewer in influencing responses. 
The SGRQ has been found to be useful in assessing patients with SSc-ILD (Beretta 2007, 
Wallace 2015).
Cough will be assessed using the Leicester Cough Index, which is a validated tool in chronic 
cough and chronic obstructive pulmonary disease (Birring 2003, Berkhof 2012). Nonproductive 
cough is a characteristic symptom of ILD in general, and SSc-ILD in particular. In the SLS I 
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trial, 73% of subjects reported cough at enrollment, representing the second most common non-
Raynaud’s symptom. This trial indicated that cough severity and frequency correlated with FVC 
% predicted, and cough frequency decreased significantly after a 12-month period of 
cyclophosphamide therapy compared with placebo. Of note, at baseline, compared to 
non-coughers, subjects with cough had lower DLCO and higher dyspnea and fibrosis score on 
HRCT (Theodore 2012). 
The EQ-5D, measures health outcomes and is standardized for use across many indications and 
regions. It can be used for health outcomes including QoL and also economic analyses. 
Applicable to a wide range of health conditions and treatments, the EQ-5D health questionnaire 
provides a simple descriptive profile and a single-index value for health status.
Please note:  Patient-reported Outcome questionnaires should be completed before any other 
procedures, as per the Schedules of Assessments (Table 1 and Table 2).
Questionnaires will be performed in the following order:
! Patient’s Global Assessment 
! SHAQ
! Mahler BDI (at Day 1) followed by Mahler TDI at the subsequent visits, by the request of the 
author of the Mahler TDI
! SGRQ
! Leicester Cough Index
! EQ-5D
! Physician’s Global Assessment (VAS).
Since SSc is a multi-organ disease, it is critical to assess the overall disease activity of subjects. 
This is done routinely in clinical practice for a complete understanding of the clinical status. If 
efficacy is seen for abituzumab in the treatment of SSc-ILD, which is the manifestation 
associated with highest morbidity and mortality and thus unmet need, this will open the 
possibility to further investigate whether abituzumab could have benefit for other SSc 
manifestations. Assessment of manifestations of SSc other than ILD over time during the trial is 
also important to confirm that possible efficacy in SSc-ILD did not come at the expense of 
worsening in other organ systems. The expectation is that there will be trends towards 
improvement in the overall SSc severity (assessed by the Combined Response Index for 
Systemic Sclerosis [CRISS]) and specifically the skin scores (assessed by mRSS and ulcer 
count) which will be assessed only in those subjects with diffuse cutaneous SSc (dcSSc) at 
baseline.
The mRSS instrument is a validated tool and has been shown to be feasible, reliable, valid, and 
responsive to change in multicenter clinical trials (Khanna 2007). There was a significant change 
in the mRSS in the cyclophosphamide arm compared with the placebo arm in the SLS I trial. 
The digital ulcer count is commonly included in trials of scleroderma skin disease.
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The CRISS includes measures that assess change in skin and ILD, functional disability (as 
assessed by HAQ-DI), and Patient and Physician Global Assessments. In addition, the index 
captures clinically meaningful declines in internal organ involvement that indicate the subject 
has not improved during the clinical trial.
Safety 
The safety profile of abituzumab remains to be established in subjects with SSc-ILD.
5.2.6
Rationale for Exploratory Objectives 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2.7
Inclusion of Special Populations
Not applicable.
5.3
Selection of Trial Population
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled into the trial 
as subjects. Prior to performing any trial assessments not part of the subject’s routine medical 
care, the Investigator will ensure that the subject has provided written informed consent 
following the procedure described in Section 9.2.
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5.3.1
Inclusion Criteria
Subjects are eligible for this trial if they fulfill all of the following inclusion criteria:
1.
Female or male subjects aged between 18 and 75 years of age who provide informed written 
consent.
2.
Subjects fulfilling the 2013 ACR/EULAR criteria for classification of SSc (van den Hoogen 
2013; see Appendix IV).
3.
Disease duration of < 7 years from first non-Raynaud’s symptom.
4.
According to central readings: DLCO ≥30% predicted, FVC 40% to 85% predicted1, and 
ratio of FVC % predicted to DLCO % predicted < 1.8. A ratio of FVC % predicted to 
DLCO % predicted ≥1.8 is acceptable if right heart catheterization within 3 months of 
Screening revealed no pulmonary hypertension. If these criteria are met, then HRCT of 
lungs will be performed, and must show at least 5% fibrosis for subjects to be eligible.
1 The FVC % predicted that is reported by central reading will be rounded to the nearest 
whole number. If the number that follows the decimal point is ≤4, the FVC % predicted
will be rounded down to the next whole number; if it is ≥5, the FVC % predicted will be 
rounded up to the next whole number.
5.
Use of the same mycophenolate regimen (ie, stable dose) in a range of 1.5 to 3 g/day of 
MMF or 1080 to 2160 mg/day of MPS, for at least 2 months prior to the Screening Visit and 
continued through Day 1 of the Treatment Period.
6.
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 
two effective methods of contraception, including at least one highly effective method that 
can achieve a failure rate of < 1% per year, when used consistently and correctly, and one 
other reliable method during the treatment period and for at least 90 days after the last dose 
of study treatment.
Examples of contraceptive methods with a failure rate of < 1% per year (highly effective 
contraceptive methods) include:
! combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation1 (oral, intravaginal, transdermal)
! progesterone-only hormonal contraception associated with inhibition of ovulation1 (oral, 
injectable, implantable2)
! intrauterine device (IUD)2
! intrauterine hormone-releasing system (IUS)2
! bilateral tubal occlusion2
! vasectomized partner2,3
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! sexual abstinence4
1 Hormonal contraception may be susceptible to interaction with the IMP, which may 
reduce the efficacy of the contraception method.
2 Contraception methods in the context of this guidance are considered to have low user 
dependency.
3 Vasectomized partner is a highly effective birth control method provided that the partner 
is the sole sexual partner of the woman of childbearing potential trial participant and that 
the vasectomized partner has received medical assessment of the surgical success.
4 In the context of this guidance, sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject.
Barrier methods supplemented with the use of a spermicide could be considered as a reliable 
method.
For men (including those who have undergone a vasectomy): agreement to remain abstinent 
or use a condom during the treatment period and for at least 12 months after the last dose of 
study treatment and agreement to refrain from donating sperm during this same period.
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
In addition to male contraception, agreement to advise female partners of childbearing 
potential to use highly effective contraception during the study and for at least 12 months 
after the last dose of study treatment.
Upon termination of participation in this clinical study, patients continuing on MMF must 
continue effective contraception as required by the SPC.  
5.3.2
Exclusion Criteria
Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria:
1.
Any condition that in the Investigator’s opinion constitutes an inappropriate risk or a 
contraindication for participation in the trial or that could interfere with the trial objectives, 
conduct, or evaluation.
2.
Renal impairment (glomerular filtration rate [GFR] < 45 mL/min/1.73 m2 as calculated by 
the Modification of Diet in Renal Disease equation) calculated by the central laboratory as 
follows:
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GFR (mL/min per 1.73 m2) = 175 ∃standardized serum creatinine -1.154 ∃age -0.203 ∃1.212 
(if black) ∃0.742 (if female)
3.
Urine dipstick with ≥3+ protein and urine protein:creatinine ratio > 2 mg/mg. Urine 
protein:creatinine ratio will be determined only if urine dipstick indicates ≥3+ protein.
4.
Known diagnosis of obstructive lung disease/emphysema as defined by forced expiratory 
volume in 1 second (FEV1)/FVC ratio < 0.65 and/or significant emphysematous change on 
screening HRCT according to the central reader.
5.
Other clinically significant abnormalities on HRCT not attributable to scleroderma or 
emphysema as defined above, which in the Investigator’s opinion make enrollment in the 
trial inappropriate.
6.
Known diagnosis of other significant respiratory disorders in the opinion of the Investigator.
7.
Pulmonary hypertension that fulfills at least one of the following:
!
Currently being treated with systemic therapy targeted to PAH or pulmonary 
hypertension;
!
Considered by the Investigator to require initiation of systemic targeted PAH therapy;
!
History of transthoracic echocardiography showing at least one of the following (unless 
right heart catheterization subsequent to these measures did not reveal pulmonary 
hypertension): tricuspid regurgitation jet > 2.8 m/sec, right atrial enlargement (major 
dimension > 53 mm), right ventricular enlargement (mid cavity dimension > 35 mm), 
moderate to severe left ventricular dysfunction;
!
At screening, N-terminal prohormone brain natriuretic peptide (NT pro-BNP) > 3 ∃the 
upper limit of normal (ULN), unless, for example, right heart catheterization performed 
within 3 months of the Screening Visit did not reveal pulmonary hypertension.
8.
Current clinical diagnosis of another inflammatory connective tissue disease (eg, systemic 
lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, or dermato/polymyositis); 
concomitant scleroderma-associated myopathy, fibromyalgia, and secondary Sjögren’s 
syndrome are allowed.
9.
Clinical suspicion of or recent evidence of significant aspiration within the previous 
6 months, such as chemical induced pneumonitis or aspiration pneumonia.
10. Active clinically significant viral, bacterial, or fungal infection, or any major episode of 
infection requiring hospitalization or treatment with parenteral anti-infectives within 
4 weeks prior to screening or during the Screening Period, or completion of oral 
anti-infectives within 2 weeks before screening or use of oral anti-infectives during the 
Screening Period. Vaginal candidiasis, onychomycosis, and chronically suppressed oral 
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herpes simplex virus would not be exclusionary. Prophylaxis for Pneumocystis jiroveci
pneumonia according to local guidelines will be permitted.
11. History of or positive human immunodeficiency virus (HIV), hepatitis C antibody and/or 
polymerase chain reaction or hepatitis B surface antigen (HBsAg) and/or hepatitis B core 
antibody (total and/or immunoglobulin M [IgM]) antibody at screening.
12. History of or current diagnosis of active tuberculosis (TB), or untreated latent TB infection 
(LTBI), determined by a TB skin test with purified protein derivative as evidenced by 
induration ≥5 mm or a positive QuantiFERON-TB or positive or borderline T-SPOT 
(Elispot) test performed locally, or centrally as needed, either at screening or documented 
with results within 3 months of the Screening Visit. Subjects who have previously 
completed appropriate and documented LTBI treatment or who are undergoing current 
treatment for LTBI will not be required to be tested. 
If the subject is undergoing current treatment for LTBI, they must have received at least 
4 continuous weeks of an appropriate LTBI treatment prior to the Screening Visit (ie, start 
of trial treatment) without evidence of re-exposure. If on LTBI treatment at the Screening 
Visit, the subject will be expected to complete an appropriate LTBI treatment regimen to 
remain in the trial:
!
Subjects with current household contacts with active TB will also be excluded unless 
treated and evidence of household contacts being treated;
!
Indeterminate QuantiFERON-TB or T-SPOT tests may be repeated once, and will be 
considered positive if retest results are positive or indeterminate.
13. Presence of uncontrolled or New York Heart Association (NYHA) Class 3 or 4 congestive 
heart failure (refer to Appendix III).
14. History of cancer, except adequately treated (ie, no evidence of recurrence within 5 years 
prior to screening) basal cell or squamous cell carcinomas of the skin (no more than 3 total 
in lifetime) or carcinoma in situ of the cervix.
15. Known hypersensitivity to abituzumab or any component of the formulated abituzumab.
16. Current smoker (including e-cigarettes) or smoking within 4 weeks of screening.
17. Use of agents other than mycophenolate (MPS or MMF) considered by the Investigator to 
have immunomodulating, immunosuppressive, or potential scleroderma disease-modifying 
properties within 2 months of the Screening Visit. Examples of these agents include, but are 
not limited to, pirfenidone, nintedanib, methotrexate, azathioprine, leflunomide, calcineurin 
inhibitors, D-penicillamine, Potaba, and AIMSPRO. The use of cyclophosphamide within 
5 months of the Screening Visit is not permitted. Hydroxychloroquine or chloroquine are 
permitted if dose has been stable for at least 4 weeks before the Screening Visit.
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18. Use of systemic corticosteroids above 10 mg/day prednisone equivalent within 4 weeks of 
screening, during the Screening Period, or expected during the treatment period. Inhaled 
corticosteroids are not considered systemic and are permitted. Topical corticosteroids are 
permitted.
19. Use of any biologic agent within 12 weeks or 5 half-lives, whichever is longer, of screening.
20. History of anti-CD20 B-cell depleting therapy, eg, rituximab or ocrelizumab, within 
6 months prior to the Screening Visit.
21. Use of any anticoagulant or antiplatelet agent (aspirin ≤350 mg daily is permitted).
22. Clinically significant or predefined abnormalities in laboratory tests:
!
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline 
phosphatase (AP) level > 2.5∃ULN;
!
Total bilirubin > 1.5∃ULN (other than that due to known Gilbert’s disease);
!
Hemoglobin < 5.0 mmol/L (9 g/dL), white blood cell count < 2.5 ∃109/L, or platelets 
< 100 ∃109/L);
!
International normalized ratio (INR) or partial thromboplastin time (PTT) > 2.0∃ULN;
!
Thyroid-stimulating hormone (TSH) < 0.01 or ≥7.1 mIU/L.
23. Individuals who cannot receive intravenous infusions (ie, difficult venous access).
24. History of alcohol or drug abuse for 1 year prior to screening in the opinion of the 
Investigator.
25. Pregnancy (documented by serum pregnancy test at screening or urine pregnancy test on 
Day 1) and/or breastfeeding/lactation within 3 months of the Screening Visit.
26. Subjects with a past medical history of thrombotic, thromboembolic, or abnormal bleeding 
events including concomitant antiphospholipid antibody syndrome (per
Sydney 
classification criteria (Gomez-Puerta 2014, Miyakis 2006). Subjects should be questioned 
specifically for thrombosis, phlebitis, embolism, etc. at screening to establish negative 
history. Subjects with known lupus anticoagulant and/or anticardiolipin and/or anti-b2 
glycoprotein antibodies alone should not be excluded.
27. Legal incapacity or limited legal capacity.
28. Receipt of a live/attenuated vaccine within 12 weeks prior to the Screening Visit or subjects 
who are expecting to receive any live virus or bacterial vaccinations during the trial, or up to 
3 months after the last dose of study drug, are not permitted. Seasonal influenza vaccination 
is permitted if the inactivated vaccine formulation is administered.
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29. Major surgery requiring hospitalization within 4 weeks prior to the Screening Visit and any 
planned major surgery for the duration of the trial. Subjects with a history of lung resection.
30. Have a history of a major organ transplant (eg, heart, lung, kidney, or liver) or 
hematopoietic stem cell/marrow transplant or are due to receive transplantation.
31. Severe gastrointestinal disease requiring parenteral nutrition.
5.4
Criteria for Initiation of Trial Treatment
All subjects who meet the inclusion and none of the exclusion criteria are eligible for 
randomization to one of the treatment groups.
5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from Trial Therapy 
A subject must be withdrawn from IMP if any of the following occur: 
! Enrollment despite violation of an inclusion and/or exclusion criterion which, in the 
Investigator’s and/or Sponsor’s opinion, makes discontinuation of the subject necessary. 
! Participation in any other interventional trial during the duration of this trial for which the 
Investigator or Sponsor considers discontinuation of the IMP necessary. 
! Occurrence of pregnancy.
! Anaphylaxis, anaphylactoid, or other severe or life-threatening hypersensitivity reactions to 
IMP, based on Investigator judgment. Such cases should be discussed with the Medical 
Monitor.
! Occurrence of any other AE for which discontinuation of IMP is desired or considered 
necessary by the Investigator, Sponsor, and/or the subject.
! Noncompliance, judged as significant by the Investigator or Sponsor including 
noncompliance with the required trial considerations.
! Discontinuation of LTBI therapy before complete, if present at the Screening Visit. 
! Surgery considered by the Investigator or Sponsor to be major.
! Occurrence of any other clinical condition or circumstances for which discontinuation is 
considered necessary by the Investigator and/or the Sponsor/designee.
! Significant disease progression which in the Investigator’s opinion requires initiation of 
rescue therapy, such as cyclophosphamide or other local standard of care treatment (see 
Section 6.5.5) or other new treatment considered to have immunosuppressive or 
immunomodulating properties.
If a subject discontinues IMP, then the subject should complete the early termination visit and 
then the remaining scheduled visits. At a minimum, the subject is expected to complete the trial 
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visits at Weeks 12, 24, 36, 52, 64, 76, 88, and 104, as well as the Safety Follow-up period Week 
12 visit. Subjects with discontinued IMP can come to the other scheduled visits during the trial 
period according to the Investigator's judgment. 
Subjects who withdraw from the treatment period would have an early termination visit followed 
by entrance into the Safety Follow-up Period. 
Subjects who withdraw from the trial (eg, withdraw consent, lost to follow-up, or death; see 
Section 5.5.2) would not have any additional trial visits.
It is important for site investigators to retain each subject through the end of the trial for 
prevention of missing data. Systematic and consistent attempts are needed to contact subjects 
who fail to actively maintain contact with the site Investigator. The nature, method, and 
frequency of such contact should be recorded in the source documents, including number of 
telephone calls, day of week, and time of such calls and source of information.
5.5.2
Withdrawal from the Trial
Subjects may withdraw from the trial at any time without giving a reason. Withdrawal of consent 
will be considered withdrawal from the trial. Subjects wishing to withdraw from the trial should 
be asked to complete the early termination visit, if not already performed.
A subject must be withdrawn if any of the following occur during the trial:
! Withdrawal of the subject’s consent
! Death of subject
! Subject lost to follow up.
5.6
Premature Termination of the Trial
The clinical trial may be terminated prematurely or suspended at the request of Health 
Authorities or if new safety or efficacy information leads to an unfavorable risk-benefit judgment 
for IMP. The Sponsor may discontinue the trial if it becomes unjustifiable for medical or ethical 
reasons, for poor enrollment, or because of discontinuation of clinical development of 
abituzumab.
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards 
(IRBs) will be informed about the discontinuation of the trial in accordance with applicable 
regulations.
5.7
Definition of End of Trial
A clinical trial protocol may not be considered closed as long as:
! Any subject is still receiving any IMP;
! Visits specified by the protocol are still taking place;
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! Procedures or interventions according to the protocol are still being undertaken in any subject; 
! The post-treatment safety follow up period, defined in the clinical trial protocol as being part 
of the trial, has not yet been completed for any subject.
The Survival follow up period will end with the end of trial.
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
The term “Investigational Medicinal Product” refers to the active substance or placebo being 
tested or used in a clinical trial. 
6.1
Description of the Investigational Medicinal Product
The active pharmaceutical ingredient in abituzumab drug product is a recombinant, 
de-immunized monoclonal antibody of the IgG2 subclass that is thought to block ligand binding 
to human αv-integrins.
 
 
 
 
 
6.2
Dosage and Administration
In the Double-blind Treatment Period, subjects will be randomized in a 2:2:1 ratio to receive one 
of the following treatments: abituzumab 1500 mg, placebo, or abituzumab 500 mg, respectively. 
Treatment will be given as an intravenous infusion over approximately 1 hour every 4 weeks.
The infusion time should not be less than 1 hour. Close observation of the subject is 
recommended for a period of at least 1 hour after administration of IMP. The last IMP/placebo
administration will be at the Week 100 visit.
If administration of IMP or placebo cannot be performed within the specified protocol visit 
window, the decision to administer IMP or placebo outside of the window will be determined on 
a case-by-case basis after a discussion with the Medical Monitor and the Sponsor’s Medical 
Director.
6.3
Assignment to Treatment Groups
After completion of all screening evaluations, all eligible subjects will be randomly allocated in a 
2:2:1 randomization ratio to 1 of the 3 treatment groups: abituzumab 1500 mg, placebo, or 
abituzumab 500 mg, respectively. Randomization in permuted blocks will be conducted by a 
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central interactive voice/web response system (IVRS/IWRS) provider. Randomization will be 
stratified by baseline FVC % predicted (< 70% versus ≥70%) and by duration of mycophenolate 
use at baseline (< 6 months versus ≥6 months). 
 
 
6.4
Noninvestigational Medicinal Products to be Used
Not applicable.
6.5
Concomitant Medications and Therapies
All concomitant medications taken by the subject during the trial, from the date of signature of 
the informed consent are to be recorded in the appropriate section of the electronic case report 
form (eCRF), noting the name, dose, duration, and indication of each drug. Nondrug 
interventions and any changes to a concomitant medication or other intervention should also be 
recorded in the eCRF.
6.5.1
Permitted Medicines
Any medications, other than those excluded or listed as prohibited, that are considered necessary 
for the subject’s welfare, and that do not interfere with the trial conduct or assessment, may be 
given at the Investigator’s judgment. The Investigator will record all concomitant medications 
and procedures throughout the trial. 
Seasonal influenza vaccination is permitted if the inactivated vaccine formulation is 
administered. Prophylaxis for Pneumocystis jiroveci pneumonia according to local guidelines 
will be permitted.
Standard of Care in SSc
Treatment for SSc-ILD, including proton pump inhibitors, prokinetic drugs, antibiotics, 
medications for systemic blood pressure control and/or Raynaud’s symptoms, topical 
nitroglycerin, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, selective 
serotonin reuptake inhibitors, and nonsteroidal anti-inflammatory drugs can be used or initiated 
during the trial. Oral corticosteroids up to 10 mg/day prednisone equivalent is permitted during 
the trial (doses given are for a total daily dose of prednisone; corticosteroids other than 
prednisone may be used instead at the equivalent doses; see Appendix II).
Dosing of mycophenolate must be kept stable during the Double-blind Treatment Period, unless 
a change in dose is warranted by clinically meaningful disease progression (see Section 6.5.5). 
Hydroxychloroquine or chloroquine are permitted if dose has been stable for at least 4 weeks 
prior to the Screening Visit.
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Low-dose aspirin (< 350 mg/day) for cardiovascular prophylaxis is permitted during the trial. 
Paracetamol (acetaminophen) up to 3 g/day may be initiated for pain control of SSc symptoms 
during the trial. Any change, either in existing dosing or initiation of new therapy, should be 
recorded.
The criteria for clinically meaningful disease progression and associated changes in SSc therapy 
are described in Section 6.5.5.
6.5.2
Prohibited Medicines
Medications for treatment of PAH are not permitted during the Screening or Double-blind 
Treatment Periods. These medications include, but are not limited to, phosphodiesterase-5 
inhibitors (eg, sildenafil), ERAs (eg, bosentan), prostanoids (epoprostenol, treprostinil), and 
riociguat. These medications can be used for treatment of conditions other than PAH, such as 
Raynaud’s symptoms. If subjects meet criteria for rescue medication (see Section 6.5.5), then 
such therapy can be initiated. 
The use of agents other than mycophenolate (MPS or MMF) considered by the Investigator to 
have immunomodulating, immunosuppressive, or potential scleroderma disease-modifying 
properties within 2 months of the Screening Visit is not permitted. The use of cyclophosphamide 
within 5 months of the Screening Visit is not permitted.
Receipt of a live/attenuated vaccine within 12 weeks prior to the Screening Visit is not permitted. 
Live virus or bacterial vaccinations during the trial, or up to 3 months after the last dose of study 
drug are not permitted.
6.5.3
Other Interventions
Not applicable.
6.5.4
Special Precautions
Abituzumab may have adverse effects common to monoclonal antibodies as well as compounds 
with anti-integrin activity and antiangiogenic potential. 
 
 
 
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 two 
effective methods of contraception, including at least one highly effective method that can 
achieve a failure rate of < 1% per year, when used consistently and correctly, and one other 
reliable method during the treatment period and for at least 90 days after the last dose of study 
treatment.
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Examples of contraceptive methods with a failure rate of < 1% per year (highly effective 
contraceptive methods) include:
! combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation1 (oral, intravaginal, transdermal)
! progesterone-only hormonal contraception associated with inhibition of ovulation1 (oral, 
injectable, implantable2)
! IUD2
! IUS2
! bilateral tubal occlusion2
! vasectomized partner2,3
! sexual abstinence4
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce 
the efficacy of the contraception method.
2 Contraception methods in the context of this guidance are considered to have low user 
dependency.
3 Vasectomized partner is a highly effective birth control method provided that the partner is 
the sole sexual partner of the woman of childbearing potential trial participant and that the 
vasectomized partner has received medical assessment of the surgical success.
4 In the context of this guidance, sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle 
of the subject.
Barrier methods supplemented with the use of a spermicide could be considered as a reliable 
method.
For men (including those who have undergone a vasectomy): agreement to remain abstinent or 
use a condom during the treatment period and for at least 12 months after the last dose of study 
treatment and agreement to refrain from donating sperm during this same period.
Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.
In addition to male contraception, agreement to advise female partners of childbearing potential 
to use highly effective contraception during the study and for at least 12 months after the last 
dose of study treatment.
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Upon termination of participation in this clinical study, patients continuing on MMF must 
continue effective contraception as required by the SPC.
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions
Subjects with cutaneous AESI thought to be related to IMP and Grade ≥3 in severity should 
have the IMP withheld. If subsequently the event has sufficiently resolved, re-initiation of IMP at 
half of the original dose may be considered by the Investigator after discussion with the CRO 
Medical Monitor.
Clinically Meaningful Disease Progression
Subjects meeting one or both of the below criteria will be considered as having clinically 
meaningful disease progression:
1. SSc-ILD: one of the following (in the absence of causative intercurrent illness) on at least 
2 occasions within approximately 4 weeks (per OMERACT criteria):
! Relative decrease from baseline in FVC % predicted ≥10%;
! Relative decrease from baseline in FVC % predicted of ≥5% to < 10% and relative 
decrease from baseline in DLCO % predicted ≥15%.
2. SSc progression other than ILD: new onset of one or more of the following:
! Scleroderma renal crisis;
! Left ventricular failure (defined as ejection fraction ≤45%);
! Pulmonary arterial hypertension requiring treatment.
Subjects with clinically meaningful disease progression of SSc-ILD should be considered for 
change in therapy according to the guidance below:
! Subjects taking submaximal doses of mycophenolate (MMF < 3 g/day or MPS < 2160 mg/day 
should have an increase to 3 g/day or 2160 mg/day, respectively, as tolerated. The IMP should 
be continued (unless meeting criteria for withdrawal from IMP, refer to Section 5.5.1).
! Subjects taking maximal doses of mycophenolate should have the IMP discontinued and be 
treated according to the local standard of care. If a nonbiologic immunosuppressant (such as 
cyclophosphamide [intravenous or oral]) is initiated, then mycophenolate must be 
discontinued. Subjects withdrawn from IMP should complete the early termination visit.
After the change in therapy as described above for progression of SSc-ILD, subjects would fulfill 
criteria for further disease progression if meeting 1 of the 2 specified criteria based on change in 
FVC and DLCO (ie, using the clinical data from the time of change in therapy as the new 
‘baseline’).  Such subjects should be switched from mycophenolate to other local standard of 
care with discontinuation of IMP.
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Subjects with clinically meaningful progression of SSc other than ILD should be treated 
according to the local standard of care, at the discretion of the Investigator.
If a subject discontinues IMP, then the subject should complete the early termination visit and 
then the remaining scheduled visits (refer to Table 1 and Table 2). All subjects will be followed 
up by the site for survival from the last visit on trial until death or end of the trial. New onset or 
worsening of manifestations of scleroderma that are not captured by the pulmonary function 
tests, mRSS, or digital ulcer score, should be reported as AEs. On the eCRF AE page, such 
events should be marked as ‘yes’ in response to the question “Is this a manifestation of 
worsening scleroderma?”.
If the ILD on HRCT worsens significantly according to the Investigator, then subjects can have 
the mycophenolate treatment increased to the protocol-specified maximal dose (i.e., 3 g/day 
MMF or 2160 mg/day MPS).
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines.
Six vials will be packed in white cartons with foam inserts and a single panel/booklet label 
attached to the vial and carton.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
 
Detailed information on infusion bags and medical devices 
to be used for the preparation of the dilutions and subsequent administration will be provided in 
the manual of preparation. To prepare the dilutions, preparation steps must be accomplished by 
adequately trained personnel using aseptic techniques.
 
 
 
 
 
 
 
