Conditions: Lung Diseases, Interstitial
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 444
Healthy volunteers: no

Brief summary:
The main objective is to assess long term safety of treatment with oral nintedanib in patients with Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD).

Detailed description:

Arms:
arm 1: Patients with Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD) who took part in the parent trials 1199.214 (Nintedanib or Placebo) or 1199-0340 (Nintedanib). Patients continued in this trial and received Nintedanib 150 mg (milligram) twice daily (bid) unless they had reduced their dose to 100 mg bid trial medication (Nintedanib or Placebo) in the parent trial.

Patients receiving 100 mg bid trial medication at the end of the parent trial could receive either Nintedanib 100 mg bid or 150 mg bid at the discretion of the investigator.

Interventions: intervention 1: Nintedanib
Intervention descriptions: intervention 1: Administered twice daily

Protocol document:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
Nintedanib
Protocol date:
30 May 2017
Trial number:
1199.225
Revision date:
13 Aug 2020
Title of trial:
An open-label extension trial to assess the long term safety of 
nintedanib in patients with ‘Systemic Sclerosis associated Interstitial 
Lung Disease’ (SSc-ILD) SENSCIS®- ON
Coordinating
Investigator:
Trial site(s):
Multi-centre trial conducted in approximately 30 countries; identical 
to sites which enrolled patients into 1199.214 and into 1199-0340
Clinical phase:
III
Objective(s):
The primary objective of this trial is to assess the long-term safety of 
nintedanib treatment in patients with Systemic Sclerosis associated 
Interstitial Lung Disease who have completed (did not prematurely 
discontinue trial medication) the phase III parent trial SENSCIS®
(1199.214) and to assess the safety of the ongoing nintedanib 
treatment in patients with Systemic Sclerosis associated Interstitial 
Lung Disease who have completed the phase I drug-drug interaction 
(DDI) trial 1199-0340.
Methodology:
Extension trial to evaluate the long term tolerability and safety of 
Nintedanib


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Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
Nintedanib
Protocol date:
30 May 2017
Trial number:
1199.225
Revision date:
13 Aug 2020
No. of patients: 
total entered:
Approximately 400 patients
each treatment:
Not applicable
Diagnosis:
Systemic Sclerosis associated Interstitial Lung Disease
Main criteria
for inclusion:
Patients who have completed (did not prematurely discontinue trial 
medication) SENSCIS® (1199.214) or 1199-0340.
Test product(s):
Nintedanib
dose:
Nintedanib
150 mg bid (300 mg daily) or 100 mg bid (200 mg daily) 
mode of 
administration:
p. o.
Comparator products:
Not applicable
dose:
mode of 
administration:
Duration of treatment:
Treatment duration for each patient will be variable. Treatment will 
be stopped if a reason for withdrawal is met. The trial is estimated 
to last approximately 34 months.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
Nintedanib
Protocol date:
30 May 2017
Trial number:
1199.225
Revision date:
13 Aug 2020
Endpoints
The primary endpoint is the incidence of overall adverse events 
over the course of the extension trial. 
Safety criteria:
Adverse events, physical examination including weight, vital signs, 
laboratory evaluations.
Statistical methods:
Descriptive statistics of adverse events and other safety parameters.




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Footnotes:
*In case of dose change (reduction or re-escalation) additional visits have to be included (refer to Section 6.2.4)
1 Visit 1 should occur at least one day after trial completion of SENSCIS® (Follow up Visit) or 1199-0340 (End of Treatment/end of Study Visit). Visit 2 of this extension trial is to be scheduled:
∀
within a maximum of 12 weeks after last drug intake in SENSCIS® (please see also Section 6.2.1)
∀
within a maximum of 1 week after last drug intake in 1199.340 
2 Combining of Visit 1 and Visit 2: 
∀
For patients who completed SENSCIS®, Visit 1 and Visit 2 may occur on the same day if the period between the last available laboratory test within SENSCIS® and Visit 2 of the 
extension trial (1199.225) is ≤ 6 weeks.
∀
For patients who completed 1199-0340, Visit 1 and Visit 2 are always scheduled on the same day. 
If medical condition is not stable and new Adverse Events occurred, a new laboratory test has to be performed. For patients performing Visit 1 and Visit 2 on the same day, eligibility assessment 
will be based on laboratory data from last laboratory test available within SENSCIS® / 1199-0340. In case Visit 1 and Visit 2 takes place on the same day, laboratory tests, physical examination 
and vital signs are performed only once on that day and are recorded under Visit 2 in the eCRF
3 The patient is required to sign informed consent prior to any trial related activities
4 Only medical conditions that are occurring concomitantly at the time of screening will be recorded as baseline conditions in the eCRF, including any ongoing AEs from SENSCIS® or 1199-
0340 respectively. 
5 Cautionary note: dependent on concomitant treatment additional safety monitoring should be considered at discretion of the investigator. Intermediate lab tests (a-Visits) do not necessarily 
need to be a site visit.
6 ß-HCG will be performed at central lab at Visit 2 only. Urine dipstick pregnancy tests will be provided centrally and should be performed in all women of childbearing potential every 4-6 
weeks: at least every visit and if necessary, additionally at home or at a local doctor / laboratory. If urine test is not acceptable to local authorities, a blood test can be done at a local laboratory. 
Woman of childbearing potential will be instructed accordingly
7 Only after the dedicated biobanking Informed Consent has been received
8 Self-reported outcome questionnaires must always be done by patients in a quiet place prior to any other visit procedure
9 Same scheme should be repeated as often as needed: one complete visit every 16 weeks and one intermediate visit (a-visit) in between (every 16 weeks)
10 End of Treatment Visit to be performed if a reason for withdrawal is met (refer to Section 3.3.4)
11 A follow-up (FU) visit should be planned for 7 days after last drug intake in case trial medication had to be discontinued permanently due to adverse events
12 At selected sites (if the locally required language version is available)


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOWCHART.........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................14
1.1
MEDICAL BACKGROUND.............................................................................14
1.2
DRUG PROFILE................................................................................................15
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................17
1.4
BENEFIT - RISK ASSESSMENT.....................................................................18
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................21
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........21
2.1.1
Main Objectives...................................................................................................21
2.1.2
Primary Endpoint(s)...........................................................................................21
2 1 3
Secondary Endpoint(s)
21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................23
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................24
3.3
SELECTION OF TRIAL POPULATION .......................................................24
3.3.1
Main diagnosis for trial entry ............................................................................24
3.3.2
Inclusion criteria .................................................................................................24
3.3.3
Exclusion criteria ................................................................................................25
3.3.4
Withdrawal of patients from therapy or assessments .....................................26
3.3.4.1
Withdrawal from trial treatment ...........................................................................26
3.3.4.2
Recommendation to discontinue nintedanib.........................................................27
3.3.4.3
Withdrawal of consent for trial participation........................................................28
3.3.4.4
Discontinuation of the trial by the sponsor...........................................................28
4.
TREATMENTS...................................................................................................29
4.1
INVESTIGATIONAL TREATMENTS ...........................................................29
4.1.1
Identity of the Investigational Medicinal Products..........................................29
4.1.2
Method of assigning patients to treatment groups and selection of dose.......29
4.1.3
Drug assignment and administration of doses for each patient......................30
4.1.4
Blinding and procedures for unblinding...........................................................30
4.1.4.1
Blinding.................................................................................................................30
4.1.4.2
Unblinding and breaking the code ........................................................................31




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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................51
6.2.1
Screening..............................................................................................................51
6.2.2
Treatment period(s)............................................................................................52
6.2.3
Trial Completion and Follow Up Period...........................................................53
6.2.4
Dose modification visit........................................................................................53
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................54
7.1
STATISTICAL DESIGN - MODEL.................................................................54
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................54
7.3
PLANNED ANALYSES.....................................................................................54
7.3.1
Primary endpoint analyses.................................................................................54
7.3.2
Secondary endpoint analyses .............................................................................54
7.3.4
Safety analyses.....................................................................................................55
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................56
7.4
INTERIM ANALYSES ......................................................................................56
7.5
HANDLING OF MISSING DATA ...................................................................56
7.6
RANDOMISATION ...........................................................................................56
7.7
DETERMINATION OF SAMPLE SIZE .........................................................56
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................57
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................57
8.2
DATA QUALITY ASSURANCE ......................................................................58
8.3
RECORDS...........................................................................................................58
8.3.1
Source documents ...............................................................................................58
8.3.2
Direct access to source data and documents.....................................................59
8.3.3
Storage period of records ...................................................................................60
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................60
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........60
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................60
8.6
TRIAL MILESTONES.......................................................................................61
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................61
8.8
PROTOCOL VIOLATIONS .............................................................................62
8.9
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY..............................................................................63
9.
REFERENCES....................................................................................................64
9.1
PUBLISHED REFERENCES............................................................................64
9.2
UNPUBLISHED REFERENCES......................................................................65
10.
APPENDICES.....................................................................................................66
10.1
PATIENT REPORTED OUTCOME QUESTIONNAIRES ..........................66




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ABBREVIATIONS
AE
Adverse Event
ACE
Angiotensin-Converting-Enzyme
ACR
American College of Rheumatology
AE(s)
Adverse Event(s)
AESI
Adverse Event of Special Interest
ALK
Alkaline Phosphatase
ALT
Alanine Aminotransferase
(anti-)RNA Pol 
Anti-RNA polymerase III Antibodies
AST
Aspartate Aminotransferase
ATS / ERS
American Thoracic Society / European Respiratory Society
AUC
Area Under the Curve
BI
Boehringer Ingelheim
bid
Bis in die (twice daily dosing)
BNP
Brain Natriuretic Peptide
CA
Competent Authority
CI
Confidence Interval
CK
Creatine Kinase
Cmax
Maximum measured concentration of the analyte in plasma
CML
Local Clinical Monitor 
CNS
Central Nervous System
CO
Carbon Monoxide
COPD
Chronic Obstructive Pulmonary Disease
CRA(s)
Clinical Research Associate(s)
CRO
Clinical Research Organisation
CT
Concomitant Therapy
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP3A4
Cytochrome P450 3A4
DDI
Drug-Drug Interaction
DEDP
Drug Exposure during Pregnancy
DILI
Drug-Induced Liver Injury
dL
Decilitre
DoH
Declaration of Helsinki
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
e.g.
Example given
EMA
European Medicines Agency
EOT
End of Treatment
EudraCT
European Clinical Trials Database
EULAR
European League against Rheumatism
FDA
Food and Drug Administration


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FEV1
Forced Expiratory Volume in 1 second
FGFR
Fibroblast Growth Factor Receptor
FU
Follow-up
g
Gram
GAVE
Gastric antral vascular ectasia
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GI
Gastrointestinal
GIT
Gastrointestinal tract
GLI
Global Lung Initiative
GP
General Practitioner
h
Hour
Hb
Haemoglobin
HCG
Human chorionic gonadotropin
Hct
Haematrocrit
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
i.e.
id est
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
INR
International Normalised Ratio
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
I.U. s. c.
International Unit sub cutaneous
Lck
Lymphocyte-specific protein tyrosine kinase
LDH
Lactate Dehydrogenase
Lyn
Lymphocyte antigen receptor-associated tyrosine kinases
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
Milligram
min
Minute
mL
Millilitre
mm
Millimetre
mmHg
Millimetres of mercury
mmol
Millimolar
nRTK
Non-Receptor Tyrosine Kinase
PAH
Pulmonary Arterial Hypertension
(p) PDGF / R
(polyclonal) Platelet Derived Growth Factor / Receptor
PFT
Pulmonary Function Test
P-gp
P-glycoproteine (MDR1)
PH
Pulmonary Hypertension
PI / IC
Patient Information / Informed Consent
p. o.
per os (oral)




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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Systemic Sclerosis (SSc) is a devastating disease of unknown etiology. The pathogenesis of 
SSc is characterized by systemic (multi-organ) immunological, vascular and fibrotic 
abnormalities. It is a rare disorder, an orphan disease, with prevalence rate of approximately 
50 to 300 in US, 20 to 50 in Asia and 100 to 200 per million in Europe (R14-4918, R14-
4927).
Patients suffer from multiple organ fibrosis, leading to chronic disability and premature 
death. Aside from skin, the lung is most often involved, but the disease may also manifest as 
proliferative and obliterative vascular abnormalities, kidney disease, oesophageal and 
gastrointestinal involvement (hypomotility), cardiac disorders and muscle disease. SSc-
related mortality is mainly driven by interstitial lung disease and pulmonary arterial 
hypertension. Median survival is 5–8 years in SSc associated Interstitial Lung Disease (ILD) 
(P14-07919).
At time of writing the Protocol, no approved SSc treatment was available, for chronic 
treatment of SSc-ILD. To date, nintedanib is the only drug approved in several countries for 
the treatment of patients with scleroderma-associated interstitial lung disease (SSc-ILD).
Immunosuppressive therapy has been proposed as a treatment of SSc with limited controlled 
data.
According to the EULAR treatment guidelines (P15-00879) there are no therapies mandated 
for SSc-ILD. Cyclophosphamide, a lymphocyte-modulating agent, may have some effect on 
forced vital capacity (FVC) (R14-5407). EULAR recommends considering 
cyclophosphamide for the treatment of SSc-ILD, but its use is limited in regard of treatment 
duration due to its toxicity. Methotrexate may be considered for treatment of skin 
manifestations of early diffuse SSc (P15-00879). Small controlled, uncontrolled and 
retrospectively controlled studies suggest some immunosuppressive regimens (such as 
mycophenolate, azathioprine, tocilizumab, ciclosporine A) may have effect in selected 
manifestations of SSc. However, larger placebo-controlled studies are lacking (P15-00879). 
Endothelin receptor antagonists failed to show significant effects on pulmonary fibrosis 
outcomes in several large studies.
The rationale for development of nintedanib in SSc-ILD is based on the pre-clinical evidence 
of potential effects in SSc and clinical evidence of antifibrotic activity of nintedanib in 
Idiopathic Pulmonary Fibrosis (IPF) along with an acceptable safety profile. Investigation in 
a patient population with active SSc-ILD accompanied by varying degrees of skin and other 
organ fibrosis is medically rational. Nintedanib may offer a long term antifibrotic 
maintenance treatment option for SSc, a medical indication with high unmet medical need. 


