Conditions: Idiopathic Pulmonary Fibrosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 89
Healthy volunteers: no

Brief summary:
This clinical study will evaluate the safety and tolerability of combination treatment of nintedanib and pirfenidone in participants with IPF. Eligible participants must have received pirfenidone for at least 16 weeks on a stable dose. Nintedanib will be added on Day 1 of the study as a combination treatment for IPF for 24 weeks.

Detailed description:

Arms:
arm 1: Participants with IPF will receive pirfenidone at 1602-2403 milligrams per day (mg/day) dose and nintedanib at the 200-300 mg/day dose up to 24 weeks.

Interventions: intervention 1: Nintedanib intervention 2: Pirfenidone
Intervention descriptions: intervention 1: Participants with IPF will receive nintedanib at the 200-300 mg/day dose up to 24 weeks. intervention 2: Participants with IPF will receive pirfenidone at 1602-2403 mg/day dose up to 24 weeks.

Protocol document:
Prot_001.pdf: 









































































































































































SAP_000.pdf: 
 
Official Title: 
An Exploratory Multicenter, Open-Label, Single Arm Study of the 
Safety and Tolerability of Pirfenidone (Esbriet®) in Combination 
With Nintedanib (Ofev®) in Patients With Idiopathic Pulmonary 
Fibrosis 
NCT Number: 
NCT02598193 
Document Date: 
Statistical Analysis Plan Version 1: 21-Nov-2016 
Statistical Analysis Plan Version 2: 17-May-2017 
 
 
 
 
 
 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
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Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
1 
STATISTICAL ANALYSIS PLAN 
TITLE: 
AN EXPLORATORY MULTICENTER, OPEN-LABEL, SINGLE 
ARM STUDY OF THE SAFETY AND TOLERABILITY OF 
PIRFENIDONE (ESBRIET®) IN COMBINATION WITH 
NINTEDANIB (OFEV®) IN PATIENTS WITH IDIOPATHIC 
PULMONARY FIBROSIS  
 
PROTOCOL NUMBER: 
MA29895 
STUDY DRUG: 
Pirfenidone (Esbriet®) and nintedanib (Ofev®) 
VERSION NUMBER: 
Version 1.0 Final, 21Nov2016 
IND NUMBER: 
67,284 
EUDRACT NUMBER: 
2015-003280-11 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
 
 (F. Hoffmann-La Roche Ltd)  
DATE FINAL: 
21 November 2016 
 
 
 




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STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
Not applicable, as this is the first version of the Statistical Analysis Plan.   
 


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TABLE OF CONTENTS 
SIGNATURE PAGE .............................................................................................. 2 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 3 
1. 
BACKGROUND ............................................................................................ 9 
2. 
STUDY DESIGN ........................................................................................... 9 
2.1 
Protocol Synopsis .................................................................. 10 
2.2 
Outcome Measures ............................................................... 10 
2.2.1 
Primary Efficacy Outcome Measures .................................... 10 
2.2.2 
Secondary Efficacy Outcome Measures ................................ 10 
2.2.3 
Exploratory Efficacy Outcome Measures ............................... 10 
2.2.4 
Patient-Reported Outcome Measures ................................... 10 
2.2.5 
Safety Outcome Measures .................................................... 11 
2.3 
Determination of Sample Size ............................................... 11 
2.4 
Analysis Timing ..................................................................... 12 
3. 
STUDY CONDUCT ..................................................................................... 12 
3.1 
Randomization Issues ........................................................... 12 
3.2 
Independent Review Facility .................................................. 12 
3.3 
Data Monitoring ..................................................................... 13 
4. 
STATISTICAL METHODS .......................................................................... 13 
4.1 
Analysis Populations ............................................................. 13 
4.1.1 
Full Analysis Set .................................................................... 13 
4.1.2 
Per Protocol Population ......................................................... 14 
4.1.3 
Pharmacokinetic-Evaluable Population ................................. 14 
4.1.4 
Safety Population .................................................................. 14 
4.2 
Trial Periods, Observation and analysis times ....................... 14 
4.2.1 
Study Days ............................................................................ 14 
4.2.2 
Baseline and Screening Observations ................................... 14 
4.2.3 
On-treatment Assessments ................................................... 15 
4.2.4 
Post-treatment Assessments ................................................. 15 
4.2.5 
Treatment Start and Stop Dates ............................................ 15 
4.2.6 
Cut-off points ......................................................................... 16 