 
However, from a microbiological point of view, the diluted solution should be used 
just after and is not intended to be stored unless reconstitution and dilution has taken place in 
controlled and validated aseptic conditions. If not used immediately, in-use storage times and 
conditions prior to use are the responsibility of the user. 
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The IMP must be stored at the Investigator’s site safely and separately from other drugs under 
locked conditions. Only a pharmacist or a person designated by him/her will have access to the 
IMP and will prepare the IMP infusions. A detailed description of the preparation procedure will 
be provided prior to trial start in a separate Manual of Preparation.
6.8
Investigational Medicinal Product Accountability
The Investigator is responsible for ensuring IMP accountability, including reconciliation of drugs 
and maintenance of records.
! Upon receipt of IMP, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate documentation and 
returning it to the location specified. A copy will be archived for the Investigator Site File.
! Dispensing of IMP will be recorded on the appropriate drug accountability forms so that 
accurate records will be available for verification at each monitoring visit.
! Trial center IMP accountability records will include the following:
! Confirmation of IMP receipt, in good condition and in the defined temperature range;
! The inventory of IMP provided for the clinical trial and prepared at the site;
! The volume administered to each subject;
! The disposition (including return, if applicable) of any unused IMP;
! Dates, quantities, kit numbers, expiry dates, and the individual subject trial numbers.
The Investigator site should maintain records, which adequately document that subjects were 
provided the volume specified in this protocol, and all IMPs provided were fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present trial. No IMP 
that is dispensed to a subject may be redispensed to a different subject.
A trial monitor will periodically collect the IMP accountability forms.
6.9
Assessment of Investigational Medicinal Product Compliance
The IMP will be administered by intravenous infusion by the Investigator or delegate. The 
Investigator or designee will record the date and time of the start and end of each infusion in the 
subject’s medical records and in the eCRF.
The exact volumes of IMP given at each infusion will also be documented in the eCRF. If 
treatment is interrupted during infusion, the clinical staff will estimate the volume received by 
the subject and document this in the eCRF.
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Any reasons for noncompliance must be documented, including, but not limited to:
! Missed visits
! Interruptions in the schedule of administration.
6.10
Blinding
This trial will be double-blinded.
Packaging and labeling will be prepared to protect the blinded status of the trial. Each kit will be 
labeled by the manufacturer with a unique kit number. Blinding will be maintained throughout 
the trial duration, unless an emergency unblinding occurs.
All breaks of the trial blind must be adequately documented.
Prior to the start of the trial, an IDMC will be formed to monitor interim safety data on a regular 
basis to ensure the safety of subjects in this trial. The IDMC will review the results of interim 
futility analysis and make a recommendation to the Sponsor on continuing or stopping the trial 
for futility, based on the criteria in the IDMC charter. 
An independent statistical center will support the IDMC for safety analysis and the interim 
futility analysis. 
A team from the Sponsor, independent of the CRO trial team, will be tasked with review of the 
unblinded interim analysis results. Details will be provided in the Firewall Charter.
The primary analysis will be performed by the Sponsor/CRO staff while the trial is ongoing for 
subjects who are still under trial treatment during the second year. To ensure the integrity of the 
trial conduct, results of primary analysis will be generated on the aggregate group level and 
reviewed by a restricted group to limit initial dissemination. The access of individual treatment 
information will be controlled so as not to impact the trial conduct. The sites and subjects remain 
blinded until the end of the trial. 
The bioanalytical laboratory(ies) responsible for the analysis of the PK samples will be allowed 
to be unblinded to treatment so as not to analyze the samples from the placebo-treated subjects. 
The subject identifiers will be masked from any results of the PK analyses transferred to the 
Sponsor before the final database lock.
It is acknowledged that in the case of safety events, certain subject treatment information may be 
unintentionally revealed in the aggregate output of the primary analysis. The Sponsor considers it 
is a small risk and can be mitigated by using a restricted results review team to limit initial 
dissemination. 
The Sponsor may decide to continue or terminate the trial following the primary analysis. The 
IDMC will be informed of the outcome of the primary analysis and will remain in place for 
monitoring subject safety until the end of the trial.
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6.11
Emergency Unblinding
The trial blind may be broken for an individual only if knowledge of the IMP is essential for 
clinical management of the subject. The Investigator must promptly explain the reason for any 
unblinding of an IMP to the Sponsor without revealing the result to any Sponsor employee 
except the designated Drug Safety representative (using the Emergency Unblinding Notification 
Form). The Investigator must record the date of unblinding and the reason in the eCRF. Contact 
information for breaking the blind in an emergency is given on the subject emergency card 
provided to each subject (see Section 9.4).
If IMP is unblinded by the Investigator, the subject will be discontinued from treatment and 
followed up as appropriate.
Under certain circumstances, Drug Safety may be required to unblind the treatment assignment 
for an individual subject following an SAE or other serious event; for example, if an expedited 
regulatory report is required. See Section 7.4 for further details on expedited reporting and SAEs. 
6.12
Treatment of Overdose
An overdose is defined as any amount of IMP greater than the assigned dose for an individual 
subject enrolled in the trial. Even if it does not meet other criteria for an SAE, any overdose must 
be recorded in the Trial Medication section of the eCRF and reported to Drug Safety in an 
expedited manner using the SAE Report Form, and following the procedure in Section 7.4. As 
the Investigator is blinded to the treatment group, it should be assumed that the subject received 
abituzumab 1500 mg and the overdose should be reported in a blinded manner, eg, without 
previous unblinding of the subject.
As no antidote or nondrug therapy is available, the Investigator should use clinical judgment 
when treating an overdose of the IMP.
6.13
Medical Care of Subjects after End of Trial
The Sponsor will not provide any additional care to subjects after they leave the trial period 
because such care should not differ from what is normally expected for patients with SSc-ILD. 
During the survival follow up period, subjects will be treated according to the local standard of 
care. 
7
Trial Procedures and Assessments
7.1
Schedule of Assessments
Prior to performing any trial assessments that are not part of routine medical care for the subject, 
the Investigator will obtain written informed consent as described in Section 9.2. 
Each subject’s participation in the trial consists of a Screening Period, a Double-blind Treatment 
Period, and a Safety Follow-up Period. Details for the procedures and the Schedules of 
Assessments are provided in Table 1 and Table 2.
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7.1.1
Screening Period
The subject’s eligibility will be assessed at a Screening Visit that will occur within 42 days prior 
to Day 1. After providing written informed consent, the assessments described in Table 1 will be 
performed.
If at screening, the subject meets all of the protocol inclusion and none of the exclusion criteria 
(including complete history of immunosuppressive, immunomodulating, and potential 
scleroderma disease-modifying medications as well as history of other medications in the 
previous year), the subject will be considered as eligible and will be enrolled in the trial and 
randomized. Subjects who fail to meet the protocol-specified criteria for randomization or 
dosing, or withdraw their consent before randomization, are considered screening failures. If the 
Investigator feels a particular screening assessment is aberrant and retesting could confirm 
eligibility, these may be repeated under the same subject number, provided the retest is 
performed within the same screening period. A subject who was considered a screen failure may 
be re-screened (only once per subject). Re-screening is not encouraged. However, on a 
case-by-case basis with permission of the Medical Monitor and the Sponsor’s Medical Director, 
a subject who has not met all of the eligibility criteria within the original screening period may 
be permitted to be re-screened one time. An HRCT would not need to be repeated if completed 
within 2 months of the re-screening visit. Any TB test, including negative TB skin test with 
purified protein derivative, QuantiFERON-TB, or T-SPOT, would not need to be repeated if 
completed within 3 months of the re-screening visit. Each subject must be re-consented before 
re-screening occurs. A new subject number will be assigned and all screening assessments have 
to be repeated.
The following information, as a minimum should be collected for screen failure subjects: 
informed consent, demographics, reason for screen failure, AEs from the date of informed 
consent until subject is considered screen failure by the Investigator, and the Investigator`s 
signature. 
7.1.2
Double-blind Treatment Period
All subjects will return to the trial center on Days 1, 15, and 29, then every 4 weeks through 
Week 104. Visit windows of ∀3 days through Week 52 and ∀5 days for Weeks 56 through 104 
are permitted. Beginning on Day 1, subjects will receive their assigned dose of IMP as an 
intravenous infusion every 4 weeks with the last IMP administration at the Week 100 visit. 
Efficacy, safety, HRQoL, PK, and 
 assessments will be performed as described in 
Table 1 and Table 2.
All visit dates up to Week 104 and the end of the Safety Follow-up Period will be calculated 
based on Day 1. Any assessments specified on the schedules of assessments may be performed at 
an unscheduled visit and, if performed, should be documented on the eCRF.
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7.1.3
Safety Follow-up Period
Subjects who complete the 104-week treatment period will return to the trial center 4 and 
12 weeks (∀5 days) after the Week 104 visit for the Safety Follow-up Visits. 
Subjects who are withdrawn from IMP should complete the early termination visit as soon as 
possible, but within 2 weeks of IMP discontinuation, and then the remaining scheduled visits. At 
a minimum, the subject is expected to complete the trial visits at Weeks 12, 24, 36, 52, 64, 76, 
88, and 104, as well as the Safety Follow-up period Week 12 visit. Subjects with discontinued 
IMP can come to the other scheduled visits during the trial period according to the Investigator's 
judgment. 
Subjects who withdraw from the treatment period would have an early termination visit followed 
by entrance into the Safety Follow-up Period. 
Subjects who withdraw from the trial (eg, withdraw consent, lost to follow-up, or death; see 
Section 5.5.2) would not have any additional trial visits.
Assessments will be performed as described in Table 2.
7.1.4
Survival Follow-up
All subjects will be assessed for survival by the site every 12 weeks (∀1 week) from the last visit 
on the trial until death or end of the trial. Each subject’s vital status, and date of death if known, 
will be recorded in the eCRF. Systematic and consistent attempts will be made to contact 
subjects who fail to actively maintain contact with the site Investigator (see Section 5.5.1).
7.2
Demographic and Other Baseline Characteristics
At screening, the following demographic data will be collected: date of birth, sex (gender), 
height, weight, race, and ethnicity. In addition, a complete medical history (including a history of 
SSc-ILD), 
medication 
history 
(including 
complete 
history 
of 
immunosuppressive, 
immunomodulating, and potential scleroderma disease-modifying medications, as well as history 
of other medications in the previous year), and history of surgical procedures will be collected. 
Other baseline measurements such as clinical laboratory parameters, ECG, vital signs, and 
physical examination will also be assessed.
7.3
Efficacy Assessments
Efficacy assessments include evaluation of lung function (FVC and DLCO) and lung 
abnormalities on HRCT. Assessments will be performed as described in Table 1 and Table 2.
Relative change is defined as percentage change from baseline FVC percent predicted (eg, 
change from FVC 80% predicted to FVC 70% predicted corresponds to an absolute change of 
10% and a relative change of 12.5%).
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In this trial, full volume HRCT of the chest will be performed at Sponsor-qualified imaging 
centers per guidelines outlined in an imaging manual. High resolution computer tomography will 
be performed on all trial subjects during the Screening Period and at Months 6, 12, and 24 
(Weeks 24, 52, and 104; or early termination, if applicable). To ensure comparability, the same 
scan, equipment, method, and technique used during the baseline HRCT scan should be used for 
all the subsequent HRCT scans. For all subjects, HRCT scans will be performed with no contrast 
agent administration, reconstructed every 0.6 to 2 mm, using a low-dose protocol.
The HRCT images will be analyzed by computer-based quantitative scoring system and also by 
visual review by a central imaging review panel. The HRCT analysis will focus on changes 
visual and CAD scores for lobar lung fibrosis evaluation. Changes in the lung fibrosis scores 
from the Screening Period HRCT will be used to evaluate the treatment responses. 
Detailed imaging procedures of HRCT will be defined in a separate imaging manual, and 
detailed image analysis procedures of HRCT will be defined in an imaging review charter.
Radiation Dose
The radiation dose that results from the entire scan can be described as having a whole body 
effective dose of 2.1 milliSieverts (mSv). Thus, for the 4 scans given over the 104 weeks 
(2 years) in this trial, the estimated total body effective dose would be 8.4 mSv. The average 
annual exposure from natural sources of radiation in the USA, for example, is approximately 
3.0 mSv per year, and a radiation worker (such as a radiologic technologist or a radiologist) is 
allowed 50 mSv per year, for a total of 6.0 and 100 mSv, respectively, over 2 years. Therefore, 
this trial delivers the equivalent of approximately 1.4 times the expected natural radiation 
exposure and 8.4% of what a radiation worker is allowed over a 2-year period. This is considered 
acceptable, given the potential utility of the derived data.
7.4
Assessment of Safety
The safety profile of the IMP will be assessed through the recording, reporting, and analysis of 
baseline medical conditions, AEs, physical examination findings including vital signs and 
laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by each subject will be 
performed from the time of giving informed consent and throughout the trial. The Investigator 
will report any AEs, whether observed by the Investigator or reported by the subject (see Section 
7.4.1.2). The reporting period for AEs is described in Section 7.4.1.3.
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
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AE can therefore be 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 IMP. 
A TEAE is defined as any event not present prior to the initiation of the IMP or any event 
already present that worsens in either severity or frequency following exposure to the IMP.
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the National Cancer Institute (NCI) - CTCAE, Version 4.03 
(publication date: 14 June 2010), a descriptive terminology that can be used for AE reporting.
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided.
If a particular AE’s severity is not specifically graded by the guidance document, the Investigator 
is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following his or her 
best medical judgment.
The 5 general grades are:
! Grade 1 or Mild
! Grade 2 or Moderate
! Grade 3 or Severe 
! Grade 4 or Life-threatening 
! Grade 5 or Death.
According to Sponsor convention, any clinical AE with severity of Grade 4 or 5 must also be 
reported as an SAE. However, a laboratory abnormality of Grade 4, such as anemia or 
neutropenia, is considered serious only if the condition meets one of the serious criteria 
described below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (for example, 
sudden death or unexplained death), the death per se might then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to IMP (including 
any other non-IMPs, radiation therapy, etc.) using the following definitions. Decisive factors for 
the assessment of causal relationship of an AE to the IMP include, but may not be limited to, 
temporal relationship between the AE and the IMP, known side effects of IMP, medical history, 
concomitant medication, course of the underlying disease, or trial procedures.
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Unrelated:
Not 
reasonably 
related 
to 
the 
IMP. 
The 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the IMP under study in this clinical 
trial protocol. A reasonable alternative explanation must be available.
Related:
Reasonably 
related 
to 
the 
IMP. 
The 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the IMP under study in this clinical 
trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
ECG trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation or are considered otherwise medically important by 
the Investigator. If a laboratory abnormality fulfills these criteria, the identified medical 
condition (for example, anemia or increased ALT) must be reported as the AE rather than the 
abnormal value itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
! Results in death.
! Is life-threatening. (Note: The term “life-threatening” refers to an event in which the subject is 
at risk of death at the time of the event, not an event that hypothetically might have caused 
death if it was more severe.)
! Requires inpatient hospitalization or prolongs an existing hospitalization.
! Results in persistent or significant disability or incapacity.
! Is a congenital anomaly or birth defect.
! Is otherwise considered to be medically important. (Note: Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.)
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is 
also considered an SAE, as described in Section 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (for 
example, an overnight stay to facilitate chemotherapy and related hydration therapy application) 
are not considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
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prolongation of an elective hospitalization (for example, undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the initial trial visit that do not worsen in severity or frequency 
during the trial are defined as Baseline Medical Conditions, and are not to be considered AEs.
However, if adverse signs or symptoms occur in association with disease progression then these 
should be recorded as AEs.
Adverse Events of Special Interest
All blistering or Grade ≥3 AEs in the skin and subcutaneous tissue disorders SOC will be 
designated as AESI. Any cutaneous reaction of Grade 1 or 2 that is not responding to specific 
treatment or is worsening will also be designated as an AESI. The occurrence of cutaneous AESI 
or SAEs will be reviewed by an independent panel of dermatologists to provide guidance for 
further investigation and interpretation of these events, and advise the IDMC whether any actions
to modify clinical trial conduct should be considered.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the Investigator. 
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the 
eCRF. All SAEs must be additionally documented and reported using the appropriate report form 
as described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and times when it is important to assess the time of AE onset relative to the 
recorded treatment administration time), its severity, its causal relationship with the trial 
treatment, any other potential causal factors, any treatment given or other action taken, including 
dose modification or discontinuation of the IMP, and its outcome. In addition, serious cases 
should be identified and the appropriate seriousness criteria documented. 
For suspected anaphylactic events, including infusion-related reactions, Investigators should 
utilize the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network criteria (Sampson 2006).
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
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a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia)
b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
subject (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that subject (minutes to several hours):
a. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that person’s 
baseline
Adapted from Sampson 2006
Specific guidance can be found in the eCRF Completion and Monitoring Conventions provided 
by the Sponsor.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in 
the trial (date of first signature of first informed consent) and continues through the post-
treatment Safety Follow-up Period. 
Any SAE assessed as related to IMP must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of IMP. 
7.4.1.4
Procedure for Reporting Serious Adverse Events 
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or its designee in writing. All written reports should be transmitted using the SAE 
Report Form, which must be completed by the Investigator following specific completion 
instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an SAE report form must be provided immediately thereafter. 
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Relevant pages from the eCRF may be provided in parallel (for example, medical history and 
concomitant drugs). Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report, and autopsy report). In all cases, the information 
provided on the SAE Report Form must be consistent with the data about the event recorded in 
the eCRF.
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, and other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee 
and (as applicable) to allow the Sponsor to meet strict regulatory timelines associated with 
expedited safety reporting obligations.
Requests for follow-up will usually be made via the responsible Monitor, although in exceptional 
circumstances the Global Drug Safety department may contact the Investigator directly to obtain 
further information or to discuss the event. 
Any AESI will be reported according to the procedure for SAEs described above.
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/Institutional Review Boards, and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial subjects to the IEC/IRB that approved the 
trial.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the trial or alter the 
IEC’s/IRB’s approval/favorable opinion to continue the trial.” In particular and in line with 
respective regulations, the Sponsor/designee will inform the Investigator of AEs that are both 
serious and unexpected and are considered to be related to the administered product (“suspected 
unexpected serious adverse reactions” or SUSARs). The Investigator should place copies of 
Safety Reports in the Investigator Site File. National regulations with regard to Safety Report 
notifications to Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
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For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with 
that Directive and with the related Detailed Guidance documents.
7.4.1.6
Monitoring of Subjects with Adverse Events
Adverse events are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) 
and are assessed for final outcome at the Safety Follow-up Visits. All SAEs ongoing at the 
Safety Follow-up Visit must be monitored and followed up by the Investigator until stabilization 
or until the outcome is known, unless the subject is documented as “lost to follow-up”. 
Reasonable attempts to obtain this information must be made and documented. It is also the 
responsibility of the Investigator to ensure that any necessary additional therapeutic measures 
and follow-up procedures are performed. 
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (for example, 
resulting from a drug interaction with a contraceptive medication) are considered to be AEs. 
However, all pregnancies with an estimated conception date during the period defined in 
Section 7.4.1.3 must be recorded by convention in the AE page/section of the eCRF. The same 
rule applies to pregnancies in female subjects and to pregnancies in female partners of male 
subjects. The Investigator must notify the Sponsor/designee in an expedited manner of any 
pregnancy using the Pregnancy Report Form, which must be transmitted according to the same 
process as described for SAE reporting in Section 7.4.1.4. 
Investigators must actively follow up, document, and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from IMP immediately. The Sponsor/designee must be notified without delay 
and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
The Sponsor should receive a list of laboratory normal ranges before shipment of IMP. Any 
change in laboratory normal ranges during the trial should be forwarded to the Sponsor and 
.
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Blood and urine samples will be collected for the clinical laboratory tests in Table 4, following 
the timing noted in the Schedule of Assessments (Table 1 and Table 2). All samples should be 
clearly identified. Samples will be collected, processed, and stored in accordance with the 
directions provided in the 
 Flow Chart. Urine pregnancy tests analyses are to be 
performed locally. All other parameters will be analyzed at the central laboratories. 
Table 4
Clinical Laboratory Testing
Clinical Chemistry 
Routine Hematology 
Urinalysis (dipstick)
Gamma glutamyl transferase 
Hematocrit
pH
ALT
Hemoglobin
Specific gravity
Albumin
Mean cellular hemoglobin 
Leukocytes
AP
Mean cellular hemoglobin 
concentration 
Nitrite
AST
Glucose
Bilirubin – direct (only if total bilirubin 
is outside the normal range)
Mean cellular volume 
Ketones
Platelet count
Protein
Bilirubin – total
Red blood cell count
Blood
Calcium
Red cell distribution width 
Chloride
White blood cell count and differential
Additional Urinalysis
Bicarbonate
Urine protein:creatinine ratio 
(performed if dipstick urinalysis 
reveals at least 3+ protein)
Microscopy if blood present
Serum creatinine
Glucose
Coagulation (at screening only)
Potassium
Prothrombin time
Protein – total
Activated partial thromboplastin time
Immunogenicity
Sodium
Anti-abituzumab antibodies
Urea
Uric acid
C-reactive protein 
TSH (at screening only)
NT pro-BNP (at screening only)
ALT = alanine aminotransferase, AP = alkaline phosphatase, AST = aspartate aminotransferase, 
NT pro-BNP = N-terminal prohormone brain natriuretic peptide, TSH = thyroid-stimulating hormone.
Other laboratory assessments include the following:
! Serum pregnancy test in female subjects of childbearing potential;
! Urine pregnancy test in female subjects of childbearing potential, to be performed locally;
! HIV, hepatitis C, and hepatitis B (HBsAg, hepatitis B core antibody [IgM and total]) 
serologies;
! HbA1c may be evaluated for subjects with diabetes, at the discretion of the Investigator, and 
by forwarding a prior request to the Medical Monitor and notification to the Sponsor’s 
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Medical Director. Samples may be collected at any time point judged appropriate by the 
Investigator with Medical Monitor approval. Testing will be conducted by a local laboratory.
! Tuberculosis testing as requested by Investigator.
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
Vital signs, physical examinations, and locally read 12-lead ECGs will be performed and 
documented throughout the trial at the time points specified in the Schedule of Assessments 
(Table 1 and Table 2). Blood pressure and pulse rate should be measured after the subject has 
been in the sitting position for at least 10 minutes. The ECGs will be read in accordance with
local practice.
7.5
Pharmacokinetics
Serum samples for the determination of abituzumab concentrations will be collected from all 
subjects at the time points given in Table 1. In a subset of subjects who give separate consent to 
provide additional PK samples (rich PK sampling), additional samples will be collected at the 
time points given in Table 1 (see footnote i).
For the PK evaluation, serum levels of abituzumab will be analyzed by the bioanalytical 
laboratory using an appropriate validated method.
The actual date and time of sample collection will be recorded.
Instructions for the collection, storage, handling, and shipping of PK samples will provided in 
the 
 Flow Chart.
 
 
 
 
 
 
 
 
 
 
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8
Statistics
8.1
Sample Size
Based on reference data from randomized clinical trials in SSc-ILD and IPF, an expected 
improvement of 150 mL in the annual rate of absolute FVC change (mL) is assumed for 
abituzumab 1500 mg versus placebo with a common standard deviation of 300 mL.
 
 
 
 
 
 
 
 
 The inclusion of abituzumab 500 mg in 
conjunction with abituzumab 1500 mg will support abituzumab exposure-response analysis for 
dosing optimization.
A blinded sample size review is planned after at least 50% of the subjects complete their first 
year on treatment. The review will either lead to an increase in the total sample size or to a 
continuation of the trial with the original sample size. Following Kieser 2003, the estimated
one-sample variance will be adjusted for bias. If the adjusted standard deviation is more than 
10% larger than the hypothesized standard deviation (ie, 330 mL or more), then the sample size 
may be increased by up to 40 subjects. Details will be provided in the Statistical Analysis Plan.
Hypothesis Testing
The primary endpoint is the annual rate of absolute FVC change in volume (mL). 
! The null hypothesis is:
H0: There is no improvement in annual rate of absolute FVC change for the abituzumab 
1500 mg arm compared with the placebo arm on top of stable mycophenolate.
! The alternative hypothesis is:
H1: There is an improvement in annual rate of absolute FVC change for the abituzumab 
1500 mg arm compared with the placebo arm on top of stable mycophenolate. 
8.2
Randomization
Once all eligibility criteria have been met, subjects will be randomly assigned to 1 of the 
3 treatment groups of the trial: abituzumab 1500 mg, placebo, or abituzumab 500 mg in a ratio of 
2:2:1, respectively.
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Randomization will be conducted in permuted blocks by a central IVRS/IWRS provider and 
stratified by baseline FVC % predicted (< 70% versus ≥70%) and by duration of mycophenolate 
use at baseline (< 6 months versus ≥6 months).
8.3
Endpoints
8.3.1
Primary Endpoint
The primary endpoint for the trial is annual rate of absolute FVC change in volume (mL). This 
endpoint will be assessed after all subjects have either completed 52 weeks of treatment or 
prematurely discontinued from the trial. The primary efficacy analysis will be conducted on all 
observed FVC data during the trial for all subjects regardless of their adherence to treatment or 
use of rescue therapies. The primary efficacy analysis will be performed using the modified 
Intent-to-Treat (mITT) population.
8.3.2
Secondary Endpoints
The key secondary efficacy endpoints for the trial include the following: 
! Change in dyspnea from baseline as measured by the Mahler TDI at Week 52;
! Absolute change from baseline in SGRQ total score at Week 52;
! Absolute change from baseline in mRSS at Week 52 in subjects with diffuse cutaneous skin 
involvement at baseline;
! Absolute change from baseline in QLF in the region of highest severity at Week 52;
! Overall survival.
Other secondary efficacy endpoints for the trial include:
! Proportion of subjects with clinically meaningful progression of SSc by meeting Criterion 1 
(ILD) by Week 52 and by Week 104 (refer to Section 6.5.5 for the definition of clinically 
meaningful progression);
! Proportion of subjects with clinically meaningful progression of SSc by meeting Criterion 2 
(SSc progression other than ILD) by Week 52 and by Week 104; 
! Proportion of subjects with clinically meaningful progression by Week 52 and by Week 104; 
! Proportion of subjects with absolute decrease from baseline of FVC % predicted ≥10% on 
2 or more consecutive occasions at least 4 weeks apart by Week 52 and by Week 104;
! Time to first clinically meaningful progression;
! Absolute change from baseline in FVC % predicted up to Week 104;
! Absolute change from baseline in DLCO % predicted up to Week 104;
! Absolute change from baseline in transfer coefficient of the lung for carbon monoxide (KCO) 
at Week 104;
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! Absolute change from baseline in QLF in the region of highest severity at Week 104;
! Absolute change from baseline in quantitative HRCT analyses of extent of total ILD up to 
Week 104.
8.3.3
Safety Endpoints
Safety endpoints in this trial include the following:
! The nature, incidence, severity, relationship, and outcome of AEs, SAEs, and AESIs from 
screening up to Week 116;
! Number of subjects with treatment-emergent AEs, SAEs, and AESIs from baseline up to 
Week 116;
! Treatment-emergent changes in clinical laboratory measures, ECGs, and vital signs from 
baseline up to Week 116;
! Incidence of subjects with positive ADA titers from baseline up to Week 116.
8.3.4
Other Endpoints
Quality of Life endpoints in this trial include the following:
! Proportion of subjects with Mahler TDI worsening ≥2 up to Week 104;
! Proportion of subjects with Mahler TDI worsening ≥2 up to Week 104 for subjects with 
Mahler BDI of ≥2;
! Change in dyspnea from baseline as measured by the Mahler TDI up to Week 104;
! Change in dyspnea from baseline as measured by the Mahler TDI up to Week 104 for subjects 
with Mahler BDI ≥2;
! Absolute change from baseline for each of the following HRQoL questionnaires up to 
Week 104:
!
Leicester Cough Index
!
SGRQ
!
Physician’s Global Assessment
!
Patient’s Global Assessment
!
SHAQ
!
EQ-5D.
Skin fibrosis endpoints include the following:
! In subjects with dcSSc: 
a.Absolute change from baseline in mRSS up to Week 104,
b. Proportion of subjects with change from baseline in mRSS up to Week 104 according to 
the following categories:
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! Worsened (absolute increase of ≥5 points and relative increase ≥25%) 
! Improved (absolute decrease ≥5 points and relative decrease ≥25%) 
! Stable (do not meet either Worsened or Improved category)
! In subjects with digital ulcers at baseline: absolute change from baseline in digital ulcer count 
up to Week 104.
Combined response endpoints include the following:
! Proportion of responders as defined by CRISS up to Week 104.
8.3.5
Pharmacokinetic Endpoints
Pharmacokinetic endpoints include the following:
! Abituzumab concentrations;
! PK parameters (eg, Cmax and Cmin). Further PK parameters will be derived by population PK.
8.3.6
Other Exploratory Assessments
!
 
 
 
 
 
 
 
 
8.4
Analysis Sets
8.4.1
Modified Intent-to-Treat
The mITT Population is defined as all randomized subjects who receive at least 1 dose of IMP 
(including placebo). Subjects will be analyzed according to their randomized treatment. All 
endpoint analyses other than safety will be performed using the mITT population. 
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8.4.2
Intent-to-Treat
The Intent-To-Treat (ITT) Population will consist of all randomized subjects. Subjects will be 
analyzed according to their randomized treatment. 
8.4.3
Per-Protocol
The Per-Protocol (PP) Population will consist of all randomized and treated subjects who do not 
have any clinically important protocol deviations. Subjects will be analyzed according to their 
randomized treatment. 
The following are criteria for inclusion in the PP Population:
! Compliance with all entry criteria;
! Absence of clinically important clinical trial protocol violations with respect to factors likely 
to affect the efficacy of treatment;
! Adequate compliance with and sufficient exposure to IMP.
The criteria will be defined in detail in the Statistical Analysis Plan, and clinically important 
protocol violators to be excluded from the PP Population will be identified prior the database 
lock for the primary analysis.
The analysis of the primary endpoint and the key secondary endpoints will be repeated using the 
PP Population as an additional sensitivity analysis.
8.4.4
Safety
The Safety Population will consist of all randomized subjects who receive at least 1 dose of IMP 
(including placebo) and have at least 1 postdose safety assessment. All safety analyses will be 
performed using this population. Subjects in the Safety Population will be analyzed according to 
the actual treatment received during the trial.
8.5
Description of Statistical Analyses
8.5.1
General Considerations
An outline of key statistical analyses is provided below. Full details of planned analyses will be 
provided in the Statistical Analysis Plan, to be finalized and approved prior to the interim futility 
analysis.
It is the intention of this trial that all subjects will adhere to the same visit schedule regardless of 
whether they have discontinued IMP prematurely. In addition, subjects who discontinue early 
from IMP will undergo an early termination visit to perform the same assessments scheduled for 
the Week 104 visit. 
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Multiple Comparisons/Multiplicity
During the primary analysis, hypothesis testing of the primary endpoint and key secondary 
endpoints will be formally performed for the abituzumab 1500 mg versus placebo under the 
family-wise Type I error rate following a hierarchical testing procedure to control for 
multiplicity. For these endpoints, statistical significance will be met at one-sided p < 0.025 and 
the corresponding two-sided 95% confidence intervals will be provided. 
 
 
Subgroups
The primary and key secondary endpoints and key safety data will be analyzed by subgroup. The 
subgroups of interest will be prespecified in the Statistical Analysis Plan, including the 
stratification factors of baseline FVC % predicted (< 70% versus ≥70%) and duration of prior 
mycophenolate use (< 6 months versus ≥6 months).
8.5.2
Analysis of Primary Endpoints
The primary endpoint will be analyzed using a random coefficients linear regression model with 
absolute change from baseline in observed FVC volume (mL) as the outcome variable. The 
change in FVC volume is assumed to be linear within each subject over the course of the trial. 
The model will include random coefficients for intercept and time, fixed-effect terms for 
treatment and time, treatment-by-time as the interaction term, and adjusting for baseline FVC, 
duration of prior mycophenolate use at baseline, age, sex, and height. Time is the duration (in 
years) between each postbaseline FVC assessment and baseline assessment. Missing data will be 
assumed to be missing-at-random (MAR). The analysis of the primary endpoint and other 
efficacy endpoints will be conducted to include all the data collected during the trial for all 
subjects regardless of their adherence to treatment or use of rescue therapies. 
Sensitivity analysis will be performed to evaluate the potential effect of missing data on the 
robustness of the efficacy results, including tipping point analyses to assess the different 
assumptions about the missing outcomes and to explore the plausibility of missing data 
assumptions under which the conclusions change. The tipping point analysis will allow 
assumptions about the missing outcomes on the treatment arms to vary independently and will 
also include scenarios where dropouts on abituzumab arm have worse outcomes than dropouts 
on placebo arm. Details will be described in the Statistical Analysis Plan. 
The linearity assumption for the absolute FVC change in volume over time will be examined. 
The time course of trends in absolute FVC over time will be presented using observed data 
collected at multiple time points for each subject. The mean value of absolute FVC and the 
treatment effect on mean change from baseline in absolute FVC will be presented for each 
treatment arm over time. 
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Supportive analysis will be performed to analyze the difference in annual rates using the absolute 
change from baseline in FVC% predicted. The absolute change in FVC% predicted at Week 52 
and at Week 104 will be also analyzed using a ranked analysis of covariance (ANCOVA) model. 
Missing outcome due to reasons other than death will be replaced with imputed values based on 
the worst outcome carried forward (WOCF) during the trial. Missing outcome due to death will 
be ranked worse than others and ordered according to the time from randomization to death, with 
the shortest time to death as the worst rank. 
A continuous responder analysis will be performed using absolute change in FVC% predicted at 
Week 52 and at Week 104. Missing data will be imputed by WOCF for reasons other than death. 
Missing data due to death are considered non responders and imputed by the observed highest 
decline in FVC% predicted among all subjects. A continuous responder curve will be plotted for 
each treatment arm in a graph to display the relative benefit of abituzumab across the entire 
range of response. The x-axis shows the absolute change from baseline in FVC% predicted at 
Week 52. The y-axis shows the corresponding percentage of subjects achieving that level of 
FVC% predicted decline or greater. A positive treatment effect is demonstrated by consistent 
separation of the curves across different level of response. A cut-off point of at least 10% decline 
in FVC% predicted will be performed for a binary responder analysis.
8.5.3
Analysis of Secondary Endpoints
Analysis of Key Secondary Efficacy Endpoints
The key secondary endpoints will be tested for abituzumab 1500 mg versus placebo, using data 
for subjects on trial treatment, in the following order after the primary endpoint is met.
1. The Mahler TDI at Week 52 will be analyzed using a mixed-effects model adjusting for 
baseline FVC% predicted, duration of prior mycophenolate use at baseline, and Mahler 
BDI. 
2. The absolute change in SGRQ total score at Week 52 will be analyzed using a 
mixed-effects model adjusting for baseline FVC% predicted, duration of prior 
mycophenolate use at baseline, and baseline SGRQ score.
3. The absolute change from baseline in mRSS at Week 52 in subjects with dcSSc at 
baseline will be analyzed using a mixed-effects model adjusting for baseline FVC% 
predicted, duration of prior mycophenolate use at baseline, and baseline mRSS.
4. The absolute change from baseline in QLF in the region of highest severity at Week 52 
will be analyzed using an ANCOVA model adjusting for baseline FVC% predicted, 
duration of prior mycophenolate use at baseline, and baseline QLF. 
5. Overall survival will be analyzed using a stratified log-rank test and presented by 
Kaplan-Meier estimates and 95% confidence interval, including the survival data 
available up to the analysis cut-off date. A Cox proportional hazards regression model 
will be used to obtain hazard ratios and 95% confidence intervals adjusting for baseline 
FVC% predicted and duration of prior mycophenolate use at baseline.
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The mixed-effects model will include random intercept, treatment, and visit as fixed effect terms, 
treatment-by-visit as the interaction term, adjusting for baseline covariates. An unstructured 
covariance matrix will be used as the default option. Missing data is assumed MAR. 
Missing data for binary endpoint will be imputed as non-responders.
Analysis of Other Secondary Efficacy Endpoints
 
 
 
 
 
 
Analysis of Safety Endpoints
Adverse events will be summarized by treatment group, by severity, and by relationship to IMP. 
Serious AEs, AEs leading to treatment discontinuation, and AESI will be summarized by 
treatment group. 
Summary statistics will be used to present changes from baseline in continuous laboratory and 
vital sign data. Shift tables will be used to present changes in categorical laboratory parameters. 
Figures may be generated to assist safety evaluation.
Analysis of Quality of Life Endpoints
Quality of life endpoints will be summarized according to their scoring instructions. Continuous 
variable will be analyzed using ANCOVA unless otherwise specified. Categorical variable will 
be analyzed using categorical methods. Details will be specified in the Statistical Analysis Plan.
Pharmacokinetic Analyses
A Population PK model will be developed. The influence of covariates on PK parameters will be 
assessed. From the final Population PK model, individual estimates of the PK parameters and 
exposure parameters (AUC, Cmax, and Cmin) will be derived. The exposure parameters may be 
used for further exposure-response assessment.
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8.6
Interim and Additional Planned Analyses
The interim futility analysis on the primary endpoint will be performed by an independent third 
party statistician when approximately 88 subjects have either completed 52 weeks of treatment 
or prematurely discontinued from the trial. The results of interim analysis will be reviewed 
confidentially by IDMC. The futility boundary is non-binding (to be specified in the IDMC 
charter). Additional analysis of the primary and secondary endpoints is allowed at the IDMC’s 
discretion and supported by the independent third-party statistician. Based on the totality of the 
information at interim, the IDMC will make a recommendation to the Sponsor on continuing or 
stopping the trial for futility. There is no prespecified boundary for efficacy, therefore there is no 
alpha spending for the interim analysis. 
The primary analysis will be performed by the Sponsor/Contract Research Organization staff 
when all subjects have either completed 52 weeks of treatment or prematurely discontinued from 
the trial. Results will be generated on the aggregate group level and reviewed by a restricted 
group to limit initial dissemination. The access of individual treatment information will be 
controlled to not impact the trial conduct. 
The sites and subjects remain blinded until the end of the trial. The trial will continue as planned
and a final treatment analysis will be performed when all subjects have either completed 
104 weeks of treatment or prematurely discontinued from the trial. 
The final database will be locked after all subjects have completed the 12 weeks of safety 
follow-up or prematurely discontinued from the trial. A final follow-up analysis will be 
performed after the final database lock.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at the site and will ensure that the trial 
is performed in accordance with this protocol, the ethical principles outlined in the Declaration 
of Helsinki, ICH GCP, and any other applicable regulations. The Investigator must ensure that 
only subjects who have given informed consent are included in the trial.
According to United States Code of Federal Regulations Part 54.2 (e), for trials conducted in any 
country that could result in a product submission to the United States Food and Drug 
Administration (FDA) for marketing approval and could contribute significantly to the 
demonstration of efficacy and safety of an IMP (which are considered “covered clinical trials” by 
the FDA), the Investigator and all subinvestigators are obliged to disclose any financial interest 
which they, their spouses, or their dependent children may have in the Sponsor or the Sponsor’s 
product under study. This information is required during the trial and for 12 months following 
completion of the trial.
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9.2
Subject Information and Informed Consent
An unconditional prerequisite for each subject prior to participation in the trial is written 
informed consent, which must be given before any trial-related activities are carried out. 
Adequate information must therefore be given to the subject by the Investigator or an appropriate 
designee (if local regulations permit) before informed consent is obtained. 
A subject information sheet must be prepared in the local language in accordance with ICH GCP 
and will be provided by the Sponsor for the purpose of obtaining informed consent. In addition 
to providing this written information to a potential subject, the Investigator or a designee will 
inform the subject verbally of all pertinent aspects of the trial, using language chosen so that the 
information can be fully and readily understood by laypersons. The subject will be given 
sufficient time to read the information and the opportunity to ask questions and to request 
additional information and clarification.
If permitted by national regulations, a person other than the Investigator may inform the subject 
about the trial and sign the Informed Consent Form, as above.
After the information is provided by the Investigator, the Informed Consent Form must be signed 
and dated by the subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived so that the forms can be retrieved at any time for monitoring, auditing, 
and inspection purposes. A copy of the signed and dated information and Informed Consent 
Form should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to informed 
consent, the Investigator will revise the subject information sheet and any other written 
information to be provided to the subjects and submit them to the IRB for review and opinion. 
Using the approved revised subject information sheet and other written information, the 
Investigator will explain the changes to the previous version to each trial subject and obtain new 
written consent for continued participation in the trial. The subject will be given sufficient time 
to read the information and the opportunity to ask questions and to request additional information 
and clarification about the changes.
Rich Pharmacokinetic Sampling Informed Consent
All subjects who are enrolled in the trial will be eligible to participate in the optional rich PK 
analysis. As participation is optional, the subjects willing to participate will need to sign a 
specific PK Informed Consent Form.
 
 
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9.3
Subject Identification and Privacy
A unique number will be assigned to each subject, immediately after informed consent has been 
obtained. This number will serve as the subject’s identifier in the trial as well as in the clinical 
trial database. All subject data collected in the trial will be stored under the appropriate subject 
number. Only the Investigator will be able to link trial data to an individual subject via an 
identification list kept at the site. For each subject, original medical data will be accessible for 
the purposes of source data verification by the Monitor, audits, and regulatory inspections, but 
subject confidentiality will be strictly maintained.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing subject data. Subjects will be informed accordingly, and will be requested to give 
their consent on data handling procedures in accordance with national regulations.
Storage and analyses of samples will be handled according to the specifications as described in 
the Informed Consent Form. 
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by the Sponsor for 
use during trial participation in order to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial and to give health care providers access to any 
information about this participation that may be needed to determine the course of medical 
treatment for the subject. The information provided on the Emergency Medical Support card will 
include the process for emergency unblinding.
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, he/she will answer 
any questions. Any subsequent action (for example, unblinding) will follow the standard process 
established for Investigators.
In cases where the Investigator is not available, the Sponsor provides the appropriate means to 
contact a Sponsor physician. This includes the provision of a 24-hour contact number at a call 
center, whereby the health care providers will be given access to the appropriate Sponsor 
physician to assist with the medical emergency and to provide support for the potential 
unblinding of the subject concerned.
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9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage will be provided for each country participating in the trial. Insurance 
conditions shall meet good local standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review 
Board
Prior to commencement of the trial at a given site, this clinical trial protocol will be submitted 
together with its associated documents (subject information sheet and Informed Consent Forms) 
to the responsible IEC/IRB for its favorable opinion or approval, which will be filed in the 
Investigator Site File. A copy will be filed in the Sponsor Trial Master File at 
.
The IEC/IRB will be asked to document the date of the meeting at which the favorable opinion 
or approval was given and the members and voting members present. Written evidence of 
favorable opinion or approval that clearly identifies the trial, the clinical trial protocol version 
and the Subject Information and Informed Consent Form version reviewed should be provided. 
Where possible, copies of the meeting minutes should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC/IRB, 
before implementation of substantial changes (see Section 10.5). Relevant safety information 
will be submitted to the IEC/IRB during the course of the trial in accordance with national 
regulations and requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, Investigational 
Medicinal Product Dossier, Subject Information and Informed Consent Form) will be submitted 
or notified to the Health Authorities in accordance with all local and national regulations for each 
site.
10
Trial Management
10.1
Case Report Form Handling
Refer to the eCRF Completion Guidelines for eCRF handling instructions. 
The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a 
complete, accurate, legible, and timely fashion. The data in the eCRF should be consistent with 
the relevant source documents.
The Investigator or designee is responsible for ensuring that the data collected in the course of 
this trial are accurate and documented appropriately on all applicable forms or eCRF. They will 
then be processed, evaluated, and stored in anonymous form in accordance with applicable data 
protection regulations. The Investigator must ensure that the eCRFs and any other associated 
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documents forwarded to Sponsor or its designated organization contain no mention of any 
subject names.
For patient-reported outcome data, such as HRQoL, electronic patient reported outcome will be 
used.
The data will be entered into a validated database. 
 Data Management will be 
responsible for data processing, in accordance with 
’ standard operating procedures. 
Database lock will occur once quality control and quality assurance procedures have been 
completed. Portable document format files of the eCRFs will be provided to the Investigators at 
the completion of the trial.
The Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model 
(SDTM) standards, required by the FDA for the submission of trial data, are followed by Merck 
Serono. Merck Serono General Data Standards and, if applicable, Therapeutic Area Data 
Standards, as well as Merck Serono SDTM Guidelines, will be used in all clinical trials as 
predefined in the applicable Merck Serono SOP, Working Instructions, and Guidelines, to create 
the Case Report Forms (CRFs), the SDTM delivery package (SDTM domains, define.xml, 
Reviewer’s Guide, SDTM annotated CRF), and the operational database; any exemptions need to 
be discussed and decided by the Project Team. In addition it is intended to convert non-SDTM
trial data from legacy trials, and possibly ongoing trials not conducted by Merck Serono, into an 
FDA submission compliant CDISC-SDTM format. Individual trial data and documents will be 
migrated into the ICMS (Integrated CDISC-based Data Model and System, a cross-functional 
platform designed to maintain the data of all current and future projects). These measures will 
facilitate the integration of data across multiple trials and projects so that more comprehensive 
data pools can be generated. If significant non-SDTM format data already exists for a drug, trials 
may not be converted to, or delivered in, SDTM format, if decided by the Project Team and 
agreed by Senior Management. The Program Data Manager ensures that data standards are 
harmonized across all trials within this development program.
10.2
Source Data and Subject Files
Source data are defined as all data in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial that are necessary for the 
reconstruction and evaluation of the trial. 
The Investigator must keep a file (medical file and original medical records) on paper or 
electronically for every subject in the trial. It must be possible to identify each subject by using 
this subject file. This file will contain the demographic and medical information for the subject 
listed below and should be as complete as possible. 
! Subject’s full name, date of birth, sex, height, and weight;
! Medical history and concomitant diseases;
! Prior and concomitant therapies (including changes during the trial);
! Trial identification, that is, the Sponsor trial number for this clinical trial, and subject number;
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! Dates for entry into the trial (informed consent) and visits to the site;
! Any medical examinations and clinical findings predefined in this clinical trial protocol;
! All AEs;
! Date that the subject left the trial including any reason for early withdrawal from the trial or 
IMP (if applicable).
All documents containing source data must be filed, including, but not limited to: HRCT, CT, or 
magnetic resonance imaging scan images, lung function test results, ECG recordings, and 
laboratory results. Such documents must bear the subject number and the date of the procedure. 
If possible, this information should be printed by the instrument used to perform the assessment 
or measurement. As necessary, medical evaluation of such records should be performed; all 
evaluations should be documented, signed, and dated by the Investigator.
Electronic subject files will be printed whenever the Monitor performs source data verification. 
Printouts must be signed and dated by the Investigator, countersigned by the Monitor and kept in 
a safe place at the site.
10.3
Investigator Site File and Archiving
Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial and 
updated as necessary. The file must be available for review by the Monitor, during Sponsor 
audits and for inspection by Health Authorities during and after the trial, and must be safely 
archived for at least 15 years (or longer, per local requirements or as otherwise notified by the 
Sponsor) after the end of the trial. The documents to be archived include the Subject 
Identification List and the signed subject Informed Consent Forms. If archiving of the 
Investigator Site File is no longer possible at the site, the Investigator must notify the 
Sponsor/designee.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per 
ICH GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance, and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP, and any other applicable 
regulations. The site Monitor will perform visits to the trial center at regular intervals. The trial 
will be monitored using a risk-based approach and the details of the model will be described in 
the Clinical Operational Plan.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance 
activities. Audits may be conducted at any time during or after the trial to ensure the validity and 
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integrity of the trial data. Representatives of the Quality Assurance unit from the Sponsor or a 
designated organization, as well as Health Authorities, must be permitted to access all trial 
documents and other materials at the site, including the Investigator Site File, the completed 
eCRFs, all IMP and IMP accountability records, and the original medical records or files for 
each subject.
10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in writing. Substantive amendments 
will usually require submission to the Health Authorities and to the relevant IEC/IRB for 
approval or favorable opinion. In such cases, the amendment will be implemented only after 
approval or favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health 
Authorities only where requested by pertinent regulations. Any amendment that could affect the 
subject’s agreement to participate in the trial requires additional informed consent prior to 
implementation following the process as described in Section 9.2.
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report will be written by the Sponsor in consultation 
with the CRO and any other relevant committees or groups, following the guidance in ICH Topic 
E3. 
10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoints and will 
include data from all trial centers. The Investigator will inform the Sponsor in advance about any 
plans to publish or present data from the trial. Any publications and presentations of the results 
(abstracts in journals or newspapers, oral presentations, etc.), either in whole or in part, by 
Investigators or their representatives will require review by the Sponsor before submission. The 
Sponsor will not suppress publication, but maintains the right to delay publication in order to 
protect intellectual property rights.
Posting of data on clinicaltrials.gov is planned and will occur 12 months after the last clinic visit 
of the final trial subject or another appropriate date to meet applicable requirements.
11
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Assassi S, del Junco D, Sutter K, et al. Clinical and genetic factors predictive of mortality in 
early systemic sclerosis. Arthritis Rheum. 2009;61:1403-11.
Balbir-Gurman A, Braun-Moscovici Y. Scleroderma – New aspects in pathogenesis and 
treatment. Best Pract Res Clin Rheumatol. 2012;26:13-24.
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Baron M, Sutton E, Hudson M, et al. The relationship of dyspnoea to function and quality of life 
in systemic sclerosis. Ann Rheum Dis. 2008;67:644-50.
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review of pirfenidone and nintedanib. N Engl J Med. 2015;372(13):1189-91.
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changes in fibrotic reticular patterns on HRCT in scleroderma lung disease treated with oral 
cyclophosphamide. Eur Radiol. 2011;21:2455-65.
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with Idiopathic Pulmonary Fibrosis. N Engl J Med. 2014;370:2083-92.
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carbon monoxide uptake in the lung. Eur Respir J. 2005;26(4):720-35.
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the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 
2006;4:295–306.
Moore OA, Goh N, Corte T, et al. Extent of disease on high-resolution computed tomography 
lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease. 
Rheumatology (Oxford). 2013;52(1):155-60.
Richeldi L, du Bois RM, Raghu G, et al. Efficacy and Safety of Nintedanib in Idiopathic 
Pulmonary Fibrosis. N Engl J Med. 2014;370:2071-82.
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.
Steen VD, Medsger TA. Severe organ involvement in systemic sclerosis with diffuse 
scleroderma. Arthritis Rheumatism. 2000;43:2437-44.
Steen VD, Medsger TA. The value of the health assessment questionnaire and special patient-
generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis 
Rheumatism. 1997;41:1984-91.
Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma 
lung disease. N Engl J Med. 2006;354:2655-66 and supplementary addenda.
Tashkin DP, Volkmann ER, Tseng CH, et al. Relationship between quantitative radiographic 
assessments of interstitial lung disease and physiological and clinical features of systemic 
sclerosis. Ann Rheum Dis. 2014;0:1-8. 
Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide 
in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, 
parallel group trial. Lancet Respir Med. 2016;4(9):708-19.
Theodore AC, Tseng CH, Li N, et al. Correlation of cough with disease activity and treatment 
with cyclophosphamide in scleroderma interstitial lung disease: findings from the Scleroderma 
Lung Study. Chest. 2012;142(3):614-21.
van den Hoogen F, Khanna D, Fransen J, et al. 2013 Classification criteria for systemic sclerosis: 
an American college of rheumatology/European league against rheumatism collaborative 
initiative. Ann Rheum Dis. 2013;72:1747–55.
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Volkmann ER, Roth M, Elashoff R, et al. Safety and Tolerability of Cyclophosphamide Versus 
Mycophenolate for Systemic Sclerosis-Related Interstitial Lung Disease [abstract]. Arthritis 
Rheumatol. 2015; 67 (suppl 10).
Wallace B, Kafaja S, Furst DE. Reliability, validity and responsiveness to change of the Saint 
George’s Respiratory Questionnaire in early diffuse cutaneous systemic sclerosis. Rheumatol 
(Oxford). 2015 Aug;54(8):1369-79.
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12
Appendices
Appendix I:
Signature Pages and Responsible Persons for the Trial
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Signature Page – Protocol Lead
Trial Title:
A 
Phase 
II, 
randomized, 
double-blind, 
placebo-controlled, parallel-group, multicenter trial 
to evaluate the efficacy and safety of abituzumab in 
subjects with systemic sclerosis-associated interstitial 
lung disease (SSc-ILD)
IND Number:
EudraCT Number:
2015-005023-11
Clinical Trial Protocol Date / 
Version:
26 July 2017/Version 5.0
Protocol Lead:
I approve the design of the clinical trial:
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Institution:
EMD Serono Research & Development Institute, Inc.
Address:
45A Middlesex Turnpike
Billerica, MA 01821 USA
Telephone number:
Fax number:
E-mail address:
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Signature Page –Coordinating Investigator
Trial Title
A 
Phase 
II, 
randomized, 
double-blind, 
placebo-controlled, parallel-group, multicenter trial to 
evaluate the efficacy and safety of abituzumab in 
subjects with systemic sclerosis-associated interstitial 
lung disease (SSc-ILD)
IND Number
EudraCT Number
2015-005023-11
Clinical Trial Protocol Date / 
Version
26 July 2017/Version 5.0
I approve the design of the clinical trial and I understand and will conduct the trial according to 
the clinical trial protocol, any approved protocol amendments, International Council for
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Coordinating Investigator for all countries, except in North America
Institution:
 