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The herein described clinical trial is planned as an open label extension trial following
SENSCIS® (1199.214) and 1199-0340 respectively.
The phase III trial SENSCIS® (1199.214) was investigating and has proven the safety and 
efficacy of nintedanib in Systemic Sclerosis interstitial lung disease (P19-04387).
The phase I trial 1199-0340 was investigating the drug-drug interaction of nintedanib and 
oral contraceptives in female patients with SSc-ILD (c26582112).
In the following, the acronym SENSCIS® will be used for trial 1199.214, standing for Safety 
and Efficacy of Nintedanib in Systemic Sclerosis (EudraCT no. 2015-000392-28).
1.2
DRUG PROFILE
Nintedanib is a small molecule that inhibits a distinct spectrum of receptor tyrosine kinases 
(RTKs) and non-receptor tyrosine kinases (nRTKs) including VEGFR (vascular endothelial 
growth factor receptor), PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast 
growth factor receptor), and Src family kinases (Src, Lck and Lyn belonging to a family of 
proto-oncogene tyrosine-protein kinases).
All of these growth factor pathways and their down-stream signal cascades have been 
demonstrated to be involved in the pathogenesis of fibrotic tissue remodelling.
In experiments with dermal fibroblasts from patients with SSc, nintedanib inhibited migration 
and proliferation, reduced the expression of extracellular matrix markers, and attenuated 
transformation to myofibroblast. In four animal models of SSc with different features, 
nintedanib effectively attenuated skin and lung fibrosis, reduced extracellular matrix 
deposition in skin and lung, attenuated myofibroblast accumulation in skin and lung and 
reduced dermal thickening. Nintedanib also reduced dermal microvascular endothelial cell 
apoptosis and effectively attenuated pulmonary vascular remodelling by reducing the number 
of vascular smooth muscle cells and occluded pulmonary vessels.
A soft gelatin capsule formulation of nintedanib is used in humans. Maximum plasma 
concentrations occur between 2 - 4 hours after oral administration. Steady state is reached at 
latest within one week of dosing. After food intake, a trend towards an increased systemic 
exposure (around 20%) and a delayed absorption was observed compared to administration 
under fasted conditions. Nintedanib is preferentially distributed in plasma with a blood to 
plasma ratio of 0.87 and the terminal half-life is in the range of 7 to 19 h. The absolute 
bioavailability of nintedanib is slightly below 5%.
Nintedanib is mainly eliminated via faeces.
Coadministration of nintedanib with the P-glycoprotein (P-gp) inhibitor ketoconazole 
increased exposure to nintedanib by 60-70% based on area under the curve (AUC) and by 
80% based on a maximum measured concentration of the analyte in plasma (Cmax) in a 
dedicated drug-drug interaction (DDI) trial. 


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In a DDI trial with the P-gp inducer rifampicin, exposure to nintedanib decreased to 50.3% 
based on AUC and to 60. 3% based on Cmax upon coadministration with rifampicin 
compared to administration of nintedanib alone. 
The clinical efficacy of nintedanib has been studied in over 1400 patients with IPF in one 
phase II dose finding trial (TOMORROW) including four different doses of nintedanib, and 
two replicate phase III (INPULSIS® 1 and 2) trials. These were randomised, double-blind, 
placebo-controlled trials comparing treatment with nintedanib twice daily to placebo for 
52 weeks. A statistically significant reduction in the annual rate of decline of FVC (in mL) 
was demonstrated in patients receiving nintedanib 150 mg bid compared to patients receiving 
placebo. The treatment effect of nintedanib 150 mg bid compared to placebo on FVC was 
consistent in all 3 studies, i.e. a relative reduction of decline of approximately 50%. 
Supporting the effect of nintedanib on slowing disease progression (P14-07514, P11-11216), 
nintedanib 150 mg bid significantly reduced the risk of first acute exacerbation compared 
with placebo in INPULSIS® 2 and in the TOMORROW trial and reduced the risk of acute 
exacerbations (adjudicated) by 68% in a pre-specified sensitivity analysis of pooled data from 
the INPULSIS® trials.
In the Phase III trial 1199.214 (SENSCIS®) in patients with SSc-ILD, nintedanib, at a dose of 
150 mg bid, significantly reduced the annual rate of decline in 
 after 52 weeks of 
treatment. The relative treatment effect, of a ~44% reduction in the annual rate of FVC 
decline compared with placebo, was in the same range as that previously observed in IPF. No 
effect of nintedanib on skin fibrosis or health-related quality of life was observed. No effect 
of nintedanib was seen on skin thickness and in patient-reported outcomes. There was no 
difference in mortality between the groups; however, the trial was not powered to detect such 
difference.
The safety profile of nintedanib has been investigated comprehensively in clinical Phase II to 
IV trials in patients with IPF, as well as postmarketing. The safety profile in phase III clinical 
trials in patients with SSc-ILD and patients with progressive fibrosing ILDs was generally 
consistent with that observed in the population of patients with IPF.
The risks of treatment with nintedanib in adult patients are primarily related to the 
gastrointestinal tract (nausea, vomiting, diarrhoea, abdominal pain, pancreatitis) and to drug 
induced liver injury/increases in liver enzymes (aspartate aminotransferase [AST], alanine 
transaminase [ALT], alkaline phosphatase [ALK], gamma-glutamyl transferase [GGT] and 
bilirubin). 
Based on data from clinical trials and post-marketing with nintedanib in IPF patients and 
supported by population pharmacokinetic models, patients with low body weight (<65 kg), 
Asian and female patients have a higher risk of liver enzyme elevations with nintedanib 
treatment.
The most frequently reported adverse event in the clinical trials was diarrhoea, which was 
mild to moderate in intensity for the majority of patients and led to treatment discontinuation 


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in less than five percent of patients treated with nintedanib. Nausea, vomiting and weight 
decrease and decreased appetite have also been associated with nintedanib treatment. 
Risks of nintedanib treatment also include hypertension, bleeding, thrombocytopenia, 
gastrointestinal perforations, and thromboembolism. Thus, patients treated with full-dose 
anticoagulation or at known risk for bleeding were excluded from the INPULSIS® trials. 
Although cardiac disorder adverse events were balanced between the nintedanib and placebo 
groups, a higher proportion of patients (1.6%) in the nintedanib groups had myocardial
infarctions compared to the placebo groups (0.5%). Conversely, a lower proportion of 
patients in the nintedanib groups had other ischemic heart disease, which includes terms such 
as coronary artery disease, angina pectoris, coronary angioplasty, coronary artery stenosis, 
myocardial ischemia, coronary artery stent insertion, electrocardiogram (ECG) ST segment 
depression. The clinical significance of this finding is unknown, and further observation is 
needed. No imbalances were found in SENSCIS®.
No evidence of QT prolongation was observed for nintedanib in the clinical trial program. As 
some tyrosine kinase inhibitors are known to exert an effect on QT, caution should be 
exercised when administered nintedanib in patients who may develop QT prolongation.
For patients finalizing the 52 week trial treatment in the TOMORROW and INPULSIS®
trials, participation, open label extension trials (1199.35 and 1199.33) were offered. Long 
term treatment in these open label extension trials have confirmed the safety profile observed 
in the phase II and III trials.
Nintedanib was developed in Idiopathic Pulmonary Fibrosis (IPF) and approved by Food and 
Drug Administration (FDA) and European Medicines Agency (EMA) in October 2014 and 
January 2015 respectively.
Nintedanib was developed in Systemic Sclerosis associated ILD and approved by Food and 
Drug Administration (FDA) and European Medicines Agency (EMA) in September 2019 and 
April 2020 respectively.
See also Investigator’s Brochure (IB) nintedanib in Idiopathic Pulmonary Fibrosis, Systemic
Sclerosis, Progressive Fibrosing Interstitial Lung Disease (c01783972) for more details.
1.3
RATIONALE FOR PERFORMING THE TRIAL
The aim of this extension trial is to provide nintedanib treatment for all patients who have 
completed (did not prematurely discontinue trial medication) the phase III parent trial 
SENSCIS® or the phase I trial 1199-0340 and who may have experienced benefit from the
trial medication and wish to receive treatment.
This extension trial is designed to evaluate long term tolerability and safety of Nintedanib and 
the survival in SSc-ILD patients treated for a longer period of time. In addition, lung function 


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tests and assessment of the modified Rodnan Skin Score as well as patient and physician 
reported outcome measures will be performed. 
1.4
BENEFIT - RISK ASSESSMENT
Initiating and amplifying events in SSc-ILD and IPF are described to be different, but 
culminate in fibroblast activation and myofibroblast accumulation that represent the final 
common pathways of lung fibrosis in both SSc-associated ILD and IPF (P14-07919). 
Nintedanib inhibits migration, proliferation and transformation of fibroblasts and thereby 
addresses this common pathway.
As shown for IPF patients, patients with SSc-ILD may also benefit from lesser decline in 
lung function and hence slower disease progression as a result of treatment with nintedanib.
The safety profile and the tolerability of nintedanib are expected to be similar in patients with 
IPF and SSc-ILD. 
Based on the efficacy and safety shown in IPF patients, and considering the similarity of the 
pharmacological rationale between IPF and SSc, the same dose regimen of 150 mg 
nintedanib bid is considered appropriate.
The risks of treatment with nintedanib have been well delineated in patients with the fibrotic 
lung disease IPF. These risks are primarily related to the gastrointestinal tract (nausea, 
vomiting, diarrhoea, abdominal pain), and are usually managed with supportive therapy and 
with temporary or permanent dose reduction to 100 mg bid. In some cases, temporary 
interruption or permanent drug discontinuation is necessary. A reduction in appetite and 
weight decrease has also been reported in patients treated with nintedanib. Patients with SSc 
may already suffer from gastrointestinal symptoms and will be monitored for such events. 
Parenteral fed patients will be excluded from the trial.
Drug induced liver injury, increases in liver enzymes and bilirubin have been reported with 
the use of nintedanib and liver enzymes must be followed closely during treatment (see also 
Section 4.2.1.2). Nintedanib must be dose-reduced, or interrupted in the event of hepatic 
toxicity and further treatment withheld until recovery of the abnormal laboratory parameters.
Concomitant therapies with a known overlap in side effects with nintedanib (e.g. 
gastrointestinal [GI] adverse events, increase of AST, ALT, bilirubin) or concomitant use of 
therapies that interact with metabolism of nintedanib (through UGT1A1 and P-gp) should be 
used with caution and patients should be closely monitored (see Section 4.2.2.2).
Potential risks of nintedanib treatment also include gastrointestinal perforations, 
thromboembolism and bleeding. Therefore, patients who have planned major elective 
surgery, suffer from severe peripheral vascular disease, requiring full dose therapeutic 
anticoagulation, fibrinolysis or high-dose antiplatelet therapy will be excluded from this trial. 
Patients with severe pulmonary hypertension, Child Pugh A/B/C and Scleroderma renal crisis 
will not be included in this trial. Those patients will either not have been included in the 


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parent trial as per Inclusion/Exclusion criteria or discontinued in the parent trial due to these 
conditions occurring as adverse events.
The mode of action of nintedanib indicates a high potential for teratogenicity and 
embryotoxicity, including fetotoxicity and lethality. In women of childbearing potential 
receiving nintedanib, contraceptive measures must be employed 28 days before treatment 
initiation, during the treatment and for a period of 3 months after last drug intake.
To address the organ-specific manifestations, immunosuppressive agents (e.g. 
mycophenolate, cyclophosphamide, methotrexate, azathioprine, prednisone) are commonly 
used and need to be considered although appropriate randomised-controlled data for these 
therapies are lacking.
The concomitant use of immunosuppressive agents as well as of non-immunosuppressive 
therapies for other SSc manifestations as for digital ulcers (e.g. bosentan), GI symptoms (e.g. 
proton pump inhibitors, prokinetic drugs), renal crisis (e.g. angiotensin-converting-enzyme 
inhibitor [ACE inhibitors]), pulmonary hypertension / pulmonary arterial hypertension (PH / 
PAH) (e.g. bosentan, sildenafil, epoprostenol) are not restricted. Cautionary notes are 
included in the protocol (Section 4.2.2.2) with regard to such therapies whose safety profile 
could interfere with that of nintedanib.
Safety of the patients will be monitored at site visits, including physical examinations, safety 
laboratory and specific monitoring procedure to follow-up potential hepatic enzyme 
elevation, to exclude pregnancy, to follow-up electrocardiographic assessments, and to 
monitor blood pressure, renal function, hypertension, and digital ulcers. Treatment with 
nintedanib must be discontinued and appropriate therapeutic measures taken in patients who 
develop severe symptoms of gastrointestinal toxicity not amenable to symptomatic treatment 
with standard measures or severe liver enzyme elevations or other severe adverse events as 
specified in Section 3.3.4.
Even if the balance of safety and efficacy from SENSCIS® is still unknown at the time point 
the patients are rolled over into the open label extension trial, long-term treatment is 
considered justifiable as there is currently no pharmacotherapy for long-term use approved to 
modify or prevent systemic progression of SSc/SSc-ILD.
To address current practice (although randomised-controlled data for these therapies are 
scarce), patients on a stable background therapy of mycophenolate, methotrexate or low dose 
prednisone were eligible in SENSCIS®.
In trial 1199-0340 patients on certain background therapy including mycophenolate and other 
treatments were excluded due to their potential effect on the PK assessment. 
Continuation or initiation of immunosuppressives or other treatments or changes in their dose 
is allowed in the open label extension taking into consideration cautionary notes.


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All patients will receive active treatment in this trial. Patients who were randomized to 
placebo in SENSCIS® will be receiving the active drug for the first time. Therefore the same 
close monitoring will be conducted as in SENSCIS® for the first 3 months of the trial.
Based on the pharmacological mechanism, existing non-clinical, clinical and post-marketing 
data there is no indication that treatment with nintedanib may increase the risk for infection 
with SARS-CoV-2 or for worsening the disease course of COVID-19.
It is currently unknown if SSc or SSc-LD conveys a higher risk for adverse outcomes in case 
of COVID-19.
The trial related risk to the COVID-19 pandemic situation is the general risk of travelling to 
site and being at site for assessments with increased infection risk for lung function testing. 
Risk mitigation and possible modifications are described in Section 6.1 and in Appendix 10.3
The extrapolated benefit risk ratio of chronic treatment with nintedanib 150 mg bid, with the 
possibility to be interrupted or reduced to nintedanib 100 mg bid during periods of 
intolerability, is judged positive for patients with SSc-ILD.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main Objectives
The main objective is to assess long term safety of treatment with oral nintedanib in patients 
with Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD).
2.1.2
Primary Endpoint(s)
The primary endpoint is the incidence (number and % of patients) of overall adverse events 
over the course of this extension trial.
2.1.3
Secondary Endpoint(s)
Not applicable.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multi-centre, multi-national, prospective, open label extension clinical trial. It is 
anticipated that approximately 400 patients with SSc-ILD will complete the parent trial
SENSCIS® and approximately 14 patients will complete 1199-0340 as planned. These
patients will be eligible for enrolment in this extension trial. Patients who withdrew treatment 
prematurely in SENSCIS® / 1199-0340 will not be eligible for this open label extension trial.
After signing Informed Consent and if all eligibility criteria are met, patients will initiate 
treatment with nintedanib (Visit 2). Patients will be assigned to a dose of 150 mg bid if the 
patients last dose in SENSCIS® / 1199-0340 was 150 mg bid and to a dose of either 100 mg 
bid or 150 mg bid at the discretion of the investigator, if patients were on 100 mg bid of 
blinded trial medication in SENSCIS® / 1199-0340 (please refer to Section 4.1.2).
Once assessment of the pivotal trial SENSCIS® and resulting risk-benefit of Nintedanib has 
been concluded upon, patients that are on a reduced dose of trial medication may increase 
dose to 150 mg bid Nintedanib at the discretion of the investigator.
The trial will continue for long term data collection, as long as a reasonable number of 
patients enabling analyses remain in the trial. Treatment duration for each patient will be 
variable. Patients will continue to receive treatment until they meet a reason for 
discontinuation (refer to section 3.3.4.4) or until access to nintedanib is obtained outside the 
clinical trial. The trial is estimated to last a total of approximately 5 ½ years. 
Treatment will be stopped if a reason for withdrawal is met (refer to Section 3.3.4).
Figure 3.1: 1 Transition from parent trial SENSCIS® / 1199-0340