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4.3 
Analysis of Treatment Group Comparability .......................... 16 
4.4 
Analysis of Study Conduct ..................................................... 16 
4.4.1 
Patient Disposition ................................................................. 16 
4.4.2 
Major Protocol Deviations ...................................................... 17 
4.4.3 
Demographic and Baseline Characteristics ........................... 17 
4.5 
Efficacy Analysis .................................................................... 18 
4.5.1 
Primary Efficacy Endpoints .................................................... 18 
4.5.2 
Secondary Efficacy Endpoints ............................................... 18 
4.5.3 
Exploratory Efficacy Endpoints .............................................. 19 
4.5.4 
Analyses of Patient-Reported Outcomes ............................... 19 
4.5.5 
Sensitivity Analyses ............................................................... 20 
4.5.6 
Subgroup Analyses ............................................................... 20 
4.6 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 21 
4.7 
Safety Analyses ..................................................................... 21 
4.7.1 
Treatment Completion/Early Discontinuation ......................... 22 
4.7.2 
Exposure of Study Medication ............................................... 23 
4.7.3 
Adverse Events ..................................................................... 24 
4.7.4 
Deaths ................................................................................... 27 
4.7.5 
Pregnancies ........................................................................... 27 
4.7.6 
Laboratory Data ..................................................................... 28 
4.7.7 
Vital Signs .............................................................................. 29 
4.7.8 
ECG ....................................................................................... 29 
4.7.9 
Previous and Concomitant Medication .................................. 30 
4.8 
Missing Data .......................................................................... 30 
4.9 
Visit Windows ........................................................................ 31 
4.10 
Interim Analyses .................................................................... 32 
4.11 
Biomarker Analyses ............................................................... 32 
5. 
REFERENCES ........................................................................................... 33 
 




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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
%FVC  
Percent predicted forced vital capacity  
ACS  
Acute coronary syndrome  
AE  
Adverse event  
AEGT  
Standard Adverse Event  Group Terms 
ALT  
Alanine aminotransferase  
AST  
Aspartate aminotransferase  
BID  
Twice daily  
BMI  
Body mass index  
BP  
Blood pressure  
CI  
Confidence interval  
CTCAE  
Common Terminology Criteria for Adverse Events  
d  
Day  
DLco  
Carbon monoxide diffusing capacity  
ECG  
Electrocardiogram  
eCRF  
Electronic Case Report Form  
EOT 
End of Treatment  
FVC 
Forced vital capacity  
GCP  
Good clinical practice  
GI  
Gastrointestinal  
HR  
Heart rate  
ICF  
Informed consent form  
ICH  
International Conference on Harmonisation  
iDMC  
Independent Data Monitoring Committee  
IPF  
Idiopathic pulmonary fibrosis  
IRB  
Institutional Review Board  
  
 
  
LPLV  
Last patient, last visit  
MACE  
Major Adverse Cardiac Event  
MedDRA  
Medical Dictionary for Regulatory Activities  
ms  
Millisecond  
PRO  
Patient-reported outcome  
QD  
Once daily  
QTcF  
QT interval corrected using Fridericia’s formula  
SAE  
Serious adverse event  


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TEAE  
Treatment-emergent adverse event  
TESAE  
Treatment-emergent serious adverse event  
TID  
Three times daily  
TMS 
Trial Management System 
UA  
Unstable angina 
ULN  
Upper limit of normal  
WHO  
World Health Organization  
 
 


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1. 
BACKGROUND 
As described in the Clinical Study Protocol (CSP) (Section 1.3), the mechanism of action 
of pirfenidone in Idiopathic Pulmonary Fibrosis (IPF) has not been established (Esbriet® 
EU SmPc and US label 2014), while nintedanib is thought to act by inhibiting multiple 
RTKs and nRTKs (Esbriet® US label 2014). Because multiple co-activated pathways are 
involved in the pathogenesis of IPF, experts have suggested that targeted therapies may 
work better in combination (Wuyts et al. 2014). Furthermore, experience in other 
pulmonary diseases (e.g., asthma, chronic obstructive pulmonary disease, and 
pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 18 / Protocol MA29895, 
Version 2 pulmonary hypertension) has demonstrated the value of moving from 
monotherapy to combination therapy.  
The positive benefit risk assessment of both drugs have been established in respective 
Phase II and Phase III programs which led to approval in the EU, the US, Japan and 
many other countries worldwide. Both drugs demonstrated that pulmonary function could 
be significantly improved in IPF patients, while the safety and tolerability profile was 
considered acceptable.  
Considering the overlap in the gastrointestinal (GI) and hepatic Adverse Events (AEs) 
associated with these two drugs, it is worthwhile to characterize the safety and 
tolerability of nintedanib when added to pirfenidone as a combination treatment using the 
doses recommended in the respective pirfenidone and nintedanib labels.  
This prospective study will evaluate the safety and tolerability of 24 weeks of nintedanib 
combination treatment in patients with IPF who are on a stable dose of pirfenidone with 
demonstrated tolerability. The study is not designed to evaluate the efficacy of 
combination treatment, nor is it designed to assess the safety and tolerability of adding 
pirfenidone to ongoing nintedanib treatment. 
 