Address:
Telephone number:
Fax number:
E-mail address:
 
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Signature Page –Coordinating Investigator
Trial Title
A 
Phase 
II, 
randomized, 
double-blind, 
placebo-controlled, parallel-group, multicenter trial to 
evaluate the efficacy and safety of abituzumab in 
subjects with systemic sclerosis-associated interstitial 
lung disease (SSc-ILD)
IND Number
EudraCT Number
2015-005023-11
Clinical Trial Protocol Date / 
Version
26 July 2017/Version 5.0
I approve the design of the clinical trial and I understand and will conduct the trial according to 
the clinical trial protocol, any approved protocol amendments, International Council for
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Coordinating Investigator for sites in North America
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
 
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Signature Page – Principal Investigator
Trial Title
A 
Phase 
II, 
randomized, 
double-blind, 
placebo-controlled, parallel-group, multicenter trial to 
evaluate the efficacy and safety of abituzumab in 
subjects with systemic sclerosis-associated interstitial 
lung disease (SSc-ILD)
IND Number
EudraCT Number
2015-005023-11
Clinical Trial Protocol Date / 
Version
26 July 2017/Version 5.0
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that I 
understand and will conduct the trial according to the clinical trial protocol, any approved 
protocol amendments, International Council for Harmonisation Good Clinical Practice (Topic 
E6) and all applicable Health Authority requirements and national laws.
I also affirm that I understand that Health Authorities may require the Sponsors of clinical trials 
to obtain and supply details about ownership interests in the Sponsor or Investigational 
Medicinal Product and any other financial ties with the Sponsor. The Sponsor will use any such 
information solely for the purpose of complying with the regulatory requirements. I therefore 
agree to supply the Sponsor with any necessary information regarding ownership interest and 
financial ties including those of my spouse and dependent children, and to provide updates as 
necessary to meet Health Authority requirements.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Sponsor Responsible Persons not Named on the Cover Page
Name, academic 
degree:
Function / Title:
Institution:
EMD Serono Research and Development Institute, Inc.
Address:
45A Middlesex Turnpike
Billerica, MA 01821
USA
Telephone number:
Fax number:
E-mail address:
Name, academic 
degree:
Function / Title:
Institution:
EMD Serono Research and Development Institute, Inc.
Address:
45A Middlesex Turnpike
Billerica, MA 01821
USA
Telephone number:
Fax number:
E-mail address:
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Appendix II: Prednisone Equivalence Calculation
Medication
Equivalent (mg) to 1 mg of Prednisone
Betamethasone
0.15
Cortisone
5
Dexamethasone
0.15
Hydrocortisone
4
Prednisolone
1
Methylprednisone
0.8
Triamcinolone
0.8
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Appendix III:New York Heart Association (NYHA) Criteria
NYHA Class 1:
Cardiac disease, but without resulting limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, 
or anginal pain.
NYHA Class 2: 
Cardiac disease resulting in slight limitation of physical activity. Subjects are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain. 
NYHA Class 3: 
Cardiac disease resulting in marked limitation of physical activity. Subjects 
are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
NYHA Class 4: 
Cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be 
present even at rest. If any physical activity is undertaken, discomfort is 
increased.
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Appendix IV: Criteria for the Classification of Systemic Sclerosis
Table A1 The American College of Rheumatology/European League Against Rheumatism 
criteria for the classification of systemic sclerosis* 
Item 
Sub-item(s) 
Weight/ 
score†
Skin thickening of the fingers of both hands 
extending proximal to the metacarpophalangeal 
joints (sufficient criterion)
--
9
Skin thickening of the fingers (only count the 
higher score)
Puffy fingers
Sclerodactyly of the fingers (distal to the 
metacarpophalangeal joints but proximal to the 
proximal interphalangeal joints)
2
4
Fingertip lesions (only count the higher score)
Digital tip ulcers 
Fingertip pitting scars
2
3
Telangiectasia
--
2
Abnormal nailfold capillaries
--
2
Pulmonary arterial hypertension and/or interstitial 
lung disease (maximum score is 2)
Pulmonary arterial hypertension 
Interstitial lung disease
2
2
Raynaud’s phenomenon
--
3
SSc-related autoantibodies (anticentromere, 
anti-topoisomerase I [anti–Scl-70], anti-RNA 
polymerase III) (maximum score is 3)
Anticentromere 
Anti–topoisomerase I 
Anti–RNA polymerase III
3
SSc, systemic sclerosis. 
* These criteria are applicable to any patient considered for inclusion in a systemic sclerosis study. The criteria are 
not applicable to patients with skin thickening sparing the fingers or to patients who have a scleroderma-like 
disorder that better explains their manifestations (eg, nephrogenic sclerosing fibrosis, generalised morphea, 
eosinophilic fasciitis, scleredema diabeticorum, scleromyxedema, erythromyalgia, porphyria, lichen sclerosis, graft-
versus-host disease, diabetic cheiroarthropathy). 
† The total score is determined by adding the maximum weight (score) in each category. Patients with a total score 
of ≥9 are classified as having definite systemic sclerosis. 
Reproduced from van den Hoogen, et al (2013).
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Table A2 Definitions of items/sub-items in the American College of 
Rheumatology/European League Against Rheumatism criteria for the 
classification of systemic sclerosis
Item 
Definition
Skin thickening
Skin thickening or hardening not due to scarring after injury, trauma, 
etc.
Puffy fingers
Swollen digits - a diffuse, usually nonpitting increase in soft tissue 
mass of the digits extending beyond the normal confines of the joint 
capsule. Normal digits are tapered distally with the tissues following 
the contours of the digital bone and joint structures. Swelling of the 
digits obliterates these contours. Not due to other causes such as 
inflammatory dactylitis.
Fingertip ulcers or pitting scars
Ulcers or scars distal to or at the proximal interphalangeal joint not 
thought to be due to trauma. Digital pitting scars are depressed 
areas at digital tips as a result of ischaemia, rather than trauma or 
exogenous causes.
Telangiectasia
Telangiectasiae are visible macular dilated superficial blood vessels, 
which collapse upon pressure and fill slowly when pressure is 
released. Telangiectasiae in a scleroderma-like pattern are round 
and well demarcated and found on hands, lips, inside of the mouth, 
and/or are large mat-like telangiectasiae. Distinguishable from 
rapidly filling spider angiomas with central arteriole and from dilated 
superficial vessels.
Abnormal nailfold capillary pattern 
consistent with systemic sclerosis
Enlarged capillaries and/or capillary loss with or without pericapillary 
haemorrhages at the nailfold. May also be seen on the cuticle.
Pulmonary arterial hypertension
Pulmonary arterial hypertension diagnosed by right-sided heart 
catheterisation according to standard definitions.
Interstitial lung disease
Pulmonary fibrosis seen on high-resolution CT or chest radiography, 
most pronounced in the basilar portions of the lungs, or occurrence 
of ‘Velcro’ crackles on auscultation, not due to another cause such 
as congestive heart failure.
Raynaud’s phenomenon
Self-reported or reported by a physician, with at least a 2-phase 
colour change in finger(s) and often toe(s) consisting of pallor, 
cyanosis, and/or reactive hyperemia in response to cold exposure or 
emotion; usually one phase is pallor.
SSc-related auto antibodies
Anticentromere antibody or centromere pattern seen on antinuclear 
antibody testing, anti–topoisomerase I antibody (also known as 
anti-Scl-70 antibody), or anti-RNA polymerase III antibody. Positive 
according to local laboratory standards.
SSc, systemic sclerosis.
Reproduced from van den Hoogen, et al (2013).
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Appendix V: Protocol Amendments and List of Changes
Previous Protocol Amendments 
Table of Amendments
Amendment 
Number
Substantial
(Y/N)
Date
Region or Country
Included in the 
current document
(Y/N)
1
Y
02 Feb 2016
Global
Y
2
Y
16 May 2016
Global (except in the 
USA, Argentina, 
Australia, Israel, and 
Turkey)a
Y
3
Y
14 September 2016
Global (except in the 
USA, Argentina, 
Australia, Israel, and 
Turkey)
Y
4
Y
27 September 2016
Local (USA, 
Argentina, Australia, 
Israel, and Turkey) a
N
a
Protocol Amendment 4 is applicable or submitted only to sites in the USA, Argentina, Australia, Israel, and 
Turkey. For this reason, details of this amendment are not included in the current document. Protocol Amendment 3 
(Protocol Version 4.0) was the last applicable version in all other countries prior to the current document.
Amendment 1
Rationale
The purpose of this protocol amendment is:
! To remove the Dyspnea-12 index assessment;
! To decrease the frequency of select quality of life assessments;
! To specify the required visits following discontinuation of Investigational Medicinal Product 
(IMP);
! To update the number of planned sites;
! To include criteria for the classification of systemic sclerosis to the protocol appendices;
! To include minor corrections and clarifications to the clinical trial protocol.
The changes to be made to the clinical trial protocol and the rationale for the changes are 
described below.
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Major Scientific Changes
Removal of the Dyspnea-12 Index
The Dyspnea-12 index has been removed because the symptom of dyspnea is considered to be 
adequately assessed through the Mahler index as well as components of the St. George 
Respiratory Questionnaire (SGRQ).  The Mahler index was used in the scleroderma lung study 
(SLS I) and was associated with a significant difference between active drug 
(cyclophosphamide) and placebo. The SGRQ has been used to reveal treatment effects in 
multiple pulmonary diseases, including restrictive disease such as idiopathic pulmonary fibrosis 
(IPF).
Decrease in Frequency of Select Quality of Life Assessments
The frequency of assessment for the Scleroderma Health Assessment Questionnaire (SHAQ), 
Leicester Cough Index, Patient Global Assessment, EQ-5D, and Physician Global Assessment is 
decreased from approximately every 12 weeks to approximately every 24 weeks. This reduction 
maintains the ability of the trial to meet its objectives, while also affording a lower burden on 
subjects and trial site staff.
Required Visits Following Discontinuation of IMP 
The Sponsor recognizes that assessment of all randomized subjects through the complete trial 
period is important for interpretation of the trial results and treatment responses. To meet this 
objective, the protocol will require all subjects to complete the trial visits in which the efficacy 
and safety assessments are done. These assessments include the pulmonary function tests, 
high-resolution computed tomography (HRCT), and subject questionnaires as well as the safety 
laboratories and assessments of adverse events. In order to promote subject retention for 
completion of the trial visits even after discontinuation of IMP, subjects will not be required to 
return to the clinic for trial visits every 4 weeks (as done for those continuing to receive IMP). 
All of the trial visits are available for the subject to attend, however, at the Investigator’s 
discretion if follow-up every 4 weeks is considered appropriate.
Update of number of planned sites
The number of planned sites is increased from 50 to 60 sites globally to reflect the current 
enrollment strategy.
Addition of criteria for classification of systemic sclerosis
Detailed criteria for the classification of systemic sclerosis are added to Appendix IV for use by 
the Investigators.
Administrative and Editorial Changes
The Schedule of Assessments has been revised to present the Week 104 and Early Termination 
visits in separate columns to facilitate data collection for subjects who discontinue IMP; to 
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clarify the rich pharmacokinetic samples are collected at Weeks 8 and 16; and to make minor 
editorial changes for clarity.
Analysis of the diffusion capacity of the lung for carbon monoxide (DLCO) was not always 
noted to refer to the DLCO % predicted.  This has been clarified.  
Notation is added that the method of performance of the pulmonary function tests will be 
specified in the manual of procedures.
Text has been revised to clarify the last IMP administration will occur at the Week 100 visit.
Text has been updated to remove area under the concentration-time curve (AUC) from the 
planned pharmacokinetic parameters and to indicate further parameters will be derived by 
population pharmacokinetics.
Standard language describing Clinical Data Interchange Standards Consortium (CDISC) 
standards has been added.
The clinical team has been changed from 
.
The address and telephone number for 
.
List of Changes
Changes to the clinical trial protocol text are presented in the table below. Additions and 
amended text are shown in bold. If the original clinical trial protocol text was already bold, 
changes are shown in bold and underlined, deletions are marked using strike-through.
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Comparison with Clinical Trial Protocol Version 1.0, 04 Dec 2015
Change
Section
Page
Previous Wording
New Wording
Update of date 
and version 
number
Throughout
04 Dec 2015/Version 1.0
2 Feb 2016/Version 2.0
Update 
organization name
List of Abbreviations
9
ICH
International Conference on Harmonization
ICH
International Conference on Council for
Harmonization
Update number of 
planned sites
Synopsis, Trial 
Centers/countries
11
This trial will be conducted at approximately 
50 sites globally, including, but not limited to, North
America and the European Union.
This trial will be conducted at approximately 
5060 sites globally, including, but not limited to, 
North America and the European Union.
Clarify last dose of 
IMP
Synopsis, 
Methodology
13
Approximately 175 subjects will be randomized in a 
2:2:1 ratio to receive abituzumab 1500 mg, 
placebo, or abituzumab 500 mg, respectively, given 
as an intravenous infusion over 1 hour every 4 
weeks for 104 weeks.
Approximately 175 subjects will be randomized in a 
2:2:1 ratio to receive abituzumab 1500 mg, 
placebo, or abituzumab 500 mg, respectively, given 
as an intravenous infusion over 1 hour every 4 
weeks for 104 weeks with the last IMP 
administration at the Week 100 visit.
Clarification of 
DLCO 
measurement
Synopsis, 
Methodology
13
! Relative decrease from baseline in FVC % 
predicted ≥5% to <10% AND relative decrease 
from baseline in the diffusion capacity of the lung 
for carbon monoxide (DLCO) ≥15%.
! Relative decrease from baseline in FVC % 
predicted ≥5% to <10% AND relative decrease 
from baseline in the diffusion capacity of the lung 
for carbon monoxide (DLCO) % predicted ≥15%.
Specify required 
visits after IMP 
discontinuation
Synopsis, 
Methodology
13-14
Subjects who discontinue IMP for any reason will 
complete the early termination visit. Even if IMP is 
discontinued, subjects will complete the remainder 
of the scheduled trial visits, including the Safety 
Follow-up Visits, unless the subject is withdrawn 
from the trial. All subjects will be followed up by the 
site for survival from the subject’s last trial visit until 
death or the end of the trial.
If a subject discontinues IMP, then the subject 
should complete the early termination visit and 
then the remaining scheduled visits. At a 
minimum, the subject is expected to complete 
the trial visits at Weeks 12, 24, 36, 52, 64, 76, 88, 
and 104, as well as the Safety Follow-up period 
Week 12 visit. Subjects with discontinued IMP 
can come to the other scheduled visits during 
the trial period according to the Investigator's 
judgment. 
Subjects who withdraw from the treatment 
period would have an early termination visit 
followed by entrance into the Safety Follow-up 
Period. 
Subjects who withdraw from the trial (eg, 
withdraw consent, lost to follow up, or death) 
would not have any additional study visits.
Subjects who discontinue IMP for any reason will 
complete the early termination visit. Even if IMP is 
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Change
Section
Page
Previous Wording
New Wording
discontinued, subjects will complete the remainder 
of the scheduled trial visits, including the Safety 
Follow-up Visits, unless the subject is withdrawn 
from the trial.
All subjects will be followed up by the site for 
survival from the subject’s last trial visit until death 
or the end of the trial.
Remove 
Dyspnea-12 index
Synopsis, Quality of 
life endpoints
15-16
! Absolute change from baseline for each of the 
following HRQoL questionnaires up to Week 
104:
• Leicester Cough Index
• SGRQ
• Physician’s Global Assessment
• Patient’s Global Assessment
• Dyspnea-12
• Scleroderma Health Assessment 
Questionnaire (SHAQ)
• EQ-5D.
! Absolute change from baseline for each of the 
following HRQoL questionnaires up to Week 
104:
• Leicester Cough Index
• SGRQ
• Physician’s Global Assessment
• Patient’s Global Assessment
• Dyspnea-12
• Scleroderma Health Assessment 
Questionnaire (SHAQ)
• EQ-5D.
Update planned 
pharmacokinetic 
parameters
Synopsis, 
Pharmacokinetic 
endpoints
16
Abituzumab concentrations and PK parameters 
(eg, AUC, Cmax, and Cmin).
Abituzumab concentrations and PK parameters 
(eg, AUC, Cmax, and Cmin).
Clarify last dose of 
IMP
Synopsis, 
Investigational 
medicinal product: 
dose/mode of 
administration/dosing 
schedule
17
Abituzumab 1500 or 500 mg will be administered 
as an intravenous infusion over 1 hour once every 
4 weeks up to Week 104 (2 years) on top of 
background therapy.
Abituzumab 1500 or 500 mg will be administered 
as an intravenous infusion over 1 hour once every 
4 weeks with the last IMP administration at the 
Week 100 visit up to Week 104 (2 years) on top of 
background therapy.
Clarify last dose of 
IMP
Synopsis, Reference 
therapy: dose/mode 
of administration/
dosing schedule
17
Placebo (citrate buffered saline) will be 
administered as an intravenous infusion over 1 
hour once every 4 weeks up to Week 104 (2 years) 
on top of background therapy.
Placebo (citrate buffered saline) will be 
administered as an intravenous infusion over 1 
hour once every 4 weeks with the last 
administration at the Week 100 visitup to Week 
104 (2 years) on top of background therapy.
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Remove Dyspnea-
12 index; 
Decrease 
frequency of select 
quality of life 
assessments; 
minor clarifications
Schedules of 
Assessments
19-23
Refer to Amendment 1 - Tables 1 and 2, below.
Refer to Amendment 1 - Tables 1 and 2, below.
Update number of 
planned sites
Section 2
24
The trial will be conducted at approximately 50 sites 
globally, including, but not limited to, North America 
and the European Union (EU).  Approximately 15 
sites are planned in the USA.
The trial will be conducted at approximately 50 60
sites globally, including, but not limited to, North 
America and the European Union (EU).  
Approximately 15 sites are planned in the USA.
Update 
organization name
Section 2
24
The Coordinating Investigators (for all countries, 
except in North America: 
, 
; for sites in 
: 
 
, represent all 
Investigators for decisions and discussions 
regarding this trial, consistent with the International 
Conference on Harmonisation (ICH) Topic E6 Good 
Clinical Practice (GCP; hereafter referred to as ICH 
GCP). The Coordinating Investigators will provide 
expert medical input and advice relating to trial 
design and execution and are responsible for the 
review and signoff of the clinical trial report.
The Coordinating Investigators (for all countries, 
except in North America:
 
; for sites in 
: 
 
, represent all 
Investigators for decisions and discussions 
regarding this trial, consistent with the International 
Conference onCouncil for Harmonisation (ICH) 
Topic E6 Good Clinical Practice (GCP; hereafter 
referred to as ICH GCP). The Coordinating 
Investigators will provide expert medical input and 
advice relating to trial design and execution and are 
responsible for the review and signoff of the clinical 
trial report.
Clarify last dose of 
IMP
Section 5.1
30
Approximately 175 subjects will be randomized in a 
2:2:1 ratio to receive abituzumab 1500 mg, 
placebo, or abituzumab 500 mg, respectively, given 
by intravenous infusion over 1 hour every 4 weeks 
for 104 weeks.
Approximately 175 subjects will be randomized in a 
2:2:1 ratio to receive abituzumab 1500 mg, 
placebo, or abituzumab 500 mg, respectively, given 
by intravenous infusion over 1 hour every 4 weeks 
with the last IMP administration at the Week 100 
visitfor 104 weeks.
Specify required 
visits after IMP 
discontinuation
Section 5.1
31
Subjects who meet the criteria for clinically 
meaningful progression of SSc-ILD (see Section 
6.5.5) during the Double-blind Treatment Period or 
Follow up Period should have a change in 
background therapy. Subjects taking less than the 
maximal specified dose of mycophenolate (3 g/day 
MMF or 2160 mg/day MPS) can have the 
mycophenolate dose increased while IMP is 
continued. Subjects taking the maximal specified 
Subjects who meet the criteria for clinically 
meaningful progression of SSc-ILD (see Section 
6.5.5) during the Double-blind Treatment Period or 
Follow up Period should have a change in 
background therapy. Subjects taking less than the 
maximal specified dose of mycophenolate (3 g/day 
MMF or 2160 mg/day MPS) can have the 
mycophenolate dose increased while IMP is 
continued. Subjects taking the maximal specified 
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dose of mycophenolate who have clinically 
meaningful progression should have the IMP 
discontinued and be treated according to the local 
standard of care. If an immunosuppressant (such 
as cyclophosphamide [oral or intravenous]) is 
initiated, then mycophenolate must be 
discontinued. Subjects who discontinue IMP for any 
reason should complete the early termination visit. 
Even if IMP is discontinued, subjects will complete 
the remainder of the scheduled trial visits, including 
the Safety Follow-up Visits, unless the subject is 
withdrawn from the trial. Regardless of treatment 
completion or not, all subjects will be followed up by 
site for survival from the subject’s last visit on the 
trial until death or end of the trial. Subjects who 
have clinically meaningful progression of SSc other 
than ILD should be treated according to the local 
standard of care.
dose of mycophenolate who have clinically 
meaningful progression should have the IMP 
discontinued and be treated according to the local 
standard of care. If an immunosuppressant (such 
as cyclophosphamide [oral or intravenous]) is 
initiated, then mycophenolate must be 
discontinued. Subjects who discontinue IMP for any 
reason should complete the early termination visit. 
Even if IMP is discontinued, subjects will complete 
the remainder of the scheduled trial visits, including 
the Safety Follow-up Visits, unless the subject is 
withdrawn from the trial. 
If a subject discontinues IMP, then the subject 
should complete the early termination visit and 
then the remaining scheduled visits. At a 
minimum, the subject is expected to complete 
the trial visits at Weeks 12, 24, 36, 52, 64, 76, 88, 
and 104, as well as the Safety Follow-up period 
Week 12 visit.  Subjects with discontinued IMP 
can come to the other scheduled visits during 
the trial period according to the Investigator's 
judgment. 
Subjects who withdraw from the treatment 
period would have an early termination visit 
followed by entrance into the Safety Follow-up 
Period. 
Subjects who withdraw from the trial (eg, 
withdraw consent, lost to follow-up, or death; 
see Section 5.5.2) would not have any additional 
trial visits.
Regardless of treatment completion or not, all 
subjects will be followed up by site for survival from 
the subject’s last visit on the trial until death or end 
of the trial. Subjects who have clinically meaningful 
progression of SSc other than ILD should be 
treated according to the local standard of care.
Indicate pulmonary 
function tests will 
be described 
separately
Section 5.2.4
35
Not applicable.
Pulmonary function tests will be performed 
according to the American Thoracic Society and 
European Respiratory Society 
recommendations. Detailed procedures for 
performing pulmonary function assessments 
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are included in a separate manual of 
procedures.
Remove 
Dyspnea-12 index 
and clarify 
endpoints
Section 5.2.5
35-36
The measures endorsed by the OMERACT working 
group as the ‘inner core’ measures for ILD (Khanna 
2015) include the following: Leicester Cough Index, 
Patient’s Global Assessment, Medical Outcomes 
Study Short Form (SF-36), Medical Research 
Council chronic dyspnea scale, Dyspnea-12, and 
SGRQ, as well as ‘functional status’ (this will be 
assessed by the Scleroderma Health Assessment 
Questionnaire [SHAQ]), overall ILD on HRCT, FVC 
% predicted, and all-cause mortality. For this trial, 
the SF-36 is not considered necessary because the 
other measures are considered adequate to assess 
the SSc disease-specific manifestations of this 
population, and thus SF-36 is not included in this 
trial. The assessments in this trial that are not part 
of the inner core include the Mahler index and the 
Physician’s Global Assessment. The Mahler 
Dyspnea Index is advised to be included as this has 
been shown in the SLS I trial to show a statistically 
significant difference between the 
cyclophosphamide and placebo groups (p <0.001). 
The Physician’s Global Assessment is done rapidly 
via a visual analogue scale (VAS) and is standard 
in many trials for overall assessment of subjects.
The measures endorsed by the OMERACT working 
group as the ‘inner core’ measures for ILD (Khanna 
2015) include and included in this trial are the 
following: Leicester Cough Index, Patient’s Global 
Assessment, Medical Outcomes Study Short Form 
(SF-36), Medical Research Council chronic 
dyspnea scale, Dyspnea-12, and SGRQ, as well as 
‘functional status’ (this will be assessed by the 
Scleroderma Health Assessment Questionnaire 
[SHAQ]), overall ILD on HRCT, FVC % predicted, 
and all-cause mortality. For this trial, the SF-36 is 
not considered necessary because the other 
measures are considered adequate to assess the 
SSc disease-specific manifestations of this 
population, and thus SF-36 is not included in this 
trial. The assessments in this trial that are not part 
of the inner core include the Mahler index and the 
Physician’s Global Assessment. The Mahler 
Dyspnea Index is advised to be included as this has 
been shown in the SLS I trial to show a statistically 
significant difference between the 
cyclophosphamide and placebo groups (p <0.001). 
The Physician’s Global Assessment is done rapidly 
via a visual analogue scale (VAS) and is standard 
in many trials for overall assessment of subjects.
Remove 
Dyspnea-12 index
Section 5.2.5
36
As dyspnea is a central feature of SSc-ILD and is 
an independent predictor of function and HRQoL, it 
will be assessed using 3 indices: the Mahler index, 
the Dyspnea-12, and the SGRQ (Baron 2008). The 
Mahler Transition Dyspnea Index (TDI) fulfills 
OMERACT criteria for feasibility, reliability, and 
validity, and in moderate ILD, subject changes in 
Mahler TDI score were observed (Khanna 2009). 
The TDI is sensitive to change. The Baseline 
Dyspnea Index (BDI)-TDI measures changes in 
dyspnea severity from the baseline as established 
by the BDI. The computerized version appears to 
have eliminated earlier concerns regarding the role 
of the interviewer in influencing responses.
As dyspnea is a central feature of SSc-ILD and is 
an independent predictor of function and HRQoL, it 
will be assessed using 23 indices: the Mahler index, 
the Dyspnea-12, and the SGRQ (Baron 2008). The 
Mahler Transition Dyspnea Index (TDI) fulfills 
OMERACT criteria for feasibility, reliability, and 
validity, and in moderate ILD, subject changes in 
Mahler TDI score were observed (Khanna 2009). 
The TDI is sensitive to change. The Baseline 
Dyspnea Index (BDI)-TDI measures changes in 
dyspnea severity from the baseline as established 
by the BDI. The computerized version appears to 
have eliminated earlier concerns regarding the role 
of the interviewer in influencing responses.
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Dyspnea-12 index
Section 5.2.5
36
Dypspnea-12 has been found to be a valid and 
reliable measure of dyspnea in patients with ILD 
(Yorke 2011). The SGRQ has also been found to 
be useful in assessing patients with SSc-ILD 
(Beretta 2007, Wallace 2015).
Dypspnea-12 has been found to be a valid and 
reliable measure of dyspnea in patients with ILD 
(Yorke 2011). The SGRQ has also been found to 
be useful in assessing patients with SSc-ILD 
(Beretta 2007, Wallace 2015).
Add reference to 
classification 
criteria
Section 5.3.1
38
2. Subjects fulfilling the 2013 ACR/European 
League Against Rheumatism criteria for 
classification of SSc.
2. Subjects fulfilling the 2013 ACR/European 
League Against Rheumatism criteria for 
classification of SSc (van den Hoogen 2013; 
see Appendix IV).
Specify required 
visits after IMP 
discontinuation
Section 5.5.1
42
If subjects are withdrawn from IMP, they will be 
expected to complete an early termination visit 
followed by continuation of all scheduled 
assessments through the end of the trial (ie, 
including through the Safety Follow-up Period). It is 
important for site investigators to retain each 
subject through the end of the trial for prevention of 
missing data. Systematic and consistent attempts 
are needed to contact subjects who fail to actively 
maintain contact with the site Investigator. The 
nature, method, and frequency of such contact 
should be recorded in the source documents, 
including number of telephone calls, day of week, 
and time of such calls and source of information.
If a subject discontinues IMP, then the subject 
should complete the early termination visit and 
then the remaining scheduled visits. At a 
minimum, the subject is expected to complete 
the trial visits at Weeks 12, 24, 36, 52, 64, 76, 88, 
and 104, as well as the Safety Follow-up period 
Week 12 visit. Subjects with discontinued IMP 
can come to the other scheduled visits during 
the trial period according to the Investigator's 
judgment. 
Subjects who withdraw from the treatment 
period would have an early termination visit 
followed by entrance into the Safety Follow-up 
Period. 
Subjects who withdraw from the trial (eg, 
withdraw consent, lost to follow-up, or death; 
see Section 5.5.2) would not have any  
additional trial visits.If subjects are withdrawn 
from IMP, they will be expected to complete an 
early termination visit followed by continuation of all 
scheduled assessments through the end of the trial 
(ie, including through the Safety Follow-up Period).
It is important for site investigators to retain each 
subject through the end of the trial for prevention of 
missing data. Systematic and consistent attempts 
are needed to contact subjects who fail to actively 
maintain contact with the site Investigator. The 
nature, method, and frequency of such contact 
should be recorded in the source documents, 
including number of telephone calls, day of week, 
and time of such calls and source of information.
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Clarify last dose of 
IMP
Section 6.2
44
In the Double-blind Treatment Period, subjects will 
be randomized in a 2:2:1 ratio to receive one of the 
following treatments: abituzumab 1500 mg, 
placebo, or abituzumab 500 mg, respectively. 
Treatment will be given as an intravenous infusion 
over approximately 1 hour every 4 weeks for 104 
weeks.  The infusion time should not be less than 1 
hour.
In the Double-blind Treatment Period, subjects will 
be randomized in a 2:2:1 ratio to receive one of the 
following treatments: abituzumab 1500 mg, 
placebo, or abituzumab 500 mg, respectively. 
Treatment will be given as an intravenous infusion 
over approximately 1 hour every 4 weeks with the 
last IMP administration at the Week 100 visitfor 
104 weeks.  The infusion time should not be less 
than 1 hour.
Clarification of 
DLCO 
measurement
Section 6.5.5 
46
1.
SSc-ILD: one of the following (in the absence of 
causative intercurrent illness) on at least 
2 occasions within approximately 4 weeks (per 
OMERACT criteria):
! Relative decrease from baseline in FVC % 
predicted ≥10%;
! Relative decrease from baseline in FVC % 
predicted of ≥5% to <10% and relative decrease 
from baseline in DLCO ≥15%.
1.
SSc-ILD: one of the following (in the absence of 
causative intercurrent illness) on at least 
2 occasions within approximately 4 weeks (per 
OMERACT criteria):
! Relative decrease from baseline in FVC % 
predicted ≥10%;
! Relative decrease from baseline in FVC % 
predicted of ≥5% to <10% and relative decrease 
from baseline in DLCO % predicted ≥15%.
Specify required 
visits after IMP 
discontinuation
Section 6.5.5
47
Even if IMP is discontinued, subjects will complete 
the remainder of the scheduled trial visits, including 
the Safety Follow-up Visits, unless the subject is 
withdrawn from the trial. All subjects will be 
followed up by the site for survival from the last visit 
on trial until death or end of the trial. New onset or 
worsening of manifestations of scleroderma that 
are not captured by the pulmonary function tests, 
mRSS, or digital ulcer score, should be reported as 
AEs. On the eCRF AE page, such events should 
be marked as ‘yes’ in response to the question “Is 
this a manifestation of worsening scleroderma?”.
If a subject discontinues IMP, then the subject 
should complete the early termination visit and 
then the remaining scheduled visits (refer to 
Table 1 and Table 2)Even if IMP is discontinued, 
subjects will complete the remainder of the 
scheduled trial visits, including the Safety Follow-
up Visits, unless the subject is withdrawn from the 
trial. All subjects will be followed up by the site for 
survival from the last visit on trial until death or end 
of the trial. New onset or worsening of 
manifestations of scleroderma that are not 
captured by the pulmonary function tests, mRSS, 
or digital ulcer score, should be reported as AEs. 
On the eCRF AE page, such events should be 
marked as ‘yes’ in response to the question “Is this 
a manifestation of worsening scleroderma?”.
Clarify last dose of 
IMP
Section 7.1.2
51
All subjects will return to the trial center on Days 1, 
15, and 29, then every 4 weeks through Week 104. 
Visit windows of ∀3 days through Week 52 and ∀5 
days for Weeks 56 through 104 are permitted. 
Beginning on Day 1, subjects will receive their 
assigned dose of IMP as an intravenous infusion
All subjects will return to the trial center on Days 1, 
15, and 29, then every 4 weeks through Week 104. 
Visit windows of ∀3 days through Week 52 and ∀5 
days for Weeks 56 through 104 are permitted. 
Beginning on Day 1, subjects will receive their 
assigned dose of IMP as an intravenous infusion 
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every 4 weeks up to Week 104. Efficacy, safety, 
HRQoL, PK, and 
 assessments will be 
performed as described in Table 1 and Table 2.
every 4 weeks with the last IMP administration at 
the Week 100 visit up to Week 104. Efficacy, 
safety, HRQoL, PK, and 
 assessments 
will be performed as described in Table 1 and 
Table 2.
Minor clarification 
of text
Specify required 
visits after IMP 
discontinuation
Section 7.1.3
51
Subjects who complete the 104 weeks of treatment 
will return to the trial center 4 and 12 weeks (∀5 
days) after the Week 104 visit for the Safety Follow 
up Visits.
Subjects who are withdrawn from IMP should 
complete the early termination visit. Unless the 
subject is withdrawn from the trial, subjects 
withdrawn from IMP should also be followed 
through the remainder of the scheduled trial visits, 
including the Safety Follow-up Visits.
Subjects who complete the 104-weeks of treatment 
period will return to the trial center 4 and 12 weeks 
(∀5 days) after the Week 104 visit for the Safety 
Follow up Visits.
Subjects who are withdrawn from IMP should 
complete the early termination visit as soon as 
possible, but within 2 weeks of IMP 
discontinuation, and then. Unless the subject is 
withdrawn from the trial, subjects withdrawn from 
IMP should also be followed through the remainder 
of the scheduled trial visits, including the Safety 
Follow-up Visits. the remaining scheduled visits. 
At a minimum, the subject is expected to 
complete the trial visits at Weeks 12, 24, 36, 52, 
64, 76, 88, and 104, as well as the Safety Follow-
up period Week 12 visit. Subjects with 
discontinued IMP can come to the other 
scheduled visits during the trial period 
according to the Investigator's judgment. 
Subjects who withdraw from the treatment 
period would have an early termination visit 
followed by entrance into the Safety Follow-up 
Period. 
Subjects who withdraw from the trial (eg, 
withdraw consent, lost to follow-up, or death; 
see Section 5.5.2) would not have any 
additional trial visits.
Minor text revision 
for clarity
Section 7.3
52
Efficacy assessments include evaluation of lung 
function using spirometry (FVC, DLCO, and TLC) 
and lung abnormalities on HRCT. Assessments will 
be performed as described in Table 1 and Table 2.
Efficacy assessments include evaluation of lung 
function using spirometry (FVC, DLCO, and TLC) 
and lung abnormalities on HRCT. Assessments will 
be performed as described in Table 1 and Table 2.
Remove 
Dyspnea-12 index
Section 8.3.4
64
!
Absolute change from baseline for each of the 
following HRQoL questionnaires up to Week 
104:
• Leicester Cough Index
!
Absolute change from baseline for each of the 
following HRQoL questionnaires up to Week 
104:
• Leicester Cough Index
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• SGRQ
• Physician’s Global Assessment
• Patient’s Global Assessment
• Dyspnea-12
• Scleroderma Health Assessment 
Questionnaire (SHAQ)
• EQ-5D.
• SGRQ
• Physician’s Global Assessment
• Patient’s Global Assessment
• Dyspnea-12
• Scleroderma Health Assessment 
Questionnaire (SHAQ)
• EQ-5D.
Update planned 
pharmacokinetic 
parameters
Section 8.3.5
64
Pharmacokinetic endpoints include the following:
!
Abituzumab concentrations;
!
PK parameters (eg, AUC, Cmax, and Cmin). 
Pharmacokinetic endpoints include the following:
!
Abituzumab concentrations;
!
PK parameters (eg, AUC, Cmax, and Cmin). 
Further PK parameters will be derived by 
population PK.
Add standard text 
for CDISC 
standards
Section 10.1
73
Not applicable.
The Clinical Data Interchange Standards 
Consortium (CDISC) Study Data Tabulation 
Model (SDTM) standards, required by the FDA 
for the submission of trial data, are followed by 
Merck Serono. Merck Serono General Data 
Standards and, if applicable, Therapeutic Area 
Data Standards, as well as Merck Serono SDTM 
Guidelines, will be used in all clinical trials as 
predefined in the applicable Merck Serono SOP, 
Working Instructions, and Guidelines, to create 
the Case Report Forms (CRFs), the SDTM 
delivery package (SDTM domains, define.xml, 
Reviewer’s Guide, SDTM annotated CRF), and 
the operational database; any exemptions need 
to be discussed and decided by the Project 
Team. In addition it is intended to convert non-
SDTM trial data from legacy trials, and possibly 
ongoing trials not conducted by Merck Serono, 
into an FDA submission compliant CDISC-
SDTM format. Individual trial data and 
documents will be migrated into the ICMS 
(Integrated CDISC-based Data Model and 
System, a cross-functional platform designed to 
maintain the data of all current and future 
projects). These measures will facilitate the 
integration of data across multiple trials and 
projects so that more comprehensive data 
pools can be generated. If significant non-SDTM 
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format data already exists for a drug, trials may 
not be converted to, or delivered in, SDTM 
format, if decided by the Project Team and 
agreed by Senior Management. The Program 
Data Manager ensures that data standards are 
harmonized across all trials within this 
development program.
Add reference
Section 11
78
Not applicable
van den Hoogen F, Khanna D, Fransen J, et al. 
2013 Classification criteria for systemic 
sclerosis: an American college of 
rheumatology/European league against 
rheumatism collaborative initiative. Ann Rheum 
Dis. 2013;72:1747–55.
Remove unneeded 
reference
Section 11
78
Yorke J, Swigris J, Russell AM, et al. Dyspnea-12 
Is a Valid and Reliable Measure of Breathlessness 
in Patients With Interstitial Lung Disease. Chest. 
2011;139(1):159-64.
Yorke J, Swigris J, Russell AM, et al. Dyspnea-12 
Is a Valid and Reliable Measure of Breathlessness 
in Patients With Interstitial Lung Disease. Chest. 
2011;139(1):159-64.
Update 
coordinating 
investigator 
contact information
Signature page –
Coordinating 
Investigator
82
 