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The trial will be conducted as a prospective, open-label design. This design is appropriate for 
this rollover trial assessing the long-term safety on nintedanib in patients with SSc-ILD. 
The purpose of this trial is to offer to all patients who completed SENSCIS® / 1199-0340 as 
planned, the option to receive nintedanib treatment if they perceive an individual benefit. The 
decision to continue treatment will be made by the patient following a discussion with the 
investigator. The aim of the trial is to allow treatment continuation to individual patients; 
therefore, randomization, blinding and use of placebo would not be appropriate.
The planned assessments are a subset of the assessments done in SENSCIS® / 1199-0340 and 
an additional patient related outcome score to assess gastrointestinal symptoms and their 
impact on the patient.
3.3
SELECTION OF TRIAL POPULATION
It is anticipated that approximately 400 patients will complete the SENSCIS® trial on 
treatment with nintedanib or placebo and that approximately 14 patients will complete the 
1199-0340 trial. These patients will be allowed to participate in this open label extension 
trial. At the time point of the start of the open label extension trial it is not known what 
treatment the patients had received in SENSCIS®. Patients previously on active treatment will 
continue, patients who received placebo will initiate treatment with nintedanib for the first 
time at Visit 2 of the extension trial. Patients who completed 1199-0340 had open-label 
treatment with nintedanib and will continue with nintedanib treatment in 1199.225.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Patients with SSc-ILD will be included in this trial if they fulfil all the inclusion and do not 
present any of the exclusion criteria.
Only patients who have completed the SENSCIS® / 1199-0340 on treatment (i.e. did not early 
permanently discontinue blinded treatment) are eligible. Patients should enrol into the 
extension trial as soon as possible after conclusion of SENSCIS® / 1199-0340.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Patients who completed the SENSCIS® / 1199-0340 trial per protocol and did not 
permanently discontinue study treatment


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2. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
3. Women of childbearing potential1 must be ready and able to use highly effective methods 
of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year
when used consistently and correctly as well as one barrier method for 28 days prior to
nintedanib treatment initiation, during the trial and for 3 months after last intake of 
nintedanib. A list of contraception methods meeting these criteria is provided in the 
patient information.
3.3.3
Exclusion criteria
1. AST, ALT > 3 x ULN
2. Bilirubin > 2 x ULN
3. Creatinine clearance <30 mL/min calculated by Cockcroft–Gault formula (Appendix 
10.2).
4. Clinically relevant anaemia at investigators discretion. 
5. Bleeding risk, any of the following
a.
Known genetic predisposition to bleeding according to the judgement of the 
investigator
b. Patients who require 
i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K 
antagonists, direct thrombin inhibitors, heparin, hirudin)
ii. High dose antiplatelet therapy. 
[Note: Prophylactic low dose heparin or heparin flush as needed for 
maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 
I.U. s. c. per day), as well as prophylactic use of antiplatelet therapy (e.g. 
acetyl salicylic acid up to 325 mg/day, or clopidogrel at 75 mg/day, or 
equivalent doses of other antiplatelet therapy) are not prohibited].
c.
Hemorrhagic central nervous system (CNS) event after completion of the 
parent trial SENSCIS® / 1199-0340.
d. Any of the following after last treatment of SENSCIS® / 1199-0340:
i. Haemoptysis or haematuria
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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ii. Active gastro-intestinal bleeding or GI – ulcers
iii. Gastric antral vascular ectasia (GAVE)
iv. Major injury or surgery (investigators judgement).
e.
Coagulation parameters: International normalised ratio (INR) >2, prolongation 
of prothrombin time (PT) and partial thromboplastin time (PTT) by >1.5 x 
ULN at Visit 1.
6. New major thrombo-embolic events developed after completion of the parent trial
SENSCIS® / 1199-0340:
a.
Stroke;
b. Deep vein thrombosis;
c.
Pulmonary embolism;
d. Myocardial infarction.
7. Major surgery (major according to the investigator’s assessment) performed within the 
next 3 months
8. Time period > 12 weeks between last drug intake in SENSCIS® or > 1 week between last 
nintedanib intake in trial 1199-0340 and Visit 2 of this trial
9. Usage of any investigational drug after completion of SENSCIS® / 1199-0340, or planned 
usage of an investigational drug during the course of this trial.
10. A disease or condition which in the opinion of investigator may put the patient at risk 
because of participation in this trial (e.g. clinically relevant intestinal pseudoobstruction)
or limit the patient’s ability to participate in this trial
11. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
them an unreliable trial subject or unlikely to complete the trial
12. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin).
13. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
14. Previous enrolment in this trial
3.3.4
Withdrawal of patients from therapy or assessments
3.3.4.1
Withdrawal from trial treatment 
Nintedanib has to be permanently discontinued in the following circumstances
∀
The patient experiences signs of hepatic injury, defined in Section 4.2.1.2
∀
In the opinion of the investigator, the patient experiences unacceptable adverse events 
despite dose adjustments and supportive care.


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∀
Use of concomitant treatment as defined in Section 4.2.2.
∀
Parenteral feeding requirement.
∀
The patient can no longer be treated with trial medication for other medical reasons
∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing 
or able to stick to the trial requirements in the future
∀
Pregnancy (refer to Section 5.2.11)
∀
If a patient becomes pregnant during the trial, nintedanib needs to be stopped and the 
patient should be followed up until birth or otherwise termination of the pregnancy. 
The data of the patient will be collected and reported in the clinical trial report (CTR) 
until patient´s last visit and any events thereafter will be reported in the BI drug safety 
database. Refer to Section 5.2.11 for detailed information on event reporting in case of 
pregnancy.
3.3.4.2
Recommendation to discontinue nintedanib
In the following cases discontinuation of nintedanib is highly recommended. Only in special 
circumstances, the investigator, upon thorough assessment of all available clinical data and 
taking into consideration the potential risks associated with administration of nintedanib, may 
decide not to withdraw the trial medication, even though one or more of the below mentioned 
criteria are fulfilled. In such a case, continuation of treatment with trial medication should be 
discussed with the patient, and the decision and reasoning documented in the source data.
∀
Major surgery, including any abdominal or intestinal surgery.
∀
Anti-coagulation. Patients who require full-dose therapeutic anticoagulation (e.g. 
vitamin K antagonists, heparin, hirudin, direct thrombin inhibitors, etc.), or high-dose 
antiplatelet therapy. (Prophylactic low dose heparin or heparin flush as needed for 
maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s. c. per 
day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 
325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet 
therapy is allowed.).
∀
Major thrombo-embolic events e.g. stroke, deep vein thrombosis, pulmonary 
embolism, myocardial infarction.
∀
Confirmed severe hypertension, uncontrolled under treatment (≥160/100 mmHg), 
∀
Unstable cardiac angina
∀
Increased risk of bleeding e.g. hemorrhagic CNS event, gross / frank haemoptysis or 
haematuria, active gastro-intestinal bleeding or GI-ulcers.


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∀
Scleroderma renal crisis
∀
Significant pulmonary hypertension defined by any of the following:
-
Previous clinical or echocardiographic evidence of significant right heart 
failure
-
History of right heart catheterisation showing a cardiac index ≤ 2 l/min/m²
-
PH requiring therapy (parenteral or oral with epoprostenol, treprostinil, 
selexipag)
For conditions that allow treatment interruption please refer to Section 4.2.1.
3.3.4.3
Withdrawal of consent for trial participation
An individual patient is to be withdrawn from trial participation 
∀
if the patient withdraws consent for trial participation, without the need to justify the 
decision
∀
if the patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, adverse events, other diseases, or pregnancy)
Given the patient’s agreement, the patient will undergo the procedures for trial 
discontinuation and follow up as outlined in the Flowchart and Section 6.2.3.
For all patients, the reason for withdrawal (e.g. adverse events) must be recorded in the 
Electronic Case Report Form (eCRF). These data will be included in the trial database and 
will be reported.
3.3.4.4
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
2. Marketing authorization, availability for compassionate use or early access program 
offered by the sponsor (depending on local laws),
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS 
4.1.1
Identity of the Investigational Medicinal Products
All patients will be treated with nintedanib in this trial; there is no active comparator or 
placebo.
Substance:
Nintedanib
Pharmaceutical formulation:
Soft gelatine capsule
Source:
BI Pharma GmbH # Co. KG
Unit strength:
150 mg, 100 mg
Posology:
bid
Route of administration:
Oral (swallowed)
4.1.2
Method of assigning patients to treatment groups and selection of dose
The objective of the SENSCIS® was to assess the efficacy and safety of a dose of 150 mg bid 
compared to placebo. Patients have been randomized either to blinded Nintedanib or to 
blinded placebo 150 mg bid. Dose reductions from 150 mg bid Nintedanib/placebo to 100mg 
bid Nintedanib/placebo were allowed to manage adverse events.
The objective of the trial 1199-0340 was to assess the potential influence of continuous intake 
of nintedanib on the systemic exposure of ethinylestradiol and levonorgestrel when 
administered in combination. The patients have all been treated with open label nintedanib. 
Also in trial 1199-0340 dose reductions from 150 mg bid nintedanib to 100mg bid nintedanib 
were allowed to manage adverse events.
Patients having taken 150 mg bid trial medication (active drug or placebo, blinded in 
SENSCIS®) at the end of SENSCIS® / 1199-0340 will start treatment with nintedanib 150 mg 
bid in the current extension trial.
Patients who receive 100 mg bid active drug or placebo within SENSCIS® / 1199-0340 will 
be allowed to start treatment with 100 mg or increase their nintedanib dose to 150 mg bid at 
the discretion of the investigator.
Interactive Response Technology (IRT) will be used to assign medication numbers to eligible 
patients. Distribution of nintedanib to sites will be triggered by IRT. Details on the IRT
system are provided in the ISF.
After subsequent conclusions on benefit/risk upon unblinded data from SENSCIS®, patients 
who permanently reduced to 100 mg bid will be allowed to increase their nintedanib dose to 
150 mg bid at the discretion of the investigator. Dose increase will need to be assigned 
through IRT during an additional visit (refer to Section 6.2.4).


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4.1.3
Drug assignment and administration of doses for each patient
The treatment for an individual patient will be assigned by means of an IRT contact during 
Visits 2, 3, 4, 5, 6, 7 and following Visits. Patient will receive active drug at a dosage of 
150 mg bid or 100 mg bid.
Trial medication will consist of 1 capsule twice daily throughout the trial. Wallets covering 4 
weeks + 5 days reserve treatment (1 wallet = 6 blisters with 10 capsules each, plus 1 blister 
reserve) will be dispensed to the patient:
∀
1 wallet at day 1 (Visit 2) (30 days plus 5 days reserve).
∀
2 wallets at Visit 3 (60 days plus 10 days reserve).
∀
3 wallets at Visits 4 and 5 (90 days plus 15 days reserve).
∀
4 wallets at Visit 6, 7 and following (120 days plus 20 days reserve).
Nintedanib will be administered orally on a twice daily basis (bid). The patients should 
swallow the trial medication unchewed together with a glass of water (~250 mL), and should 
observe a dose interval of 12 hours. Nintedanib needs to be taken at the same time every day 
(between 06:00 and 11:00 in the morning, and between 18:00 and 23:00 in the evening). 
Because nintedanib may cause stomach discomfort, it is recommended to take the trial 
medication with food.
A forgotten dose should be skipped if the time window to the next dose is less than 8 hours. 
The next dose should be taken as scheduled. 
Nintedanib should only be dispensed to participating patients according to the protocol by 
authorised personnel as documented in the form “Investigator’s Trial Staff”.
The dose can be interrupted or reduced without prior interruption, i.e., immediately stepping 
down from 150 mg bid to 100 mg bid at the discretion of the investigator if necessary due to 
adverse events. Dose adjustions require a special trial visit according to procedures described 
in Section 4.2.1. Restart and re-escalation is possible as described in Section 4.2.1.
4.1.4
Blinding and procedures for unblinding
4.1.4.1
Blinding
In this open-label trial, treatment allocation will not be concealed throughout the trial. The 
eCRF will contain information on actual treatment.
The previous treatment received in SENSCIS® (active drug or placebo) will remain unknown 
until the database lock of SENSCIS® and until subsequent conclusions on benefit/risk. No 
individual unblinding regarding treatment received in SENSCIS® should occur prior to this 
point in time.
This is not applicable for patients who participated in trial 1199-0340, since they received 
open-label nintedanib treatment.


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4.1.4.2
Unblinding and breaking the code
Not applicable.
4.1.5
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated clinical research 
organisation (CRO). They will be packaged and labelled in accordance with the principles of 
Good Manufacturing Practice (GMP). Initial supply and re-supply to the sites will be 
managed via an IRT system. The IRT will assign an appropriate kit to each patient and will 
also monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
Primary trial material will be capsules containing 150 mg of nintedanib (or 100 mg of 
nintedanib if dose is reduced). All trial medication will be packaged in blister cards. Each 
blister card will contain 10 capsules. Seven blisters cards will be packaged into one child-
resistant tamper-evident wallet (i.e. 70 capsules/wallet). Each wallet will be labelled with a 
multi-language booklet according to the requirements of the participating countries.
One wallet covers for one month of treatment.
Details of packaging and the description of the label will be provided in the ISF.
Re-supplies of trial medication are planned due to the short expiry date and the long duration 
of the trial. The medication for re-supply will be packaged in an identical manner as the 
medication for initial supply.
4.1.6
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
All unused trial medication must be returned to the sponsor or appointed CRO. Receipt, 
usage and return must be documented on the respective forms. Account must be given for any 
discrepancies.


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4.1.7
Drug accountability
The investigator will receive the investigational drugs delivered by a clinical research 
organisation (CRO) appointed by the sponsor, when the following requirements are fulfilled:
∀
Approval of the trial protocol by the institutional review board (IRB) / ethics 
committee (EC).
∀
Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the investigational site.
∀
Approval/notification of the regulatory authority, e.g. competent authority.
∀
Availability of the curriculum vitae of the Principal Investigator.
∀
Availability of a signed and dated clinical trial protocol.
∀
In countries where it is required, availability of the proof of a medical license for the 
Principal Investigator.
∀
In the US, availability of Form 1572.
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each patient, and the return to the sponsor or appointed CRO.
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The
investigator will maintain records that document adequately that the patients were provided 
the doses specified in the CTP and reconcile all investigational products received from the 
sponsor. At the time of return to the sponsor or appointed CRO, the investigator must verify 
that all unused or partially used drug supplies have been returned by the clinical trial patient 
and that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Rescue medications to reverse the action of nintedanib are not available.
Dose reduction (from 150 mg bid to 100 mg bid) or treatment interruption should be 
considered to manage adverse events. No further dose reduction is possible for patients on the 
100 mg bid dose. In case of persistent adverse events observed at this dose, or severe effects 
at 150 mg bid, permanent treatment discontinuation should be considered.
Treatment interruption and reduction and reescalation are repeatedly possible.