2. 
STUDY DESIGN 
This is a multicenter, international, open-label, single-arm safety and tolerability study of 
pirfenidone/nintedanib combination treatment in patients with IPF who have been on a 
stable dose of pirfenidone with demonstrated tolerability. In this study, a stable 
pirfenidone dose will be defined as 1602–2403 mg/d (801 mg twice daily [BID] or three 
times daily [TID]). Up to approximately 60 clinical centers in the US, Europe, and 
Canada are expected to enroll up to approximately 80 patients. Patients who are 
withdrawn from the study will not be replaced.  
At the start of Screening, patients will have been on pirfenidone for at least 16 weeks 
and on a stable dose (1602–2403 mg/d) for at least 28 days; also, the dose must be 
expected to remain within that range throughout the study. In addition, in the 28 days 
before the start of Screening, patients must not have experienced either a new or 


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ongoing moderate or severe adverse reaction considered by the Investigator to be 
related to pirfenidone, or an interruption of pirfenidone treatment for > 7 days for any 
reason. 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2. For additional details, please see the Protocol Amendment 
Version 3, 21 June 2016 (and its Appendices). 
2.2 
OUTCOME MEASURES 
The primary objective for this study is to investigate the safety and tolerability of adding 
nintedanib to treatment with pirfenidone in patients with IPF. Consequently, the primary 
objectives of this study focus on safety and tolerability and not efficacy. 
2.2.1 
Primary Efficacy Outcome Measures 
Not applicable. 
2.2.2 
Secondary Efficacy Outcome Measures 
Not applicable. 
2.2.3 
Exploratory Efficacy Outcome Measures 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
2.2.4 
Patient-Reported Outcome Measures 
 
 
 
  
 


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2.2.5 
Safety Outcome Measures 
The primary safety outcome measure is: 
 
Proportion of patients who complete 24 weeks of combination treatment on 
pirfenidone at a dose of 1602–2403 mg/d and nintedanib at a dose of 200–300 
mg/d. 
Secondary safety outcome measures are: 
 
Proportion of patients who discontinue pirfenidone, nintedanib, or both study 
treatments because of adverse events before the Week 24 visit, 
 
Total number of patient days of combination treatment with pirfenidone at a dose 
of 1602–2403 mg/d and nintedanib at a dose of 200–300 mg/d, 
 
Total number of days from the initiation of combination treatment to 
discontinuation of pirfenidone, nintedanib, or both study treatments, 
 
Frequency and timing of Adverse Events (AEs) and Serious Adverse Events 
(SAEs). 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 80 patients was selected based on the AE 
discontinuation rates after one year observed in the randomized Phase 3 pirfenidone 
studies and the randomized Phase 2 and 3 nintedanib studies (pirfenidone 14.6% AE 
discontinuation [Esbriet® US label 2014]; nintedanib 21% AE discontinuation [Ofev® US 
label 2014]). Given that for pirfenidone the discontinuation rate after 24 weeks was 6%-
8% in studies PIPF-004 and PIPF-006 it is a reasonable assumption that the nintedanib 
discontinuation rate was around 10%-11%. As in this study of combination treatment, it 
is possible that the addition of nintedanib to ongoing pirfenidone treatment could 
increase the proportion of patients who discontinue because of an AE, given the overlap 
in the GI and hepatic effects of pirfenidone and nintedanib.  
Assuming 85% of the patients complete 24 weeks of combination treatment, a sample 
size of 80 patients would be expected to yield an actual completion rate of 77.2% - 
92.8% using a 95% confidence interval (CI). Table 1 shows the 95% CIs associated with 
projected completion rates of 75%, 80%, 85%, 90% or 95%, assuming an 80-patient 
sample size. 