Update clinical 
team lead contact 
information
Sponsor 
Responsible Persons
86
Merck KGaA
Frankfurter Str. 250
Postcode: F135/302
64293 Darmstadt, Germany
 
 
Merck KGaAEMD Serono Research and 
Development Institute, Inc.
Frankfurter Str. 250 
Postcode: F135/302
64293 Darmstadt, Germany
45A Middlesex Turnpike
Billerica, MA 01821
USA
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Addition of criteria 
for classification of 
systemic sclerosis
Appendix IV
NA
NA
See copies of Tables A1 and A2, given below.
Amendment 1 - Table 1
Schedule of Assessments – Screening through Week 52
Trial Period
Screening
Weeks During Double-blind Treatment Period (Visit Window ∀3 days)
Week
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
Trial Day
-28 to -1
1
15
29
57
85
113
141
169
197
225
253
281
309
337
365
Informed consent
X
Inclusion/exclusion criteria
X
Xa
Pharmacokinetic informed consent (Rich 
PK sampling only)
X
Demographic data
X
SSc-ILD and other medical history, 
medications, surgery/procedures
X
HRCT
X
X
X
12-lead ECG (locally read)
X
X
X
Tuberculosis assessment
X
Serum virology (HIV, HCV, HBV)
X
Serum pregnancy test c
X
PT, aPTT, TSH, and NT pro-BNP
X
Urine pregnancy test c,d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
Xe
X
Xe
Xe
Xe
Xe
X
Xe
Xe
Xe
Xe
Xe
Xe
X
Vital signs, weight, height f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Questionnaires Mahler BDI/TDI and SGRQ 
X
X
X
X
X
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Screening
Weeks During Double-blind Treatment Period (Visit Window ∀3 days)
Week
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
Trial Day
-28 to -1
1
15
29
57
85
113
141
169
197
225
253
281
309
337
365
g
Patient’s Global Assessment, Leicester 
Cough Index, SHAQ, EQ-5D, and 
Physician’s Global Assessment g
X
X
X
Randomization
X
IMP administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sampling h
X
X
X
X
Rich PK sampling i
X
X
X
X
X
Routine hematology, clinical chemistry, 
urinalysis dipstick j
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary function tests (FVC, TLC) with 
DLCO k
X
X
X
X
X
X
mRSS
X
X
X
X
X
Digital ulcer counts l
X
X
X
X
X
Serum for ADA
X
X
X
Sample for autoantibodies
X
X
X
Concomitant medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA = antidrug antibodies; AE = adverse event; aPTT = activated partial thromboplastin time; BDI = Baseline Dyspnea Index; DLCO = diffusion capacity of the 
lung for carbon monoxide; ECG = electrocardiogram; FVC = forced vital capacity; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; HRCT = high-resolution computed tomography; IMP = investigational medicinal product; mRSS = modified Rodnan skin score; 
PK = pharmacokinetic; PT = prothrombin time; SGRQ = St. George Respiratory Questionnaire; SHAQ = Scleroderma Health Assessment Questionnaire; 
SSc-ILC = systemic sclerosis-associated interstitial lung disease; TDI = Transition Dyspnea Index; TLC = total lung capacity; TSH = thyroid-stimulating hormone; 
VAS = visual analog scale.
a
Subject eligibility (based on screening assessments of the inclusion and exclusion criteria) must be checked again on Day 1 prior to randomization.
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c
For women of childbearing potential or who are postmenopausal for less than 2 years. At Day 1, if the urine test is negative, the subject can be randomized and 
receive the first dose of IMP.
d
Performed locally per local constraints and regulations.
e
Focused physical examination only, according to standard of care.
f
Vital signs include 10-minute seated arterial blood pressure, pulse rate, and body temperature. Height will be measured at Day 1 only. Weight will be measured 
at Weeks 0, 24, 52, 76, and 104. Body weight will be measured with a balance beam scale, if possible.
g
Questionnaires should be completed before any other procedures are performed. Questionnaires should be performed in the following order: Patient’s Global 
Assessment, SHAQ, Mahler BDI (at Day 1) followed by Mahler TDI at the subsequent visits, St. George Respiratory Questionnaire SGRQ, Dyspnea-12,
Leicester Cough Index, and EQ-5D. The Physician’s Global Assessment (VAS) may be performed after other assessments at the visit are completed.
h
For all subjects, samples will be collected predose and immediately after the end of IMP infusion at Weeks 0 (Day 1), 4, 8, and 16.
i
For subjects who have provided PK informed consent for the rich PK sampling, additional samples will be collected on Days 3, 5, 15, and 22 (in addition to 
the pre- and postdose samples at Weeks 0, 4, 8, and 16; see footnote h).
j
See Section 7.4.3 for list of routine laboratory assessments. Urine protein:creatinine ratio to be performed if dipstick urinalysis reveals at least 3+ protein. 
Microscopic urinalysis to be performed if blood is present.
k
The TLC should be performed at Weeks 0, 24, 52, 76, and 104. The DLCO measurements will be corrected for hemoglobin level, and spirometry assessments
will be centrally adjudicated.
l
Digital ulcers are those distal to the metacarpal phalangeal joints. New or worsening digital ulcers, or at any other site on the body, will be captured as AEs.
n
Adverse events should also be assessed for occurrence during the periods between trial visits.
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Amendment 1 - Table 2
Schedule of Assessments – Week 56 through Safety Follow-up
Trial Period
Weeks During Double-blind Treatment Period (Visit Window ∀5 days)
Safety 
Follow-up 
Number 
weeks post 
last dose 
(∀5 days)
Survival 
Follow-
up Post 
Last Trial 
Visit
Week
56
60
64
68
72
76
80
84
88
92
96
100
104/
ETa
ETa
4
12
Every 12 
Weeks
Trial Day
393
421
449
477
505
533
561
589
617
645
673
701
729
HRCT
X
X
12-lead ECG (locally read)
X
X
X
X
Urine pregnancy test b,c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
Xd
Xd
Xd
Xd
Xd
X
Xd
Xd
Xd
Xd
Xd
Xd
X
X
Xd
X
Vital signs, weight e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Questionnaires Mahler TDI and 
SGRQ f
X
X
X
X
X
X
Patient’s Global Assessment, 
Leicester Cough Index, SHAQ, 
EQ-5D, and Physician’s Global 
Assessment f
X
X
X
IMP administration
X
X
X
X
X
X
X
X
X
X
X
X
Routine hematology, clinical 
chemistry, urinalysis g
X
X
X
X
X
X
X
X
X
X
Pulmonary function tests (FVC, 
TLC) with DLCO h
X
X
X
X
X
X
mRSS
X
X
X
X
X
X
Digital ulcer counts i
X
X
X
X
X
X
Serum for ADA
X
X
X
X
X
Sample for autoantibodies
X
X
Concomitant 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Trial Period
Weeks During Double-blind Treatment Period (Visit Window ∀5 days)
Safety 
Follow-up 
Number 
weeks post 
last dose 
(∀5 days)
Survival 
Follow-
up Post 
Last Trial 
Visit
Week
56
60
64
68
72
76
80
84
88
92
96
100
104/
ETa
ETa
4
12
Every 12 
Weeks
Trial Day
393
421
449
477
505
533
561
589
617
645
673
701
729
medications/procedures
Adverse events j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital status k
X
ADA = antidrug antibodies; AE = adverse event; BDI = Baseline Dyspnea Index; DLCO = diffusion capacity of the lung for carbon monoxide; ECG = 
electrocardiogram; ET = early termination; FVC = forced vital capacity; HRCT = high resolution computed tomography; IMP = investigational medicinal product; 
mRSS = modified Rodnan skin score; SGRQ = St. George Respiratory Questionnaire; SHAQ = Scleroderma Health Assessment Questionnaire; TDI = 
Transition Dyspnea Index; TLC = total lung capacity; VAS = visual analog scale.
a
Subjects who discontinue IMP for any reason should complete the ET visit as soon as possible, but within 2 weeks of IMP discontinuation,. Unless the 
subject is withdrawn from the trial, subjects should also complete and then the remainder remaining of the scheduled trial visits, including the Safety Follow-
up Visits, even if IMP is discontinued. At a minimum, the subject is expected to complete the trial visits at Weeks 12, 24, 36, 52, 64, 76, 88, and 104, as 
well as the Safety Follow-up period Week 12 visit. Subjects with discontinued IMP can come to the other scheduled visits during the trial period 
according to the Investigator's judgment. Subjects who withdraw from the treatment period would have an early termination visit followed by 
entrance into the Safety Follow-up Period. Subjects who withdraw from the trial (eg, withdraw consent, lost to follow-up, or death; see Section 5.5.2) 
would not have any additional trial visits.  All subjects will be followed up by the site approximately every 12 weeks for survival from the subject’s 
last trial visit until death or the end of the trial. 
b
For women of childbearing potential or who are postmenopausal for less than 2 years. Positive urine pregnancy tests should be confirmed with a serum test. If 
the serum pregnancy test is subsequently positive, the subject will be withdrawn from IMP.
c
Performed locally per local constraints and regulations.
d
Focused physical examination only, according to standard of care.
e
Vital signs include 10-minute seated arterial blood pressure, pulse rate, and body temperature. Weight will be measured at Weeks 0, 24, 52, 76, and 104. Body 
weight will be measured with a balance beam scale, if possible.
f
Questionnaires should be completed before any other procedures are performed. Questionnaires should be performed in the following order: Patient’s Global 
Assessment, SHAQ, Mahler BDI (at Day 1) followed by Mahler TDI at the subsequent visits, St. George Respiratory Questionnaire SGRQ, Dyspnea-12,
Leicester Cough Index, and EQ-5D. The Physician’s Global Assessment (VAS) may be performed after other assessments at the visit are completed.
g
See Section 7.4.3 for list of routine laboratory assessments. Urine protein:creatinine ratio to be performed if dipstick urinalysis reveals at least 3+ protein. 
Microscopic urinalysis to be performed if blood is present.
h
The TLC should be performed at Weeks 0, 24, 52, 76, and 104. The DLCO measurements will be corrected for hemoglobin level, and spirometry assessments 
will be centrally adjudicated.
i
Digital ulcers are those distal to the metacarpal phalangeal joints. New or worsening digital ulcers, or at any other site on the body, will be captured as AEs. 
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j
Adverse events should also be assessed for occurrence during the periods between trial visits.
k
Survival follow-up: All subjects will be assessed for survival every 12 weeks (∀1 week) from the last trial visit until death or end of the trial.
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Appendix IV: Criteria for the Classification of Systemic Sclerosis
Copy of Table A1 
The American College of Rheumatology/European League Against 
Rheumatism criteria for the classification of systemic sclerosis* 
Item 
Sub-item(s) 
Weight/ 
score†
Skin thickening of the fingers of both hands 
extending proximal to the metacarpophalangeal 
joints (sufficient criterion)
--
9
Skin thickening of the fingers (only count the 
higher score)
Puffy fingers
Sclerodactyly of the fingers (distal to the 
metacarpophalangeal joints but proximal to the 
proximal interphalangeal joints)
2
4
Fingertip lesions (only count the higher score)
Digital tip ulcers 
Fingertip pitting scars
2
3
Telangiectasia
--
2
Abnormal nailfold capillaries
--
2
Pulmonary arterial hypertension and/or interstitial 
lung disease (maximum score is 2)
Pulmonary arterial hypertension 
Interstitial lung disease
2
2
Raynaud’s phenomenon
--
3
SSc-related autoantibodies (anticentromere, 
anti-topoisomerase I [anti–Scl-70], anti-RNA 
polymerase III) (maximum score is 3)
Anticentromere 
Anti–topoisomerase I 
Anti–RNA polymerase III
3
SSc, systemic sclerosis. 
* These criteria are applicable to any patient considered for inclusion in a systemic sclerosis study. The criteria are 
not applicable to patients with skin thickening sparing the fingers or to patients who have a scleroderma-like 
disorder that better explains their manifestations (eg, nephrogenic sclerosing fibrosis, generalised morphea, 
eosinophilic fasciitis, scleredema diabeticorum, scleromyxedema, erythromyalgia, porphyria, lichen sclerosis, graft-
versus-host disease, diabetic cheiroarthropathy). 
† The total score is determined by adding the maximum weight (score) in each category. Patients with a total score 
of ≥9 are classified as having definite systemic sclerosis. 
Reproduced from van den Hoogen, et al (2013).
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Copy of Table A2 
Definitions of items/sub-items in the American College of 
Rheumatology/European League Against Rheumatism criteria for the 
classification of systemic sclerosis
Item 
Definition
Skin thickening
Skin thickening or hardening not due to scarring after injury, trauma, 
etc.
Puffy fingers
Swollen digits - a diffuse, usually nonpitting increase in soft tissue 
mass of the digits extending beyond the normal confines of the joint 
capsule. Normal digits are tapered distally with the tissues following 
the contours of the digital bone and joint structures. Swelling of the 
digits obliterates these contours. Not due to other causes such as 
inflammatory dactylitis.
Fingertip ulcers or pitting scars
Ulcers or scars distal to or at the proximal interphalangeal joint not 
thought to be due to trauma. Digital pitting scars are depressed 
areas at digital tips as a result of ischaemia, rather than trauma or 
exogenous causes.
Telangiectasia
Telangiectasiae are visible macular dilated superficial blood vessels, 
which collapse upon pressure and fill slowly when pressure is 
released. Telangiectasiae in a scleroderma-like pattern are round 
and well demarcated and found on hands, lips, inside of the mouth, 
and/or are large mat-like telangiectasiae. Distinguishable from 
rapidly filling spider angiomas with central arteriole and from dilated 
superficial vessels.
Abnormal nailfold capillary pattern 
consistent with systemic sclerosis
Enlarged capillaries and/or capillary loss with or without pericapillary 
haemorrhages at the nailfold. May also be seen on the cuticle.
Pulmonary arterial hypertension
Pulmonary arterial hypertension diagnosed by right-sided heart 
catheterisation according to standard definitions.
Interstitial lung disease
Pulmonary fibrosis seen on high-resolution CT or chest radiography, 
most pronounced in the basilar portions of the lungs, or occurrence 
of ‘Velcro’ crackles on auscultation, not due to another cause such 
as congestive heart failure.
Raynaud’s phenomenon
Self-reported or reported by a physician, with at least a 2-phase 
colour change in finger(s) and often toe(s) consisting of pallor, 
cyanosis, and/or reactive hyperemia in response to cold exposure or 
emotion; usually one phase is pallor.
SSc-related auto antibodies
Anticentromere antibody or centromere pattern seen on antinuclear 
antibody testing, anti–topoisomerase I antibody (also known as 
anti-Scl-70 antibody), or anti-RNA polymerase III antibody. Positive 
according to local laboratory standards.
SSc, systemic sclerosis.
Reproduced from van den Hoogen, et al (2013).
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Amendment 2
Rationale
The purpose of this protocol amendment is to revise the contraception requirements based on 
comments received from a Voluntary Harmonisation Procedure (VHP) review.
Major Scientific Changes
The contraception requirements for study inclusion were updated to more clearly define effective 
contraception for consistency with current Clinical Trial Facilitation Group guidelines and 
recommendations from the VHP.
Administrative and Editorial Changes
The Sponsor’s Medical Responsible contact was changed from 
 to 
. The date and version number of the protocol were changed throughout and 
new abbreviations were added to the list of abbreviations as needed.
List of Changes
Changes to the clinical trial protocol text are presented in the table below. Additions and 
amended text are shown in bold. If the original clinical trial protocol text was already bold, 
changes are shown in bold and underlined, deletions are marked using strike-through.
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Comparison with Clinical Trial Protocol Version 2.0, 02 Feb 2016 (Amendment No. 1)
Change
Section
Page
Previous Wording
New Wording
Change in 
Sponsor’s 
Responsible 
Medical
Title Page
1
Medical Responsible:
EMD Serono Research & Development Institute, Inc.
45A Middlesex Turnpike
Billerica, MA, 01821 USA
Telephone number: 
Fax number: 
Medical Responsible:
EMD Serono Research & Development Institute, Inc.
45A Middlesex Turnpike
Billerica, MA, 01821 USA
Telephone number: 
Fax number: 
More clearly define 
contraception 
methods allowed 
5.3.1
39
6. Female subjects of childbearing potential must use 
a highly effective method of contraception to prevent 
pregnancy for 4 weeks before randomization and 
must agree to continue to practice adequate 
contraception for the duration of their participation in 
the trial (up to the last Safety Follow-Up Visit). For 
the purposes of this trial, women of childbearing 
potential are defined as “All female subjects after 
puberty unless they are post-menopausal for at least 
2 years or are surgically sterile.” Highly effective 
contraception is defined as 2 barrier methods (eg, 
female diaphragm and male condoms); or 1 barrier 
method with at least one of the following: spermicide, 
a hormonal method, or an intrauterine device. Note 
that because mycophenolate affects the metabolism 
of oral contraceptives and may reduce their 
effectiveness, women receiving mycophenolate who 
are using oral contraceptives for birth control should 
employ an additional contraceptive method (eg, male 
or female barrier method).
6. Female subjects of childbearing potential must use 
a highly effective method of contraception to prevent 
pregnancy for 4 weeks before randomization and 
must agree to continue to practice adequate 
contraception for the duration of their participation in 
the trial (up to the last Safety Follow-Up Visit). For the 
purposes of this trial, women of childbearing potential 
are defined as “All female subjects after puberty 
unless they are post-menopausal for at least 2 years
or are surgically sterile.” Highly effective contraception 
is defined as 2 barrier methods (eg, female 
diaphragm and male condoms); or 1 barrier method 
with at least one of the following: spermicide, a 
hormonal method, or an intrauterine device. Note that
because mycophenolate affects the metabolism of 
oral contraceptives and may reduce their 
effectiveness, women receiving mycophenolate who 
are using oral contraceptives for birth control should 
employ an additional contraceptive method (eg, male 
or female barrier method).
6. 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 two 
effective methods of contraception, including at 
least one highly effective method that can achieve 
a failure rate of < 1% per year, when used 
consistently and correctly, and one other reliable 
method during the treatment period and for at 
least 90 days after the last dose of study 
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Change
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Previous Wording
New Wording
treatment.
Examples of contraceptive methods with a failure 
rate of < 1% per year (highly effective 
contraceptive methods) include:
•
combined (estrogen and progesterone 
containing) hormonal contraception 
associated with inhibition of ovulation1 (oral, 
intravaginal, transdermal)
•
progesterone-only hormonal contraception 
associated with inhibition of ovulation1 (oral, 
injectable, implantable2)
•
intrauterine device (IUD)2
•
intrauterine hormone-releasing system (IUS)2
•
bilateral tubal occlusion2
•
vasectomized partner2,3
•
sexual abstinence4
1
Hormonal contraception may be susceptible to 
interaction with the IMP, which may reduce the 
efficacy of the contraception method.
2
Contraception methods in the context of this 
guidance are considered to have low user 
dependency.
3
Vasectomized partner is a highly effective birth 
control method provided that the partner is the 
sole sexual partner of the woman of 
childbearing potential trial participant and that 
the vasectomized partner has received medical 
assessment of the surgical success.
4
In the context of this guidance, sexual 
abstinence is considered a highly effective 
method only if defined as refraining from 
heterosexual intercourse during the entire 
period of risk associated with the study 
treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the 
duration of the clinical trial and the preferred 
and usual lifestyle of the subject.
Barrier methods supplemented with the use of a 
spermicide could be considered as a reliable 
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Change
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Previous Wording
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method.
For men (including those who have undergone a 
vasectomy): agreement to remain abstinent or use 
a condom during the treatment period and for at 
least 12 months after the last dose of study 
treatment and agreement to refrain from donating 
sperm during this same period.
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.
In addition to male contraception, agreement to 
advise female partners of childbearing potential to 
use highly effective contraception during the 
study and for at least 12 months after the last 
dose of study treatment.
Upon termination of participation in this clinical 
study, patients continuing on MMF must continue 
effective contraception as required by the SPC.
More clearly define 
contraception 
methods allowed
6.5.4
46
Women of childbearing potential and men must use 
highly effective contraception, including 2 barrier 
methods or 1 barrier method in combination with a 
spermicide, hormonal method, or intrauterine device, 
until further availability of reproductive toxicity data.
Women of childbearing potential and men must use 
highly effective contraception, including 2 barrier 
methods or 1 barrier method in combination with a 
spermicide, hormonal method, or intrauterine device, 
until further availability of reproductive toxicity data.
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 two 
effective methods of contraception, including at 
least one highly effective method that can achieve 
a failure rate of < 1% per year, when used 
consistently and correctly, and one other reliable 
method during the treatment period and for at 
least 90 days after the last dose of study 
treatment.
Examples of contraceptive methods with a failure 
rate of < 1% per year (highly effective 
contraceptive methods) include:
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Change
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Previous Wording
New Wording
•
combined (estrogen and progesterone 
containing) hormonal contraception 
associated with inhibition of ovulation1 (oral, 
intravaginal, transdermal)
•
progesterone-only hormonal contraception 
associated with inhibition of ovulation1 (oral, 
injectable, implantable2)
•
intrauterine device (IUD)2
•
intrauterine hormone-releasing system (IUS)2
•
bilateral tubal occlusion2
•
vasectomized partner2,3
•
sexual abstinence4
1
Hormonal contraception may be susceptible to 
interaction with the IMP, which may reduce the 
efficacy of the contraception method.
2
Contraception methods in the context of this 
guidance are considered to have low user 
dependency.
3
Vasectomized partner is a highly effective birth 
control method provided that the partner is the 
sole sexual partner of the woman of
childbearing potential trial participant and that 
the vasectomized partner has received medical 
assessment of the surgical success.
4
In the context of this guidance, sexual 
abstinence is considered a highly effective 
method only if defined as refraining from 
heterosexual intercourse during the entire 
period of risk associated with the study 
treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the 
duration of the clinical trial and the preferred 
and usual lifestyle of the subject.
Barrier methods supplemented with the use of a 
spermicide could be considered as a reliable 
method.
For men (including those who have undergone a 
vasectomy): agreement to remain abstinent or use 
a condom during the treatment period and for at 
least 12 months after the last dose of study 
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Change
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Previous Wording
New Wording
treatment and agreement to refrain from donating 
sperm during this same period.
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.
In addition to male contraception, agreement to 
advise female partners of childbearing potential to 
use highly effective contraception during the 
study and for at least 12 months after the last 
dose of study treatment.
Upon termination of participation in this clinical 
study, patients continuing on MMF must continue 
effective contraception as required by the SPC.
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Amendment 3
This is a global amendment, effective 14 September 2016.
Rationale
The purpose of this protocol amendment is to:
! Clarify the role of the independent panel of dermatology experts
! Specify the period of observation after IMP administration in order to detect any delayed 
onset of sign/symptoms of infusion reactions 
! Add additional hematology time points to align with DLCO assessments
! Provide further rationale for exploratory endpoints
! Revise exclusion criteria to allow subjects with secondary Sjögren’s syndrome
! Allow prophylactic treatment for Pneumocystis jiroveci pneumonia
! Exclude the use of e-cigarettes
! Clarify allowable corticosteroid use
! Exclude the administration of vaccines from 12 weeks prior until 3 months after the study
! Exclude subjects with recent or planned major surgery or major organ transplant
! Clarify re-screening procedures
! Allow HbA1c testing in subjects with diabetes at the discretion of the Investigator and with 
Medical Monitor approval.
The changes to be made to the clinical trial protocol and the rationale for the key scientific 
changes are described below.
Major Scientific Changes
Sjögren’s syndrome: Secondary Sjögren’s syndrome is usually present in autoimmune diseases.
Over 20% of patients with systemic sclerosis, and a few with localized scleroderma also have 
secondary Sjögren syndrome, and are usually permitted in trials for rheumatic diseases.
Pneumocystis jiroveci: Approximately 1% to 2% of patients with rheumatologic diseases 
develop Pneumocystis jiroveci, usually in the setting of immunosuppressive therapy and
particularly in combined therapy, and are more likely to develop in subjects with interstitial 
pulmonary fibrosis.
Live vaccines: The use of live vaccines is contra-indicated in patients receiving 
immunosuppressive treatment or patients taking moderate or high doses of steroids. Inactivated 
vaccines can be administered safely to persons with altered immunocompetence whether the 
vaccine is a killed whole organism or a recombinant, subunit, toxoid, polysaccharide, or 
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polysaccharide protein-conjugate vaccine. Inactivated vaccines are indicated for persons with 
altered immunocompetence at the usual doses and schedules.  In addition, seasonal inactivate 
influenza vaccine is recommended.
Corticosteroids: The protocol has been updated to provide further clarification with regards to 
the use of inhaled and topical corticosteroids. Corticosteroids using these routes are minimally 
systemically absorbed and may be beneficial in several cutaneous and respiratory diseases, 
including SSc complications.
Administrative and Editorial Changes
The Schedule of Assessments was updated as follows:  
! A typographical error for the rich PK sampling time points was corrected.
! The timing of safety follow-up visits was clarified.
! Text clarifying the Mahler BDI/TDI administrator must be blinded to other assessments was 
added.
The name of the biostatistical expert has been revised to reflect a change in team membership.
The date and version number of the protocol were changed throughout and minor typographical 
errors were corrected. Minor editorial revisions were made to enhance reader understanding.
List of Changes
Changes to the clinical trial protocol text are presented in the table below. Additions and 
amended text are shown in bold. If the original clinical trial protocol text was already bold, 
changes are shown in bold and underlined; deletions are marked using strike-through.
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Comparison with Clinical Trial Protocol Version 3.0, 16 May 2016 (Amendment No. 2)
Change
Section
Page
Previous Wording
New Wording
To clarify role of 
the independent 
panel of 
dermatology 
experts
Synopsis; 
Methodology, last 
paragraph
14
During the conduct of the trial, an Independent Data 
Monitoring Committee (IDMC) will monitor safety 
data on a regular basis (to be specified in the IDMC 
charter). The IDMC will also review the results of the 
interim futility analysis conducted by an independent 
statistical center. Based on the prespecified stopping 
boundary of futility, and the totality of the information 
at interim, the IDMC will make a recommendation to 
the Sponsor on continuing or stopping the trial for 
futility. An independent panel of dermatologists will 
provide guidance for further investigation and 
interpretation of cutaneous AEs that are serious, are 
Grade 3 or higher, or are not responding to 
treatment, and make recommendations as to whether 
any subject-specific or trial-wide actions should be 
considered.
During the conduct of the trial, an Independent Data 
Monitoring Committee (IDMC) will monitor safety 
data on a regular basis (to be specified in the IDMC 
charter). The IDMC will also review the results of the 
interim futility analysis conducted by an independent 
statistical center. Based on the prespecified stopping 
boundary of futility, and the totality of the information 
at interim, the IDMC will make a recommendation to 
the Sponsor on continuing or stopping the trial for 
futility. An independent panel of dermatologists will 
provide guidance for further investigation and 
interpretation of cutaneous AEs that are serious, are 
Grade 3 or higher, or are not responding to 
treatment, and make recommendations as toadvise 
the IDMC whether any subject-specific or trial-wide 
actions to modify clinical trial conduct should be 
considered.
To harmonize
description of key 
entry criteria
within protocol 
Synopsis; Diagnosis 
and key inclusion and 
exclusion criteria, 
second paragraph
17
Subjects must not have underlying conditions that 
constitute an inappropriate risk or contraindication for 
trial participation including, but not limited to: 
significant renal impairment, obstructive lung 
disease/emphysema, pulmonary arterial 
hypertension, another inflammatory connective tissue 
disease, and/or tuberculosis. The use of agents other 
than mycophenolate (MPS or MMF) considered by 
the Investigator to have immunomodulating, 
immunosuppressive, or potential scleroderma 
disease-modifying properties within 6 months of 
screening is not allowed.
Subjects must not have underlying conditions that 
constitute an inappropriate risk or contraindication for 
trial participation including, but not limited to: 
significant renal impairment, obstructive lung 
disease/emphysema, pulmonary arterial 
hypertension, another inflammatory connective tissue 
disease (apart from scleroderma-associated 
myopathy, fibromyalgia, and secondary Sjögren’s
syndrome, which are allowed), and/or tuberculosis. 
The use of agents other than mycophenolate (MPS 
or MMF) considered by the Investigator to have 
immunomodulating, immunosuppressive, or potential 
scleroderma disease-modifying properties within 6 
months of screening is not allowed.
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Specify period of 
observation after 
dosing
Synopsis; 
Investigational 
medicinal product; 
dose/mode of 
administration/dosing 
schedule
17
Abituzumab 1500 or 500 mg will be administered as 
an intravenous infusion over 1 hour once every 
4 weeks with the last IMP administration at the 
Week 100 visit (2 years) on top of background 
therapy.
Abituzumab 1500 or 500 mg will be administered as 
an intravenous infusion over 1 hour once every 
4 weeks. Close observation of the subject is 
recommended for a period of at least 1 hour after 
administration of the IMP. with tThe last IMP 
administration is at the Week 100 visit (2 years) on 
top of background therapy.
Specify period of 
observation after 
dosing
Synopsis; Reference 
therapy; dose/mode 
of 
administration/dosing 
schedule
17
Placebo (citrate buffered saline) will be administered 
as an intravenous infusion over 1 hour once every 
4 weeks with the last administration at the Week 100 
visit (2 years) on top of background therapy.
Placebo (citrate buffered saline) will be administered 
as an intravenous infusion over 1 hour once every 
4 weeks. Close observation of the subject is 
recommended for a period of at least 1 hour after 
administration. with tThe last administration of 
placebo is at the Week 100 visit (2 years) on top of 
background therapy.
Addition of 
hematology time 
points to support 
DLCO 
assessments; 
clarification that 
timing of safety 
follow-up visits are 
after the last 
on-treatment visit; 
correction of
typographical 
error in rich PK 
sampling time 
points
Schedules of 
Assessments
20-24
Refer to Amendment 3 - Tables 1 and 2, below.
Refer to Amendment 3 - Tables 1 and 2, below.
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To clarify role of 
the independent 
panel of 
dermatology 
experts
Section 3.3; sixth 
paragraph
29
The current safety profile of abituzumab 
monotherapy includes the identified risks, allergic 
reaction, and skin rash (Grades 1-2). […] The 
occurrence of AESI or cutaneous serious AEs 
(SAEs) will be reviewed by an independent panel of 
dermatologists to provide guidance for further 
investigation and interpretation of these events, and 
determine whether any subject-specific or trial-wide
actions should be considered. An IDMC will review 
safety data to ensure safety of all subjects enrolled in 
the trial. If subjects have significant worsening of lung 
function, they may start rescue medication, as 
appropriate. No additional risk minimization 
measures are considered necessary at this time for 
studying the effects of abituzumab in subjects with 
SSc-ILD.
The current safety profile of abituzumab 
monotherapy includes the identified risks, allergic 
reaction, and skin rash (Grades 1-2). […] The 
occurrence of AESI or cutaneous serious AEs 
(SAEs) will be reviewed by an independent panel of 
dermatologists to provide guidance for further 
investigation and interpretation of these events, and 
determine advise the IDMC whether any subject-
specific or trial-wide actions to modify clinical trial 
conduct should be considered. An IDMC will review 
safety data to ensure safety of all subjects enrolled in 
the trial. If subjects have significant worsening of lung 
function, they may start rescue medication, as 
appropriate. No additional risk minimization 
measures are considered necessary at this time for 
studying the effects of abituzumab in subjects with 
SSc-ILD.
To correct 
typographical 
error in the 
number of sites
Section 5.1; first 
paragraph
30
This is a Phase II, multicenter, double-blind, placebo-
controlled, parallel-group trial to be conducted in 
adult male and female subjects with SSc-ILD who are 
treated with stable mycophenolate to explore the 
efficacy, safety, tolerability, and immunogenicity of 
multiple intravenous doses of abituzumab. Subjects 
must have had mycophenolate treatment for at least 
6 months and remained at a stable dose (1.5 to 3 
g/day of mycophenolate mofetil [MMF] or 1080 to 
2160 mg/day of sodium mycophenolate [MPS]) for at 
least 3 months. The trial will be conducted at 
approximately 50 sites globally.
This is a Phase II, multicenter, double-blind, placebo-
controlled, parallel-group trial to be conducted in 
adult male and female subjects with SSc-ILD who are 
treated with stable mycophenolate to explore the 
efficacy, safety, tolerability, and immunogenicity of 
multiple intravenous doses of abituzumab. Subjects 
must have had mycophenolate treatment for at least 
6 months and remained at a stable dose (1.5 to 3 
g/day of mycophenolate mofetil [MMF] or 1080 to 
2160 mg/day of sodium mycophenolate [MPS]) for at 
least 3 months. The trial will be conducted at 
approximately 50 60 sites globally.
To specify the 
order of patient-
reported outcome 
assessments
Section 5.2.5, 
Efficacy, paragraph 
12
37
The EQ-5D, measures health outcomes and is 
standardized for use across many indications and 
regions. It can be used for health outcomes including 
QoL and also economic analyses. Applicable to a 
wide range of health conditions and treatments, the 
EQ-5D health questionnaire provides a simple 
descriptive profile and a single-index value for health 
status.
The EQ-5D, measures health outcomes and is 
standardized for use across many indications and 
regions. It can be used for health outcomes including 
QoL and also economic analyses. Applicable to a 
wide range of health conditions and treatments, the 
EQ-5D health questionnaire provides a simple 
descriptive profile and a single-index value for health 
status.
Please note: Patient-reported Outcome 
questionnaires should be completed before any 
other procedures, as per the Schedules of 
Assessments (Table 1 and Table 2).
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Questionnaires will be performed in the following 
order:
•
Patient’s Global Assessment 
•
SHAQ
•
Mahler BDI (at Day 1) followed by Mahler TDI 
at the subsequent visits, by the request of the 
author of the Mahler TDI
•
SGRQ
•
Leicester Cough Index
•
EQ-5D
•
Physician’s Global Assessment (VAS).
To add 
 
endpoint
Section 5.2.6; first 
paragraph
37-38
 
 
 