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Table 4.2.1: 1
Allowed treatment reduction / interruption periods:
AEs considered drug related
AEs or other events not 
considered drug related
Maximum interruption
4 weeks
12 weeks
Recommended restart
with reduced dose (100 mg bid)
with the same dose (100 mg bid or 
150 mg bid)
Re-escalation
Any time to 150 mg bid
----
4.2.1.1
Management of diarrhoea
Other causes for diarrhoea should always be considered and treated accordingly (e.g. viral 
infections, SSc related diarrhoea, bacterial overgrowth, antibiotic treatment).
Diarrhoea should be managed as early as possible after onset of first symptoms with standard 
antidiarrheal symptomatic treatment, e.g. loperamide.
If diarrhoea persists despite optimal symptomatic treatment, treatment interruption and dose 
reduction of nintedanib should be considered based on the recommendations described in 
table 4.2.1.1:1.
Table 4.2.1.1: 1
Management of diarrhoea (considered related to trial medication)
Description
Symptomatic Treatment*
Action with trial medication
Diarrhoea with 
increase of <4 stools 
per day over baseline1.
Initiate anti-diarrhoeal medicines 
at first signs of symptoms (e.g. 
4 mg loperamide followed by 
2 mg after each loose stool or 
every 2-4 hours to a maximum of 
16 mg/day) until bowel 
movements cease for 12 hours.
Continue same trial medication 
dose.
Diarrhoea with 
increase of 4 to 6 
stools per day over 
baseline1.
Initiate/continue anti-diarrhoeal 
medicines;
If diarrhoea of this severity 
persists for ≥48 to 72 hours assess 
for dehydration and electrolyte 
imbalance; 
In addition, consider IV fluids and 
electrolyte replacement as 
clinically indicated.
If diarrhoea persists for ≥48 to 72 
hours despite optimal symptomatic 
care:
1.
Interrupt trial medication until 
recovery.
2.
Reduce dose to 100 mg bid 
after recovery. 
3.
Re-escalate to 150 mg bid 
within 4 weeks if deemed 
clinically appropriate.


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Table 4.2.1.1:1
Management of diarrhea (considered related to trial medication)
(cont.)
Description
Symptomatic Treatment*
Action with trial medication
Diarrhoea with 
increase of ≥7 stools 
per day over baseline1; 
stool incontinence,
or life threatening 
consequences.
Follow recommendations above.
In addition, consider stool work-
up to exclude infectious colitis; 
adequate IV fluid replacement 
≥24 hours, hospitalisation as 
clinically indicated; consider 
referral to a GI specialist to rule 
out potential differential 
diagnoses.
1.
Interrupt trial medication until 
recovery.
2.
Reduce dose to 100 mg bid 
after recovery.
3.
Consider re-escalation within 4 
weeks to 150 mg bid if deemed 
clinically appropriate.
In case of reoccurrence of diarrhoea 
of this severity despite optimal 
symptomatic treatment and dose 
reduction, treatment with trial 
medication should be permanently 
discontinued.
Footnotes:
* Other causes for diarrhoea should always be considered and treated accordingly (e.g. viral infections, SSc related 
diarrhoea, bacterial overgrowth, antibiotic treatment)
1 Baseline defined as usual stools/day prior to visit 2.
4.2.1.2
Management of liver enzyme elevation
Evaluate the concomitant use of other drugs known to cause liver enzyme elevations. For a 
detailed guidance on how to manage liver enzyme elevations, please refer to Table 4.2.1.2: 1.


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Table 4.2.1.2: 1:
Management of liver enzyme elevations
AST or ALT increase to
Signs of hepatic injury* 
(Section 5.2.11)
>1.5x to <3x
ULN
≥3x to <5x
ULN and no 
signs of hepatic 
injury
(Section 5.2.11)
≥5x to <8x
ULN and no 
signs of hepatic 
injury
(Section 5.2.11)
Visit 2 (treatment 
start )
Continue as 
planned2
Permanently 
discontinue trial 
medication 
Permanently 
discontinue trial 
medication 
Permanently discontinue
trial medication 
Any other Visit
Continue as 
planned2
Reduce dose or 
interrupt trial 
medication 3
Interrupt trial 
medication 
Permanently discontinue / 
Interrupt trial medication
CLINICAL 
EVALUATION OF 
HEPATIC INJURY5
(Section 5.2.11)
Close 
observation4
After 2 weeks or 
any time later
Close 
observation4
After 2 weeks 
or any time later
<3x ULN
≥3x ULN
< 3x ULN
≥3x ULN
Reduced: 
return to 
initial dose.
Interrupted: 
restart at 
reduced 
dose.
Monitor 
every 2
weeks for at 
least 8 weeks
Permanently 
discontinue trial 
medication
Close 
observation4
Restart at 
reduced dose
Monitor weekly 
for 4 weeks, 
then every 2
weeks for at 
least 8 weeks
Permanently discontinue 
trial medication.
Close observation4
Footnotes:
* Signs of hepatic injury are defined as
∀
ALT and/or AST ≥8 fold ULN
∀
ALT and/or AST ≥3 fold ULN and total bilirubin ≥2 fold ULN 
∀
ALT and/or AST ≥3 fold ULN and unexplained INR >1,5
∀
ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)
∀
ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right upper abdominal quadrant pain 
or tenderness, fever and/or rash
1 Investigator to confirm in writing that continuation is justified (e.g. intermittent fluctuation of transaminases).
2 According to visit schedule. Consider additional control visits as adequate.
3 To be decided by investigator, based on individual risk assessment.
4 Close observation: Re-test ALT and AST, alkaline phosphatase, total bilirubin, and eosinophils within 48 to 72 hours, then 
approximately 7 days, then approximately 2 weeks by using intermediate visit lab kit.
5 If clear evidence for alternative cause for hepatic injury was identified and resolved (i.e. relation to trial medication 
excluded, hepatic injury confirmed to have alternative explanation [other than use of IMP)): return to trial medication 
would be possible, after consultation with the sponsor. Prior to restart, liver laboratory values must be normal. Monitor 
weekly for first 4 weeks of re-introduction and every 2 weeks for the following 8 weeks.


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Initial assessment and blood sampling for liver enzyme elevation follow up should be 
performed at the investigational site. Blood samples for additional monitoring may be 
collected at the investigational site, primary care physician or external laboratory with 
specific trial lab kits and sent to the central laboratory for analysis.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Other investigational therapy is not allowed during the entire trial period and must not have 
been introduced in the interval between the parent trial SENSCIS® / 1199-0340 and 
enrolment into this open label extension trial.
4.2.2.2
Cautionary Notes
As nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4, concomitant use of 
P-gp and CYP3A4 inhibitors (e.g. erythromycin) with nintedanib may increase exposure to 
nintedanib. Patients taking potent P-gp inhibitors (e.g. ketoconazole, erythromycin or 
ciclosporine) should be monitored closely for tolerability of nintedanib.
Concomitant use of P-gp and CYP3A4 inducers (e.g. carbamazepine, phenytoin, and St. 
John’s wort) with nintedanib may decrease exposure to nintedanib. For patients taking potent 
P-gp inducers, selection of alternative treatment with no or minimal P-gp induction should be 
considered.
As the most common side effects known for nintedanib are GI effects, the concomitant use of 
medication with an overlapping safety profile (e.g. mycophenolate mofetil/ sodium) should 
be carefully considered.
Nintedanib is also associated with increases in liver enzymes and bilirubin. If in addition to 
the trial medication, a treatment is introduced that is known to induce AST/ALT elevations 
(e.g. methotrexate, bosentan), adequate measures should be taken to ensure patients safety: 
perform additional measurement of liver enzymes (ALT and AST, alkaline phosphatase, total 
bilirubin, and eosinophils) every 2 weeks for approximately 6 weeks, by using intermediated 
(a-visit) trial lab kit.
4.2.2.3
Restrictions on diet and life style
No restrictions on diet or life style.
4.2.2.4
Restrictions regarding women of childbearing potential 
The anti-angiogenic properties of nintedanib indicate a high potential for teratogenicity and
embryotoxicity, including fetotoxicity and lethality. In women of childbearing potential 
receiving nintedanib, contraceptive measures described in the patient information must be 


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employed 28 days before treatment initiation, during the trial and for a period of 3 months 
after last drug intake.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on capsule counts, treatment compliance will be calculated as the number of capsules 
taken, divided by the number of capsules which should have been taken according to the 
scheduled period, multiplied by 100. Compliance will be verified by the on-site monitor 
authorised by the sponsor.
Treatment compliance (%) =
Number of capsules actually taken ∃100
Number of capsules which should have been taken
If the number of doses taken is not between 80-120%, site personnel will explain the patient 
the importance of treatment compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENTS OF EFFICACY 
Not applicable.
5.2
ASSESSMENTS OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at timepoints specified in the Flowchart. 
It includes at a minimum general appearance, neck, lungs, cardiovascular system, abdomen, 
extremities, and skin. 
Measurement of height and body weight will be performed at the time points specified in the 
Flowchart.
All abnormal findings at baseline in the extension trial will be recorded on the Baseline 
Condition eCRF page. New abnormal findings or worsening of baseline conditions in the 
extension trial detected at the subsequent physical examinations will be recorded as adverse 
events on the appropriate eCRF page.
5.2.2
Vital signs
Systolic and diastolic blood pressure and pulse rate will be measured prior to blood sampling
with the patient seated after having rested. In case of abnormal vital signs medical work-up 
for exclusion or confirmation of a pathological condition should occur as per standard of 
care. All abnormal findings at baseline in the extension trial will be recorded on the baseline 
condition eCRF page. New abnormal findings or worsening of baseline conditions in the 
extension trial detected at the subsequent physical examinations will be recorded as adverse 
events on the appropriate eCRF page.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3:1. For the sampling time 
points please see the Flowchart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 


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The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.11 and the DILI Checklist provided in the ISF eDC system. 
The total amount of blood taken from the patient concerned over the course of the trial will 
be increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
The laboratory tests at regular site visits will include:
Table 5.2.3: 1
Laboratory tests
Category
Laboratory test 
Haematology
Red blood cell count (RBC)
Haemoglobin (Hb)
Haematocrit (Hct)
Mean corpuscular volume
White blood cell count including differential
Platelet count
Biochemistry 
Aspartate aminotransferase (AST)
Alanine transaminase (ALT)
Gamma-glutamyl transferase (GGT)
Alkaline phosphatase (ALK)
Creatine kinase (CK)
Lactate dehydrogenase (LDH)
Total protein
Total bilirubin
Brain natriuretic peptide (BNP, at V2, V5, V7 and at all regular visits every 16 
weeks until EOT)
Creatinine
Glucose (non fasting)
Uric acid
Thyroid stimulating hormone (at V2, V5 (after 6 month), V 7 (12 Month) and 
then every other year and at EOT
ß-HCG (at Visit 2 only)
Electrolytes
Sodium
Potassium
Calcium
Chloride
Inorganic phosphorus
Coagulation
International normalized ratio (INR)
Partial thromboplastin time (PTT)
Prothrombin time (PT)
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite (semiquantitative 
measurements; -, +, ++, +++)
Local Urine dipstick pregnancy test in all women of childbearing potential. If urine test is not 
acceptable to local authorities, a blood test must be done at a local laboratory.


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The laboratory tests at intermediate ‘a’ visits will include:
Table 5.2.3: 2
Laboratory tests at intermediate ‘a’ visits
Category
Laboratory test 
Biochemistry
Total protein, creatinine, electrolytes and liver function (AST, ALT, GGT, 
alkaline phosphatase, and total bilirubin)
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite (semiquantitative 
measurements; -, +, ++, +++)
Local Urine dipstick pregnancy test in all women of childbearing potential. If urine test is not 
acceptable to local authorities, a blood test must be done at a local laboratory.
Overall about 110 mL blood will be taken for standard safety laboratory during the first year 
and about 45 mL blood will be taken any other year.
If laboratory values indicate abnormality, adequate and more frequent blood sampling may be 
performed at the discretion of the investigator.
In case of liver function value elevations, close monitoring must be ensured by the 
investigator. Refer to Section 4.2.1.2 for monitoring elevations and Section 3.3.4 for 
withdrawal criteria.
Laboratory analysis will be done using central laboratory services. 
Creatinine clearance will be calculated based on serum creatinine according to Cockcroft and 
Gault (R96-0690, Appendix 10.2).
Venous whole blood will be collected in appropriate syringes provided by the sponsor 
through the assigned central laboratory. Details regarding centrifuge, processing, storage and 
shipment of samples will be determined by the central laboratory in accordance with the 
sponsor. The investigators will be informed and instructed by the central lab and detailed 
documentation will be included in the ISF.
5.2.4
Electrocardiogram
The 12-lead ECGs will be recorded as scheduled in the Flowchart. The investigator or a 
designee will evaluate whether the ECG is normal or abnormal and whether it is clinically 
relevant, if abnormal. ECGs may be repeated for quality reasons and the repeated recording 
used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.


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Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed up 
and/or treated as medically appropriate.


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5.2.10
Other safety parameters
Worsening or new onset of SSc organ involvement (e.g. renal, cardiac, GI, vasculopathy) will 
be assessed via evaluation of adverse events / serious adverse events.


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5.2.11
Assessment of adverse events
5.2.11.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
∀
results in death,
∀
is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
∀
requires inpatient hospitalisation or 
∀
prolongation of existing hospitalisation,
∀
results in persistent or significant disability or incapacity, or
∀
is a congenital anomaly / birth defect, 
or
∀
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.


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Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the duration between discontinuation of the trial medication and must be 
reported as described in section 5.2.11, subsections “AE Collection” and AE reporting to 
sponsor and timelines”.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in section 5.2.11, subsections “AE Collection” and AE reporting to sponsor and 
timelines”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request.  These events should always be 
reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
Adverse events relating to gastrointestinal perforation and hepatic injury will be considered 
AESIs.
Hepatic injury
In this trial protocol, signs of hepatic injury are defined as:
∀
ALT and/or AST ≥8 fold ULN
∀
ALT and/or AST ≥3 fold ULN and total bilirubin ≥ 2 fold ULN* 


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∀
ALT and/or AST ≥3 fold ULN and unexplained INR > 1,5*
∀
ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)*
∀
ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right 
upper abdominal quadrant pain or tenderness, fever and/or rash
* in the same blood draw sample.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to immediately stop the trial medication and need to be followed up 
according to the “drug-induced liver injury (DILI) checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST and total bilirubin) available, the investigator should make sure these parameters 
are analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
In addition the intensity of diarrhoea adverse events should be classified and recorded in the 
eCRF according to the Common Terminology Criteria for adverse events (CTCAE) version 4 
(R10-4848, Table 5.2.11.1:1).
Table 5.2.11.1:1
CTCAE Categorisation for diarrhoea
CTCAE Grade
Diarrhoea
1
Increase of <4 stools per day over baseline
2
Increase of 4 to 6 stools per day over baseline
3
Increase of ≥7 stools per day over baseline; incontinence
4 
Life threatening consequences
5
Death
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 


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confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
For Japan only: the reason for the decision on causal relationship for unlisted AEs needs to be 
provided in the CRF.


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5.2.11.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards through the Residual Effect Period (REP), of 
at least 28 days until individual patient’s end of trial: 
-all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant AESIs of which the investigator may become aware of 
by any means of communication, e.g. phone call. Those AEs should however, not be 
reported in the CRF.
Figure 5.2.11.2: 1
AE collection
The REP is defined as 28 days after the last trial medication application and will apply only 
to patients that discontinue the trial early. All AEs which occurred through the treatment 
phase and throughout the REP will be considered as on treatment, please see Section 7.3.4.
Events which occurred after the REP will be considered as post treatment events.
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours ) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.