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Table 1 
Confidence Limits for Sample Size Determination 
Number of Patients who 
completed 24 weeks  
Proportion of Patients 
who completed 24 weeks  
Lower Bound 
of 95% CI  
Upper Bound 
of 95% CI  
76 
95.0% 
90.2% 
99.8% 
72 
90.0% 
84.4% 
96.6% 
68 
85.0% 
77.2% 
92.8% 
64 
80.0% 
71.2% 
88.8% 
60 
75.0% 
65.5% 
84.5% 
CI = confidence interval 
Patients who are withdrawn from the study will not be replaced. 
2.4 
ANALYSIS TIMING 
The following analyses will be performed for this study: 
Table 2 
Analysis Timing 
Analysis 
Timing of Analysis 
First iDMC 
When the first approximately 20 patients have completed 8 weeks of 
combination treatment or permanently discontinued study treatments 
Second iDMC 
When approximately 50% of the total patient group has completed 12 
weeks of combination treatment or permanently discontinued study 
treatments 
Third iDMC 
When approximately 75% of the total patient group has completed 24 
weeks of combination treatment or permanently discontinued study 
treatments 
Final 
All patients completed 24 weeks of combination treatment or 
permanently discontinued study treatments 
Additional ad hoc meetings or data reviews can be requested at any time by the iDMC or 
the Sponsor, if warranted. 
 
3. 
STUDY CONDUCT 
The study conduct is described in Section 2 (Study design).  
3.1 
RANDOMIZATION ISSUES 
This will be an open-label trial involving only one treatment arm. 
3.2 
INDEPENDENT REVIEW FACILITY 
Not applicable. 


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3.3 
DATA MONITORING 
An independent Data Monitoring Committee (iDMC) will review safety data and advise 
on study conduct at least three times during the study. For details on timing of the safety 
reviews please see Table 2 above. Efficacy data will only be provided if requested by the 
iDMC. For details please see Section 4.10. 
 
4. 
STATISTICAL METHODS 
This is a safety and tolerability study, not designed to assess efficacy, comprising only 
one treatment group. There are no formal statistical hypothesis tests to be performed, 
and there will be no adjustments for multiplicity of endpoints or within-subgroups 
comparisons. Efficacy analyses will be limited to descriptive statistics.  
Categorical data will be summarized using frequencies and percentages (including a 
category for missing, if appropriate).  
Continuous endpoints will be summarized using descriptive statistics (mean, standard 
deviation, minimum, 25th and 75th quartiles, median, and maximum).  
Where data will be presented over time, e.g. Baseline, Week 12, Week 24, and early 
discontinuation visit, an end of treatment visit (EOT) will be added. This will include 
Week 24 data for patients who completed 24 weeks of combination treatment and data 
from the early discontinuation visit for patients who prematurely discontinued from 
combination treatment. 
Other analysis methods will be specified below, where applicable. All data recorded in 
the electronic Case Report Form (eCRF), as well as derived data that will be used in 
analyses, will be listed.  
Analyses will be presented for the total population, together with geographic region, i.e.  
US and non-US patients. Results for US and non-US will be presented as additional 
columns or additional blocks within the outputs of the total population. 
Percentages will be based on the total population or on the number of patients in the 
respective geographic region, if not otherwise specified. 
4.1 
ANALYSIS POPULATIONS 
Only one analysis population, the Safety Population, has been defined as per CSP. No 
further analysis populations will be assessed.  
4.1.1 
Full Analysis Set 
Not applicable. 


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4.1.2 
Per Protocol Population 
Not applicable. 
4.1.3 
Pharmacokinetic-Evaluable Population 
Not applicable. 
4.1.4 
Safety Population 
The Safety Population will consist of all patients who received at least one dose of 
nintedanib or pirfenidone at the Baseline visit (Day 1).  
Analyses will be produced for the Safety Population, if not otherwise specified. 
4.2 
TRIAL PERIODS, OBSERVATION AND ANALYSIS TIMES 
In case that durations are to be calculated (e.g. treatment duration), these will be derived 
based on days and converted to months and years if needed, using 30.4375 and 365.25, 
respectively, as denominator if not otherwise specified.  
4.2.1 
Study Days 
Study day is defined as the number of days since combination treatment start date, and 
is calculated as: 
 
For assessments after or on the day of start of combination treatment: 
Study day = Assessment date – Date of start of combination treatment + 1. 
 