 
 
 
 
 
 
To specify 
subjects with 
secondary 
Sjögren’s 
syndrome are 
allowed. 
Section 5.3.2; 
Exclusion Criterion 8
41
8. Current clinical diagnosis of another inflammatory 
connective tissue disease (eg, systemic lupus 
erythematosus, rheumatoid arthritis, ankylosing 
spondylitis, or dermato/polymyositis); concomitant 
scleroderma-associated myopathy and 
fibromyalgia are allowed.
8. Current clinical diagnosis of another inflammatory 
connective tissue disease (eg, systemic lupus 
erythematosus, rheumatoid arthritis, ankylosing 
spondylitis, or dermato/polymyositis); concomitant 
scleroderma-associated myopathy, and
fibromyalgia, and secondary Sjögren’s 
syndrome are allowed
To allow 
prophylactic 
treatment for 
Pneumocystis 
jiroveci 
pneumonia
Section 5.3.2; 
Exclusion Criterion 
10
41
10. Active clinically significant viral, bacterial, or 
fungal infection, or any major episode of 
infection requiring hospitalization or treatment 
with parenteral anti-infectives within 4 weeks 
prior to screening or during the Screening 
Period, or completion of oral anti-infectives 
within 2 weeks before screening or use of oral 
anti-infectives during the Screening Period. 
Vaginal candidiasis, onychomycosis, and 
chronically suppressed oral herpes simplex virus 
10. Active clinically significant viral, bacterial, or 
fungal infection, or any major episode of infection 
requiring hospitalization or treatment with 
parenteral anti-infectives within 4 weeks prior to 
screening or during the Screening Period, or 
completion of oral anti-infectives within 2 weeks 
before screening or use of oral anti-infectives 
during the Screening Period. Vaginal candidiasis, 
onychomycosis, and chronically suppressed oral 
herpes simplex virus would not be exclusionary. 
Prophylaxis for Pneumocystis jiroveci
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would not be exclusionary.
pneumonia according to local guidelines will 
be permitted.
To exclude use of 
e-cigarettes
Section 5.3.2; 
Exclusion Criterion 
16
42
16. Current smoker or smoking within 4 weeks of 
screening.
16. Current smoker (including e-cigarettes) or 
smoking within 4 weeks of screening.
To clarify 
allowable 
corticosteroid use
Section 5.3.2; 
Exclusion Criterion 
18
42
18. Use of corticosteroids above 10 mg/day 
prednisone equivalent within 4 weeks of 
screening, during the Screening Period, or 
expected during the treatment period. 
18. Use of systemic corticosteroids above 
10 mg/day prednisone equivalent within 4 weeks 
of screening, during the Screening Period, or 
expected during the treatment period. Inhaled 
corticosteroids are not considered systemic
and are permitted. Topical corticosteroids are 
permitted.
To exclude 
vaccine from 12 
weeks prior to 
study until 
3 months after the 
study. 
Section 5.3.2; New 
Exclusion Criterion 
28
41
Not applicable.
28. Receipt of a live/attenuated vaccine within 12 
weeks prior to the Screening Visit or 
subjects who are expecting to receive any 
live virus or bacterial vaccinations during the 
trial, or up to 3 months after the last dose of 
study drug, are not permitted. Seasonal 
influenza vaccination is permitted if the 
inactivated vaccine formulation is 
administered.
To exclude 
subjects with 
recent or planned 
major surgery or 
major organ 
transplant
Section 5.3.2; New 
Exclusion Criteria 29
and 30
43
Not applicable.
29. Major surgery requiring hospitalization 
within 4 weeks prior to the Screening Visit 
and any planned major surgery for the 
duration of the trial.  Subjects with lung 
resection.  
30. Have a history of a major organ transplant 
(eg, heart, lung, kidney, or liver) or 
hematopoietic stem cell/marrow transplant 
or are due to receive transplantation.
Specify period of 
observation after 
dosing
Section 6.2, Dosage 
and Administration
45
In the Double-blind Treatment Period, subjects will be 
randomized in a 2:2:1 ratio to receive one of the 
following treatments: abituzumab 1500 mg, placebo, 
or abituzumab 500 mg, respectively. Treatment will 
be given as an intravenous infusion over 
approximately 1 hour every 4 weeks with the last IMP 
administration at the Week 100 visit. The infusion 
time should not be less than 1 hour. 
In the Double-blind Treatment Period, subjects will be 
randomized in a 2:2:1 ratio to receive one of the 
following treatments: abituzumab 1500 mg, placebo, 
or abituzumab 500 mg, respectively. Treatment will 
be given as an intravenous infusion over 
approximately 1 hour every 4 weeks. with the last 
IMP administration at the Week 100 visit. The 
infusion time should not be less than 1 hour. Close 
observation of the subject is recommended for a 
period of at least 1 hour after administration of 
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IMP. The last IMP/placebo administration will be 
at the Week 100 visit.
To clarify prior 
administration of 
vaccines
Section 6.5.1, 
Permitted 
Medications
46
Any medications, other than those excluded or listed 
as prohibited, that are considered necessary for the 
subject’s welfare, and that do not interfere with the 
trial conduct or assessment, may be given at the 
Investigator’s judgment. The Investigator will record 
all concomitant medications and procedures 
throughout the trial.
Any medications, other than those excluded or listed 
as prohibited, that are considered necessary for the 
subject’s welfare, and that do not interfere with the
trial conduct or assessment, may be given at the 
Investigator’s judgment. The Investigator will record 
all concomitant medications and procedures 
throughout the trial. 
Seasonal influenza vaccination is permitted if the 
inactivated vaccine formulation is administered.
Prophylaxis for Pneumocystis jiroveci
pneumonia according to local guidelines will be 
permitted.
To clarify prior 
administration of 
vaccines
Section 6.5.2, 
Prohibited 
Medications
47
Medications for treatment of PAH are not permitted 
during the Screening or Double-blind Treatment 
Periods. These medications include, but are not 
limited to, phosphodiesterase-5 inhibitors (eg, 
sildenafil),  ERAs (eg, bosentan), prostanoids 
(epoprostenol, treprostinil), and riociguat. These 
medications can be used for treatment of conditions 
other than PAH, such as Raynaud’s symptoms. If 
subjects meet criteria for rescue medication (see 
Section 6.5.5), then such therapy can be initiated. 
The use of agents other than mycophenolate (MPS 
or MMF) considered by the Investigator to have 
immunomodulating, immunosuppressive, or potential 
scleroderma disease-modifying properties within 
6 months of screening is not permitted. 
Medications for treatment of PAH are not permitted 
during the Screening or Double-blind Treatment 
Periods. These medications include, but are not 
limited to, phosphodiesterase-5 inhibitors (eg, 
sildenafil),  ERAs (eg, bosentan), prostanoids 
(epoprostenol, treprostinil), and riociguat. These 
medications can be used for treatment of conditions 
other than PAH, such as Raynaud’s symptoms. If 
subjects meet criteria for rescue medication (see 
Section 6.5.5), then such therapy can be initiated. 
The use of agents other than mycophenolate (MPS 
or MMF) considered by the Investigator to have 
immunomodulating, immunosuppressive, or potential 
scleroderma disease-modifying properties within 
6 months of screening is not permitted. 
Receipt of a live/attenuated vaccine within 
12 weeks prior to the Screening Visit is not 
permitted. Live virus or bacterial vaccinations 
during the trial, or up to 3 months after the last 
dose of study drug are not permitted.
To clarify re-
screening 
procedures
Section 7.1.1, 
Screening Period, 
second paragraph
53-54
If at screening, the subject meets all of the protocol 
inclusion and none of the exclusion criteria (including 
complete history of immunosuppressive, 
immunomodulating, and potential scleroderma 
disease modifying medications as well as history of 
other medications in the previous year), the subject 
If at screening, the subject meets all of the protocol 
inclusion and none of the exclusion criteria (including 
complete history of immunosuppressive, 
immunomodulating, and potential scleroderma 
disease modifying medications as well as history of 
other medications in the previous year), the subject 
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will be considered as eligible and will be enrolled in 
the trial and randomized. Subjects who fail to meet 
the protocol-specified criteria for randomization or 
dosing, or withdraw their consent before 
randomization, are considered screening failures. If 
the Investigator feels a particular screening 
assessment is aberrant and retesting could confirm 
eligibility, these may be repeated under the same 
subject number, provided the retest is performed 
within the same screening period. A subject who was 
considered a screen failure may be re-screened (only 
once per subject), but a new subject number will be 
assigned and all screening assessments have to be 
repeated.
will be considered as eligible and will be enrolled in 
the trial and randomized. Subjects who fail to meet 
the protocol-specified criteria for randomization or 
dosing, or withdraw their consent before 
randomization, are considered screening failures. If 
the Investigator feels a particular screening 
assessment is aberrant and retesting could confirm 
eligibility, these may be repeated under the same 
subject number, provided the retest is performed 
within the same screening period. A subject who was 
considered a screen failure may be re-screened (only 
once per subject). Re-screening is not 
encouraged. However, on a case-by-case basis 
with permission of the Medical Monitor and the 
Sponsor’s Medical Director, a subject who has 
not met all of the eligibility criteria within the 
original screening period may be permitted to be 
re-screened one time.  Each subject must be 
re-consented before re-screening occurs., but aA
new subject number will be assigned and all 
screening assessments have to be repeated.
Correction of 
typographical 
error
Section 7.3, second 
paragraph
55
In this trial, full volume HRCT of the chest will be 
performed at Sponsor-qualified imaging centers per 
guidelines outlined in an imaging manual. High 
resolution computer tomography will be performed 
on all trial subjects during the Screening Period and 
at Months 6, 12, and 24 (Weeks 26, 52, and 104; or 
early termination, if applicable). To ensure 
comparability, the same scan, equipment, method, 
and technique used during the baseline HRCT scan 
should be used for all the subsequent HRCT scans. 
For all subjects, HRCT scans will be performed at 
TLC with no contrast agent administration, 
reconstructed every 0.6 to 2 mm, using a low-dose 
protocol.
In this trial, full volume HRCT of the chest will be 
performed at Sponsor-qualified imaging centers per 
guidelines outlined in an imaging manual. High 
resolution computer tomography will be performed 
on all trial subjects during the Screening Period and 
at Months 6, 12, and 24 (Weeks 2624, 52, and 104; 
or early termination, if applicable). To ensure 
comparability, the same scan, equipment, method, 
and technique used during the baseline HRCT scan 
should be used for all the subsequent HRCT scans. 
For all subjects, HRCT scans will be performed at 
TLC with no contrast agent administration, 
reconstructed every 0.6 to 2 mm, using a low-dose 
protocol.
To clarify role of 
the independent 
panel of 
dermatology 
experts
Section 7.4.1.1, 
Adverse Events of 
Special Interest
58
All blistering or Grade ≥3 AEs in the skin and 
subcutaneous tissue disorders SOC will be 
designated as AESI. Any cutaneous reaction of 
Grade 1 or 2 that is not responding to specific 
treatment or is worsening will also be designated as 
an AESI. The occurrence of cutaneous AESI or 
All blistering or Grade ≥3 AEs in the skin and 
subcutaneous tissue disorders SOC will be 
designated as AESI. Any cutaneous reaction of 
Grade 1 or 2 that is not responding to specific 
treatment or is worsening will also be designated as 
an AESI. The occurrence of cutaneous AESI or 
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SAEs will be reviewed by an independent panel of 
dermatologists to provide guidance for further 
investigation and interpretation of these events, and 
determine whether any subject-specific or trial-wide
actions should be considered.
SAEs will be reviewed by an independent panel of 
dermatologists to provide guidance for further 
investigation and interpretation of these events, and 
determineadvise the IDMCwhether any subject-
specific or trial-wideactions to modify clinical trial 
conductshould be considered.
Editorial revision 
to remove 
reference to 
pediatric patients, 
which is not 
applicable to this 
study
Section 7.4.1.2, 
paragraph 5, 
number3.
59 
3. Reduced BP after exposure to known allergen for 
that subject (minutes to several hours):
a. Infants and children: low systolic BP (age 
specific) or greater than 30% decrease in 
systolic BP*
ab. Adults: systolic BP of less than 90 mmHg or 
greater than 30% decrease from that person’s 
baseline
* Low systolic blood pressure for children is defined 
as less than 70 mmHg from 1 month to 1 year, 
less than (70 mmHg + [2 age])from1to10
years, and less than 90 mmHg from 11 to 17 
years.
3. Reduced BP after exposure to known allergen for 
that subject (minutes to several hours):
a. Infants and children: low systolic BP (age 
specific) or greater than 30% decrease in 
systolic BP*
ab. Adults: systolic BP of less than 90 mmHg or 
greater than 30% decrease from that person’s 
baseline
* Low systolic blood pressure for children is defined 
as less than 70 mmHg from 1 month to 1 year, 
less than (70 mmHg + [2 age])from1to10
years, and less than 90 mmHg from 11 to 17 
years.
To allow HbA1c 
testing for 
subjects with 
diabetes
Section 7.4.3, Clinical 
Laboratory 
Assessments, third 
paragraph
63
Other laboratory assessments include the following:
Serum pregnancy test in female subjects of 
childbearing potential;
Urine pregnancy test in female subjects of 
childbearing potential, to be performed locally;
HIV, hepatitis C, and hepatitis B (HBsAg, hepatitis 
B core antibody [IgM and total]) serologies;
Tuberculosis testing as requested by Investigator.
Other laboratory assessments include the following:
Serum pregnancy test in female subjects of 
childbearing potential;
Urine pregnancytest in female subjects of 
childbearing potential, to be performed locally;
HIV, hepatitis C, and hepatitis B (HBsAg, hepatitis 
B core antibody [IgM and total]) serologies;
HbA1c may be evaluated for subjects with 
diabetes,at the discretion of the Investigator 
and by forwarding a prior request to the 
Medical Monitorand notification to the 
Sponsor’s Medical Director. Samples may be 
collected at any time point judged appropriate 
by the Investigator with Medical Monitor 
approval. Testing will be conducted by a local 
laboratory.
Tuberculosis testing as requested by Investigator.
Update statistical 
team lead contact 
information
Sponsor Responsible 
Persons
87
EMD Serono Research and Development Institute, 
EMD Serono Research and Development Institute, 
Document No. 
 
Object No. 
 
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Inc.
45A Middlesex Turnpike
Billerica, MA 01821
USA
Inc.
45A Middlesex Turnpike
Billerica, MA 01821
USA
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Amendment 3 - Table 1
Schedule of Assessments – Screening through Week 52
Trial Period
Screening
Weeks During Double-blind Treatment Period (Visit Window ∀3 days)
Week
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
Trial Day
-28 to -1
1
15
29
57
85
113
141
169
197
225
253
281
309
337
365
Informed consent
X
Inclusion/exclusion criteria
X
Xa
Pharmacokinetic informed consent (Rich 
PK sampling only)
X
Demographic data
X
SSc-ILD and other medical history, 
medications, surgery/procedures
X
HRCT
X
X
X
12-lead ECG (locally read)
X
X
X
Tuberculosis assessment
X
Serum virology (HIV, HCV, HBV)
X
Serum pregnancy test c
X
PT, aPTT, TSH, and NT pro-BNP
X
Urine pregnancy test c,d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
Xe
X
Xe
Xe
Xe
Xe
X
Xe
Xe
Xe
Xe
Xe
Xe
X
Vital signs, weight, height f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Mahler BDI/TDI and SGRQ g
X
X
X
X
X
Patient’s Global Assessment, Leicester 
Cough Index, SHAQ, EQ-5D, and 
Physician’s Global Assessment g
X
X
X
Randomization
X
IMP administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Trial Period
Screening
Weeks During Double-blind Treatment Period (Visit Window ∀3 days)
Week
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
Trial Day
-28 to -1
1
15
29
57
85
113
141
169
197
225
253
281
309
337
365
PK sampling h
X
X
X
X
Rich PK sampling i
X
X
X
X
X
Routine hematology, clinical chemistry, 
urinalysis dipstick j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary function tests (FVC, TLC) with 
DLCO k
X
X
X
X
X
X
mRSS
X
X
X
X
X
Digital ulcer countsl
X
X
X
X
X
Serum for ADA
X
X
X
Sample for autoantibodies
X
X
X
Concomitant medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA = antidrug antibodies; AE = adverse event; aPTT = activated partial thromboplastin time; BDI = Baseline Dyspnea Index; DLCO = diffusion capacity of the 
lung for carbon monoxide; ECG = electrocardiogram; FVC = forced vital capacity; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; HRCT = high-resolution computed tomography; IMP = investigational medicinal product; mRSS = modified Rodnan skin score; 
PK = pharmacokinetic; PT = prothrombin time; SGRQ = St. George Respiratory Questionnaire; SHAQ = Scleroderma Health Assessment Questionnaire; 
SSc-ILC = systemic sclerosis-associated interstitial lung disease; TDI = Transition Dyspnea Index; TLC = total lung capacity; TSH = thyroid-stimulating hormone; 
VAS = visual analog scale.
a
Subject eligibility (based on screening assessments of the inclusion and exclusion criteria) must be checked again on Day 1 prior to randomization.
 
c
For women of childbearing potential or who are postmenopausal for less than 2 years. At Day 1, if the urine test is negative, the subject can be randomized and 
receive the first dose of IMP.
d
Performed locally per local constraints and regulations.
e
Focused physical examination only, according to standard of care.
f
Vital signs include 10-minute seated arterial blood pressure, pulse rate, and body temperature. Height will be measured at Day 1 only. Weight will be measured 
at Weeks 0, 24, 52, 76, and 104. Body weight will be measured with a balance beam scale, if possible.
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g
Questionnaires should be completed before any other procedures are performed. Questionnaires should be performed in the following order: Patient’s Global 
Assessment, SHAQ, Mahler BDI (at Day 1) followed by Mahler TDI at the subsequent visits, SGRQ, Leicester Cough Index, and EQ-5D. The Mahler BDI/TDI 
administrator must be blinded to other assessments. The Physician’s Global Assessment (VAS) may be performed after other assessments at the visit are 
completed.
h
For all subjects, samples will be collected predose and immediately after the end of IMP infusion at Weeks 0 (Day 1), 4, 8, and 16.
i
For subjects who have provided informed consent for the rich PK sampling, additional samples will be collected on Days 3, 5, 15, and 22 (in addition to the pre-
and postdose samples at Weeks 0, 4. 8, and 16; see footnote h).
j
See Section 7.4.3 for list of routine laboratory assessments. Urine protein:creatinine ratio to be performed if dipstick urinalysis reveals at least 3+ protein. 
Microscopic urinalysis to be performed if blood is present.
k
The TLC should be performed at Weeks 0, 24, 52, 76, and 104. The DLCO measurements will be corrected for hemoglobin level, and spirometry assessments 
will be centrally adjudicated.
l
Digital ulcers are those distal to the metacarpal phalangeal joints. New or worsening digital ulcers, or at any other site on the body, will be captured as AEs.
 
n
Adverse events should also be assessed for occurrence during the periods between trial visits.
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Amendment 3 - Table 2
Schedule of Assessments – Week 56 through Safety Follow-up
Trial Period
Weeks During Double-blind Treatment Period (Visit Window ∀5 days)
Safety 
Follow-up 
Number 
weeks post 
last dose
visit
(∀5 days)
Survival 
Follow-
up Post 
Last Trial 
Visit
Week
56
60
64
68
72
76
80
84
88
92
96
100
104
ETa
4
12
Every 12 
Weeks
Trial Day
393
421
449
477
505
533
561
589
617
645
673
701
729
HRCT
X
X
12-lead ECG (locally read)
X
X
X
X
Urine pregnancy test b,c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
Xd
Xd
Xd
Xd
Xd
X
Xd
Xd
Xd
Xd
Xd
Xd
X
X
Xd
X
Vital signs, weight e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Mahler TDI and SGRQ f
X
X
X
X
X
X
Patient’s Global Assessment, 
Leicester Cough Index, SHAQ, 
EQ-5D, and Physician’s Global 
Assessment f
X
X
X
IMP administration
X
X
X
X
X
X
X
X
X
X
X
X
Routine hematology, clinical 
chemistry, urinalysis g
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary function tests (FVC, 
TLC) with DLCO h
X
X
X
X
X
X
mRSS
X
X
X
X
X
X
Digital ulcer counts i
X
X
X
X
X
X
Serum for ADA
X
X
X
X
X
Sample for autoantibodies
X
X
Concomitant 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Trial Period
Weeks During Double-blind Treatment Period (Visit Window ∀5 days)
Safety 
Follow-up 
Number 
weeks post 
last dose
visit
(∀5 days)
Survival 
Follow-
up Post 
Last Trial 
Visit
Week
56
60
64
68
72
76
80
84
88
92
96
100
104
ETa
4
12
Every 12 
Weeks
Trial Day
393
421
449
477
505
533
561
589
617
645
673
701
729
medications/procedures
Adverse events j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital status k
X
ADA = antidrug antibodies; AE = adverse event; BDI = Baseline Dyspnea Index; DLCO = diffusion capacity of the lung for carbon monoxide; ECG = 
electrocardiogram; ET = early termination; FVC = forced vital capacity; HRCT = high resolution computed tomography; IMP = investigational medicinal product; 
mRSS = modified Rodnan skin score; SGRQ = St. George Respiratory Questionnaire; SHAQ = Scleroderma Health Assessment Questionnaire; TDI = Transition 
Dyspnea Index; TLC = total lung capacity; VAS = visual analog scale.
a Subjects who discontinue IMP for any reason should complete the ET visit as soon as possible, but within 2 weeks of IMP discontinuation, and then the 
remaining scheduled trial visits. At a minimum, the subject is expected to complete the trial visits at Weeks 12, 24, 36, 52, 64, 76, 88, and 104, as well as the 
Safety Follow-up period Week 12 visit. Subjects with discontinued IMP can come to the other scheduled visits during the trial period according to the 
Investigator's judgment. Subjects who withdraw from the treatment period would have an early termination visit followed by entrance into the Safety Follow-up 
Period. Subjects who withdraw from the trial (eg, withdraw consent, lost to follow up, or death; see Section 5.5.2) would not have any additional trial visits. All 
subjects will be followed up by the site approximately every 12 weeks for survival from the subject’s last trial visit until death or the end of the trial.
b For women of childbearing potential or who are postmenopausal for less than 2 years. Positive urine pregnancy tests should be confirmed with a serum test. If 
the serum pregnancy test is subsequently positive, the subject will be withdrawn from IMP.
c Performed locally per local constraints and regulations.
d Focused physical examination only, according to standard of care.
e Vital signs include 10-minute seated arterial blood pressure, pulse rate, and body temperature. Weight will be measured at Weeks 0, 24, 52, 76, and 104. Body 
weight will be measured with a balance beam scale, if possible.
f Questionnaires should be completed before any other procedures are performed. Questionnaires should be performed in the following order: Patient’s Global 
Assessment, SHAQ, Mahler BDI (at Day 1) followed by Mahler TDI at the subsequent visits, SGRQ, Leicester Cough Index, and EQ-5D. The Mahler BDI/TDI 
administrator must be blinded to other assessments. The Physician’s Global Assessment (VAS) may be performed after other assessments at the visit are 
completed.
g See Section 7.4.3 for list of routine laboratory assessments. Urine protein:creatinine ratio to be performed if dipstick urinalysis reveals at least 3+ protein. 
Microscopic urinalysis to be performed if blood is present.
h The TLC should be performed at Weeks 0, 24, 52, 76, and 104. The DLCO measurements will be corrected for hemoglobin level, and spirometry assessments 
will be centrally adjudicated.
I Digital ulcers are those distal to the metacarpal phalangeal joints. New or worsening digital ulcers, or at any other site on the body, will be captured as AEs. 
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j Adverse events should also be assessed for occurrence during the periods between trial visits.
k Survival follow-up: All subjects will be assessed for survival every 12 weeks (∀1 week) from the last trial visit until death or end of the trial.
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Amendment 4 (applicable only to sites in the USA, Argentina, Australia, 
Israel, and Turkey)
(not included in this document)
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Amendment 5
This is a global amendment, effective 26 July 2017.
Rationale
The purpose of this protocol amendment is to:
! Clarify that the mycophenolate regimen must be the same stable dose for at least 2 month 
prior to entering the trial.
! Extend the possible duration of the Screening Period to 6 weeks (42 days), extending the 
possible total duration of the trial to 122 weeks.
! Allow for changes in mycophenolate background therapy in cases of worsening of ILD on 
HRCT that are considered significant by the Investigator.
! Remove the assessment of TLC.
! Reduce the time window restrictions on the use of immunomodulating, immunosuppressive, 
or disease-modifying agents from 6 months to 2 months (or 5 months for cyclophosphamide).
! Specify that a ratio of FVC % predicted to DCLO % predicted of ≥1.8 is acceptable if right 
heart catheterization within 3 months of Screening revealed no pulmonary hypertension.
! Add an exclusion criterion excluding subjects with severe gastrointestinal disease requiring 
parenteral nutrition.
! Add subgroup analysis and adjustment of the mixed-effects model by duration of prior 
mycophenolate use at baseline (< 6 months versus ≥6 months).
! Clarify the source of instructions in the absence of a manual of procedures.
! Clarify procedures for IMP administration in the event of out-of-window visits.
!
! Specify that randomization will be stratified by duration of mycophenolate use at baseline
(< 6 months and ≥6 months), in addition to baseline FVC % predicted (< 70% versus ≥70%).
! Permit the use of stable doses of hydroxychloroquine and chloroquine administration for at 
least 4 weeks prior to the Screening Period.
! Specify procedures for unblinding in the review of interim analysis results and in PK 
analyses.
! Remove the requirements of repeating HRCT if completed within 2 months of the 
re-screening visit or any TB tests if completed within 3 months of the re-screening visit.
! Clarify the measurement of bicarbonate as an estimator of total carbon dioxide in clinical 
chemistry assessments.
! Specify the plans for blinded sample size review after at least 50% of subjects complete their 
first year of treatment.
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! Clarify the description of protocol deviations as clinically important, rather than major.
The changes to be made to the clinical trial protocol and the rationale for the key scientific 
changes are described below.
Major Scientific Changes
Removal of TLC endpoint and assessment: Other secondary efficacy endpoints are considered 
to sufficiently address the effect of abituzumab on pulmonary function, including assessment of 
FCV % and DLCO %. Eliminating TLC assessment removes the requirement of performing 
body plethsmography testing, affording a lower burden on subjects and trial site staff.
Review of sample size: A blinded sample size review is now planned after at least 50% of the 
subjects complete their first year on treatment. This review will either lead to an increase in the 
total sample size or to a continuation of the trial with the original sample size. Bias will be 
adjusted for, and if the adjusted standard deviation is more than 10% larger than the 
hypothesized standard deviation, then the sample size may be increased by up to 40 subjects.
Administrative and Editorial Changes
The Schedule of Assessments was updated as follows:  
! Extended the possible duration of the Screening Period to 6 weeks (42 days).
!
 
.
! Removed the assessment of TLC.
! Clarified the schedule for rich PK sampling on Days 3, 5, 15, and 22.
The Sponsor’s Medical Responsible contact was changed from 
to 
 
. The date and version number of the protocol were changed throughout and 
minor typographical errors were corrected. Minor editorial revisions were made to enhance 
reader understanding.
List of Changes
Changes to the clinical trial protocol text are presented in the table below. Additions and 
amended text are shown in bold. If the original clinical trial protocol text was already bold, 
changes are shown in bold and underlined; deletions are marked using strike-through.
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Comparison with Clinical Trial Protocol Version 4.0, 14 September 2016 (Amendment No. 3)
Change
Section
Page
Previous Wording
New Wording
Change in Sponsor’s 
Responsible Medical
Title Page
1
Medical Responsible:
EMD Serono Research & Development Institute, Inc.
45A Middlesex Turnpike
Billerica, MA, 01821 USA
Telephone number: 
Fax number: 
Medical Responsible:
EMD Serono Research & Development Institute, Inc.
45A Middlesex Turnpike
Billerica, MA, 01821 USA
Telephone number: 
 
Fax number: 
To clarify that the
mycophenolate 
regimen must be the 
same stable dose for 
at least 2 month prior 
to the Screening 
Visit.
Synopsis, 
Methodology, first 
paragraph
12
Subjects must be currently treated with 
mycophenolate for at least 6 months and at a stable 
dose (1.5 to 3 g/day of mycophenolate mofetil [MMF] 
or 1080 to 2160 mg/day of sodium mycophenolate 
[MPS]) for at least 3 months.
Subjects must be currently treated with
mycophenolate for at least 6 months and at a stable 
dose (1.5 to 3 g/day of mycophenolate mofetil [MMF] 
or 1080 to 2160 mg/day of sodium mycophenolate 
[MPS]) for at least 3 months the same 
mycophenolate regimen (stable dose) in a range 
of 1.5 to 3 g/day of mycophenolate mofetil (MMF) 
or 1080 to 2160 mg/day of sodium mycophenolate 
(MPS) for at least 2 months prior to the Screening 
Visit and continued through Day 1 of the 
Treatment Period.
To extend the 
possible duration of 
the Screening Period.
Synopsis, 
Methodology, third 
paragraph
12
The trial is composed of a Screening Period, a 
Double-blind Treatment Period, a Safety Follow up 
Period, and Survival Follow-up as follows:
! Screening Period: duration of up to 4 weeks; 
however, subjects should have the Day 1 visit as 
soon as possible after eligibility for the trial has 
been confirmed. 
The trial is composed of a Screening Period, a 
Double-blind Treatment Period, a Safety Follow up 
Period, and Survival Follow-up as follows:
! Screening Period: duration of up to 4 6 weeks; 
however, subjects should have the Day 1 visit as 
soon as possible after eligibility for the trial has 
been confirmed. 
To clarify that the use 
of nonbiologic
immunosuppressants 
would require 
discontinuation of 
mycophenolate 
treatment.
Synopsis, 
Methodology, sixth 
paragraph
5.1, Overall Trial 
Design and Plan, 
sixth paragraph
6.5.5, Management 
of Specific Adverse 
Events or Adverse 
13, 
31, 
50
If an immunosuppressant (such as 
cyclophosphamide [oral or intravenous]) is initiated, 
then mycophenolate must be discontinued.
If an a nonbiologic immunosuppressant (such as 
cyclophosphamide [oral or intravenous]) is initiated, 
then mycophenolate must be discontinued.
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Change
Section
Page
Previous Wording
New Wording
Drug Reactions, 
third paragraph, 
second bullet
To allow for changes 
in background 
therapy in cases of 
worsening ILD on 
HRCT that are 
considered by the 
Investigator.
Synopsis, 
Methodology, 
second-to-last 
paragraph
14
New onset or worsening of manifestations of 
scleroderma that are not captured by the pulmonary 
function tests, modified Rodnan skin score (mRSS), 
or digital ulcer count, should be reported as AEs.
During the conduct of the trial, an Independent Data 
Monitoring Committee (IDMC) will monitor safety 
data on a regular basis (to be specified in the IDMC 
charter). […]
New onset or worsening of manifestations of 
scleroderma that are not captured by the pulmonary 
function tests, modified Rodnan skin score (mRSS), 
or digital ulcer count, should be reported as AEs.
If the ILD on HRCT worsens significantly 
according to the Investigator, then subjects can 
have the mycophenolate treatment increased to 
the protocol-specified maximal dose (ie, 3 g/day 
MMF or 2160 mg/day MPS).
During the conduct of the trial, an Independent Data 
Monitoring Committee (IDMC) will monitor safety 
data on a regular basis (to be specified in the IDMC 
charter). […]
To remove 
assessment of TLC. 
Synopsis, 
Secondary Efficacy 
Endpoints
Section 8.3.2
15, 
66
[…]
! Absolute change from baseline in FVC % 
predicted up to Week 104;
! Absolute change from baseline in total lung 
capacity (TLC) % predicted up to Week 104;
! Absolute change from baseline in DLCO % 
predicted up to Week 104;
[…]
[…]
! Absolute change from baseline in FVC % 
predicted up to Week 104;
! Absolute change from baseline in total lung 
capacity (TLC) % predicted up to Week 104;
! Absolute change from baseline in DLCO %
predicted up to Week 104;
[…]
To clarify that the
mycophenolate 
regimen must be the 
same stable dose for 
at least 2 month prior 
to entering the trial.
Synopsis, 
Diagnosis and Key 
Inclusion and 
Exclusion Criteria, 
first paragraph
17
Male or female subjects between 18 and 75 years of 
age who provide written consent and fulfill the 2013 
American College of Rheumatology/European 
League Against Rheumatism criteria for classification 
of SSc, have been taking mycophenolate for at least 
6 months with a stable dose (1.5 to 3 g/day of MMF 
or 1080 to 2160 mg/day of MPS) for at least 
3 months, have at least 5% fibrosis of the lung on 
HRCT according to central reading, have a disease 
duration of < 7 years from the first non-Raynaud’s 
symptom, DLCO ≥30% predicted, FVC 40% to 85% 
predicted, ratio of FVC to DLCO % predicted < 1.8, 
and agree to use a highly effective method of 
Male or female subjects between 18 and 75 years of 
age who provide written consent and fulfill the 
2013 American College of Rheumatology/European 
League Against Rheumatism criteria for classification 
of SSc, have been taking mycophenolate for at least 
6 months with a stable dose (1.5 to 3 g/day of MMF 
or 1080 to 2160 mg/day of MPS) for at least 3 
months the same mycophenolate regimen (stable 
dose) in a range of 1.5 to 3 g/day of MMF or 
1080 to 2160 mg/day of MPS for at least 2 months 
prior to the Screening Visit and continued 
through Day 1 of the Treatment Period, have at 
least 5% fibrosis of the lung on HRCT according to 
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Change
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Previous Wording
New Wording
contraception for the duration of their participation in 
the trial meet the inclusion criteria.
central reading, have a disease duration of < 7 years 
from the first non-Raynaud’s symptom, DLCO ≥30% 
predicted, FVC 40% to 85% predicted, ratio of FVC 
to DLCO % predicted < 1.8, and agree to use a 
highly effective method of contraception for the 
duration of their participation in the trial meet the 
inclusion criteria.
To reduce the time 
window restrictions 
on the use of 
immunomodulating, 
immunosuppressive, 
or disease-modifying 
agents.
Synopsis, 
Diagnosis and Key 
Inclusion and 
Exclusion Criteria, 
second paragraph
17
The use of agents other than mycophenolate (MPS 
or MMF) considered by the Investigator to have 
immunomodulating, immunosuppressive, or potential 
scleroderma disease-modifying properties within 
6 months of screening is not allowed.
The use of agents other than mycophenolate (MPS 
or MMF) considered by the Investigator to have 
immunomodulating, immunosuppressive, or potential 
scleroderma disease-modifying properties within 6 
2 months of the sScreening Visit is not allowed (or 
5 months prior to the Screening Visit for 
cyclophosphamide).
To extend the 
possible duration of 
the Screening Period.
Synopsis, Planned 
Trial and Treatment 
Duration Per 
Subject
17
The planned total duration of the trial period with 
study visits is up to 120 weeks for each subject, 
including a 4-week Screening Period, a 104-week 
Double-blind Treatment Period, and a 12-week 
Safety Follow-up Period. 
The planned total duration of the trial period with 
study visits is up to 120 122 weeks for each subject, 
including a 4-week 6-week Screening Period, a 104-
week Double-blind Treatment Period, and a 12-week 
Safety Follow-up Period. 
Section 5.1, second 
paragraph
30
The planned total duration of the trial is up to 
120 weeks […]:
! Screening Period: duration of up to 4 weeks […].
The planned total duration of the trial is up to 120 
122 weeks […]:
! Screening Period: duration of up to 4 6 weeks […].
To specify 
adjustment of the 
mixed-effects model 
by duration of prior 
mycophenolate use 
at baseline.
Synopsis, 
Statistical Analysis, 
last paragraph
Section 8.5.2, first 
paragraph
18, 
70
The model will include random coefficients for 
intercept and time, fixed-effect terms for treatment 
and time, treatment-by-time as the interaction term, 
and adjusting for baseline FVC, age, sex, and height. 
The model will include random coefficients for 
intercept and time, fixed-effect terms for treatment 
and time, treatment-by-time as the interaction term, 
and adjusting for baseline FVC, duration of prior 
mycophenolate use at baseline, age, sex, and 
height. 
To extend the 
possible duration of 
the Screening Period. 
To clarify the 
schedule of rich PK 
sampling.
 