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For Japan only: all SAEs and AESIs must be reported immediately to the head of the trial 
site.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication and any possible interactions between the investigational drug(s) and a 
Non-Investigational Medicinal Product (NIMP) / Auxiliary Medicinal Product (AMP)
The following should also be recorded as an (S)AE in the CRF and SAE form (if applicable):
∀Worsening of the underlying disease or of other pre-existing conditions
∀Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of Pharmacokinetics
Not applicable.
5.3.2
Methods of sample collection
Not applicable.
5.3.4
Pharmacokinetic – Pharmacodynamic Relationship
Not applicable.
5.4
ASSESSMENT OF BIOMARKER(S) 
Not applicable.
5.4.1
Biobanking ( optional)
Patients will be asked for two additional blood samples for biobanking to allow for future 
scientific analyses. Only if a separate specific informed consent is given in accordance with 
local ethical and regulatory requirements, one additional dedicated sample of approximately 
10 mL serum will be taken at Visit 2 and one at Visit 7.
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual.
5.5
OTHER ASSESSMENTS
Not applicable.
5.6
APPROPRIATENESS OF MEASUREMENTS
The scheduled measurements are appropriate to see drug induced changes in vital signs, 
standard laboratory values and ECG. These endpoints are standard and accepted for 
evaluation of safety and tolerability of an oral drug, and they are widely used in this kind of 
trial. The timing of all measurements is presented in the Flowchart.
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flowchart. Some flexibility 
is allowed in scheduling the visits according to visit time windows as specified in the 
Flowchart. If any visit has to be rescheduled, subsequent visits should follow the original visit 
date schedule (calculated from Visit 2). The trial medication kits contain sufficient 
medication to allow for these time windows. All deviations from the planned visit schedule 
will be documented.
The trial will run until all patients have discontinued treatment or a stopping criterion is met 
according to Section 3.3.4.
In exceptional circumstances (as e.g. in pandemic situations), when it is impossible to 
conduct study visits at the study site, study visits may be performed at patient’s home or 
remotely (via telephone and/or internet based means of communication), and local lab liver 
enzyme testing. The visit may also be performed as a hybrid of home and remote visit. All 
home/remote visits need to be discussed with and authorised by the sponsor’s trial team. The 
trial team’s decision will be based on a thorough benefit-risk evaluation.
The procedures performed during a home/remote visit may be adjusted as compared to a 
regular visit, as detailed in Appendix 10.3.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening
The trial will be explained to all patients who completed SENSCIS® / 1199-0340 and are 
willing to continue or start treatment with nintedanib. No trial related procedure or data 
collection should be performed until the patient has signed the Informed Consent for the 
extension trial.
The earliest timepoint for Visit 2 of the rollover trial is one day after the last visit, namely:
∀
the Follow-Up (FU) visit in SENSCIS® or
∀
the End of Treatment (EOT) Visit in trial 1199-0340
The last timepoint for Visit 2 is:
∀
12 weeks after the last trial drug intake occurred within SENSCIS®
∀
7 days after the last trial drug intake occurred within 1199-0340
Enrolment of patient into SENSCIS®-ON should be done as soon as possible to ensure 
gapless monitoring of a patient.


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In order to assess eligibility for the extension trial, patients are required to perform a 
screening visit (Visit 1) which includes collection of samples for laboratory tests.
Visit 1 and Visit 2 may occur on the same day if the period between the last available 
laboratory test within SENSCIS® and Visit 2 of the extension trial (1199.225) is ≤ 6 weeks. If 
the medical condition is not stable and new Adverse Events occurred, a new laboratory test 
has to be performed. For patients performing Visit 1 and Visit 2 on the same day, eligibility 
assessment will be based on laboratory data from last laboratory test available within 
SENSCIS®. In case Visit 1 and Visit 2 takes place on the same day, laboratory tests, physical 
examination and vital signs are performed only once on that day and are recorded under Visit
2 in the eCRF. In case a new AE has occurred after the last visit of SENSCIS® new safety 
laboratory testing is required.
Patients who have a laboratory test value that is outside the range specified by the exclusion 
criteria may have the test repeated once to determine eligibility; however, the result must be 
available prior to Visit 2.
Details of any patient who has given informed consent for the trial but is found to be in-
eligible must be entered in the enrolment log and documented in the eCRF.
Ongoing AEs from SENSCIS® / 1199-0340 are to be documented as Baseline Condition.
6.2.2
Treatment period(s)
If the patient has been determined eligible by the investigator to enter the trial (refer to 
Section 3.3), the investigator will assign a medication number to the patient through IRT at 
Visit 2 (refer to Section 4.1.2). First dose of nintedanib within 1199.225 will be administered 
at Visit 2 in the clinic (day 1).
Additional clinic visits will be scheduled after 4, 12, 24, 36 and 52 weeks of treatment (Visits 
3-7). Liver function monitoring visits (a-visits) will be performed at 2, 8, 18, 30 and 44 weeks 
of treatment (Visits 2a, 3a, 4a, 5a and 6a). After the first year of treatment (Visit 7), complete 
clinic visits will be scheduled every 16 weeks with intermediate liver function monitoring 
visits (a-visits) every 16 weeks.
The self-reported outcome questionnaires must always be done by patients in a quiet place 
prior to any other visit procedure.
For detailed description of the trial procedures at each visit and dispensing schedule, please 
refer to the Flowchart.
End of Treatment (EOT)
If a reason for drug discontinuation is met or the trials terminated due to one of the reasons 
mentioned in Section 3.3.4 an End of treatment Visit (EOT) should be scheduled as soon as 
possible after last drug intake. Reason for discontinuation must be documented in the eCRF.
For detailed description of the trial procedures at the EOT visit, please refer to the Flowchart.


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6.2.3
Trial Completion and Follow Up Period
The End of Treatment Visit will be the trial completion visit. A Follow-up (FU) Visit is only 
to be planned for 7 days after last trial drug intake in case trial medication had to be 
discontinued permanently due to adverse events.
For detailed description of the trial procedures at the FU Visit, please refer to the Flowchart. 
If the reason for removal of a patient from the treatment is an adverse event or an abnormal 
laboratory test result, the patient must be followed until complete resolution or stabilization 
of the event for at least 7 days after onset of the event or until follow-up is considered 
adequate by the investigator and the clinical monitor.
A patient will be considered lost to follow-up if the investigator is not able to contact him/her 
despite multiple attempts. Every effort must be made; at least 2 telephone contacts plus 1 
mailing should be documented. The site must notify the clinical monitor prior to designating 
a patient as lost to follow-up.
6.2.4
Dose modification visit
Every time a dose should be reduced or increased (refer to Section 4.1.3 and Section 4.2.1) 
patients will need to come to the site for a dose modification visit where the following will be 
performed:
∀
Physical examination including measuring weight;
∀
Vital signs;
∀
Safety laboratory;
∀
Assessment of adverse events and concomitant therapy since last visit;
∀
Assignment of new dose in IRT;
∀
Dispensing of trial drug;
∀
Drug accountability.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a multicentre, multi-national, open-label clinical trial to investigate the long term 
safety of nintedanib in patients with SSc-ILD previously treated in (SENSCIS®) or 1199-
0340.
As the main objective of this extension trial is to study long-term safety, only descriptive 
statistics will be used. Some limitations due to the nature of extension trial should be 
considered when interpreting the data (bias in the selection of the population, no comparative 
arm). Further endpoints are considered as exploratory only. 
This statistical paragraph deals with the analyses to be performed on the extension trial only. 
Although data of parent trial will not be described in the scope of these analyses, they will be 
taken into account for adverse events analyses, as described in Section 7.3.4.
7.2
NULL AND ALTERNATIVE HYPOTHESES
All analyses are descriptive and exploratory in nature. No formal statistical inference is
planned.
7.3
PLANNED ANALYSES
The treated set (TS) will consist of all patients who received at least one dose of open-label 
trial medication.
The definition of important protocol violations (IPV) will be specified in the trial statistical 
analysis plan (TSAP). These IPV definitions will include consideration of important
violations of entry criteria, treatment non-compliance, restricted medications and inadequate 
follow-up of hepatic events.
Patients will be analysed according to their randomized treatment group in the previous trial
SENSCIS® / 1199-0340.
The last available value between Visit 1 and Visit 2 (before first trial drug intake) will be 
considered as the baseline, for this extension trial.
7.3.1
Primary endpoint analyses
The primary objective of the trial is to assess the safety of nintedanib, so please refer to 
Section 7.3.4. The list of main safety endpoints is included in Section 5.2.
7.3.2
Secondary endpoint analyses
Not applicable. 


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment in this extension trial and end of the 
residual effect period (REP), a period of 7 days after the last dose of trial medication in this 
extension trial, will be assigned to the treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events in this extension trial, i. e. all adverse events occurring between start of 
treatment in this extension trial until 7 days after last trial drug intake will be considered 
‘treatment-emergent’. The residual effect period is defined as 7 days.
Adverse events that start before first drug intake in this extension trial and deteriorate under 
treatment will also be considered as ‘treatment-emergent’. Other adverse events will be 
assigned to the previous trial, between-trials, screening, post-treatment, or post-trial period, as 
appropriate.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.


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Vital signs, physical examinations (including weight measurement), or other safety-relevant 
data observed at screening, baseline, during the course of the trial and at the end-of-trial 
evaluation will be assessed with regard to possible changes compared to findings before start 
of treatment.
 
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Not applicable
7.4
INTERIM ANALYSES
The first interim analysis may occur earliest in an adequate timeframe prior to or after 
SENSCIS® analysis. Additional interim analyses could be performed upon request from 
Health Authorities or for publication purpose. All the above mentioned analyses may be 
presented at each interim analysis.
7.5
HANDLING OF MISSING DATA
Missing or incomplete AE dates will be imputed according to BI rules. No imputation is 
planned for other safety criteria.
Missing or incomplete data for survival are managed by censored data analyses. No specific 
procedures need to be specified to handle them.
7.6
RANDOMISATION
Not applicable as this is an extension trial.
7.7
DETERMINATION OF SAMPLE SIZE
Not applicable as this is an extension trial. The number of patients included in this trial will 
correspond to the number of patients having completed SENSCIS® / 1199-0340 and are
willing to participate in 1199.225.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, and also of any serious breaches of the 
protocol or of ICH GCP*.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report 
or interim reports.
For Japan only: the rights of the investigator / trial site and of the sponsor with regard to 
publication of the results of this trial are described in the investigator contract / trial site’s 
contract. As a general rule, no trial results should be published prior to finalisation of the 
Clinical Trial Report or interim reports.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”


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Additional information for Japan:
The investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. The patient must be given sufficient time to consider 
participation in the trial. The investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the contents. 
The investigator must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRF) for individual patients will be provided by the sponsor. For drug 
accountability, refer to Section 4.1.7.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see Section 8.3.2). The investigator must ensure that all patient identifiers 
(e.g. patient’s name, initials, address, phone number, social security number) have properly 


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been removed or redacted from any copy of the patients’ source documents before sending 
them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)
∀
Patient participation in the trial (substance, trial number, patient number, date patient 
was informed)
∀
Dates of patient’s visits, including dispensing of trial medication
∀
Medication history
∀
Adverse events and outcome events (onset date (mandatory), and end date (if 
available))
∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)
∀
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). The CRA and auditor may review all CRFs and informed consents. The accuracy 
of the data will be verified by direct comparison with the source documents described in 
Section 8.3.1. The sponsor will also monitor compliance with the protocol and ICH GCP.


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8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the national or local requirements (whatever is longer) valid at the time of the end
of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular
∀
A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95)
∀
The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of 
biological samples and data collected in clinical trials.


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∀
Samples and data are used only if an appropriate informed consent is available.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LPDD at their site. Early termination of the trial is defined 
as the premature termination of the trial due to any reason before the end of the trial as 
specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
For Japan only: when the trial is completed, the Investigator should inform the head of the 
trial site of the completion in writing, and the head of the trial site should promptly inform the 
IRB and sponsor of the completion in writing.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The Coordinating Investigator is responsible to coordinate Investigators at the different 
centres participating in this multicentre trial. Tasks and responsibilities are defined in a 
contract. 
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in ISF. The investigators will have 


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access to the BI clinical trial portal (Clinergize) to facilitate document exchange and maintain 
electronic ISF.
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to manage the trial in accordance with applicable regulations and 
internal SOPs, direct the clinical trial team in the preparation, conduct, and reporting of the 
trial, ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and internal SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs.”
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
A list of responsible persons and relevant local information can be found in the ISF.
Central laboratory facilities will handle all laboratory analyses of the trial. Samples for 
intermediate measurements (liver enzymes, creatinine) and pregnancy tests may be collected 
at a local doctor by using trial specific lab kits that will be sent to central laboratory for 
analyses.
 
 
 
Interactive Response technology (IRT) vendor will be used in this trial.
Details will be provided in IRT Manual, the Spirometry Manual and Central Laboratory 
Manual, available in the ISF.
8.8
PROTOCOL VIOLATIONS
For Japan only: the Investigator should document any deviation from the protocol regardless 
of their reasons. Only when the protocol was not followed in order to avoid an immediate 
hazard to trial patients or for other medically compelling reason, the principal Investigator
should prepare and submit the records explaining the reasons thereof to the sponsor, and 
retain a copy of the records.


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8.9
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
For Japan only: in the event of health injury associated with this trial, the sponsor is 
responsible for compensation based on the contract signed by the trial site.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, 
Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, 
Pellegrino R, Viegi G, Wanger J. Standardisation of spirometry. Eur 
Respir J 2005. 26(2):319-338.
P11-11216
Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson 
AG, Brown KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, 
Juhel N, Klueglich M, Bois RM du. Efficacy of a tyrosine kinase 
inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011. 
365(12):1079-1087.
P14-07514
Richeldi L, et al, INPULSIS Trial Investigators. Efficacy and safety of 
nintedanib in idiopathic pulmonary fibrosis. New England Journal of 
Medicine, published on May 18, 2014, doi: 10.1056/NEJMoa1402584 N 
Engl J Med 2014. 370(22):2071-2082.
P14-07919
Herzog EL, Mathur A, Tager AM, Feghali-Bostwick C, Schneider F, 
Varga J. Interstitial lung disease associated with systemic sclerosis and 
idiopathic pulmonary fibrosis: how similar and distinct? Arthritis and 
Rheumatology, Accepted Article, Accepted: May 08, 2014, doi: 
10.1002/art.38702 Arthritis Rheumatol 2014. 66(8):1967-1978.
Pope J. Measures of systemic sclerosis (scleroderma): Health 
Assessment Questionnaire (HAQ) and Scleroderma HAQ (SHAQ), 
physician- and patient-rated global assessments, Symptom Burden Index 
(SBI), University of California, Los Angeles, Scleroderma Clinical Trials 
Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0, Baseline 
Dyspnea Index (BDI) and Transition Dyspnea Index (TDI) (Mahler's 
Index), Cambridge Pulmonary Hypertension Outcome Review 
(CAMPHOR), and Raynaud's Condition Score (RCS). Arthritis Care Res 
(Hoboken) 2011. 63(Suppl 11):S98-S111.
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 Rheum 1997. 
40(11):1984-1991.
P15-00879
Kowal-Bielecka O, et al, EUSTAR Co-Authors. EULAR 
recommendations for the treatment of systemic sclerosis: a report from 
the EULAR Scleroderma Trials and Research group (EUSTAR). Ann 
Rheum Dis 2009. 68(5):620-628.
P19-04387
Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes 
MD, et al, SENSCIS Trial Investigators. Nintedanib for systemic 
sclerosis-associated interstitial lung disease. New England Journal of 


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Medicine, published on May 20, 2019, doi: 10.1056/NEJMoa1903076; 
2019. p. 2518-2528.
R10-4848
Common terminology criteria for adverse events (CTCAE): version 4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010). 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pd f 2010.
R14-4918
Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, 
prevalence, survival, risk factors, malignancy, and environmental 
triggers. Curr Opin Rheumatol 2012. 24(2):165-170.
R14-4927
Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 
2009. 360(19):1989-2003.
Bruce B, Fries JF. The Health Assessment Questionnaire (HAQ). Clin 
Exp Rheumatol 2005. 23(Suppl 39):S14-S18.
R14-5407
Tashkin DP, et al. Cyclophosphamide versus placebo in scleroderma 
lung disease. N Engl J Med 2006. 354(25):2655-2666.
R15-1205
Clements PJ, et al. Skin thickness score in systemic sclerosis: an 
assessment of interobserver variability in 3 independent studies. J 
Rheumatol 1993. 20(11):1892-1896.
R15-2010
Ferraz MB, Quaresma MR, Aquino LRL, Atra E, Tugwell P, Goldsmith 
CH. Reliability of pain scales in the assessment of literate and illiterate 
patients with rheumatoid arthritis. J Rheumatol 1990. 17(8):1022-1024.
R96-0690
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 16 (1), 31 - 41 (1976).
Jones PW, Quirk FH, Baveystock CM. The St.George's respiratory 
questionnaire. Respir Med 1991. 85(Suppl B):25-31.
9.2
UNPUBLISHED REFERENCES
c01783972
Investigator’s Brochure Nintedanib (BIBF 1120)
c26582112
Clinical Trial Report 1199-0340


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10.
APPENDICES
10.1
PATIENT REPORTED OUTCOME QUESTIONNAIRES


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10.2
CREATININE CLEARANCE
Creatinine clearance calculation is done according to Cockroft and Gault (R96-0690).
∀
Creatinine clearance = (140 - age) x (Weight in kg) x (0.85 if female) / (72 x serum 
creatinine in mg/dL)
10.3
VISIT MODIFICATION IN EXCEPTIONAL CIRCUMSTANCES
INITIAL 
MODIFIED or ADDED 
Face-to-face patient visit performed 
by a physician/under the 
responsibility of a physician on site.
Remote or home visit performed by the investigational site 
physician/under the responsibility of the investigational site 
physician to ensure the wellbeing of a patient and to collect 
at least: Adverse Events / Concomitant Treatments and 
Drug Interruption 
Regular on site safety lab test using 
central lab kits:
∀
Haematology, Biochemistry, 
Electrolytes, Coagulation, 
Urinalysis every 16 weeks using 
central lab; Liver enzyme 
monitoring every 8 weeks, using 
central lab
∀
Pregnancy test every 4-6 weeks 
(possible at home)
∀
Under treatment with nintedanib, regular liver enzyme 
monitoring is required and needs to be ensured by the 
investigational site, but can be done at a local lab / local 
doctor. The investigator has to ensure medical review 
and proper documentation in the eCRF. Minimum 
required safety lab paramenters are AST, ALT, GGT, 
ALK and total bilirubin.
∀
Urine pregnancy tests (for women of childbearing 
potential only) are regularly required and may be done 
at local lab / local doctor, or at home. 
∀
Decision whether to continue nintedanib treatment 
should be made based on an individual risk assessment 
for that individual patient and weigh up the benefits of 
an extended lab interval to maximum 16 weeks versus 
an interruption of treatment.
∀
Medical decision has to be documented in patient’s 
source notes.
If remote patient visits and/or local liver enzyme 
monitoring cannot be performed, nintedanib treatment 
needs to be interrupted.
If liver function tests are out of the 
range, the per protocol rules apply => 
dose reduction
If the patient cannot come to site for receiving new dose 
treatment and/ or patient safety and follow up safety lab 
testing cannot be guaranteed, treatment needs to be 
interrupted.
Dispensation of study treatment on 
site
∀
Site / Depot to patient IMP shipments
∀
Patients must consent to providing contact details for 
shipping purposes 
∀
Patients should retain all unused IMP and packaging, 
and return it when they are able to return to the site.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
16 August 2017
EudraCT number
2016-003403-66
BI Trial number
1199.225
BI Investigational Product(s)
Nintedanib
Title of protocol
An open-label extension trial to assess the long 
term safety of nintedanib in patients with ‘Systemic 
Sclerosis associated Interstitial Lung Disease’ 
(SSc-ILD)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Flowchart
Description of change
Visit 3a correction : day 57 
Questionnaires: x at visit EOT 
Rationale for change
Corrections of inconsistencies
Section to be changed
Table 5.2.3: 1 Laboratory tests
Description of change
Thyroid stimulating hormone (at V2, V5 (after 6 
month), V 7 (12 Month) and then every other year 
and at EOT
Rationale for change
Clarification 
Section to be changed
5.2.3 Safety laboratory parameters
Description of change
Clarification that creatinine clearance will be 
calculated by using the Cockroft-Gault formula
Rationale for change
Corrections of inconsistencies
Section to be changed
5.2.11.2 Adverse event collection and reporting
Description of change
Removed: Similarly, potential drug exposure 


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during pregnancy must be reported if a partner of a 
male trial participant becomes pregnant. This 
requires a written consent of the pregnant partner.
Rationale for change
Correction:
The sentence was part of an underlying Clinical 
Trial Protocol template and should have been
deleted as not applicable in this trial:
There is no evidence from reproductive toxicology 
studies for adverse effects of nintedanib on male 
fertility and health status of offspring. The use of 
male contraception, especially condoms by male 
patients receiving nintedanib is not mandatory and 
female partners of male patients receiving 
nintedanib are not required to follow contraceptive 
guidelines.
Section to be changed
11.2 Creatinine clearance
Description of change
Clarification that creatinine clearance will be 
calculated by using the Cockroft-Gault formula
Rationale for change
Corrections of inconsistencies
11.2
GLOBAL AMENDMENT 2
Date of amendment
17 August 2018
EudraCT number
2016-003403-66
BI Trial number
1199.225
BI Investigational Product(s)
Nintedanib
Title of protocol
An open-label extension trial to assess the long 
term safety of nintedanib in patients with ‘Systemic 
Sclerosis associated Interstitial Lung Disease’ 
(SSc-ILD)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only


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Section to be changed
All sections 
Description of change
SENSCISTM has been changed to SENSCIS®
Rationale for change
Registration received 
Section to be changed
Synopsis, Flowchart, 1. Introduction, 3. 
Description of Design and Trial Population, 4. 
Treatments, 6.2.1. Screening, 7. Statistical methods 
and Determination of Sample Size, 11. Description 
of Global Amendments
Description of change
The listed sections of the protocol have been 
updated in order to reflect that also the 
approximately 14 patients of the trial 1199-0340 
will enter in this extension trial.
Rationale for change
To additionally assess the safety of ongoing 
nintedanib treatment in patients with Systemic 
Sclerosis associated Interstitial Lung Disease who 
have completed the phase I drug-drug interaction 
(DDI) trial 1199-0340.
Section to be changed
3.3.4.2 Recommendation to discontinue nintedanib
Description of change
Pulmonary Hypertension  (PH) requiring parenteral 
therapy (parenteral or oral with epoprostenol/, 
treprostinil, selexipag). Selexipag added.
Rationale for change
New substance in the treatment of PH
Section to be changed
5.2.3
Safety laboratory parameters
Description of change
Overall about 110 mL blood will be taken for 
standard safety laboratory during the first year and 
about 45 mL blood will be taken any other year.
Rationale for change
Clarification of collected blood volume. 
Section to be changed
6.2.4
Dose modification visit
Description of change
Safety laboratory added
Rationale for change
Corrections of inconsistencies
Section to be changed
6.2.3 Trial Completion and Follow Up Period
7.3.4 Safety analysis
Description of change
Change the residual effect period from 28 days
to 7 days
Rationale for change
Corrections of inconsistencies


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11.3
GLOBAL AMENDMENT 3
Date of amendment
13 Aug 2020
EudraCT number
2016-003403-66
BI Trial number
1199.225
BI Investigational Product(s)
Nintedanib
Title of protocol
An open-label extension trial to assess the long 
term safety of nintedanib in patients with 
‘Systemic Sclerosis associated Interstitial Lung 
Disease’ (SSc-ILD)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only


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Section to be changed
1.1 Medical Background; 1.2 Drug profile
Description of change
Section 1 was updated to ensure that current 
knowledge and recent data are reflected in the 
indroduction section.
Rationale for change
New data of pivotal trial (1199-0214) available.
Section to be changed
1.4 Benefit Risk Assessment 
Description of change
Risk assessment due to COVID-19 pandemic 
situation added
Rationale for change
New information on benefit/risk due to COVID-19 
pandemic situation.
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
The end of the trial description was revised and 
more precisely specified. Trial may last beyond 
availability of marketed drug.
Rationale for change
Clarification overall trial duration
Section to be changed
4.1.3
Drug assignment and administration of 
doses for each patient
Description of change
Amount of wallets provided to the patients at visits 
5 and 6 were described incorrect and was 
corrected.
Rationale for change
Correction of wallets given to patient per visit
Section to be changed
4.2.1
Other treatments and emergency procedures
Description of change
The wording regarding withdrawal and interruption 
of trial medication was revised to for clarification. 
Furthermore it was added that trial medication may 
be resumed in case of clear evidence for alternative 
cause for hepatic injury was identified and 
resolved. It was specified that this is only possible 
after consultation with the sponsor and if prior to 
restart, liver laboratory values are normal.. Liver 
laboratory values should be monitored weekly for 
first 4 weeks of re-introduction and every 2 weeks 
for the following 8 weeks.
Rationale for change
Revision of the recommendations for hepatic 
injury.


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Section to be changed
6.1 Visit schedule and 10.3 Visit modification in 
exceptional circumstances
Description of change
Specification that and how in exceptional 
circumstances (as e.g. in pandemic situations), 
when it is impossible to conduct study visits at the 
study site, study visits may be performed at 
patient’s home or remotely combined by using 
local laboratories.
Rationale for change
Experiences from the COVID-19 first wave 
situation; to allow flexibility in visit conduct in 
case required due to pandemic or other exceptions 
situations to ensure patients safety by ensuring 
continuous treatment.


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
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Meaning of Signature  
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SAP_001.pdf: 
 
TRIAL STATISTICAL ANALYSIS PLAN
c19924398-06
BI Trial No.:
1199.225 SENSCIS®- ON (Extension)
Title:
An open-label extension trial to assess the long term safety of 
nintedanib in patients with ‘Systemic Sclerosis associated 
Interstitial Lung Disease’ (SSc-ILD)
Including Protocol Amendment 2 [c11787364-04]
Investigational
Product(s):
OFEV®, Nintedanib
Responsible trial 
statistician(s):
   Phone: 
Date of statistical 
analysis plan:
09 JAN 2023 REVISED
Version:
4
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7.
PLANNED ANALYSIS ......................................................................................28
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........28
7.2
CONCOMITANT DISEASES AND MEDICATION......................................28
7.2.1
Baseline conditions ..............................................................................................28
7.2.2
Concomitant therapies........................................................................................28
7.3
TREATMENT COMPLIANCE ........................................................................29
7.4
PRIMARY ENDPOINT(S).................................................................................29
7.5
SECONDARY ENDPOINT(S)...........................................................................30
7.5.1
Key secondary endpoint(s) .................................................................................30
7.5.2
(Other) Secondary endpoint(s)...........................................................................30
7.7
EXTENT OF EXPOSURE .................................................................................30
7.8
SAFETY ANALYSIS..........................................................................................31
7.8.1
Adverse events .....................................................................................................31
7.8.1.1
Pre-specified adverse events of special interest ....................................................32
7.8.1.2
Adverse events with additional information collection.........................................33
7.8.1.3
Additional analysis of adverse event groupings by system...................................33
7.8.1.4
Adverse events of particular note..........................................................................33
7.8.1.5
Time at risk analyses .............................................................................................34
7.8.2
Laboratory data...................................................................................................35
7.8.2.1
Standard laboratory analyses.................................................................................35
7.8.2.2
Liver enzyme and bilirubin elevations ..................................................................35
7.8.3
Vital signs.............................................................................................................35
7.8.4
ECG ......................................................................................................................36
7.8.5
Others ...................................................................................................................36
8.
REFERENCES ....................................................................................................37
10.
HISTORY TABLE..............................................................................................44


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LIST OF TABLES
Table 6.2: 1
Important protocol deviations...........................................................................19
vital signs and laboratory measurements (haematology, coagulation, 
biochemistry – CK, glucose non-fasting, LDH, uric acid, HCG) ....................25
Table 6.7: 2
Time windowing rules for SGRQ, SHAQ, patient global VAS, SCTC GIT, 
physician global VAS, laboratory measurements (biochemistry - BNP, 
TSH) .................................................................................................................26
Table 6.7: 3
Time windowing rules for laboratory measurements (electrolytes, urinalysis, 
urine pregnancy test, biochemistry – AST, ALT, GGT, ALK, total protein, 
total bilirubin, creatinine, GFR) .......................................................................26
Table 7.2.2: 1 Concomitant therapy outputs and position in the CTR ....................................29
Table 10: 1
History table .....................................................................................................44


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
ALK 
Alkaline Phosphatase
ALT 
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATA
Anti-Topoisomerase Antibodies
ATC
Anatomical Therapeutic Chemical Classification
BI
Boehringer Ingelheim
BIcMQ
BI customised MedDRA Query
CDG
Customised Drug Grouping
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CRF
Case Report Form
GGT
Gamma-Glutamyl-Transferase
GLI
Global Lungs Initiative
HLT
High Level Term
ICH
International Conference On Harmonisation
INR
International Normalized Ratio
IPD
Important Protocol Deviation
LLT
Low Level Term
MedDRA
Medical Dictionary For Regulatory Activities
MQRM
Medical Quality Review Meeting
PN
Preferred Name
PT
Preferred Term
SD
Standard Deviation
SEM
Standard Error of the Mean
 


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Term
Definition / description
SDG
Standardised Drug Grouping 
SOC
System Organ Class
SSc
Systemic Sclerosis
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomisation.
In this document, the parent trial refers to SENSCIS® or 1199.340 trial. All analyses will be 
done in patients coming from both SENSCIS and 1199.340 trials. In addition, a selected set of 
analyses will be repeated in patients coming from SENSCIS only.
SAS® Version 9.4 (or later) will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The following further categorical endpoints were added: 


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
The primary focus is on safety endpoints. Please refer to CTP Section 2.1.2.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable.
5.2.2
Secondary endpoint(s)
Not applicable.


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5.4
OTHER VARIABLE(S)
5.4.1
Demographics and baseline characteristics
Demographics and other baseline characteristics will include the following. 