 
 
 
Schedules of 
Assessments
20-24
Refer to Amendment 5 - Tables 1 and 2, below.
Refer to Amendment 5 - Tables 1 and 2, below.
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Change
Section
Page
Previous Wording
New Wording
 To remove 
TLC-related 
assessments.
To clarify the source 
of instructions in the 
absence of a manual 
of procedures.
Section 2, 
second-to-last 
paragraph
25
Details of structures and associated procedures will 
be defined in a separate Manual of Operations, which 
will be prepared under the supervision of the clinical 
trial leader.
Details of structures and associated procedures will 
be defined in a separate Manual of Operations, which 
will be prepared under the supervision of the clinical 
trial leader the instructions and/or flow charts 
provided by each of the third-party vendors 
participating in the EMR200017-014 trial.
To clarify that the 
mycophenolate 
regimen must be the 
same stable dose for 
at least 2 month prior 
to entering the trial.
Section 5.1, first 
paragraph
30
Subjects must have had mycophenolate treatment for 
at least 6 months and remained at a stable dose 
(1.5 to 3 g/day of mycophenolate mofetil [MMF] or 
1080 to 2160 mg/day of sodium mycophenolate 
[MPS]) for at least 3 months. 
Subjects must have had mycophenolate treatment for 
at least 6 months and remained at a stable dose 
(1.5 to 3 g/day of mycophenolate mofetil [MMF] or 
1080 to 2160 mg/day of sodium mycophenolate 
[MPS]) for at least 3 months received the same 
mycophenolate treatment (ie, stable dose) in a 
range of 1.5 to 3 g/day of mycophenolate mofetil 
(MMF) or 1080 to 2160 mg/day of sodium 
mycophenolate (MPS) for at least 2 months prior 
to the Screening Visit and continued through 
Day 1 of the Treatment Period. 
To remove 
assessment of TLC. 
Section 5.1, 11th
paragraph
31
During the Double-blind Treatment Period, efficacy 
assessments will include evaluations of pulmonary 
function (forced vital capacity [FVC], total lung 
capacity [TLC], DLCO), HRCT, and PRO 
questionnaires.
During the Double-blind Treatment Period, efficacy 
assessments will include evaluations of pulmonary 
function (forced vital capacity [FVC], total lung 
capacity [TLC], and DLCO), HRCT, and PRO 
questionnaires.
To reduce the time 
window restrictions 
on the use of 
immunomodulating, 
immunosuppressive, 
or disease-modifying 
agents.
Section 5.2.3, last 
paragraph
34
Immunosuppressant and other potentially 
disease-modifying treatment use within 6 months of 
screening is likewise excluded in order to decrease 
confounding trial results. 
Immunosuppressant and other potentially 
disease-modifying treatment use within 6 2 months of 
the sScreening Visit (or cyclophosphamide use 
within 5 months of the Screening Visit) is likewise 
excluded in order to decrease confounding trial 
results. 
To clarify the source 
of instructions in the 
absence of a manual 
of procedures.
Section 5.2.4, last 
paragraph
35
Detailed procedures for performing pulmonary 
function assessments are included in a separate 
manual of procedures.
Detailed procedures for performing pulmonary 
function assessments are included in a separate 
manual of proceduresthe Instructions for Use 
 and Procedural Manual for 
DLCO testing provided by 
 
.
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To align discussion 
with the removal of 
the TLC-related 
endpoint.
Section 5.2.5, third 
paragraph
35
Total lung capacity as an additional lung function 
measurement will be included as a secondary 
endpoint. Forced vital capacity will also be assessed 
using categorical measures to define potential 
responders.
Total lung capacity as an additional lung function 
measurement will be included as a secondary 
endpoint. Forced vital capacity will also be assessed 
using categorical measures to define potential 
responders.
To specify that a ratio 
of FVC % predicted 
to DCLO % predicted 
of ≥1.8 is acceptable 
if right heart 
catheterization within 
3 months of 
Screening revealed 
no pulmonary 
hypertension, and to 
clarify the procedure 
for rounding FVC % 
predicted values.
Section 5.3.1
39
4. According to central readings: DLCO ≥30% 
predicted, FVC 40% to 85% predicted, and ratio of 
FVC % predicted to DLCO % predicted < 1.8. If these 
criteria are met, then HRCT of lungs will be 
performed, and must show at least 5% fibrosis for 
subjects to be eligible.
4. According to central readings: DLCO ≥30% 
predicted, FVC 40% to 85% predicted1, and ratio of 
FVC % predicted to DLCO % predicted < 1.8. A ratio 
of FVC % predicted to DLCO % predicted ≥1.8 is 
acceptable if right heart catheterization within 
3 months of Screening revealed no pulmonary 
hypertension. If these criteria are met, then HRCT 
of lungs will be performed, and must show at least 
5% fibrosis for subjects to be eligible.
1 The FVC % predicted that is reported by central 
reading will be rounded to the nearest whole 
number. If the number that follows the decimal 
point is ≤4, the FVC % predicted will be rounded 
down to the next whole number; if it is ≥5, the 
FVC % predicted will be rounded up to the next 
whole number.
To clarify that the 
mycophenolate 
regimen must be the 
same stable dose for 
at least 2 month prior 
to entering the trial.
Section 5.3.1
39
5. Use of mycophenolate for at least 6 months before 
the Screening Visit. The dose must be stable for at 
least 3 months prior to screening and be in the range 
as follows: MMF 1.5 to 3 g/day, MPS 1080 to 
2160 mg/day.
5. Use of mycophenolate for at least 6 months before 
the Screening Visit. The dose must be stable for at 
least 3 months prior to screening and be in the range 
as follows: MMF 1.5 to 3 g/day, MPS 1080 to 
2160 mg/daythe same mycophenolate regimen (ie, 
stable dose) in a range of 1.5 to 3 g/day of MMF 
or 1080 to 2160 mg/day or MPS, for at least 
2 months prior to the Screening Visit and 
continued through Day 1 of the Treatment Period.
To clarify the window 
for detection of 
pulmonary 
hypertension using 
right heart 
catheterization prior 
to the Screening 
Visit.
Section 5.3.2
41
7. Pulmonary hypertension that fulfills at least one of 
the following: 
[…]
! At screening, N-terminal prohormone brain 
natriuretic peptide (NT pro-BNP) > 3× the upper 
limit of normal (ULN), unless, for example, right 
heart catheterization performed within 2 months 
did not reveal pulmonary hypertension.
7. Pulmonary hypertension that fulfills at least one of 
the following: 
[…]
! At screening, N-terminal prohormone brain 
natriuretic peptide (NT pro-BNP) > 3× the upper 
limit of normal (ULN), unless, for example, right 
heart catheterization performed within 2 3 months 
of the Screening Visit did not reveal pulmonary 
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hypertension.
To reduce the time 
window restrictions 
on the use of 
immunomodulating, 
immunosuppressive, 
or disease-modifying 
agents, with the 
exception of 
cyclophosphamide.
Section 5.3.2
42
17. Use of agents other than mycophenolate (MPS or 
MMF) considered by the Investigator to have 
immunomodulating, immunosuppressive, or potential 
scleroderma disease-modifying properties within 
6 months of screening. Examples of these agents 
include, but are not limited to, pirfenidone, 
nintedanib, cyclophosphamide, methotrexate, 
azathioprine, leflunomide, calcineurin inhibitors, 
D-penicillamine, Potaba, and AIMSPRO. 
Hydroxychloroquine or chloroquine are permitted if 
dose has been stable for at least 4 weeks before 
screening.
17. Use of agents other than mycophenolate (MPS or 
MMF) considered by the Investigator to have 
immunomodulating, immunosuppressive, or potential 
scleroderma disease-modifying properties within 6 
2 months of the sScreening Visit. Examples of these 
agents include, but are not limited to, pirfenidone, 
nintedanib, cyclophosphamide, methotrexate,
azathioprine, leflunomide, calcineurin inhibitors, 
D-penicillamine, Potaba, and AIMSPRO. The use of 
cyclophosphamide within 5 months of the 
Screening Visit is not permitted.
Hydroxychloroquine or chloroquine are permitted if 
dose has been stable for at least 4 weeks before the
sScreening Visit.
To exclude subjects 
with a history of 
anti-CD20 B-cell 
depleting therapy 
within 6 months of 
the Screening Visit.
Section 5.3.2
42
20. History of anti-CD20 B-cell depleting therapy, eg, 
rituximab or ocrelizumab.
20. History of anti-CD20 B-cell depleting therapy, eg, 
rituximab or ocrelizumab, within 6 months prior to 
the Screening Visit.
To clarify exclusion of 
subjects with a 
history of lung 
resection.
Section 5.3.2
43
29. Major surgery requiring hospitalization within 4 
weeks prior to the Screening Visit and any planned 
major surgery for the duration of the trial. Subjects 
with lung resection.
29. Major surgery requiring hospitalization within 
4 weeks prior to the Screening Visit and any planned 
major surgery for the duration of the trial. Subjects 
with a history of lung resection.
To exclude subjects 
with severe 
gastrointestinal 
disease requiring 
parenteral nutrition.
Section 5.3.2
43
30. 
Have a history of a major organ transplant 
(eg, heart, lung, kidney, or liver) or hematopoietic 
stem cell/marrow transplant or are due to receive 
transplantation.
30. 
Have a history of a major organ transplant 
(eg, heart, lung, kidney, or liver) or hematopoietic 
stem cell/marrow transplant or are due to receive 
transplantation.
31.
Severe gastrointestinal disease requiring 
parenteral nutrition.
To clarify procedures 
for IMP 
administration in the 
event of 
out-of-window visits.
Section 6.2, last 
paragraph
46
In the Double-blind Treatment Period, subjects will be 
randomized in a 2:2:1 ratio to receive one of the 
following treatments: abituzumab 1500 mg, placebo, 
or abituzumab 500 mg, respectively. Treatment will 
be given as an intravenous infusion over 
approximately 1 hour every 4 weeks. The infusion 
time should not be less than 1 hour. Close 
In the Double-blind Treatment Period, subjects will be 
randomized in a 2:2:1 ratio to receive one of the 
following treatments: abituzumab 1500 mg, placebo, 
or abituzumab 500 mg, respectively. Treatment will 
be given as an intravenous infusion over 
approximately 1 hour every 4 weeks. The infusion 
time should not be less than 1 hour. Close 
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observation of the subject is recommended for a 
period of at least 1 hour after administration of IMP. 
The last IMP/placebo administration will be at the 
Week 100 visit.
observation of the subject is recommended for a 
period of at least 1 hour after administration of IMP. 
The last IMP/placebo administration will be at the 
Week 100 visit.
If administration of IMP or placebo cannot be 
performed within the specified protocol visit 
window, the decision to administer IMP or 
placebo outside of the window will be determined 
on a case-by-case basis after a discussion with 
the Medical Monitor and the Sponsor’s Medical 
Director.
To specify that 
stratification will 
occur by duration of 
mycophenolate use 
at baseline.
Section 6.3, first 
paragraph
46
After completion of all screening evaluations, all 
eligible subjects will be randomly allocated in a 2:2:1 
randomization ratio to 1 of the 3 treatment groups: 
abituzumab 1500 mg, placebo, or abituzumab 
500 mg, respectively. Randomization in permuted 
blocks will be conducted by a central interactive 
voice/web response system (IVRS/IWRS) provider. 
Randomization will be stratified by baseline FVC % 
predicted (< 70% versus ≥70%).
After completion of all screening evaluations, all 
eligible subjects will be randomly allocated in a 2:2:1 
randomization ratio to 1 of the 3 treatment groups: 
abituzumab 1500 mg, placebo, or abituzumab 
500 mg, respectively. Randomization in permuted 
blocks will be conducted by a central interactive 
voice/web response system (IVRS/IWRS) provider. 
Randomization will be stratified by baseline FVC % 
predicted (< 70% versus ≥70%) and by duration of 
mycophenolate use at baseline (< 6 months 
versus ≥6 months).
To permit the use of 
stable doses of 
hydroxychloroquine 
and chloroquine 
administration for at 
least 4 weeks prior to 
the Screening Visit.
Section 6.5.1, 
fourth paragraph
47
Dosing of mycophenolate must be kept stable during 
the Double-blind Treatment Period, unless a change 
in dose is warranted by clinically meaningful disease 
progression (see Section 6.5.5). 
Dosing of mycophenolate must be kept stable during 
the Double-blind Treatment Period, unless a change 
in dose is warranted by clinically meaningful disease 
progression (see Section 6.5.5). 
Hydroxychloroquine or chloroquine are permitted 
if dose has been stable for at least 4 weeks prior 
to the Screening Visit.
To clarify restrictions 
on the use of 
immunomodulating, 
immunosuppressive, 
or disease-modifying 
agents, including 
cyclophosphamide.
Section 6.5.2, 
second paragraph
48
The use of agents other than mycophenolate (MPS 
or MMF) considered by the Investigator to have 
immunomodulating, immunosuppressive, or potential 
scleroderma disease-modifying properties within 
6 months of screening is not permitted.
The use of agents other than mycophenolate (MPS 
or MMF) considered by the Investigator to have 
immunomodulating, immunosuppressive, or potential 
scleroderma disease-modifying properties within 6 
2 months of the sScreening Visit is not permitted. 
The use of cyclophosphamide within 5 months of 
the Screening Visit is not permitted.
To allow for changes 
in background 
Section 6.5.5, last 
paragraph
50
If a subject discontinues IMP, then the subject should 
complete the early termination visit and then the 
If a subject discontinues IMP, then the subject should 
complete the early termination visit and then the 
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therapy in cases of 
worsening ILD on 
HRCT that are 
considered significant 
by the Investigator.
remaining scheduled visits (refer to Table 1 and 
Table 2). All subjects will be followed up by the site 
for survival from the last visit on trial until death or 
end of the trial. New onset or worsening of 
manifestations of scleroderma that are not captured 
by the pulmonary function tests, mRSS, or digital 
ulcer score, should be reported as AEs. On the eCRF 
AE page, such events should be marked as ‘yes’ in 
response to the question “Is this a manifestation of 
worsening scleroderma?”
remaining scheduled visits (refer to Table 1 and 
Table 2). All subjects will be followed up by the site 
for survival from the last visit on trial until death or 
end of the trial. New onset or worsening of 
manifestations of scleroderma that are not captured 
by the pulmonary function tests, mRSS, or digital 
ulcer score, should be reported as AEs. On the eCRF 
AE page, such events should be marked as ‘yes’ in 
response to the question “Is this a manifestation of 
worsening scleroderma?”.
If the ILD on HRCT worsens significantly 
according to the Investigator, then subjects can 
have the mycophenolate treatment increased to 
the protocol-specified maximal dose (i.e., 3 g/day 
MMF or 2160 mg/day MPS).
To specify 
procedures for 
unblinded review of 
interim analysis 
results.
Section 6.10, fifth 
paragraph
53
An independent statistical center will support the 
IDMC for safety analysis and the interim futility 
analysis. 
An independent statistical center will support the 
IDMC for safety analysis and the interim futility 
analysis. 
A team from the Sponsor, independent of the 
CRO trial team, will be tasked with review of the 
unblinded interim analysis results. Details will be 
provided in the Firewall Charter.
To clarify unblinding 
procedures for PK 
analyses.
Section 6.10, sixth 
paragraph
53
The primary analysis will be performed by the 
Sponsor/CRO staff while the trial is ongoing for 
subjects who are still under trial treatment during the 
second year. To ensure the integrity of the trial 
conduct, results of primary analysis will be generated 
on the aggregate group level and reviewed by a 
restricted group to limit initial dissemination. The 
access of individual treatment information will be 
controlled so as not to impact the trial conduct. The 
sites and subjects remain blinded until the end of the 
trial. 
It is acknowledged that in the case of safety events, 
certain subject treatment information may be 
unintentionally revealed in the aggregate output of 
the primary analysis. 
The primary analysis will be performed by the 
Sponsor/CRO staff while the trial is ongoing for 
subjects who are still under trial treatment during the 
second year. To ensure the integrity of the trial 
conduct, results of primary analysis will be generated 
on the aggregate group level and reviewed by a 
restricted group to limit initial dissemination. The 
access of individual treatment information will be 
controlled so as not to impact the trial conduct. The 
sites and subjects remain blinded until the end of the 
trial. 
The bioanalytical laboratory(ies) responsible for 
the analysis of the PK samples will be allowed to 
be unblinded to treatment so as not to analyze 
the samples from the placebo-treated subjects. 
The subject identifiers will be masked from any 
results of the PK analyses transferred to the 
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Sponsor before the final database lock.
It is acknowledged that in the case of safety events, 
certain subject treatment information may be 
unintentionally revealed in the aggregate output of 
the primary analysis. 
To extend the 
possible duration of 
the Screening Period.
Section 7.1.1, first 
paragraph
54
The subject’s eligibility will be assessed at a 
Screening Visit that will occur within 28 days prior to 
Day 1. 
The subject’s eligibility will be assessed at a 
Screening Visit that will occur within 28 42 days prior 
to Day 1. 
To remove the 
requirement of 
repeating HRCT or 
QuantiFERON-TB 
tests during 
re-screening if 
completed within 2 or 
3 months, 
respectively, of the 
re-screening visit.
Section 7.1.1, 
second paragraph
54
Re-screening is not encouraged. However, on a 
case-by-case basis with permission of the Medical 
Monitor and the Sponsor’s Medical Director, a 
subject who has not met all of the eligibility criteria 
within the original screening period may be permitted 
to be re-screened one time. Each subject must be 
re-consented before re-screening occurs. A new 
subject number will be assigned and all screening 
assessments have to be repeated.
Re-screening is not encouraged. However, on a 
case-by-case basis with permission of the Medical 
Monitor and the Sponsor’s Medical Director, a 
subject who has not met all of the eligibility criteria 
within the original screening period may be permitted 
to be re- screened one time. An HRCT would not 
need to be repeated if completed within 2 months 
of the re-screening visit. Any TB test, including 
negative TB skin test with purified protein 
derivative, QuantiFERON-TB, or T-SPOT, would 
not need to be repeated if completed within 
3 months of the re-screening visit. Each subject 
must be re-consented before re-screening occurs. A 
new subject number will be assigned and all 
screening assessments have to be repeated.
To remove 
assessment of TLC. 
Section 7.3, first 
and third paragraph
56
Efficacy assessments include evaluation of lung 
function (FVC, DLCO, and TLC) and lung 
abnormalities on HRCT.
[…]
For all subjects, HRCT scans will be performed at 
TLC with no contrast agent administration, 
reconstructed every 0.6 to 2 mm, using a low-dose 
protocol.
Efficacy assessments include evaluation of lung 
function (FVC, and DLCO, and TLC) and lung 
abnormalities on HRCT.
[…]
For all subjects, HRCT scans will be performed at 
TLC with no contrast agent administration, 
reconstructed every 0.6 to 2 mm, using a low-dose 
protocol.
To clarify the source 
of instructions in the 
absence of a manual 
of procedures.
Section 7.4.3, 
second paragraph
63
Samples will be collected, processed, and stored in 
accordance with the directions provided in a separate 
Manual of Operations. 
Samples will be collected, processed, and stored in 
accordance with the directions provided in a separate 
Manual of Operationsthe 
 Flow Chart. 
To clarify 
measurement used 
Section 7.4.3, 
63
Total carbon dioxide
Total carbon dioxide Bicarbonate
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as an estimator of 
total carbon dioxide.
Table 4
To clarify the source 
of instructions in the 
absence of a manual 
of procedures.
Section 7.5, last 
paragraph
64
Instructions for the collection, storage, handling, and 
shipping of PK samples will provided in the Manual of 
Operations.
Instructions for the collection, storage, handling, and 
shipping of PK samples will provided in the Manual of 
Operations
 Flow Chart.
 
 
Section 7.5, third 
paragraph
64
 
 
 
.
To clarify the source 
of instructions in the 
absence of a manual 
of procedures.
Section 7.6, last 
paragraph
65
Details about the laboratory and 
 sampling 
and processing procedures and transportation will be 
provided in the Manual of Operations.
Details about the laboratory and 
 sampling 
and processing procedures and transportation will be 
provided in the Manual of Operations
 
Flow Chart.
To specify the plans 
for blinded sample 
size review.
Section 8.1, first 
paragraph
65
The inclusion of abituzumab 500 mg in conjunction 
with abituzumab 1500 mg will support abituzumab 
exposure-response analysis for dosing optimization.
The inclusion of abituzumab 500 mg in conjunction 
with abituzumab 1500 mg will support abituzumab 
exposure-response analysis for dosing optimization.
A blinded sample size review is planned after at 
least 50% of the subjects complete their first year 
on treatment. The review will either lead to an 
increase in the total sample size or to a 
continuation of the trial with the original sample 
size. Following Kieser 2003, the estimated 
one-sample variance will be adjusted for bias. If 
the adjusted standard deviation is more than 10% 
larger than the hypothesized standard deviation 
(ie, 330 mL or more), then the sample size may be 
increased by up to 40 subjects. Details will be 
provided in the Statistical Analysis Plan.
To specify that 
stratification will also 
occur by duration of 
mycophenolate use 
at baseline.
Section 8.2, last 
paragraph
65
Randomization will be conducted in permuted blocks 
by a central IVRS/IWRS provider and stratified by 
baseline FVC % predicted (< 70% versus ≥70%).
Randomization will be conducted in permuted blocks 
by a central IVRS/IWRS provider and stratified by 
baseline FVC % predicted (< 70% versus ≥70%)
and by duration of mycophenolate use at 
baseline (< 6 months versus ≥6 months).
To clarify the 
description of 
Section 8.4.3, first 
69
The Per-Protocol (PP) Population will consist of all 
randomized and treated subjects who do not have 
The Per-Protocol (PP) Population will consist of all 
randomized and treated subjects who do not have 
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protocol deviations as 
clinically important.
paragraph
any major protocol deviations. Subjects will be 
analyzed according to their randomized treatment. 
The following are criteria for inclusion in the PP 
Population:
! Compliance with all entry criteria;
! Absence of major clinical trial protocol violations 
with respect to factors likely to affect the efficacy of 
treatment;
! Adequate compliance with and sufficient exposure 
to IMP.
The criteria will be defined in detail in the Statistical 
Analysis Plan and major protocol violators to be 
excluded from the PP Population will be identified 
prior the database lock for the primary analysis.
any major clinically important protocol deviations. 
Subjects will be analyzed according to their 
randomized treatment. 
The following are criteria for inclusion in the PP 
Population:
! Compliance with all entry criteria;
! Absence of major clinically important clinical trial 
protocol violations with respect to factors likely to 
affect the efficacy of treatment;
! Adequate compliance with and sufficient exposure 
to IMP.
The criteria will be defined in detail in the Statistical 
Analysis Plan, and major clinically important
protocol violators to be excluded from the 
PP Population will be identified prior the database 
lock for the primary analysis.
To add duration of 
prior mycophenolate 
use to subgroup 
analysis.
Section 8.5.1, last 
paragraph
70
The subgroups of interest will be prespecified in the 
Statistical Analysis Plan, including the stratification 
factor, baseline FVC % predicted (< 70% versus 
≥70%).
The subgroups of interest will be prespecified in the 
Statistical Analysis Plan, including the stratification 
factors of, baseline FVC % predicted (< 70% versus 
≥70%), and duration of prior mycophenolate use 
(< 6 months versus ≥6 months).
To specify 
adjustment of the 
mixed-effects model 
by duration of prior 
mycophenolate use 
at baseline.
Section 8.5.3, first 
paragraph
71
Analysis of Key Secondary Efficacy Endpoints
The key secondary endpoints will be tested for 
abituzumab 1500 mg versus placebo, using data for 
subjects on trial treatment, in the following order after 
the primary endpoint is met.
1.
The Mahler TDI at Week 52 will be analyzed 
using a mixed-effects model adjusting for 
baseline FVC% predicted and Mahler BDI. 
2.
The absolute change in SGRQ total score at 
Week 52 will be analyzed using a mixed effects 
model adjusting for baseline FVC% predicted 
and baseline SGRQ score.
3.
The absolute change from baseline in mRSS at 
Week 52 in subjects with dcSSc at baseline will 
be analyzed using a mixed effects model 
adjusting for baseline FVC% predicted and 
Analysis of Key Secondary Efficacy Endpoints
The key secondary endpoints will be tested for 
abituzumab 1500 mg versus placebo, using data for 
subjects on trial treatment, in the following order after 
the primary endpoint is met.
1.
The Mahler TDI at Week 52 will be analyzed 
using a mixed-effects model adjusting for 
baseline FVC% predicted, duration of prior 
mycophenolate use at baseline, and Mahler 
BDI. 
2.
The absolute change in SGRQ total score at 
Week 52 will be analyzed using a mixed effects 
model adjusting for baseline FVC% predicted, 
duration of prior mycophenolate use at 
baseline, and baseline SGRQ score.
3.
The absolute change from baseline in mRSS at 
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baseline mRSS.
4.
The absolute change from baseline in QLF in the 
region of highest severity at Week 52 will be 
analyzed using an ANCOVA model adjusting for 
baseline FVC% predicted and baseline QLF. 
5.
Overall survival will be analyzed using a 
stratified log-rank test and presented by Kaplan 
Meier estimates and 95% confidence interval, 
including the survival data available up to the 
analysis cut-off date. A Cox proportional hazards 
regression model will be used to obtain hazard 
ratios and 95% confidence intervals adjusting for 
baseline FVC% predicted.
[…]
Analysis of Other Secondary Efficacy Endpoints
[…] A Cox proportional hazards regression model will 
be used to obtain hazard ratios and 95% confidence 
intervals adjusting for baseline FVC % predicted.
Week 52 in subjects with dcSSc at baseline will 
be analyzed using a mixed effects model 
adjusting for baseline FVC% predicted, duration 
of prior mycophenolate use at baseline, and 
baseline mRSS.
4.
The absolute change from baseline in QLF in the 
region of highest severity at Week 52 will be 
analyzed using an ANCOVA model adjusting for 
baseline FVC% predicted, duration of prior 
mycophenolate use at baseline, and baseline 
QLF. 
5.
Overall survival will be analyzed using a 
stratified log-rank test and presented by Kaplan 
Meier estimates and 95% confidence interval, 
including the survival data available up to the 
analysis cut-off date. A Cox proportional hazards 
regression model will be used to obtain hazard 
ratios and 95% confidence intervals adjusting for 
baseline FVC% predicted and duration of prior 
mycophenolate use at baseline.
[…]
Analysis of Other Secondary Efficacy Endpoints
[…] A Cox proportional hazards regression model will 
be used to obtain hazard ratios and 95% confidence 
intervals adjusting for baseline FVC % predicted and 
duration of prior mycophenolate use at baseline.
To clarify the source 
of instructions in the 
absence of a manual 
of procedures.
Section 10.1, first 
paragraph
76
Refer to the Manual of Operations for eCRF handling 
guidelines.
Refer to the Manual of Operations eCRF 
Completion Guidelines for eCRF handling 
guidelines instructions. 
Change in Sponsor’s 
Protocol Lead
Signature Page –
Protocol Lead
83
EMD Serono Research & Development Institute, Inc.
45A Middlesex Turnpike
Billerica, MA, 01821 USA
Telephone number: 
Fax number: 
EMD Serono Research & Development Institute, Inc.
45A Middlesex Turnpike
Billerica, MA, 01821 USA
Telephone number: 
 
Fax number: 
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Abituzumab
Abituzumab in SSc-ILD
EMR200017-014
153/159
Change
Section
Page
Previous Wording
New Wording
Change in Sponsor’s 
 
Sponsor 
Responsible 
Persons
87
EMD Serono Research and Development Institute, 
Inc.
45A Middlesex Turnpike
Billerica, MA 01821
USA
EMD Serono Research and Development Institute, 
Inc.
45A Middlesex Turnpike
Billerica, MA 01821
USA
Change in Sponsor’s 
 
Sponsor 
Responsible 
Persons
87
EMD Serono Research and Development Institute, 
Inc.
45A Middlesex Turnpike
Billerica, MA 01821
USA
EMD Serono Research and Development Institute, 
Inc.
45A Middlesex Turnpike
Billerica, MA 01821
USA
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Abituzumab
Abituzumab in SSc-ILD
EMR200017-014
154/159
Amendment 5 – Table 1
Schedule of Assessments – Screening through Week 52
Trial Period
Screening
Weeks During Double-blind Treatment Period (Visit Window ∀3 days)
Week
0
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
Trial Day
-28 42 to -1
1
3
5
15
22
29
57
85
113
141
169
197
225
253
281
309
337
365
Informed consent
X
Inclusion/exclusion 
criteria
X
Xa
Pharmacokinetic 
informed consent (Rich 
PK sampling only)
X
Demographic data
X
SSc-ILD and other 
medical history, 
medications, 
surgery/procedures
X
HRCT
X
X
X
12-lead ECG (locally 
read)
X
X
X
Tuberculosis 
assessment
X
Serum virology (HIV, 
HCV, HBV)
X
Serum pregnancy test c
X
PT, aPTT, TSH, and 
NT pro-BNP
X
Urine pregnancy test c,d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
Xe
X
Xe
Xe
Xe
Xe
X
Xe
Xe
Xe
Xe
Xe
Xe
X
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Abituzumab
Abituzumab in SSc-ILD
EMR200017-014
155/159
Trial Period
Screening
Weeks During Double-blind Treatment Period (Visit Window ∀3 days)
Week
0
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
Trial Day
-28 42 to -1
1
3
5
15
22
29
57
85
113
141
169
197
225
253
281
309
337
365
Vital signs, weight, 
height f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Mahler BDI/TDI and 
SGRQ g
X
X
X
X
X
Patient’s Global 
Assessment, Leicester 
Cough Index, SHAQ, 
EQ-5D, and Physician’s 
Global Assessment g
X
X
X
Randomization
X
IMP administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sampling h
X
X
X
X
Rich PK sampling i
X
X
X
X
Routine hematology, 
clinical chemistry, 
urinalysis dipstick j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary function 
tests (FVC, TLC) with 
DLCO) k
X
X
X
X
X
X
mRSS
X
X
X
X
X
Digital ulcer counts l
X
X
X
X
X
Serum for ADA
X
X
X
Sample for 
autoantibodies
X
X
X
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Abituzumab
Abituzumab in SSc-ILD
EMR200017-014
156/159
Trial Period
Screening
Weeks During Double-blind Treatment Period (Visit Window ∀3 days)
Week
0
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
Trial Day
-28 42 to -1
1
3
5
15
22
29
57
85
113
141
169
197
225
253
281
309
337
365
Concomitant 
medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events no
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA = antidrug antibodies; AE = adverse event; aPTT = activated partial thromboplastin time; BDI = Baseline Dyspnea Index; DLCO = diffusion capacity of the 
lung for carbon monoxide; ECG = electrocardiogram; FVC = forced vital capacity; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; HRCT = high-resolution computed tomography; IMP = investigational medicinal product; mRSS = modified Rodnan skin score; 
PK = pharmacokinetic; PT = prothrombin time; SGRQ = St. George Respiratory Questionnaire; SHAQ = Scleroderma Health Assessment Questionnaire; 
SSc-ILC = systemic sclerosis-associated interstitial lung disease; TDI = Transition Dyspnea Index; TLC = total lung capacity; TSH = thyroid-stimulating hormone; 
VAS = visual analog scale.
a
Subject eligibility (based on screening assessments of the inclusion and exclusion criteria) must be checked again on Day 1 prior to randomization.
 
c
For women of childbearing potential or who are postmenopausal for less than 2 years. At Day 1, if the urine test is negative, the subject can be randomized and 
receive the first dose of IMP.
d
Performed locally per local constraints and regulations.
e
Focused physical examination only, according to standard of care.
f
Vital signs include 10-minute seated arterial blood pressure, pulse rate, and body temperature. Height will be measured at Day 1 only. Weight will be measured 
at Weeks 0, 24, 52, 76, and 104. Body weight will be measured with a balance beam scale, if possible.
g
Questionnaires should be completed before any other procedures are performed. Questionnaires should be performed in the following order: Patient’s Global 
Assessment, SHAQ, Mahler BDI (at Day 1) followed by Mahler TDI at the subsequent visits, SGRQ, Leicester Cough Index, and EQ-5D. The Mahler BDI/TDI 
administrator must be blinded to other assessments. The Physician’s Global Assessment (VAS) may be performed after other assessments at the visit are 
completed.
h
For all subjects, samples will be collected predose and immediately after the end of IMP infusion at Weeks 0 (Day 1), 4, 8, and 16.
i
For subjects who have provided informed consent for the rich PK sampling, additional samples will be collected on Days 3, 5, 15, and 22 (in addition to the pre-
and postdose samples at Weeks 0, 4, 8, and 16; see footnote h).
j
See Section 7.4.3 for list of routine laboratory assessments. Urine protein:creatinine ratio to be performed if dipstick urinalysis reveals at least 3+ protein. 
Microscopic urinalysis to be performed if blood is present.
k
The TLC should be performed at Weeks 0, 24, 52, 76, and 104. The DLCO measurements will be corrected for hemoglobin level, and spirometry assessments 
will be centrally adjudicated.
l
Digital ulcers are those distal to the metacarpal phalangeal joints. New or worsening digital ulcers, or at any other site on the body, will be captured as AEs.
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Abituzumab
Abituzumab in SSc-ILD
EMR200017-014
157/159
 
no Adverse events should also be assessed for occurrence during the periods between trial visits.
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Abituzumab
Abituzumab in SSc-ILD
EMR200017-014
158/159
Amendment 5 – Table 2
Schedule of Assessments – Week 56 through Safety Follow-up
Trial Period
Weeks During Double-blind Treatment Period (Visit Window ∀5 days)
Safety 
Follow-up 
Number 
weeks post 
last visit 
(∀5 days)
Survival 
Follow-
up Post 
Last Trial 
Visit
Week
56
60
64
68
72
76
80
84
88
92
96
100
104
ETa
4
12
Every 12 
Weeks
Trial Day
393
421
449
477
505
533
561
589
617
645
673
701
729
HRCT
X
X
12-lead ECG (locally read)
X
X
X
X
Urine pregnancy test b,c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
Xd
Xd
Xd
Xd
Xd
X
Xd
Xd
Xd
Xd
Xd
Xd
X
X
Xd
X
Vital signs, weight e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Mahler TDI and SGRQ f
X
X
X
X
X
X
Patient’s Global Assessment, 
Leicester Cough Index, SHAQ, 
EQ-5D, and Physician’s Global 
Assessment f
X
X
X
IMP administration
X
X
X
X
X
X
X
X
X
X
X
X
Routine hematology, clinical 
chemistry, urinalysis g
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary function tests (FVC, 
TLC) with DLCO) h
X
X
X
X
X
X
mRSS
X
X
X
X
X
X
Digital ulcer counts i
X
X
X
X
X
X
Serum for ADA
X
X
X
X
X
Sample for autoantibodies
X
X
Concomitant 
medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Abituzumab
Abituzumab in SSc-ILD
EMR200017-014
159/159
Trial Period
Weeks During Double-blind Treatment Period (Visit Window ∀5 days)
Safety 
Follow-up 
Number 
weeks post 
last visit 
(∀5 days)
Survival 
Follow-
up Post 
Last Trial 
Visit
Week
56
60
64
68
72
76
80
84
88
92
96
100
104
ETa
4
12
Every 12 
Weeks
Trial Day
393
421
449
477
505
533
561
589
617
645
673
701
729
Adverse events j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital status k
X
ADA = antidrug antibodies; AE = adverse event; BDI = Baseline Dyspnea Index; DLCO = diffusion capacity of the lung for carbon monoxide; ECG = 
electrocardiogram; ET = early termination; FVC = forced vital capacity; HRCT = high resolution computed tomography; IMP = investigational medicinal product; 
mRSS = modified Rodnan skin score; SGRQ = St. George Respiratory Questionnaire; SHAQ = Scleroderma Health Assessment Questionnaire; TDI = Transition 
Dyspnea Index; TLC = total lung capacity; VAS = visual analog scale.
a Subjects who discontinue IMP for any reason should complete the ET visit as soon as possible, but within 2 weeks of IMP discontinuation, and then the 
remaining scheduled trial visits. At a minimum, the subject is expected to complete the trial visits at Weeks 12, 24, 36, 52, 64, 76, 88, and 104, as well as the 
Safety Follow-up period Week 12 visit. Subjects with discontinued IMP can come to the other scheduled visits during the trial period according to the 
Investigator's judgment. Subjects who withdraw from the treatment period would have an early termination visit followed by entrance into the Safety Follow-up 
Period. Subjects who withdraw from the trial (eg, withdraw consent, lost to follow up, or death; see Section 5.5.2) would not have any additional trial visits. All 
subjects will be followed up by the site approximately every 12 weeks for survival from the subject’s last trial visit until death or the end of the trial.
b For women of childbearing potential or who are postmenopausal for less than 2 years. Positive urine pregnancy tests should be confirmed with a serum test. If 
the serum pregnancy test is subsequently positive, the subject will be withdrawn from IMP.
c Performed locally per local constraints and regulations.
d Focused physical examination only, according to standard of care.
e Vital signs include 10-minute seated arterial blood pressure, pulse rate, and body temperature. Weight will be measured at Weeks 0, 24, 52, 76, and 104. Body 
weight will be measured with a balance beam scale, if possible.
f Questionnaires should be completed before any other procedures are performed. Questionnaires should be performed in the following order: Patient’s Global 
Assessment, SHAQ, Mahler BDI (at Day 1) followed by Mahler TDI at the subsequent visits, SGRQ, Leicester Cough Index, and EQ-5D. The Mahler BDI/TDI 
administrator must be blinded to other assessments. The Physician’s Global Assessment (VAS) may be performed after other assessments at the visit are 
completed.
g See Section 7.4.3 for list of routine laboratory assessments. Urine protein:creatinine ratio to be performed if dipstick urinalysis reveals at least 3+ protein. 
Microscopic urinalysis to be performed if blood is present.
h The TLC should be performed at Weeks 0, 24, 52, 76, and 104. The DLCO measurements will be corrected for hemoglobin level, and spirometry assessments 
will be centrally adjudicated.
I Digital ulcers are those distal to the metacarpal phalangeal joints. New or worsening digital ulcers, or at any other site on the body, will be captured as AEs. 
j Adverse events should also be assessed for occurrence during the periods between trial visits.
k Survival follow-up: All subjects will be assessed for survival every 12 weeks (∀1 week) from the last trial visit until death or end of the trial.
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Programming note:  
The shells use Treatment A, B & C.  
The order of the treatment groups in the tables will be as follows: 
The same order will be used for listings. 
7KLVWDEOHRIFRQWHQWVGHWDLOVZKLFK7/)VKDYHEHHQSURGXFHGIRUWKH,'0&VDQGZKLFKDUHQHZIRUWKHILQDODQDO\VLV
EMR200017-014_Sy
noptic_CSR_TOC_for
5HGWH[WLQWKHVKHOOVLVZKHUHWKH,'0&7/)KDVEHHQDGMXVWHGIRUWKHILQDODQDO\VLV 
7KHKHDGHUVZLOOEH
Protocol: EMR 200017-014 (Abituzumab) – Cutoff date: DDMMMYYYY (<Purpose>) 
------------------------------------------------------------------------------------------ 
7KHIRRWHUVZLOOEH
----------------------------------------------------------------------------------------------------------------------- 
Source: ADxx DDMMMYYYY hh:mm <creation date of ADAM dataset>; Listing 16.2.xx; SDTM package: DDMMMYYYY 
Program_path\pgm_name.sas, DDMMMYYYY hh:mm                                                       
 