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5.4.1.1
Demographic data 
∀
Gender
∀
Race (as collected in parent trial): single race respondents, multiple race respondents (all 
combinations ticked), and all race categories regardless of how many race categories 
were ticked
∀
Ethnicity (as collected in parent trial)
∀
Age [years] will be calculated as: year of informed consent in extension trial 1199.225 -
year of birth
∀
Age in classes [years] (<30; >=30 to <45; >=45 to <60; >=60 to <75; >=75)
∀
Age at randomisation in parent trial [years] (as derived in the parent trial CRF as year of 
informed consent in parent trial - year of birth)
∀
Age at randomisation in parent trial in classes [years] (<30; >=30 to <45; >=45 to <60;
>=60 to <75; >=75)
∀
Weight [kg] (at inclusion in extension trial 1199.225) as continuous variable and in 
classes (<30; ≥30 to <60; ≥60 to <90; ≥90)
∀
Height [cm] (at inclusion in extension trial 1199.225)
∀
Body mass index [kg/m2], at inclusion in extension trial 1199.225: Weight [kg] / Height 
[m] * Height [m], as a continuous variable and in classes (< 18.5; >=18.5 to <25; >=25
to <30, >=30)
5.4.1.2
Other baseline characteristics


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The following baseline efficacy variables and SSc characteristics will be summarised for the 
parent trial:
∀
FVC in mL and in % predicted at randomisation 
∀
Modified Rodnan Skin Score (mRSS)
∀
Digital ulcers count and net burden [fingers]
∀
SGRQ Total, Symptoms, Activities and Impact scores
∀
Time since first onset of non-Raynaud symptom [years]
∀
Time since first onset of Raynaud symptom [years]
∀
Time since first diagnosis of SSc-ILD [years]
∀
SSc subtype (diffuse cutaneous SSc, limited cutaneous SSc)
∀
ATA status (positive, negative)
5.4.2
Compliance
Compliance (%) at each visit is collected in the eCRF and will not be recalculated. An overall 
compliance will be calculated as a time-weighted average over all visits. Each weight will be 
based on the number of days between the compliance measurement and the previous one (or 
the date of first trial drug intake for the first compliance measurement). If compliance is 
missing for at least one expected visit then overall compliance will be missing. 
Likewise, compliance will be calculated at 1 year (up to 52 weeks [Visit 7]), at 2 years (up to 
100 weeks [Visit 10]), and at each year (based on data collected every 48 weeks).
Overall and annual compliance will be summarised and categorised into classes: <50%, 
>=50% to <80%, >=80% to <= 120%, > 120%.
5.4.3
Exposure
Exposure will be calculated during 1199.225 extension trial. The date of first trial drug intake
is recorded at visit 2.
∀
Duration of exposure [months] = (Date of last trial drug intake– date of first trial drug 
intake in extension trial 1199.225 +1 day) /30.5. Treatment interruptions will not be 
subtracted from this duration of exposure. 
∀
Duration of exposure in categories: <= 3 months (91 days); > 3 months (91 days) to 
<= 6 months (182 days); > 6 months to <= 12 months (365 days); > 12 months to <= 
18 months (547 days); > 18 months to <= 24 months (730 days); > 24 months to <=36 
months (1095 days); > 36 months to <=48 months (1460 days); > 48 months to <=60 
months (1825 days); > 60 months to <=72 months (2190 days); >72 months
∀
Duration while 150 mg bid actually taken [months]: Sum of each continuous duration 
of exposure to 150 m bid [days] /30.5. This duration of exposure will be adjusted for 
treatment interruptions, dose reductions and dose increases.


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∀
Duration while 100 mg bid actually taken [months]: Sum of each continuous duration 
of exposure to 100 m bid [days] /30.5. This duration of exposure will be adjusted for 
treatment interruptions, dose reductions and dose increases.
∀
Total dose [g]: Duration while 150 mg bid actually taken [days] * 0.3 g + duration 
while 100 mg bid actually taken [days] * 0.2 g.
∀
Dose intensity [%]: Total dose [g]*100/{0.3g*(Duration of exposure [days])}
∀
Dose intensity in categories: <= 30 %, >30% to <=50%, >50% to <=90%, >90% to
<100%, >=100%.
5.4.4
Liver enzyme and bilirubin elevations
Liver enzyme and bilirubin elevations will be reported using the following definitions: 
∀
(ALT and/or AST ≥ 3 fold ULN) AND bilirubin ≥ 2 fold ULN[1]
o
And ALK >= 2 fold ULN [1]
o
And ALK < 2 fold ULN[1]
[1] These elevations are defined within a time window of 30 days i.e. the elevation of bilirubin 
should appear within 30 days after the elevation of AST and/or ALT.
∀
ALT ≥ 5 fold ULN and/or AST ≥ 5 fold ULN
∀
ALT ≥ 3 fold ULN and/or AST ≥ 3 fold ULN
∀
ALT ≥ 1.5 fold ULN and/or AST ≥ 1.5 fold ULN
The proportion of patients presenting signs of hepatic injury will be summarised, based on the 
following definition for signs of hepatic injury:
∀
ALT and/or AST ≥8 fold ULN
∀
ALT and/or AST ≥ 3 fold ULN and total bilirubin ≥ 2 fold ULN in the same sample
∀
ALT and/or AST ≥3 fold ULN and unexplained INR > 1.5 in the same sample
∀
ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%) in the same 
sample
∀
ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right 
upper abdominal quadrant pain or tenderness, fever and/or rash within +/- 7 days of 
the abnormal ALT and/or AST laboratory test result (please refer to Section 9.2 for 
the list of relevant MedDRA preferred terms to support the derivation of a potential 
hepatic injury)
In addition, maximum individual elevations based on worst value on treatment will be defined 
as:


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∀
≥1.5 fold ULN; ≥3 fold ULN; ≥5 fold ULN; ≥8 fold ULN for AST and ALT
∀
≥1.5*ULN; ≥2 fold ULN for Bilirubin
∀
≥1.5*ULN; ≥2 fold ULN for ALK
∀
≥ 1xULN; ≥ 3 fold ULN for GGT
Note: ULN refers to the Upper Limit of Normal from the Central Laboratory analyzing 
samples from this extension trial. 


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5.4.6
Safety time-to-event analyses
∀
Time to first dose reduction [days]
∀
Time to first treatment interruption [days]
∀
Time to permanent treatment discontinuation [days]
∀
Time to first dose reduction or treatment interruption [days]
∀
Time to first liver enzyme elevation (ALT and/or AST >=3xULN). 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For treatment specifications, see Section 4 of CTP.
The different periods of interest, as per CTP flow chart, are the following:
Note: the last day of each of the periods is excluded from the period. It defines the first day of 
the subsequent period.
∀
Previous trial: 
o
If date of informed consent in 1199.225 and first trial drug intake in 1199.225 
occur after or on last trial drug intake in SENSCIS plus 28 days plus one day  
or date of trial completion in parent trial (SENSCIS or 1199.340) plus one day, 
then previous trial period is defined as: 
from informed consent in parent trial to the last trial drug intake in SENSCIS
plus 28 days plus one day or to the date of trial completion in parent trial 
(SENSCIS or 1199.340) plus one day, whichever occurs later
o
If date of informed consent in 1199.225 or first trial drug intake in 1199.225 
occur before last trial drug intake in SENSCIS plus 28 days plus one day or  
date of trial completion in parent trial (SENSCIS or 1199.340), then previous 
trial period is defined as: 
from informed consent in parent trial to date of informed consent in 1199.225 
∀
Between-trials (optional[a]): from end of previous trial period (see above) to date of 
informed consent in 1199.225
∀
Screening (optional[a]): from date of informed consent in 1199.225 to first trial drug 
intake in 1199.225
∀
Treatment period: from first trial drug intake in 1199.225 (or re-start of treatment if
interruption) to last trial drug intake (or date of interruption if interruption) plus one
day
∀
Off-treatment (optional[a]): from date of start of interruption to re-start of treatment
∀
Residual effect period: from the last trial drug intake plus one day to last trial drug 
intake plus 7 days plus one day
∀
Follow-up (optional[a]): from last trial drug intake plus 7 days plus one day (after 
residual effect period) to date of last contact as collected in the end of study CRF page
plus one day. This period is only created if last trial drug intake took place more than 7
days before the last contact as collected in the end of study CRF page.


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∀
Post-study: from the last trial drug intake plus 7 days plus one day to database lock
or from the date of last contact as collected in the end of study CRF page (after follow-
up period) plus one day to database lock, whichever occurs later
[a] This period is optional insofar as it does not necessarily exist for all patients.
For safety analyses (Section 7.8), data from the treatment period, possible off-treatment 
periods and residual effect period will be considered as on-treatment.
6.2
IMPORTANT PROTOCOL DEVIATIONS
As there is no Per Protocol Set planned in this trial, none of the iPDs will lead to exclusion 
from a patient set. However the proportion of patients with iPDs will be presented for 
completeness purposes and to demonstrate the adherence to the CTP.
Table 6.2: 1
Important protocol deviations
Category/Code
Description
Requirements
Excluded 
from
A
Entrance Criteria Not 
Met
A1
Inclusion criteria not 
met
A1.7
Parent study not 
completed
Inclusion criteria 1 not met 
(or trial drug prematurely 
discontinued according to 
CRFs data)
Automatic IPD
None
A2
Exclusion criteria met
A2.1
Patient has laboratory 
values that indicate 
additional risk: 
a)
>3xULN for 
AST/ALT 
b)
>2xULN for
Bilirubin
c)
Creatinine clearance 
< 30 mL /min 
(Cockcroft-Gault 
formula)
Laboratory values out of 
range or missing at entry in 
the trial (visit 1 or visit 2) 
according to the database
Automatic IPD
None
A2.2
Patient with other 
disease(s) which are 
excluded as per exclusion 
criteria
At least one of exclusion 
criteria 4, 5, 6, 7, 10, 12  met
Automatic IPD for exclusion 
criteria 4, 6, 7, 10, 12  and 
manual for exclusion 
criterion 5
None
A2.3
Forbidden previous 
therapy
Exclusion criteria 5, 9
Manual IPD based on 
exclusion criteria and / or to 
be identified at the site level 
on the manual PD log
None


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Table 6.2: 1
Important protocol deviations (cont’d)
Category/Code
Description
Requirements
Excluded 
from
A2.4
Potential risk related to 
fetotoxicity
Inclusion criteria 3 not met or 
exclusion criteria 13 met
Automatic IPD
None
A2.5
Time period between 
parent trial and
Visit 2 not observed
Exclusion criteria 8 met 
AND (time period >
12 weeks, i.e. ≥13 weeks
between last trial drug intake 
of 1199.214 and Visit 2 of 
this study according to CRFs 
data or time period >
1 week, i.e. ≥2 weeks 
between last trial drug intake 
of 1199.340 and Visit 2 of 
this study)
Automatic IPD
None
A2.6
Any condition that makes
them an unreliable trial 
subject or unlikely to 
complete the trial
Exclusion criteria 11 met
Automatic IPD
None
A2.7
Previous enrolment in this 
trial
Exclusion criteria 14 met
Automatic IPD
None
B
Informed Consent
B1
Informed consent not 
given 
Inclusion criteria 2 not met 
Automatic IPD
None
B2
Informed consent given 
too late
CRF date of informed 
consent is after date of Visit 
1. Signature of the wrong 
Informed Consent version, 
and later signature of the 
correct one will also be part 
of this IPD category
Manual IPD
None
B3
Informed consent not 
given or withdrawn for 
biobanking but 
biobanking done
According to database and 
CRF page informed consent 
for biobanking
Automatic IPD
None
C
Trial medication and 
randomisation
C1
Incorrect trial medication 
taken
Wrong medication number.
Medication kit assigned at 
visit 2 does not match 
treatment dose actually
received by
patient
Automatic IPD
None
C2
Trial medication not 
interrupted (or 
interruption done too late)
when ALT or AST ≥5 
fold ULN
Based on liver enzyme 
elevation and interruptions 
reported during the trial
Manual IPD
None


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Table 6.2: 1
Important protocol deviations (cont’d)
Category/Code
Description
Requirements
Excluded 
from
C3
Trial 
medication 
not 
permanently discontinued 
after signs of liver enzyme 
elevations were observed 
that 
a) are indicative of hepatic 
injury 
as 
defined 
in 
Section 5.4.4
b) correspond to ALT or 
AST ≥3 fold ULN 
despite dose reduction or 
treatment interruption for 
2 weeks or more
All patients where signs of 
liver enzyme elevations are 
not dealt with according to the 
requirements of the CTP and 
no 
confirmed 
alternative 
cause found (as confirmed by 
BI medicine) for the potential 
drug-induced livery injury 
(DILI) event.
Manual IPD based on review 
of MQRM listings 
None
D
Concomitant 
Medication
D1
Patient received 
prohibited concomitant 
therapies (see Section 
4.2.2.1 of the CTP)
Investigational therapies are
not allowed
Review of MQRM listings
and / or to be identified at the 
site level on the manual PD
log. 
None
E
Missing data
E1
Patient without any 
physical assessment for
more than 6 months 
although under study
medication
Prior to the start of COVID-
19 disruption, no vital signs 
>6 months. After the start of 
COVID-19 disruption, no 
vital signs or local labs >6 
months. 
Manual IPD
None
E2
Flow chart not observed 
for the planning of visit 1 
and 2
Visit 1 and Visit 2 occurred 
on the same date whereas the 
period between last available 
laboratory test within 
SENSCISTM or 1199-0340 
and Visit 2 of the extension 
trial (1199.225) is > 6 weeks 
(i.e. ≥7 weeks)
Automatic IPD
None
6.3
SUBJECT SETS ANALYSED
All analyses will be performed on the Treated Set, as defined in Section 7.3 of the CTP, 
including patients coming from SENSCIS and 1199.340.  
Patients will be analysed according to their randomised treatment group in the parent trial 
(placebo or nintedanib) and overall (Total column). Patients from 1199.340 will be combined 
with placebo patients from SENSCIS in the outputs, due to their short exposure to nintedanib 
during 1199.340. Patients in the placebo column are those who initiated nintedanib in the 
extension study, whilst patients in the nintedanib column are those who continued nintedanib. 


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The column of main interest in the tables will be the total column (includes both treatment 
groups) as all patients are treated with nintedanib during the extension study.
In addition, a selected set of analyses will be repeated in patients coming from SENSCIS only
(see Section 9.6 for further details) and in patients with pulmonary hypertension at baseline 
(see Section 9.7 for further details).
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in a statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS


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6.6.2
Other endpoints
6.6.2.1
Concomitant therapies
In case of (partially) missing start and end dates of concomitant therapies, the dates will be 
imputed so that the extent of exposure to the concomitant therapy is maximal, i.e. the first day 
(month) of the month (year) for incomplete start dates and the last day (month) of the month 
(year) for incomplete end dates.
6.6.2.2
Safety endpoints
Missing or incomplete AE dates will be imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (2).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
As a general rule, the last assessment/measurement before the date of first trial drug intake 
(included) will be used as baseline (possibly Visit 1 assessment if no available value at Visit 
2).
Visit windowing will be performed as described in Tables 6.7: 1, 6.7: 2 and 6.7: 3, in order to 
assign data to the relevant study visit based on the actual day of the assessment. Data will be 
analysed using the re-calculated visits in the statistical tables. However, in the listings, all 
visits performed will be displayed (even if outside time-window), along with the re-calculated 
visit. No time-windowing will be performed for the follow-up visit (all follow-up visits will 
be displayed in the tables / listings whenever they were performed).


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Table 6.7: 1
Time windowing rules for 
physical exam, 
vital signs and laboratory measurements (haematology, coagulation, biochemistry – CK, 
glucose non-fasting, LDH, uric acid, HCG)
Time window of actual day [1]
Allocated to
Start day
End day 
(included)
Length of 
the time-
window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
1
1
1
1 or 2[2]
Baseline
1
2
57
56
3
4 weeks
29
58
127
70
4
12 weeks
85
128
211
84
5
24 weeks
169
212
309
98
6
36 weeks
253
310  
421
112
7
52 weeks
365
422
533
112
8
68 weeks
477
534
645
112
9 (p)
Every 16 
weeks 
thereafter
589 (Vp)
Vp + 1+
(Vp+1-Vp)/2
Vp+1 + (Vp+2 -
Vp+1)/2
(Vp+2 – Vp) /2
p+1
…
Vp+1
Vp denotes the planned day of the visit
[1] First trial drug intake date in extension trial is taken into account as a reference to calculate time windows
[2] Depending on the last assessment before first trial drug intake (included), refer to Section 6.7 for baseline 
definition


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Table 6.7: 2
Time windowing rules for 
 
laboratory measurements (biochemistry - BNP, TSH)
Time window of actual day [1]
Allocated to
Start day
End day 
(included)
Length of 
the time-
window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
1
1
1
2
Baseline
1
2
267
266
5
24 weeks
169
268
421
154
7
52 weeks
365
422
533
112
8 (p)
Every 16 weeks 
thereafter
477 (Vp)
Vp + 1+ 
(Vp+1-Vp)/2
Vp+1 + (Vp+2 -
Vp+1)/2
(Vp+2 – Vp) /2
p+1
…
Vp+1
Vp denotes the planned day of the visit
[1] First trial drug intake date in extension trial is taken into account as a reference to calculate time windows
Table 6.7: 3
Time windowing rules for laboratory measurements (electrolytes, urinalysis, 
urine pregnancy test, biochemistry – AST, ALT, GGT, ALK, total protein, total bilirubin, 
creatinine, GFR)
Time window of actual day [1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
1
1
1
1 or 2[2]
Baseline
1
2
22
21
2a
2 weeks
15
23
43
21
3
4 weeks
29
44
71
28
3a
8 weeks
57
72
106
35
4
12 weeks
85
107
148
42
4a
18 weeks
127


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Table 6.7: 3
Time windowing rules for laboratory measurements (electrolytes, urinalysis, 
urine pregnancy test, biochemistry – AST, ALT, GGT, ALK, total protein, total bilirubin, 
creatinine, GFR) (cont’d) 
Time window of actual day [1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
149
190
42
5
24 weeks
169
191
232
42
5a
30 weeks
211
233
281
49
6
36 weeks 
253
282
337
56
6a
44 weeks
309
338
393
56
7 (p)
52 weeks 
365 (Vp)
Vp + 1+ 
(Vp+1-Vp)/2
Vp+1 + (Vp+2 -
Vp+1)/2
(Vp+2 – Vp) /2
p+1
Every 8 weeks
Vp+1
Vp denotes the planned day of the visit
[1] First trial drug intake date in extension trial is taken into account as a reference to calculate time windows
[2] Depending on the last assessment before first trial drug intake (included), refer to Section 6.7 for baseline 
definition


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7.
PLANNED ANALYSIS
All analyses described in this section will be done on the Treated Set. 
The list of analyses planned in patients coming from SENSCIS parent trial only is included in 
Section 9.6.
For End-Of-Text tables, the set of summary statistics is: N / Mean / SD / Min / Median / Max. 
In descriptive statistics tables, mean, SD and median will be rounded to one additional digit 
than the raw individual value. 
In case some endpoints show some extreme data, quartiles and percentiles will be presented 
additionally.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
7.2.1
Baseline conditions
A summary of baseline conditions will be provided by randomised treatment group in parent 
trial (and overall), System Organ Class (SOC) and Preferred Term (PT). SOC and PT will be 
sorted by descending frequency (over the Total column). 
7.2.2
Concomitant therapies
Concomitant therapies will be described over several study periods:
∀
Baseline therapies will be defined as treatments with a start date before first trial drug 
intake in extension trial and a stop date after or on the day of the first trial drug intake
in extension trial (or ongoing after first trial drug intake in extension trial).
∀
On-treatment concomitant therapies are defined as treatments with a start date after or 
on the day of first trial drug intake in extension trial and before or on the day of last trial 
drug intake in extension trial.


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∀
Post-study drug discontinuation therapies are defined as treatments with a start date after 
last trial drug intake in extension trial and before or on the last contact as collected in 
the end of study CRF page. This aims at flagging concomitant treatments taken by 
patients after they have stopped the study drug.
Table 7.2.2:1 summarises the concomitant therapy outputs which will be provided for each 
category of concomitant therapy created.
Summaries by ATC and preferred name (PN) will use the ATC3 code, and will be sorted by 
alphabetical ATC class and decreasing frequency of PN in the Total column within ATC 
class.
Summaries by Customised Drug Grouping (CDG) will be sorted alphabetically by the name 
of the CDG and by decreasing frequency of PN in the Total column within a CDG. CDGs are 
built using WHO-DD Standardised Drug Groupings (SDG), Sub-SDGs and ATC4 levels. 
CDGs are listed in Section 9.3.
Table 7.2.2: 1 Concomitant therapy outputs and position in the CTR
By ATC and PN
By CDG and PN
Baseline therapies
16.1.13.1
15.1
On-treatment concomitant therapies
16.1.13.1
16.1.13.1
All on-treatment concomitant 
therapies* with a frequency >2% (in 
the Total column)
16.1.13.1
Not required
All on-treatment concomitant 
therapies*
16.1.13.1
15.1
Post-study drug discontinuation 
therapies
Not required
16.1.13.1
* including baseline therapies.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINT(S)
The primary objective of the trial is to assess the safety of Nintedanib, so please refer to 
Section 7.8 for detailed analyses.


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint(s)
This section is not applicable as no secondary endpoint has been specified in the protocol.
7.7
EXTENT OF EXPOSURE
A summary table showing the duration on treatment in extension trial (both mean and 
frequency in classes, see Section 5.4.3) will be presented as well as a summary table showing 
the duration on actual treatment dose (both mean and frequency in classes, see Section 5.4.3)
and off-treatment duration. This will take into account the actual dose following dose 
reductions or increases.
A summary of treatment interruptions will be performed including number of patients with at 
least one interruption, number and reason of interruptions, as well as time to first interruption 
(both mean and frequency in classes, see Section 5.4.3). A similar summary will be performed 
for dose changes.
For the above mentioned analyses, data will be presented over 52 weeks, 100 weeks, 148 
weeks as well as over the whole trial.


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The proportion of patients on each dose actually taken at inclusion in 1199.225 will be 
displayed according to:
- the dose actually taken at the end of parent trial (by parent trial treatment group and 
all combined)
- last dose actually taken in 1199.225 extension trial
A table displaying the disposition of patients and the conclusion of patients’ participation, and 
a table displaying the primary reason for non-inclusion will be provided. 
A Kaplan-Meier plot of time to permanent treatment discontinuation will be produced. 
Similarly, Kaplan-Meier plots will be performed for time to first dose reduction, for time to 
first treatment interruption and for time to first dose reduction or treatment interruption. Plots 
will be done by randomised treatment group in parent trial and overall. The 25th, median and 
75th percentiles derived from the Kaplan-Meier plots of these time-to-event endpoints will be 
presented as well. No statistical tests will be performed.
For all the above mentioned time to event endpoints, a summary table of time to first onset 
and number of patients with an event will be presented. The time to onset of first event [days] 
will also be summarised by categories : <= 1 month (30 days), > 1 month (30 days) to <= 2 
months (61 days), > 2 months (61 days) to <= 3 months (91 days);   > 3 months (91 days) to 
<= 6 months (182 days); > 6 months (182 days) to <= 1 year (365 days); > 1 year (365 days) 
to <= 2 years (730 days); > 2 years (730 days) to <=3 years (1095 days), > 3 years (1095 
days).
7.8
SAFETY ANALYSIS
All safety analyses will be performed on treated patients.
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of subjects with AEs and NOT on the number of 
AEs.
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:
•
All AE attributes are identical (LLT, intensity, action taken, therapy required, seriousness, 
reason for seriousness, relationship [investigator defined drug-relatedness], outcome, AE 
of special interest).
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 occurrences 
is given if the second occurrence started on the same day or on the day after the end of the 
first occurrence).
For further details on summarisation of AE data, please refer to (2,3).


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The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake in extension 
trial till last drug intake + 7 days will be assigned to the on-treatment period and described 
according to randomised treatment in parent trial. All adverse events occurring before first 
drug intake will be assigned to ‘previous trial’, ‘Between-trials’ or ‘screening’.
All adverse events occurring after the last trial drug intake will be assigned to ‘residual effect 
period’ or ‘follow-up’ or ‘post-study’ (for listings only). For details on the treatment 
definition, see Section 6.1.
According to ICH E3 (4), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = drug withdrawn’ or ‘action taken = dose reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy 
An overall summary of adverse events will be presented by randomised treatment in parent 
trial (and Total).
The frequency of patients with AEs will be summarised by randomised treatment in parent 
trial (and Total), primary system organ class (SOC) and preferred term (PT). This will be 
presented using a >5% cut-off in the CTR and repeated without the cut-off in the CTR 
appendices.
Separate tables will be provided for patients with other significant AEs according to ICH E3 
(4), for patients with serious AEs (SAEs), for patients with severe AEs, for patients with AEs 
leading to dose reduction, for patients with AEs leading to treatment interruption, for patients 
with AEs leading to discontinuation of trial drug, for patients with investigator defined drug-
related AEs, for patients with AEs leading to death and for patients with investigator defined 
drug-related AEs leading to death. The frequency of patients with serious adverse events 
occurring with incidence in preferred term > 1% will be presented as well.
In addition a table will be provided for patients with investigator defined drug-related SAEs. 
This will be based on the number of patients with AE events that are both serious and 
investigator defined drug-related.
Data will be presented over 52 weeks, 100 weeks, 148 weeks as well as over the whole trial.
The SOCs will be sorted by default alphabetically; PTs will be sorted by frequency in the 
Total column (within SOC).
7.8.1.1
Pre-specified adverse events of special interest
Gastrointestinal perforations and hepatic injury are adverse events of special interest (AESI) 
pre-specified in the CTP Section 5.2.11.1. These are investigator reported on the eCRF and 
will be identified using this information for this analysis. The frequency of patients with pre-
specified AESI will be summarised by randomised treatment in parent trial (and Total), 
primary SOC and preferred term (PT).


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7.8.1.2
Adverse events with additional information collection
Diarrhoea and bleeding are AEs with additional AE-specific information collected on the 
eCRF. These are investigator reported on the eCRF and will be identified using this 
information for this analysis. That is if the diarrhoea information has been completed for an 
adverse event then the adverse event will be considered as diarrhoea for this analysis 
regardless of subsequent MedDRA coding of the verbatim term. Likewise, if the bleeding 
information has been completed for an adverse event then the adverse event will be 
considered as bleeding for this analysis regardless of subsequent MedDRA coding of the 
verbatim term.
The additional information collected will be summarised at the AE level (occurrence level) 
rather than at the patient level separately for diarrhoea and bleeding.
Bleeding AEs will also be summarised by system and safety topic, see Section 7.8.1.3 for 
further details.
For the above mentioned analyses, data will be presented over 52 weeks, 100 weeks, 148 
weeks as well as over the whole trial.
7.8.1.3
Additional analysis of adverse event groupings by system
Further adverse event groupings by system and safety topic have been defined outside the trial 
protocol as medically relevant to the clinical development program and are specified in (8). 
The frequency of patients with AEs within these groupings will be summarised by system, 
randomised treatment group in the parent trial (and overall), safety topic and preferred term. 
Separate tables will be provided for patients with investigator defined drug-related AEs, 
serious AEs (SAEs), drug-related serious AEs and bleeding AEs. Data will be presented over 
52 weeks, 100 weeks, 148 weeks as well as over the whole trial.
7.8.1.4
Adverse events of particular note 
Gastro-intestinal adverse events (diarrhoea, nausea, vomiting, dehydration, weight decrease 
and decreased appetite) are considered as AEs of particular note.
Specific tables will be created in order to describe adverse events of particular note in the 
extension trial:
-
Summary of AEs including intensity, seriousness, clinical consequences (permanent 
dose reduction, drug discontinuation or drug interruption), drug relationship, therapy 
for event and outcome
-
Summary of AEs including time to onset, number and duration of episodes
In the summary of adverse events of particular note including intensity, seriousness, clinical 
consequences, drug relationship, therapy for event and outcome: for patients with several 
episodes, the worst intensity, relationship, outcome and clinical consequence during 
on−treatment period will be displayed. For clinical consequences, the worst category is 


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considered to be “Drug withdrawn”, then “Dose reduced”, “Dose not changed” and finally 
“Dose increased”. Worst to best outcome are: “Fatal”, “Recovered/Resolved with sequelae”, 
“Not Recovered/Not Resolved”, “Recovered/ Resolved”, “Unknown”.
Depending on the number of patients having such AEs, a Kaplan-Meier plot of time to first 
adverse event of particular note may be drawn by randomised treatment in parent trial (and 
Total).
In addition, for pairs of selected adverse events (from diarrhoea, nausea, vomiting, decreased 
appetite, dehydration, weight decreased as defined in (8) , the frequency of patients with 
concurrent AEs will be summarised by treatment where concurrence is defined as an overlap 
of at least one day.
7.8.1.5
Time at risk analyses
Time at risk analyses of AEs over 1199.225 trial will be presented. Time at risk and incidence 
rates per 100 patient years will be calculated based on the first onset of an AE in the extension 
trial.
For a specific AE, the total AE time at risk [years] is defined as the sum of time at risk [days] 
across all contributing patients / 365.25, with for each patient the time at risk [days] defined 
as follows:
∀
Date of first onset of the AE – date of first study medication administration in 
extension trial +1 day for patients with the specific AE
∀
End of time at risk – date of first study medication administration in extension trial + 1 
day for patients without the specific AE. The end of time at risk is the min (date of last 
trial drug intake + 7 days, database lock date).
The AE incidence rate [1/100 Patient years (pt-yrs)] = 100 * number of patients with specific 
AE / total specific AE time at risk [years]
A summary by randomised treatment in parent trial (and Total), primary system organ class 
(SOC) and preferred term (PT) will be presented. 
Separate tables will be provided for patients with other significant AEs according to ICH E3 
(4), for patients with serious AEs (SAEs), for patients with severe AEs, for patients with AEs 
leading to permanent dose reduction, for patients with AEs leading to permanent dose 
discontinuation, for patients with investigator defined drug-related AEs and for patients with 
AEs leading to death, for investigator defined drug-related SAEs, for investigator defined 
drug-related AEs leading to death and pre-specified AESI. The summary of patients with 
SAEs will also be presented restricted to incidence in preferred term > 1%.
Time at risk analyses of AEs, investigator defined drug-related AEs and SAEs within 
groupings by system will be also summarised by randomised treatment in parent trial (and 
Total), safety topic and preferred term.








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10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP.
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections changed
Brief description of change
1
31-JAN-2020
None
This is the final TSAP without any 
modification
2
19-FEB-2020
All
Pre-archive formatting checks 
implemented
3
06-APR-2020
6.7
Time windows for laboratory 
assessments updated for consistency 
with protocol
4
09-JAN-2023
5.4.1
5.4.2
6.2
7.7/7.8.1/7.8.1.2/
7.8.1.3/7.8.2.1/7.8.2.2
7.8.2.2
A2.5 updated to include 1199.340 
condition and E1 updated to include 
local labs after COVID-19 disruption 
date and therefore now a manual iPD
Outputs will be displayed over 52, 
100, 148 weeks and over the whole 
trial
Time to elevation categories 
condensed