Page 1 of x 
 
 
Placebo 
Abituzumab 500 mg 
Abituzumab 1500 mg 
Total 
 
 
 
 
 
 
 
 
 
 


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15.1: Demographic and Baseline Data 
15.1.1: Subject Disposition 
Table 15.1.1.1: Subject Disposition Status  

 
Treatment A 
Treatment B 
Treatment C 
Total 
 
Number of screened subjects(a), n  
 
 
 
 
xx  
    
Number of screen failures, n  
 
     
 
xx  
    Subject did not meet all eligibility 
criteria 
         
        
 
xx  
    Withdrew informed consent 
 
 
 
xx 
    Progressive disease 
 
 
 
xx  
    Adverse event 
 
 
 
xx  
    Lost to follow-up 
 
 
 
xx 
    Death 
 
 
 
xx 
    Other 
 
 
 
xx   
    Missing 
 
 
 
xx 
 
 
 
 
 
Randomized subjects, n (%) 
xx (100.0)    
xx (100.0)  
xx (100.0)  
xx (100.0)   
    Baseline FVC <70% predicted  
xx (xx.x)     
xx (xx.x)    
xx (xx.x)     
xx (xx.x)     
    Baseline FVC ≥70% predicted  
xx (xx.x)     
xx (xx.x)    
xx (xx.x)     
xx (xx.x)     
Received no treatment, n (%)* 
xx (xx.x)     
xx (xx.x)    
xx (xx.x)     
xx (xx.x)     
Treatment Ongoing, n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Treatment Completed, n (%)  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Shell continues on the next page 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15.1: Demographic and Baseline Data 
15.1.1: Subject Disposition 
Table 15.1.1.1: Subject Disposition Status  

 
Treatment A 
Treatment B 
Treatment C 
Total 
Subjects who discontinued trial 
treatment, n (%) 
xx (xx.x)      
xx (xx.x)      
xx (xx.x)      
xx (xx.x)     
    Adverse Event 
xx (xx.x)      
xx (xx.x)      
xx (xx.x)      
xx (xx.x)     
    Lost to Follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
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xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Progressive disease 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Withdrew Consent 
xx (xx.x)      
xx (xx.x)      
xx (xx.x)      
xx (xx.x)     
    Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Subjects who discontinued trial treatment 
and withdrew from the treatment period, n 
(%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Subjects who withdrew from the trial, n  
(%) 
xx (xx.x)      
xx (xx.x)      
xx (xx.x)      
xx (xx.x)   
    Adverse Event 
xx (xx.x)      
xx (xx.x)      
xx (xx.x)      
xx (xx.x)     
    Lost to Follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Protocol non-compliance 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Progressive disease 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Withdrew Consent 
xx (xx.x)      
xx (xx.x)      
xx (xx.x)      
xx (xx.x)     
    Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Note: Percentages for ‘Subjects who discontinued trial treatment’ are based on the number of subjects who received at  
      least one infusion of trial treatment. All other percentages are based on the number of subjects randomized. 
      No subjects were randomized under the new stratification level of < 6 months prior mycophenolate duration, so 
      this stratification factor has not been presented. 
      * Number of subjects who received no treatment based on current exposure data. 
  
 
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15.1: Demographic and Baseline Data  
15.1.4: Demographic Characteristics 
Table 15.1.4.1: Demographic Characteristics - SAF Analysis Set 
 
 
 
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Treatment A 
N=xxx (100%) 
Treatment B 
N=xxx (100%) 
Treatment C 
N=xxx (100%) 
Total 
N=xxx (100%) 
Sex, n (%) 
    Male 
    Female 
    Missing 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Race, n (%) 
    White                       
    Black or African American  
    Asian 
    American Indian or Alaska Native 
    Native Hawaiian or Other Pacific Islander 
    Other 
    Missing (including not collected at site) 
 
xx (xx.x)    
xx (xx.x) 
xx (xx.x) 
xx (xx.x)    
xx (xx.x)    
xx (xx.x)    
xx (xx.x) 
 
xx (xx.x)    
xx (xx.x) 
xx (xx.x) 
xx (xx.x)    
xx (xx.x)    
xx (xx.x)    
xx (xx.x) 
 
xx (xx.x)    
xx (xx.x) 
xx (xx.x) 
xx (xx.x)    
xx (xx.x)    
xx (xx.x)    
xx (xx.x) 
 
xx (xx.x)   
xx (xx.x) 
xx (xx.x) 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x) 
Ethnicity, n (%) 
    Hispanic or Latino                       
    Not Hispanic or Latino 
 
xx (xx.x)    
xx (xx.x) 
 
xx (xx.x)    
xx (xx.x) 
 
xx (xx.x)    
xx (xx.x) 
 
xx (xx.x)   
xx (xx.x) 
Age (Years) 
    n (%)                      
    Missing (%) 
 
    Mean ±SD 
    Median 
    Q1; Q3 
    Min; Max 
 
xx (xx.x)    
xx (xx.x) 
 
xx ±xx.xx 
xx 
xx; xx 
xx; xx 
 
xx (xx.x)    
xx (xx.x) 
 
 xx ±xx.xx 
xx 
xx; xx 
xx; xx 
 
xx (xx.x)    
xx (xx.x) 
 
 xx ±xx.xx 
xx 
xx; xx 
xx; xx 
 
xx (xx.x)   
xx (xx.x) 
 
 xx ±xx.xx 
xx 
xx; xx 
xx; xx 


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15.1: Demographic and Baseline Data  
15.1.4: Demographic Characteristics 
Table 15.1.4.1: Demographic Characteristics - SAF Analysis Set 
 

 
 
 
 
 
 
 
 
 
Note: Age is relative to the date of informed consent. 
 
 
 
 
Treatment A 
N=xxx (100%) 
Treatment B 
N=xxx (100%) 
Treatment C 
N=xxx (100%) 
Total 
N=xxx (100%) 
Age categories, n (%) 
    < 35 years 
    >= 35 - < 50 years 
    >= 50 - < 76 years 
    Missing 
 
xx (xx.x)    
xx (xx.x) 
xx (xx.x) 
xx (xx.x)    
 
xx (xx.x)    
xx (xx.x) 
xx (xx.x) 
xx (xx.x)    
 
xx (xx.x)    
xx (xx.x) 
xx (xx.x) 
xx (xx.x)    
 
xx (xx.x)   
xx (xx.x) 
xx (xx.x) 
xx (xx.x)   


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15.1: Demographic and Baseline Data 
15.1.5: Medical History 
Table 15.1.5.1: Medical History - SAF Analysis Set 

Primary System Organ Class 
     Preferred Term 
Treatment A 
N=xxx (100%) 
n (%) 
Treatment B 
N=xxx (100%)  
n (%) 
Treatment C 
N=xxx (100%)  
n (%) 
Total 
N=xxx (100%)  
n (%) 
Subjects with at least one Medical History 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC1 
     PT1 
     PT2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC2 
     PT1 
     PT2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
MedDRA version xx.x. 
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15.1: Demographic and Baseline Data 
15.1.6: Other Baseline Characteristics  
Table 15.1.6.1: Disease History − SAF Analysis Set 

 
Treatment A 
N=xxx (100%) 
Treatment B 
N=xxx (100%)  
Treatment C 
N=xxx (100%)  
Total 
N=xxx (100%)  
Time since date of diagnosis (years) 
    n (%)                      
    Missing (%) 
 
    Mean ±SD 
    Median 
    Q1; Q3 
    Min; Max 
 
xx (xx.x)    
xx (xx.x) 
 
xx ±xx.xx 
xx 
xx; xx 
xx; xx 
 
xx (xx.x)   
xx (xx.x) 
 
 xx ±xx.xx 
xx 
xx; xx 
xx; xx 
 
xx (xx.x)   
xx (xx.x) 
 
 xx ±xx.xx 
xx 
xx; xx 
xx; xx 
 
xx (xx.x)    
xx (xx.x) 
 
 xx ±xx.xx 
xx 
xx; xx 
xx; xx 
Subject status/ disease history, n (%)    
    Diffuse cutaneous SSc  
    Limited cutaneous SSc  
    SSc sine scleroderma 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Systemic sclerosis symptom history (a), n (%)    
    Skin thickening 
    Digital ulcers 
    Synovitis and/or joint contracture 
    Tendon friction rubs 
    C .K. elevation and/or weakness 
    Atrophy: Upper extremity 
    Atrophy: Lower extremity 
    Atrophy: Right extremity 
    Atrophy: Left extremity 
    Esophagus: Dysphagia 
    Esophagus: Reflux 
    Stomach: Early satiety 
    Stomach: Vomiting 
    Intestinal: Diarrhea 
    Intestinal: Bloating 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
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15.1: Demographic and Baseline Data 
15.1.6: Other Baseline Characteristics  
Table 15.1.6.1: Disease History − SAF Analysis Set 

 
Treatment A 
N=xxx (100%) 
Treatment B 
N=xxx (100%)  
Treatment C 
N=xxx (100%)  
Total 
N=xxx (100%)  
    Intestinal: Constipation 
    Incontinence 
    Hypertension 
    Renal crisis 
    Dyspnea (significant)  
    Palpitations (significant)  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x)
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x)
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x)
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x)
ACR/EULAR Classification Criteria for Systemic 
Sclerosis (b), n (%)    
    Skin thickening of the fingers of both hands 
extending proximal to the metacarpophalangeal joints 
    Skin thickening of the fingers: Puffy fingers 
    Skin thickening of the fingers: Sclerodactyly of 
the fingers 
    Fingertip lesions: Digital tip ulcers 
    Fingertip lesions: Fingertip pitting scars 
    Telangiectasia 
    Abnormal nailfold capillaries 
    Lung involvement: Pulmonary arterial hypertension 
    Lung involvement: Interstitial lung disease 
    Raynaud's Phenomenon 
    
 
    
 
    
 
III 
 
 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: Partial date of diagnosis is imputed as follows: In case the day of diagnosis is missing, then the day will be     
      imputed as the 1st. In case the month of diagnosis is missing, then the month will be imputed as January. 
(a) Counts are the number of subjects who reported ‘Yes’ to the questions. 
(b) Counts are the number of subjects who reported ‘Present’ to the questions. 
 
 
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15.1: Demographic and Baseline Data 
15.1.7: Previous and Concomitant Medications, Procedures, Follow-up Treatments 
Table 15.1.7.1: Previous Medication − SAF Analysis Set 

ATC-2nd Level 
     Preferred Term 
Treatment A 
N=xxx (100%) 
n (%) 
Treatment B 
N=xxx (100%)  
n (%) 
Treatment C 
N=xxx (100%)  
n (%) 
Total 
N=xxx (100%)  
n (%) 
Subjects with at least one Previous Medication 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ATC1 
     MED1 
     MED2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
ATC2 
     MED1 
     MED2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
WHO Drug Dictionary version Enhanced September 2016. 
Note: If a subject has more than one medication within a ATC class/preferred term, the subject was counted once in that 
      ATC class/preferred term.  
      In case multiple ATC's are assigned to a medication, all ATC's will be reported. 
       
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Table 15.1.7.2: Concomitant Medication − SAF Analysis Set 
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15.2: Efficacy Data  
15.2.1: Annual Rate of Absolute FVC Change in Volume (mL) 
Table 15.2.1.1: FVC Volume (mL) Observed and Change from Baseline by Visit - mITT Analysis Set  
Visit /  
   Statistic 
Treatment A 
N=xxx 
 
Treatment B 
N=xxx 
 
Treatment C 
N=xxx 
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
   Missing (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
   Median 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
   Q1; Q3 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
   Min; Max 
xx; xx 
 
 
xx; xx 
 
 
xx; xx 
 
 
 
 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
   Missing (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
   Median 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
   Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
   Min; Max 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
 
 
 
 
 
 
 
 
Week 24 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
   Missing (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
   Median 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
   Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
   Min; Max 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. If such a value is missing  
      then the last value prior to the first trial treatment administration will be used. 
      Percentages are based on the number of subjects present in the trial at that visit. 
Programming note: Only display visits where FVC assessment is scheduled to be done and where there is data available. 
 
 
Repeat table 15.2.1.1 for: 
Table 15.2.1.2: FVC % Predicted Observed and Change from Baseline by Visit - mITT Analysis Set 
 
 


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15.2: Efficacy Data  
15.2.2: Key Secondary Endpoints 
Table 15.2.2.1: Change in Dyspnea from Baseline as Measured by the Mahler TDI - mITT Analysis Set  

Visit / 
  Statistic 
Treatment A 
N=xxx  
 
Treatment B  
N=xxx  
 
Treatment C 
N=xxx  
 
 
 
 
 
 
Baseline 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
 
xxx (xx.x) 
 
xxx (xx.x) 
   Missing (%) 
xxx (xx.x) 
 
xxx (xx.x) 
 
xxx (xx.x) 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
   Median 
xx.x 
 
xx.x 
 
xx.x 
   Q1; Q3 
xx.x; xx.x 
 
xx.x; xx.x 
 
xx.x; xx.x 
   Min; Max 
xx; xx 
 
xx; xx 
 
xx; xx 
 
 
 
 
 
 
Week 12 
 
 
 
 
 
 Change from Baseline 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
 
xxx (xx.x) 
 
xxx (xx.x) 
   Missing (%) 
xxx (xx.x) 
 
xxx (xx.x) 
 
xxx (xx.x) 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
   Median 
xx.x 
 
xx.x 
 
xx.x 
   Q1; Q3 
xx.x; xx.x 
 
xx.x; xx.x 
 
xx.x; xx.x 
   Min; Max 
xx; xx 
 
xx; xx 
 
xx; xx 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Repeat table 15.2.1.1 for: 
Table 15.2.2.2: mRSS Total Score Observed and Change from Baseline by Visit - mITT (dcSSc) Analysis Set  
Programming note: Only display visits where mRSS assessment is scheduled to be done and where there is data available. 
Add the following footnote: 
Note: dcSSc = diffuse cutaneous systemic sclerosis. Only subjects with dcSSc at baseline are included in the mRSS summary. 
 
 


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15.2: Efficacy Data  
15.2.2: Key Secondary Endpoints 
Table 15.2.2.3: Absolute Change from Baseline in SGRQ Total Score - mITT Analysis Set  
 Visit/ 
    Statistic
Treatment A 
N=xxx 
 
Treatment B  
N=xxx  
 
Treatment C 
N=xxx  
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
  Baseline 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
   Missing (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
   Median 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
   Q1; Q3 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
   Min; Max 
xx; xx 
 
 
xx; xx 
 
 
xx; xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Week 12 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
   Missing (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
   Median 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
   Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
   Min; Max 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15.2: Efficacy Data  
15.2.2: Secondary Endpoints 
Table 15.2.2.4: Clinically Meaningful Disease Progression - mITT Analysis Set  

 
Treatment A 
N=xxx (100%) 
n (%) 
Treatment B 
N=xxx (100%)  
n (%) 
Treatment C 
N=xxx (100%)  
n (%) 
 
 
 
 
Number of Subjects with Clinically Meaningful 
Disease Progression 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Trial Treatment Discontinued 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
SSc-ILD Progression  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Relative decrease from baseline in FVC % 
predicted >10% * 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Relative decrease from baseline in FVC % 
predicted of >5% to <10% and relative decrease 
in DLCO % predicted >15% * 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
  Mycophenolate dose increased 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  New immunosuppressant or biologic drug 
initiated 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
  Trial Treatment Discontinued 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
SSc Progression other than ILD 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Scleroderma renal crisis 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Left ventricular failure (defined as 
ejection fraction <45%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Pulmonary arterial hypertension requiring 
treatment 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Other 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 Trial Treatment Discontinued 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
* Confirmed on 2 occasions within 4 weeks. 
Note: A subject may have both SSc-ILD progression and SSc progression other than ILD at the same time, and may  
      progress more than once. 
 
Repeat table 15.2.1.1 for: 
Table 15.2.2.5: DLCO (mmol of CO/min/kPa) Observed and Change from Baseline by Visit - mITT Analysis Set  
Programming note: Only display visits where DLCO assessment is scheduled to be done and where there is data available.


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Repeat table 15.2.1.1 for: 
Table 15.2.2.6: Absolute Change from Baseline in QLF - mITT Analysis Set 
Table 15.2.2.7: DLCO % Predicted Observed and Change from Baseline by Visit - mITT Analysis Set  
 
Programming note: Only display visits where DLCO assessment is scheduled to be done and where there is data available. 

Table 15.2.3.1: KCO Observed and Change from Baseline by Visit - mITT Analysis Set  
Table 15.2.3.2: Extent of total ILD Observed and Change from Baseline by Visit - mITT Analysis Set  

 


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15.2: Efficacy Data  
15.2.4: QoL Endpoints 
Table 15.2.4.1: Leicester Cough Index Total Score – Observed and Change from Baseline - mITT Analysis Set 
Visit/ 
    Statistic
Treatment A 
N=xxx 
 
Treatment B  
N=xxx  
 
Treatment C 
N=xxx  
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
  Baseline 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
   Missing (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
   Median 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
   Q1; Q3 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
   Min; Max 
xx; xx 
 
 
xx; xx 
 
 
xx; xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Week 24 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
   Missing (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
   Median 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
   Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
   Min; Max 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Baseline is defined as the last non-missing measurement prior to randomization. If such a value is missing  
      then the last value prior to the first trial treatment administration will be used. 
      Percentages are based on the number of subjects present in the trial at that visit. 
Note: The domain score is the sum of all scores in that domain divided by the number of questions in that domain  
      (ranging from 1 to 7). The total score is the sum of all domain scores (ranging from 3 to 21). 
 
Repeat table 15.2.4.1 for: 
Table 15.2.4.2: Physician’s Global Assessment – Observed and Change from Baseline - mITT Analysis Set  

Update footnotes: 
Note: Baseline is defined as the last non-missing measurement prior to randomization. If such a value is missing  
      then the last value prior to the first trial treatment administration will be used. 
      Percentages are based on the number of subjects present in the trial at that visit. 
Note: The Physician’s Global Assessment consists of one question that is answered on a VAS from of 0 to 100,  


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      where 0 is the most positive response and 100 is the most negative. 
 
 
Repeat table 15.2.4.1 for: 
Table 15.2.4.3: Patient’s Global Assessment – Observed and Change from Baseline - mITT Analysis Set  
Update footnote to say ‘Patient’s Global Assessment‘ instead of ‘Physician’s Global Assessment‘ 

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15.2: Efficacy Data  
15.2.4: QoL Endpoints 
Table 15.2.4.4: SHAQ – VAS Scores – Observed and Change from Baseline - mITT Analysis Set 
VAS category/  
  Visit/ 
    Statistic
Treatment A 
N=xxx  
 
Treatment B  
N=xxx  
 
Treatment C 
N=xxx  
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
Pain: 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
   Missing (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
   Median 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
   Q1; Q3 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
   Min; Max 
xx; xx 
 
 
xx; xx 
 
 
xx; xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 24 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
   Missing (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
   Median 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
   Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
   Min; Max 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Baseline is defined as the last non-missing measurement prior to randomization. If such a value is missing  
      then the last value prior to the first trial treatment administration will be used. 
      Percentages are based on the number of subjects present in the trial at that visit. 
Note: The VAS are scored from 0 to 100, where 0 is the most positive response and 100 is the most negative. 
 
 
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15.2: Efficacy Data  
15.2.4: QoL Endpoints 
Table 15.2.4.5: EQ-5D VAS Score – Observed and Change from Baseline - mITT Analysis Set 
Visit/ 
    Statistic
Treatment A 
N=xxx  
 
Treatment B  
N=xxx  
 
Treatment C 
N=xxx  
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
   Missing (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
   Median 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
   Q1; Q3 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
   Min; Max 
xx; xx 
 
 
xx; xx 
 
 
xx; xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 24 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
   Missing (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
   Median 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
   Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
   Min; Max 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Baseline is defined as the last non-missing measurement prior to randomization. If such a value is missing  
      then the last value prior to the first trial treatment administration will be used. 
      Percentages are based on the number of subjects present in the trial at that visit. 
Note: The EQ-5D VAS is numbered from 0 to 100 where the endpoints are labelled ‘Best health you can imagine’ (100) 
      and ‘Worst health you can imagine’ (0).  
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15.2: Efficacy Data  
15.2.5: Skin Fibrosis Endpoints 
Table 15.2.5.1: Digital Ulcer Count – Observed and Change from Baseline - mITT Analysis Set 
Ulcer Type/ 
  Visit/ 
    Statistic
Treatment A 
N=xxx  
 
Treatment B  
N=xxx  
 
Treatment C 
N=xxx  
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
Observed 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
Active: 
 
 
 
 
 
 
 
 
  Baseline 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
   Missing (%) 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
 
xx.x ±xx.xx 
 
   Median 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
   Q1; Q3 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
 
xx.x; xx.x 
 
   Min; Max 
xx; xx 
 
 
xx; xx 
 
 
xx; xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Week 12 
 
 
 
 
 
 
 
 
   n (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
   Missing (%) 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
 
xx.x ±xx.xx 
xx.x ±xx.xx 
   Median 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
   Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
 
xx.x; xx.x 
xx.x; xx.x 
   Min; Max 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
 
xx; xx 
xx; xx 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Baseline is defined as the last non-missing measurement prior to randomization. If such a value is missing  
      then the last value prior to the first trial treatment administration will be used. 
      Percentages are based on the number of subjects present in the trial at that visit. 
Note: Only subjects with digital ulcers at baseline continue with the digital ulcer assessment throughout the trial. 
      The total count is the sum of all active, undetermined and healed ulcers. 
 
 
 
 
 
 
 
 
 
 


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15.3: Safety Data 
15.3.0: Treatment Compliance and Exposure 
Table 15.3.0.1: Duration of Treatment (weeks) – SAF Analysis Set 
 
 
Treatment A 
Treatment B 
Treatment C 
 
N=xxx (100%) 
N=xxx (100%) 
N=xxx (100%) 
 
 
 
 
Duration of treatment (weeks), n (%) 
 
 
 
   >=4 and <=28 weeks 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   >28 and <=52 weeks 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   >52 and <=76 weeks 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   >76 and <=100 weeks 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   >100 weeks 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
   n (%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
   Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
xx.x ±xx.xx 
   Median 
xx.x 
xx.x 
xx.x 
   Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
xx.x; xx.x 
   Min; Max 
xx; xx 
xx; xx 
xx; xx 
 
 
 
 
Note: Duration of treatment (weeks) is calculated as:  
     (Last infusion date prior to data cut-off – first infusion date + 28) / 7 days. 
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15.3: Safety Data 
15.3.0: Treatment Compliance and Exposure 
Table 15.3.0.2: Number of Infusions – SAF Analysis Set 
 
 
Treatment A 
Treatment B 
Treatment C 
 
N=xxx (100%) 
N=xxx (100%) 
N=xxx (100%) 
 
 
 
 
Total number of infusions received, n (%) 
 
 
 
   1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   >1 and <=8 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   >8 and <=14 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   >14 and <=20 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   >20 and <=26 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   >26  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
   n (%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
    Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
xx.x ±xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
    Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
xx.x; xx.x 
    Min; Max 
xx; xx 
xx; xx 
xx; xx 
 
 
 
 
Total number of infusions across all subjects, n 
xxx 
xxx 
xxx 
 
 
 
 
 
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15.3: Safety Data 
15.3.0: Treatment Compliance and Exposure 
Table 15.3.0.2b: Treatment Adherence – SAF Analysis Set 
 
 
Treatment A 
Treatment B 
Treatment C 
 
N=xxx (100%) 
N=xxx (100%) 
N=xxx (100%) 
 
 
 
 
Adherence with Treatment, n (%) 
 
 
 
 
 
 
 
    n (%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
    <80% 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    80% - 100% 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    >100% - 120% 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    >120% 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
    Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
xx.x ±xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
    Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
xx.x; xx.x 
    Min; Max 
xx; xx 
xx; xx 
xx; xx 
 
 
 
 
Note: Adherence by subject is calculated as: (sum of actual volume received/ sum of planned volume, up to and  
      including their last dose recorded on their treatment termination visit)*100. 
      For the continuous summary, values >100% are set to 100%. 
 
 
 
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15.3: Safety Data 
15.3.0: Treatment Compliance and Exposure 
Table 15.3.0.3: Infusion Duration and Volume – SAF Analysis Set 
 
 
Treatment A 
Treatment B 
Treatment C 
 
N=xxx (100%) 
N=xxx (100%) 
N=xxx (100%) 
 
 
 
 
Mean infusion duration (hours) 
 
 
 
    n (%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
xx.x ±xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
    Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
xx.x; xx.x 
    Min; Max 
xx; xx 
xx; xx 
xx; xx 
 
 
 
 
Mean actual volume infused (mL) 
 
 
 
    n (%) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Mean ±SD 
xx.x ±xx.xx 
xx.x ±xx.xx 
xx.x ±xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
    Q1; Q3 
xx.x; xx.x 
xx.x; xx.x 
xx.x; xx.x 
    Min; Max 
xx; xx 
xx; xx 
xx; xx 
 
 
 
 
Note: Summary statistics are based on the mean infusion duration and mean volume received per subject. 
 
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15.3: Safety Data 
15.3.0: Treatment Compliance and Exposure 
Table 15.3.0.4: Dose Adjustments – SAF Analysis Set 
 
 
Treatment A 
Treatment B 
Treatment C 
 
N=xxx (100%) 
N=xxx (100%) 
N=xxx (100%) 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
Number of subjects without any dose adjustment (a) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Number of subjects with at least one dose 
adjustment 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Dose adjusted: 
 
 
 
    Adverse Event 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Other 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
    No dose:  
 
 
 
    Adverse Event 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Missed Dose 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Other 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
     
 
 
 
    Number of subjects with at least one missed 
visit (b) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Note: A subject may have more than one reason if they have more than one dose adjustment, so will be counted under each 
      reason. 
(a) Subjects without any dose adjustment do not include subjects with missed visits. 
(b) Subjects with missed visits may not be counted under ‘Dose adjusted’ or ‘No dose’ due to not completing the ‘STUDY 
TREATMENT ADMINISTRATION DETAILS’ eCRF page at the missed visit. 
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15.3: Safety Data 
15.3.0: Treatment Compliance and Exposure 
Table 15.3.0.5: Infusion Outcome – SAF Analysis Set 
 
 
Treatment A 
Treatment B 
Treatment C 
 
N=xxx (100%) 
N=xxx (100%) 
N=xxx (100%) 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
Number of subjects with all infusions completed as 
planned 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Number of subjects with at least one infusion not 
completed as planned 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Adverse Event (other than infusion-related reaction 
or overdose) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Infusion-related reaction 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Overdose 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
    Other 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Note: A subject may have more than one reason if they have more than one infusion not completed as planned, so will be   
      counted under each reason. 
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15.3: Safety Data 
15.3.1: Display of Adverse Events 
Table 15.3.1.1: Overview of Treatment Emergent Adverse Events (TEAEs) – SAF Analysis Set 
 
 
 
Number of Subjects with: 
Treatment A 
N=xxx (100%) 
n (%) 
Treatment B 
N=xxx (100%) 
n (%) 
Treatment C 
N=xxx (100%) 
n (%) 
 
 
 
 
Any TEAE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related TEAE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any serious TEAE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related serious TEAE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any grade >=3 TEAE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any grade >=4 TEAE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related grade >=3 TEAE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related grade >=4 TEAE 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any TEAE leading to death 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related TEAE leading to death 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Any treatment emergent AESI 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related treatment emergent AESI  
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any serious treatment emergent AESI 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
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15.3: Safety Data 
15.3.1: Display of Adverse Events 
Table 15.3.1.1: Overview of Treatment Emergent Adverse Events (TEAEs) – SAF Analysis Set 
 
 
 
Number of Subjects with: 
Treatment A 
N=xxx (100%) 
n (%) 
Treatment B 
N=xxx (100%) 
n (%) 
Treatment C 
N=xxx (100%) 
n (%) 
 
 
 
 
Any trial treatment related serious treatment 
emergent AESI 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any grade >=3 treatment emergent AESI 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any grade >=4 treatment emergent AESI 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related grade >=3 treatment 
emergent AESI 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related grade >=4 treatment 
emergent AESI 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any treatment emergent AESI leading to death 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related treatment emergent AESI 
leading to death 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
NCI-CTCAE version 4.03. 
Note: TEAEs are defined as events that start within the day of first dose of trial treatment until 28 days after last  
      dose of treatment. 
      Related TEAEs are events with relationship missing, unknown or related. 
      AESI = Adverse Event of Special Interest. 
 
 
 


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15.3: Safety Data 
15.3.1: Display of Adverse Events 
Table 15.3.1.2: Overview of TEAEs Leading to Discontinuation / Dose Reduction of Treatment – SAF Analysis Set 
 
 
 
Number of Subjects with: 
Treatment A 
N=xxx (100%) 
n (%) 
Treatment B 
N=xxx (100%) 
n (%) 
Treatment C 
N=xxx (100%) 
n (%) 
 
 
 
 
Any TEAE leading to temporary discontinuation of trial 
treatment 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related TEAE leading to temporary 
discontinuation of trial treatment 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any TEAE leading to permanent discontinuation of trial 
treatment 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related TEAE leading to permanent 
discontinuation of trial treatment 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any TEAE leading to dose reduction of trial treatment 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Any trial treatment related TEAE leading to dose reduction 
of trial treatment 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Note: TEAEs are defined as events that start within the day of first dose of trial treatment until 28 days after last  
      dose of treatment. 
      Related TEAEs are events with relationship missing, unknown or related. 
 
 


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15.3: Safety Data 
15.3.1: Display of Adverse Events 
Table 15.3.1.3: TEAE by Primary System Organ Class (SOC) and Preferred Term (PT) – SAF Analysis Set 
 
 
Primary System Organ Class 
   Preferred Term 
Treatment A 
N=xxx (100%) 
n (%) 
Treatment B 
N=xxx (100%) 
n (%) 
Treatment C 
N=xxx (100%) 
n (%) 
Subjects with at least one event 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
SOC1 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   PT11 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   PT12 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   PT13 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
SOC2 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   PT21 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   PT22 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
MedDRA version 19.1. 
Note: TEAEs are defined as events that start within the day of first dose of trial treatment until 28 days after last  
      dose of treatment. 
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Repeat table 15.3.1.3 for: 
Table 15.3.1.4: Trial Treatment Related TEAEs by SOC and PT – SAF Analysis Set 
Add footnote:Related TEAEs are events with relationship missing, unknown or related. 

Table 15.3.1.5: Serious TEAEs by SOC and PT – SAF Analysis Set  
Table 15.3.1.6: Trial Treatment Related Serious TEAEs by SOC and PT – SAF Analysis Set  
Add footnote:Related TEAEs are events with relationship missing, unknown or related. 

Table 15.3.1.7: Non-serious TEAEs by SOC and PT at a Frequency Threshold of 5% – SAF Analysis Set 
Add footnote: Frequency threshold of 5% in any treatment group.
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15.3: Safety Data 
15.3.1: Display of Adverse Events 
Table 15.3.1.8: TEAEs by Worst Grade, SOC and PT – SAF Analysis Set 
 
 
Treatment A 
N=xxx (100%) 
 
Treatment B 
N=xxx (100%) 
 
Treatment C 
N=xxx (100%) 
Primary System Organ 
Class 
   Preferred Term 
Any 
Grade 
n (%) 
Grade 
>=3 
n (%) 
Grade 
>=4 
n (%) 
Grade 
5 
n (%) 
 
Any 
Grade 
n (%) 
Grade 
>=3 
n (%) 
Grade 
>=4 
n (%) 
Grade 
5 
n (%) 
 
Any 
Grade 
n (%) 
Grade 
>=3 
n (%) 
Grade 
>=4 
n (%) 
Grade 
5 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects with at  
least one event 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC1 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
   PT11 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
   PT12 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC2 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
   PT21 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
xxx 
(xx.x) 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MedDRA version 19.1, NCI-CTCAE version 4.03. 
Note: Any grade includes ‘Missing’ grade. Worst grade per subject/SOC/PT is reported. 
      TEAEs are defined as events that start within the day of first dose of trial treatment until 28 days after last  
      dose of treatment. 
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Repeat table 15.3.1.8 for: 
Table 15.3.1.9: Trial Treatment Related TEAEs by Worst Grade, SOC and PT – SAF Analysis Set 
Add footnote:Related TEAEs are events with relationship missing, unknown or related. 
 
Repeat table 15.3.1.3 for: 
Table 15.3.1.10: TEAEs Leading to Death by SOC and PT – SAF Analysis Set 
Table 15.3.1.11: TEAEs Leading to Trial Treatment Discontinuation by SOC and PT – SAF Analysis Set 
Table 15.3.1.12: TEAEs Leading to Dose Reduction of Trial Treatment by SOC and PT – SAF Analysis Set 
Table 15.3.1.13: TEAEs Leading to Withdrawal from Trial by SOC and PT – SAF Analysis Set 
Table 15.3.1.14: Treatment Emergent AESIs by SOC and PT – SAF Analysis Set 
 
Add footnote: AESI = Adverse Event of Special Interest. 
 


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15.3: Safety Data 
15.3.2: Listings of Deaths, Other Serious and Significant Adverse Events 
Table 15.3.2.1: Deaths by Primary Reason – SAF Analysis Set 
 
 
Treatment A 
N=xxx (100%) 
n (%) 
Treatment B 
N=xxx (100%) 
n (%) 
Treatment C 
N=xxx (100%) 
n (%) 
 
 
 
 
Subjects who died 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
Primary reason for death 
 
 
 
   Progressive disease and/or disease related condition 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Event unrelated to trial treatment 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Event related to trial treatment 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
   Unknown 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
Note: Reason as reported on death CRF page. 
 
 


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15.3: Safety Data 
15.3.2: Listings of Deaths, Other Serious and Significant Adverse Events 
Table 15.3.2.3: Listing of Serious TEAEs – SAF Analysis Set 
 
 
AE 
No 
 
Preferred Term/ 
Investigator Term 
 
Start/ End 
Date of AE 
 
Dur. of  
AE (days) 
Onset Rel.to 
Trial 
Treat. 
Rel. to  
Trial 
Treat. 
 
 
Grade 
Action on 
Trial 
Treat.(a) 
 
 
Outcome(b) 
Rel. Day  
from 
First Admin. 
 
 
 
 
 
 
 
 
 
 
Treatment Arm: Treatment A, Subject ID: XXXXXXXXXX, Age: xx, Sex: X, Race: XXXXXXX 
Treatment Administration: First Date: DDMONYYYY, Last Date: DDMONYYYY, Number of infusions: xx 
X 
XXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXX 
DDMONYYYY/ 
DDMONYYYY 
xx 
Before 
Unrelated 
1 
No change 
Res. 
xx 
Treatment Arm: Treatment A, Subject ID: XXXXXXXXXX, Age: xx, Sex: X, Race: XXXXXXX 
Treatment Administration: First Date: DDMONYYYY, Last Date: DDMONYYYY, Number of infusions: xx 
X 
XXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXX 
DDMONYYYY/ 
DDMONYYYY 
xx 
During 
Related 
2 
Reduced 
Ong. 
xx 
Treatment Arm: Treatment B, Subject ID: XXXXXXXXXX, Age: xx, Sex: X, Race: XXXXXXX 
Treatment Administration: First Date: DDMONYYYY, Last Date: DDMONYYYY, Number of infusions: xx 
X 
XXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXX 
DDMONYYYY/ 
DDMONYYYY 
xx 
After 
Unrelated 
3 
Interrupted Res. w. sequ. 
xx 
 
 
 
 
 
 
 
 
 
 
MedDRA version 19.1, NCI-CTCAE version 4.03. 
Note: (a) Action: No change = Dose not changed, Reduced = Dose reduced, Interrupted = Drug interrupted,  
       Withdrawn = Drug withdrawn, N/A = Not applicable. 
      (b) Outcome: Change = Change in severity, Res. = Resolved, Res. w. sequ. = Resolved with sequelae,  
       Ong. = Ongoing, Fatal = Fatal, Unknown = Unknown. 
 
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15.3: Safety Data 
15.3.5: Clinical Laboratory Evaluations 
Table 15.3.5.1: Hematology – Shift from Baseline to Worst On-treatment Value – SAF Analysis Set 
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Worst On-treatment Value 
Laboratory Test 
Treatment 
Baseline  
Classification 
Low 
n (%) 
Normal  
n (%) 
High  
n (%) 
Missing  
n (%) 
Total  
n (%) 
PARAM1 (Unit1) 
Treatment A  
N=XXX 
Low 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (100.0) 
 
 
Normal 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (100.0) 
 
 
High 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (100.0) 
 
 
Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (100.0) 
 
 
Total 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (100.0) 
 
 
 
 
 
 
 
 
 
Treatment B 
N=XXX 
Low 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (100.0) 
 
 
Normal 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (100.0) 
 
 
High 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (100.0) 
 
 
Missing 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (100.0) 
 
 
Total 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (xx.x) 
xxx (100.0) 
 
……… 
 
 
 
 
 
 
 
Note: Baseline is the last measurement prior to the first dose of any trial treatment. 
      Normal category includes low values for high parameters and high values for low parameters. 

Repeat table 15.3.5.1 for: 
Table 15.3.5.2: Clinical Chemistry – Shift from Baseline to Worst On-treatment Value – SAF Analysis Set 
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15.3: Safety Data 
15.3.5: Clinical Laboratory Evaluations 
Table 15.3.5.3: Hematology – Shift in Toxicity Grading from Baseline to Highest Grade – SAF Analysis Set 
 
 
 
 
Worst NCI-CTCAE Grade 
Laboratory  
Test 
Treatment 
Baseline  
NCI-
CTCAE  
Grade 
Grade 0  
n (%) 
Grade 1  
n (%) 
Grade 2  
n (%) 
Grade 3  
n (%) 
Grade 4  
n (%) 
Missing  
n (%) 
Total  
n (%) 
 
 
 
 
 
 
 
 
 
 
PARAM1  
(Unit1) 
Treatment A 
N=xxx 
Grade 0 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (100.0) 
 
 
Grade 1 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (100.0) 
 
 
Grade 2 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (100.0) 
 
 
Grade 3 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (100.0) 
 
 
Grade 4 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (100.0) 
 
 
Missing 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (100.0) 
 
 
Total 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (100.0) 
 
 
 
 
 
 
 
 
 
 
 
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15.3: Safety Data 
15.3.5: Clinical Laboratory Evaluations 
Table 15.3.5.3: Hematology – Shift in Toxicity Grading from Baseline to Highest Grade – SAF Analysis Set 
 
 
 
 
Worst NCI-CTCAE Grade 
Laboratory  
Test 
Treatment 
Baseline 
NCI-
CTCAE  
Grade 
Grade 0  
n (%) 
Grade 1  
n (%) 
Grade 2  
n (%) 
Grade 3  
n (%) 
Grade 4  
n (%) 
Missing  
n (%) 
Total  
n (%) 
 
 
 
 
 
 
 
 
 
 
 
Treatment B 
N=xxx 
Grade 0 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Grade 1 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Grade 2 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Grade 3 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Grade 4 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Missing 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Total 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
 
 
Shell continues on the next page 
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15.3: Safety Data 
15.3.5: Clinical Laboratory Evaluations 
Table 15.3.5.3: Hematology – Shift in Toxicity Grading from Baseline to Highest Grade – SAF Analysis Set 
 
 
 
 
Worst NCI-CTCAE Grade 
Laboratory  
Test 
Treatment 
Baseline 
NCI-
CTCAE  
Grade 
Grade 0  
n (%) 
Grade 1  
n (%) 
Grade 2  
n (%) 
Grade 3  
n (%) 
Grade 4  
n (%) 
Missing  
n (%) 
Total  
n (%) 
 
 
 
 
 
 
 
 
 
 
 
Treatment C 
N=xxx 
Grade 0 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Grade 1 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Grade 2 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Grade 3 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Grade 4 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Missing 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
 
Total 
xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) xxx (xx.x) 
xxx (100.0) 
 
NCI-CTCAE version 4.03. 
Note: Baseline is the last measurement prior to the first dose of any trial treatment. 
 


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Repeat table 15.3.5.3 for: 
Table 15.3.5.4: Clinical Chemistry – Shift in Toxicity Grading from Baseline to Highest Grade – SAF Analysis Set 
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KLJK(//\PSKRF\WHVORZ(/1HXWURSKLOV(/«
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15.3: Safety Data 
15.3.5: Clinical Laboratory Evaluations 
Figure 15.3.5.5: Boxplot of Change from Baseline for ALT Values by Visit – SAF Analysis Set 
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Programming note: The y-axis label should be “<PARAM> Change from Baseline (<units>). The x-axis label should be “Visit”. 
For the partially unblinded outputs, the Treatment Group legend will show “Treatment A” etc. 
Use only the following colors (applies to all figures): Cyan, Magenta, Yellow & Black. Also use different symbols for 
each treatment group.
 


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Repeat figure 15.3.5.5 for: 
Figure 15.3.5.6: Boxplot of Change from Baseline for AST Values by Visit – SAF Analysis Set 

Figure 15.3.5.7: Boxplot of Change from Baseline for Total Bilirubin Values by Visit – SAF Analysis Set 

Figure 15.3.5.8: Boxplot of Change from Baseline for Total White Blood Count Values by Visit – SAF Analysis Set 

Figure 15.3.5.9: Boxplot of Change from Baseline for Neutrophils Values by Visit – SAF Analysis Set 
 
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16.2.1: Subject Disposition  
Listing 16.2.1.1: Subject Disposition and Withdrawals – Screening Analysis Set 
 
 
 
Treatment 
Group 
 
 
Subject 
Identifier 
 
 
Screening  
Date 
 
Randomized?/ 
Date 
Randomized/ 
Stratification 
Factor (a) 
Withdrew 
Prior to 
Being 
Treated? 
 
In SAF 
Analysis 
Set? 
Withdrew 
from trial 
treatment/ 
Reason for 
Withdrawal 
 
 
Date of  
Last Dose 
Discont-
inued 
Trial?/ 
Primary 
Reason 
Date 
Discont-
inued 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
A 
XXXXXXX 
DDMMMYYYY 
Yes/DDMMMYYYY/ 
FVC <70% 
XXX 
XXX 
Yes/XXXXXXXX
XXXX 
DDMMMYYYY 
Yes/ 
xxxxxxxx 
DDMMMYYYY 
 
XXXXXXX 
DDMMMYYYY 
Yes/DDMMMYYYY/ 
FVC ≥70% 
XXX 
XXX 
No 
 
No 
 
 
XXXXXXX 
DDMMMYYYY 
Yes/DDMMMYYYY/ 
XXXXXX 
XXX 
XXX 
No 
 
No 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
B 
XXXXXXX 
DDMMMYYYY 
Yes/DDMMMYYYY/ 
XXXXXX 
XXX 
XXX 
No 
 
No 
 
 
… 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(a) Stratification Factor from eCRF: FVC <70% = Baseline FVC <70% predicted, FVC ≥70% = Baseline FVC ≥70% predicted. 
 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. 
 
 
Programming Note: If a subject is screened but not yet randomized, treatment group will be Not Randomized. If they are 
screen failed then treatment group is Screen Failures. 
If there are subjects in the Not Randomized group then add the following footnote (note indentation to line up with 
baseline footnote): 
     ‘Not Randomized’ treatment group contains subjects who are still in screening at time of data cutoff. 
Ensure any “Other” reasons for treatment and trial termination are specified, “Other: xxxxxx”. 
 
 
 
 
 
 
 
 


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16.2.1: Subject Disposition  
Listing 16.2.2.1: Important Protocol Deviations – ITT Analysis Set 
 
 
 
 
 
 
 
Treatment 
Group 
 
 
Subject 
Identifier 
Type 
Deviation details 
 
 
 
 
 
 
 
 
Treatment A 
XXXXXXX 
Eligibility and Entry Criteria 
Efficacy Criteria
XXXXXXXXXXXXXX/  
XXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX 
 
XXXXXXX 
XXXXXXXXXXX 
XXXXXXXXXXXX
XXXXXXXXXXXXXX  
XXXXXXXXXXXXXXXXXX 
 
XXXXXXX 
XXXXXXXXXXX 
XXXXXXXXXXXX 
XXXXXXXXXXXXXX  
XXXXXXXXXXXXXXXXXX 
 
…… 
 
 
 
 
 
 
Treatment B 
XXXXXXX 
XXXXXXXXXXX 
XXXXXXXXXXXX 
XXXXXXXXXXXXXX  
XXXXXXXXXXXXXXXXXX 
 
… 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
Programming note: Present each deviation on a new line.
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16.2.4: Demographic Data 
Listing 16.2.4.1: Subject Demographics – SAF Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Sex 
 
Birth Date 
 
Age 
(years) 
 
Race 
 
Ethnicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
A 
XXXXXXX 
Male 
DDMMMYYYY 
XX 
XXXXXXX 
XXXXX 
 
XXXXXXX 
Female 
     YYYY 
XX 
XXXXXXX 
XXXXX 
 
XXXXXXX 
XXXX 
DDMMMYYYY 
XX 
XXXXXXX 
XXXXX 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
B 
XXXXXXX 
XXXX 
DDMMMYYYY 
XX 
XXXXXXX 
XXXXX 
 
… 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Age is relative to the date of informed consent. 
 
 
 
 
 
 
 
 


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16.2.4: Demographic Data 
Listing 16.2.4.2: Subject Medical History – SAF Analysis Set 

 
Treatment 
Group 
 
Subject 
Identifier 
 
System Organ 
Class 
 
Preferred 
Term 
 
Verbatim 
Text 
 
Start Date 
 
End Date  
 
Related to 
Study 
Condition? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
A 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
DDMMMYYYY 
Ongoing 
Yes 
 
 
XXXXXXX 
XXXXXXX 
XXXXXXX 
DDMMMYYYY 
DDMMMYYY 
No 
 
 
XXXXXXX 
XXXXXXX 
XXXXXXX 
DDMMMYYYY 
XXXXXXXX 
Unknown 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
B 
XXXXXXX 
XXXXXXX 
XXXXXXX 
XXXXXXX 
DDMMMYYYY 
XXXXXXXX 
 
 
… 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MedDRA version xx.x. 
 
 
Programming note: MedDRA version 19.1 or highest at time of data transfer. 
 
 


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16.2.4: Demographic Data 
Listing 16.2.4.3: Subject Disease History – SAF Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Date of 
Diagnosis 
Time Since 
Date of 
Diagnosis 
(years) 
Status
 
Systemic Sclerosis 
Symptom History (a) 
 
ACR/EULAR Classification 
Criteria for Systemic 
Sclerosis (b) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A XXXXXXX 
DDMMMYYYY 
XX.XX 
Diffuse 
cutaneous SSc 
Skin Thickening/ 
Tendon friction rubs/ 
XXXXXXX 
Fingertip lesions: 
Fingertip pitting scars/
Abnormal nailfold 
capillaries/ XXXXXX  
 
XXXXXXX 
DDMMMYYYY 
XX.XX 
Limited 
cutaneous SSc 
XXXXXXX/ XXXXXXX / 
XXXXXXXXX/ XXXXXX 
XXXXXXX/ XXXXXXX / 
XXXXXXXXX/ XXXXXX 
 
XXXXXXX 
DDMMMYYYY 
XX.XX 
XXXXXXX 
XXXXXXX/ XXXXXXX / 
XXXXXXXXX/ XXXXXX 
XXXXXXX/ XXXXXXX / 
XXXXXXXXX/ XXXXXX 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment B XXXXXXX 
DDMMMYYYY 
XX.XX 
XXXXXXXX 
XXXXXXX/ XXXXXXX / 
XXXXXXXXX/ XXXXXX 
 
 
… 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
(a) Where ‘Yes’ was selected on the eCRF. 
(b) Where ‘Present’ was selected on the eCRF. 
Note: Time since date of diagnosis is relative to date of informed consent. 
 
 
 
Programming note: Concatenate all Systemic Sclerosis Symptom History sub-categories where ‘Yes’ is ticked on the eCRF, 
concatenate all ACR/EULAR Classification Criteria for Systemic Sclerosis sub-categories where ‘Present’ is ticked on 
the eCRF.  
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16.2.4: Demographic Data 
Listing 16.2.4.4: Previous Medications – SAF Analysis Set 

 
Treatment 
Group 
 
Subject 
Identifier 
 
ATC Level 2/ 
Preferred Term/ 
Reported Name
 
Start Date/ 
End Date 
(Trial Day) 
 
Dose 
(Unit) 
 
Frequency 
 
Route 
 
Reason 
(Indication) 
 
Reason(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
A 
XXXXXXX 
XXXXXXXXXXXX/ 
XXXXXXXX/ 
XXXXXXXX
DDMMMYYY 
(xx) / 
DDMMMYYY 
(xx) 
XXX xx XX 
XX 
XXXXXXXX 
Adverse event/ 
Disease related 
condition 
 
 
XXXXXXXXXXXX/ 
XXXXXXXX/ 
XXXXXXXX 
DDMMMYYY 
(xx) / 
DDMMMYYY 
(xx) 
XXX xx Other: XXX XX 
XXXXXXXX 
XXXXXXX 
 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
B 
XXXXXXX 
XXXXXXXXXXXX/ 
XXXXXXXX/ 
XXXXXXXX 
DDMMMYYY 
(xx) / 
DDMMMYYY 
(xx) 
XXX  
XX 
Other: 
XX 
XXXXXXXXXXXX 
XXXXXX 
 
… 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WHO Drug Dictionary version Enhanced September 2016. 
Note: In case multiple ATCs are assigned to a medication, all ATCs will be reported.                                      
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Repeat listing 16.2.4.4 for: 
Listing 16.2.4.5: Concomitant Medications – SAF Analysis Set 
&KDQJH³3UHYLRXV0HGLFDWLRQ´WR³&RQFRPLWDQW0HGLFDWLRQ´
Listing 16.2.4.6: Background Therapy – SAF Analysis Set 
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16.2.5: Treatment Compliance and Exposure 
Listing 16.2.5.1: Trial Treatment Administration Details – SAF Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
 
Preparation 
Date 
(Time)/  
Kit Number 
 
Admin. 
Start Date 
(Time)/  
End Date 
(Time) 
 
Duration 
of 
infusion 
(hours) 
 
Change in 
Dose? 
Planned 
Volume 
(mL)
Actual 
Volume 
(mL)
 
Infusion 
Completed 
as Planned? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
A 
XXXXXXX 
XXXXXXX 
DDMMYYY 
(HH:MM)/ 
XXXX 
DDMMYYY 
(HH:MM)/ 
DDMMYYY 
(HH:MM) 
XX.XX 
No 
XXX 
XXX 
No: Adverse 
event 
 
 
XXXXXXX 
DDMMYYY 
(HH:MM)/ 
XXXX
DDMMYYY 
(HH:MM)/ 
DDMMYYY 
(HH:MM) 
XX.XX 
Dose 
adjusted: 
Adverse 
event 
XXX 
XXX 
Yes 
 
 
XXXXXXX 
DDMMYYY 
(HH:MM)/ 
XXXX
DDMMYYY 
(HH:MM)/ 
DDMMYYY 
(HH:MM) 
XX.XX 
XXXXXXX 
XXX 
XXX 
XXX 
 
 
XXXXXXX* 
 
 
 
No dose: 
Missed 
visit 
XXX 
 
No: Other, 
No dose: 
missed 
visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* = Visit derived due to the subject not completing the “STUDY TREATMENT ADMINISTRATION DETAILS” eCRF page at the missed 
visit. 
Note: Admin. = Administration. 
      Duration of infusion is calculated as: End time of administration – start time of administration. 
 
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16.2.5: Treatment Compliance and Exposure 
Listing 16.2.5.2: Overall Exposure to Trial Treatment – SAF Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Treatment 
Duration 
(weeks) 
 
Number of  
Infusions 
 
Number of Dose 
Adjustments 
 
Number of Infusions 
Not Completed as 
Planned 
Overall Treatment 
Adherence (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A XXXXXXX 
XXX 
XX 
X 
X 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment duration is calculated as: (Last infusion date prior to data cut-off – first infusion date + 28) 
       / 7 days. 
      Subject overall treatment adherence is calculated as: (sum of actual volume received/ sum of planned  
      Volume, up to and including their last dose recorded on their treatment termination visit)*100. 
 
 
 
 


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16.2.6: Efficacy Data 
Listing 16.2.6.1: FVC Volume (mL) and FVC % Predicted – mITT Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
 
Date of 
Assessment 
(Trial Day) 
 
FVC (mL) 
 
 
FVC % Predicted 
 
Observed 
Change from 
Baseline 
 
Observed 
Change from Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
A 
XXXXXXX 
XXXXXXX 
DDMMMYYYY (xx) 
XX* 
 
 
XX* 
 
 
 
XXXXXXX 
DDMMMYYYY (xx) 
XX
XX 
 
XX
XX 
 
 
XXXXXXX 
DDMMMYYYY (xx) 
XX
XX 
 
XX
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Baseline value. 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. If such a value is missing  
      then the last value prior to the first trial treatment administration will be used. 
      Trial day is defined relative to the date of randomization. 
 
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16.2.6: Efficacy Data 
Listing 16.2.6.2: mRSS Total Score – mITT Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
 
Date of Assessment 
(Trial Day) 
 
mRSS Total Score 
 
Observed 
Change from Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A 
XXXXXXX 
XXXXXXX 
DDMMMYYYY (xx) 
XX* 
 
 
 
XXXXXXX 
DDMMMYYYY (xx) 
XX
XX 
 
 
XXXXXXX 
DDMMMYYYY (xx) 
XX
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
* Baseline value. 
^ = diffuse cutaneous systemic sclerosis at baseline. 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. If such a value is missing  
      then the last value prior to the first trial treatment administration will be used. 
      Trial day is defined relative to the date of randomization. 
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16.2.6: Efficacy Data 
Listing 16.2.6.3: Clinically Meaningful Disease Progression – mITT Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Date of 
Progression 
(Trial Day) 
 
 
 
 
 
SSc-ILD progression 
 
Progression Criteria 
Fulfilled  
Was 
Mycophenolate 
Dose 
Increased? 
Was a New 
Immunosuppressant 
or Biologic Drug 
Initiated? 
Was the Trial 
Treatment 
Discontinued? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A XXXXXXX 
DDMMMYYYY (xx) 
SSc-ILD: Relative 
decrease from 
baseline in FVC % 
predicted >10% 
No 
No 
No 
 
 
DDMMMYYYY (xx) 
SSc other than ILD: 
Scleroderma renal 
crisis 
 
 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Trial day is defined relative to the date of randomization. 

 
 
 
Programming note: Only display subjects with clinically meaningful disease progression. Concatenate all details 
selected for SSc other than ILD (including the free text details for ‘Other’). If both SSc-ILD and SSc other than ILD 
were selected on the same date, then display on a new line.
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16.2.6: Efficacy Data 
Listing 16.2.6.4: DLCO – mITT Analysis Set 
 
* Baseline value. 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. If such a value is missing  
      then the last value prior to the first trial treatment administration will be used. 
      Trial day is defined relative to the date of randomization. 

 




 
 
 
 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
 
Visit 
 
Date of 
Assessment 
(Trial Day) 
 
DLCO as recorded on 
eCRF 
 
 
 
DLCO Result in SI Unit 
(mmol of CO/min/kPa) 
 
 
 
DLCO % Predicted 
Observed (unit) 
 
Observed  Change from 
Baseline  
 
Observed  
Change 
from 
Baseline  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
A 
XXXXXXX 
 
XXXXXX 
DDMMMYYYY 
(xx) 
XX (xxx) 
 
XX* 
 
 
XX* 
 
 
 
XXXXXX 
DDMMMYYYY 
(xx) 
XX (xxx)
 
XX
XX 
 
XX 
XX 
 
 
XXXXXX 
DDMMMYYYY 
(xx) 
XX (xxx)
 
XX
XX 
 
XX 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.6: Efficacy Data 
Listing 16.2.6.5: KCO – mITT Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
 
Date of 
Assessment 
(Trial Day) 
Test 
overread 
grading 
VA 
DLCO/ VA 
KCO 
Observed 
Change from 
baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A XXXXXXX 
XXXXXXX 
DDMMMYYYY (xx) 
Acceptable 
xx 
xx+ 
xx* 
 
 
 
XXXXXXX 
DDMMMYYYY (xx) 
Unacceptable 
xx 
xx 
xx 
xx 
 
 
XXXXXXX 
DDMMMYYYY (xx) 
xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Baseline value. 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. 
      Trial day is defined relative to the date of randomization. 
 
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16.2.6: Efficacy Data 
Listing 16.2.6.6: Digital Ulcers – mITT Analysis Set 
 
* Baseline value. 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. 
  CFB = Change from Baseline.  
      Trial day is defined relative to the date of randomization. 
 
  
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Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
Completed 
Status 
 
Date of 
Assessment 
(Trial Day) 
Number of 
Total 
Digital 
Ulcer 
count 
Active Ulcers 
Undetermined 
Ulcers 
Healed Ulcers 
Absolute 
Value 
CFB 
Absolute 
Value 
CFB 
Absolute 
Value 
CFB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A XXXXXXX 
 
XXXXXX 
Done 
DDMMMYYYY 
(xx) 
XXX* 
 
XXX* 
 
XXX* 
 
XXX 
 
 
XXXXXX 
Not Done 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
XXXXXXX 
DDMMMYYYY 
(xx) 
XXX 
XXX XXX 
XXX XXX 
XXX XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.6: Efficacy Data 
Listing 16.2.6.7: Mahler BDI/TDI – mITT Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
 
Date of 
Assessment 
(Trial Day) 
 
Question 
Score 
Done/ Not done 
- Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A 
XXXXXXX 
XXXXXXX DDMMMYYYY (xx) 
Done 
Functional Imapairment 
x 
 
 
 
 
 
Magnitude of Task 
x 
 
 
 
 
 
Magnitude of Effort 
x 
 
 
 
 
 
Total 
x 
 
 
XXXXXXX DDMMMYYYY (xx) 
Done 
Changes in Functional Impairment 
x 
 
 
 
 
 
Changes in Magnitude of Task 
x 
 
 
 
 
 
Changes in Magnitude of Effort 
x 
 
 
 
 
 
Total 
x 
 
 
XXXXXXX DDMMMYYYY (xx) 
Not done – 
Subject felt 
too ill 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. The BDI is completed at 
      baseline and the TDI is completed at subsequent visits. 
      Trial day is defined relative to the date of randomization. 
 
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16.2.6: Efficacy Data 
Listing 16.2.6.8: SGRQ – Question Scores – mITT Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
 
Date of 
Assessment 
(Trial Day) 
 
Question 
(component) 
Answer(s) 
Weight 
Done/ Not done 
- Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A 
XXXXXXX 
XXXXXXX DDMMMYYYY (xx) 
Done 
xxxxxx (S) 
xxxx 
x 
 
 
 
 
 
xxxxxx (I) 
xxxx 
x 
 
 
 
 
 
 
xxxxx 
x 
 
 
 
 
 
… 
xxxxx 
x 
 
 
XXXXXXX DDMMMYYYY (xx) 
Done 
 
xxxx 
x 
 
 
 
 
 
 
xxxxxx 
x 
 
 
 
 
 
 
xxxx 
x 
 
 
 
 
 
 
xxxxxx 
x 
 
 
XXXXXXX DDMMMYYYY (xx) 
Not done – 
Subject felt 
too ill 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Component abbreviations: S = Symptoms, I = Impacts, A = Activity. 
      Trial day is defined relative to the date of randomization. 
 
 
 


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16.2.6: Efficacy Data 
Listing 16.2.6.9: SGRQ – Component and Total Scores – mITT Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
 
Date of 
Assessment 
(Trial Day) 
 
Component 
Score 
 
Done/ Not done 
- Reason 
Change from 
baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A 
XXXXXXX 
XXXXXXX DDMMMYYYY (xx) 
Done 
Symptoms 
x 
 
 
 
 
 
 
Activity 
x 
 
 
 
 
 
 
Impacts 
x 
 
 
 
 
 
 
Total 
x* 
 
 
 
XXXXXXX DDMMMYYYY (xx) 
Done 
Symptoms 
x 
 
 
 
 
 
 
Activity 
x 
 
 
 
 
 
 
Impacts 
x 
 
 
 
 
 
 
Total 
x 
x 
 
 
XXXXXXX DDMMMYYYY (xx) 
Not done – 
Subject felt 
too ill 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Baseline value (total scores only).  
Note: Baseline is defined as the last non-missing measurement prior to randomization. 
      Trial day is defined relative to the date of randomization. 
      The component score is 100 x summed weights from all positive items in that component divided by the sum of 
      weights for all items in that component. The total score is 100 x summed weights from all positive items in the 
      questionnaire divided by the sum of weights for all items in the questionnaire.  
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16.2.6: Efficacy Data 
Listing 16.2.6.10: Leicester Cough Index – Question Scores – mITT Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
 
Date of 
Assessment 
(Trial Day) 
 
Question (domain) 
Score 
Done/ Not done 
- Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A 
XXXXXXX 
XXXXXXX DDMMMYYYY (xx) 
Done 
xxxxxx (P) 
x 
 
 
 
 
 
xxxxx (Psy) 
x 
 
 
 
 
 
xxxxx (S) 
x 
 
 
 
 
 
 
 
 
 
XXXXXXX DDMMMYYYY (xx) 
Done 
xxxxx 
x 
 
 
 
 
 
xxxxxx 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
XXXXXXX DDMMMYYYY (xx) 
Not done – 
Subject felt 
too ill 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Trial day is defined relative to the date of randomization. 
      Domain abbreviations: P = Physical, Psy = Psychological, S = Social.  
      1 is the most negative score, 7 is the most positive score. 
 
 
 


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16.2.6: Efficacy Data 
Listing 16.2.6.11: Leicester Cough Index – Domain and Total Scores – mITT Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
 
Date of 
Assessment 
(Trial Day) 
 
Domain 
Score 
 
Done/ Not done 
- Reason 
Change from 
baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A 
XXXXXXX 
XXXXXXX DDMMMYYYY (xx) 
Done 
Physical 
x 
 
 
 
 
 
 
Psychological 
x 
 
 
 
 
 
 
Social 
x 
 
 
 
 
 
 
Total 
x* 
 
 
 
XXXXXXX DDMMMYYYY (xx) 
Done 
Physical 
x 
 
 
 
 
 
 
Psychological 
x 
 
 
 
 
 
 
Social 
x 
 
 
 
 
 
 
Total 
x 
x 
 
 
XXXXXXX DDMMMYYYY (xx) 
Not done – 
Subject felt 
too ill 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Baseline value (total score only). 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. 
      Trial day is defined relative to the date of randomization. 
      Domain scores are the sum of all scores in the domain divided by the number of questions within  
      that domain.  
 
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16.2.6: Efficacy Data 
Listing 16.2.6.12: Physician’s Global Assessment – mITT Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
 
Date of 
Assessment 
(Trial Day) 
 
Score 
 
Done/ Not done 
- Reason 
Change from baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A 
XXXXXXX 
XXXXXXX DDMMMYYYY (xx) 
Done 
x* 
 
 
 
XXXXXXX DDMMMYYYY (xx) 
Done 
x 
x 
 
 
XXXXXXX DDMMMYYYY (xx) 
Not done – 
Subject felt 
too ill 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Baseline value. 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. 
      Trial day is defined relative to the date of randomization. 
      The score is based on the question: “On a scale of 0–100, where would you rate the overall effect systemic 
      sclerosis has on your patient at this time”, where 0 = has no effect at all and 100 = worst possible 
      effect. 
 
 
Repeat listing 16.2.6.12 for: 
Listing 16.2.6.13: Patient’s Global Assessment – mITT Analysis Set 
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Update footnote: The score is based on the question: “On a scale of 0–100, where would you rate the overall effect 
systemic sclerosis has on you at this time”, where 0 = has no effect at all and 100 = worst possible effect. 
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16.2.6: Efficacy Data 
Listing 16.2.6.14: SHAQ – VAS Scores – mITT Analysis Set 
 
 
 
 
Overall 
disease 
activity 
 
Raynaud’s 
phenomenon 
 
Finger ulcers 
 
Breathing 
problems 
 
Intestinal 
problems 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Visit 
Observed 
CFB 
 
Observed 
CFB 
 
Observed 
CFB  
Observed 
CFB 
 
Observed 
CFB 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Treatment A XXXXXXX 
XXXXX 
xx* 
 
 
xx* 
 
 
xx* 
 
 
xx* 
 
 
xx* 
 
 
 
XXXXX 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
XXXXX 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
XXXXX 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXXX 
XXXXX 
xx^ 
 
 
xx^ 
 
 
xx^ 
 
 
xx^ 
 
 
xx^ 
 
 
 
XXXXX 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
XXXXX 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXXX 
XXXXX 
xx 
 
 
xx 
 
 
xx 
 
 
xx 
 
 
xx 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
* Baseline value. 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. 
      The VAS scores range from 0 (most positive response) to 100 (most negative response). 
CFB = Change from baseline.
       
 
 
 
 


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16.2.6: Efficacy Data 
Listing 16.2.6.15: EQ-5D VAS Score – mITT Analysis Set 
Treatment 
Group 
Subject   
Identifier Visit 
 
Date of Assessment 
(Trial Day) 
VAS Score 
Observed 
CFB 
 
 
 
 
 
 
Treatment 
A 
XXXXXXX 
XXXXXXX DDMMMYYYY (xx) 
X* 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
…. 
XXXXXXX 
 
DDMMMYYYY (xx) 
X* 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
* Baseline value. 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. 
      Trial day is defined relative to the date of randomization. 
      CFB = Change from Baseline. 
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16.2.6: Efficacy Data 
Listing 16.2.6.16: HRCT Results – mITT Analysis Set 

Treatment 
Group 
Subject   
Identifier Visit 
Date of 
Assessment 
(Trial Day) 
QLF (%) (a) 
 
Extent of ILD (%) 
Observed 
Change from 
Baseline 
 Observed 
Change from 
Baseline 
 
 
 
 
 
 
  
 
Treatment 
A 
XXXXXXX 
XXXXXXX DDMMMYYYY (xx) 
X* 
 
 
X* 
 
 
 
 
DDMMMYYYY (xx) 
X 
X 
 
X 
X 
 
 
 
DDMMMYYYY (xx) 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…. 
XXXXXXX 
 
DDMMMYYYY (xx) 
X* 
 
 
X* 
 
 
 
 
DDMMMYYYY (xx) 
X 
X 
 
X 
X 
 
 
 
DDMMMYYYY (xx) 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
  
 
* Baseline value. 
(a) QLF in region of highest severity. 
Note: Baseline is defined as the last non-missing assessment value prior to randomization. 
      Trial day is defined relative to the date of randomization. 
 
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16.2.7: Display of Adverse Events 
Listing 16.2.7.1: All Adverse Events – SAF Analysis Set 
 
 
 
Treatment 
Group 
 
 
Subject 
Identifier 
 
System Organ Class/ 
Preferred Term/ 
Verbatim Text 
 
 
Start Date/ 
End Date 
(Trial Day)
 
Relationship
/Timing to 
Trial Trt 
 
Toxic-
ity 
Grade 
 
Causal-
ity 
Factors 
Action Taken 
With Trial 
Trt/Other 
Action 
 
 
 
Outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
A 
XXXXXXX 
XXXXXXXXXXXXXXX/ 
DDMMMYYYY 
(xx)/ 
XXXXXXXXXX/  
X 
XX 
XXXXXXXXXX/  
XXXXXXXXX 
 
 
XXXXXXXXXXXXXXX/ 
DDMMMYYYY 
(xx) 
XXXXXXX 
 
 
XXXXXXXXXXX 
 
 
 
XXXXXXXXXXXXX+* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ Serious Adverse Event. 
# Adverse Event of Special Interest. 
* Treatment Emergent Adverse Event. 
 
Note: Trial day is defined relative to the date of randomization. 
 
 
 


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16.2.7: Display of Adverse Events 
Listing 16.2.7.2: Serious Adverse Events – SAF Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
System Organ Class/ 
Preferred Term/  
Verbatim Text 
 
Start Date/ 
End Date 
(Trial Day) 
 
Seriousness Criteria
 
Relationship/Action 
Taken with Trial Trt 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
A 
XXXXXXX 
XXXXXXXXXXXXXXX/ 
  XXXXXXXXXXXXXXX/ 
    XXXXXXXXXXXXXXX #
DDMMMYYYY 
(xx)/ 
DDMMMYYYY 
(xx) 
Requires/prolongs 
hospitalization 
XXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXX 
 
 
   
 
 
 
 
 
 
 
 
 
 
. . .  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
# Adverse Event of Special Interest. 
$ Non-Treatment Emergent Adverse Event. 
Note: Trial day is defined relative to the date of randomization. 
 
 
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16.2.7: Display of Adverse Events 
Listing 16.2.7.3: Listing of Deaths – SAF Analysis Set 
 
 
Treatment 
Group 
 
Subject 
Identifier 
 
Informed 
Consent Date 
 
Randomization 
Date 
 
First/Last 
Trial Trt. 
Date
 
Death Date 
(days since 
last dose) 
 
Primary Reason for Death 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
A 
XXXXXXX 
DDMMMYYYY
DDMMMYYYY 
DDMMMYYYY/ 
DDMMMYYYY 
DDMMMYYYY (XXX) XXXXXXXXXXXXXXXXXXXXXXXX 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
. . .  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.2.8: Clinical Laboratory Evaluations 
Listing 16.2.8.1: Hematology Parameters – SAF Analysis Set 
 
Treatment 
Group 
Subject  
Identifier 
 
Visit 
Date of  
Sample 
(Trial Day) 
 
Comment 
 
Parameter 
(Unit) 
 
Normal Range 
 
Result 
 
NCI-CTC 
grade 
(a) 
 
 
 
 
 
 
 
 
 
Treatment A XXXXXXX 
XXXXXXXX 
DDMMMYYYY 
(xx) 
XXXXXXXXXX 
XXXXXXXXXX 
XX - XX 
XXX* 
x/x 
 
 
 
 
 
XXXXXXXXXX 
XX - XX 
XXX L 
x 
 
 
 
 
 
XXXXXXXXXX 
XX - XX 
XXX H 
 
 
. . .  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(a) NCI-CTCAE version 4.03 for gradeable parameters. For parameters with both low and high grades, the grades are 
    presented as Low/High.                                                                                                            
L = value below normal range, H = value above normal range. 
* Baseline value. 
Note: Baseline is defined as the last non-missing assessment value prior to first dose of trial treatment. 
Trial day is defined relative to the date of randomization. 
 
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Listing 16.2.8.2: Clinical Chemistry Parameters – SAF Analysis Set 
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16.2.9: Other Safety Evaluations 
Listing 16.2.9.1: Vital Signs – SAF Analysis Set 
 
 
Treatment 
Group 
 
Subject  
Identifier 
 
Visit 
 
Assessment  
Date (Trial 
Day) 
Blood Pressure 
(mmHg) 
 
Pulse Rate 
(beats/min) 
 
Temperature 
(⁰C) 
(Location) 
 
Height 
(cm) 
 
Weight 
(kg) 
 
Systolic 
 
Diastolic 
 
 
 
 
 
 
 
 
 
 
Treatment A XXXXXXX 
XXXXXXXX 
DDMMMYYYY 
(xx) 
XXX 
XXX 
XXX 
XX (XXXXXX) 
XX 
XX 
 
 
XXXXXXXX 
DDMMMYYYY 
(xx) 
XXX 
XXX 
XXX 
XX (XXXXXX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
. . .  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:Trial day is defined relative to the date of randomization. 
 
 
 


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16.2.9: Other Safety Evaluations 
Listing 16.2.9.2: Electrocardiogram Data – SAF Analysis Set 
 
Treatment 
Group 
Subject  
Identifier 
 
Visit 
Assessment  
Date (Trial Day) 
 
Result 
 
Clinically Significant? (a) 
 
 
 
 
 
 
Treatment A 
XXXXXXX 
XXXXXXXX 
DDMMMYYYY (xx) 
Normal 
 
 
 
XXXXXXXX 
DDMMMYYYY (xx) 
Abnormal 
No 
 
 
XXXXXXXX 
DDMMMYYYY (xx) 
XXXXXXXXXX 
xxxxxx 
 
. . .  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
 
(a) If result is ‘Abnormal’. 
* Baseline value. 
Note: Baseline is defined as the last non-missing assessment value prior to first dose of trial treatment. 
      Trial day is defined relative to the date of randomization. 
 
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