For assessments before the day of start of combination treatment: 
Study day = Assessment date – Date of start of combination treatment 
The day of the first dose of combination treatment will be Day 1.  
4.2.2 
Baseline and Screening Observations 
 
Table 3 
Definition of Baseline and Screening Observations 
 
Definition 
Combination 
Treatment 
Start Date 
Combination Treatment Start Date is the date of first administration of 
nintedanib or pirfenidone at or after the ‘Baseline (Day 1)’ visit.  
Combination treatment start date will be used for all safety 
assessments and for the calculation of study days. 
Baseline data 
Baseline is defined as the last valid assessment prior to start of 
combination treatment. This may not be the same as the ‘Baseline 


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(Day 1)’ visit as per eCRF.  
Generally, it is assumed that measurements referring to the ‘Baseline 
(Day 1)’ visit have been performed before study drug was given. This 
applies for laboratory values, vital signs, ECG, pulmonary function 
tests and 
 
Adverse events occurring at the combination treatment start date will 
not be considered baseline, but treatment-emergent. 
Screening 
data 
Screening measurements are all the measurements performed before 
the combination treatment start date and not respecting the “baseline” 
criteria. 
 
4.2.3 
On-treatment Assessments 
On-treatment assessments will be the assessments performed on or after the 
combination treatment start date until the date of the Follow-up visit, which is planned to 
be performed 28 - 35 days after the date the subject discontinued from combination 
treatment (see Section 4.2.5 for details).  
4.2.4 
Post-treatment Assessments 
Post-treatment evaluations will be the evaluations performed later than the Follow-up 
visit. Post-treatment evaluations are not expected to occur. If there should be any, 
assessments falling into this time-window will only be listed. 
For adverse events, all AEs starting later than 28 days after the last dose of study drug 
will be considered as post-treatment. 
4.2.5 
Treatment Start and Stop Dates 
As this is a combination treatment study, different assessments with respect to study 
treatment are possible: Pirfenidone alone, nintedanib alone, and combination treatment. 
To account for this, the following definitions will be made: 
Table 4 
Definition of Treatment/Combination Treatment Start and Stop 
Dates 
 
Treatment start date 
Treatment end date 
Pirfenidone 
Date of first administration as 
recorded in the study drug log 
for pirfenidone at or after the 
Date of last administration of 
pirfenidone as recorded in the 
study drug log for pirfenidone. 


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‘Baseline (Day 1)’ visit. 
Nintedanib 
Date of first administration of 
nintedanib as recorded in the 
study drug log for nintedanib. 
Date of last administration of 
nintedanib as recorded in the study 
drug log for nintedanib. 
Combination 
treatment 
Date of first administration of 
nintedanib or pirfenidone at or 
after the ‘Baseline (Day 1)’ visit 
= Start date of combination 
treatment 
Date subject completed or early 
discontinued from combination 
treatment period as per eCRF 
(eCRF form Study Drug 
Completion/Early discontinuation). 
= Date of discontinuation from 
combination treatment 
Combination 
treatment as 
used for 
definition of 
TEAEs 
Date of first administration of 
nintedanib or pirfenidone at or 
after the ‘Baseline (Day 1)’ visit 
 
= Start date of combination 
treatment 
Maximum of last dose of either 
pirfenidone or nintedanib as per 
study drug logs.  
= Last dose date of combination 
treatment 
 
4.2.6 
Cut-off points 
The main time point for reporting of data is at the final analysis. Clinical cut-off for final 
analysis is defined as the date of last patient last visit (LPLV). Data cleaning cut-off date 
is planned for 1 week after the clinical cut-off date. After this cut-off date no additional 
data will be entered into the database. Data cleaning will be completed after 8 weeks 
after the clinical cut-off. Database extract for analysis is planned to be performed xx 
weeks after the clinical cut-off. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
This is an open-label single arm phase IV study that will assess the combination 
treatment of pirfenidone and nintedanib. Consequently, no formal assessment of 
treatment group comparability can be conducted. 
4.4 
ANALYSIS OF STUDY CONDUCT 
4.4.1 
Patient Disposition 
An overview on patient disposition, showing number and percentages of patients 
screened (as per IxRS), enrolled, treated and completed the study will be provided. For 


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patients who have early discontinued study treatment or the study, frequencies of 
reasons for early discontinuation will be provided. Patients enrolled are all patients that 
have signed informed consent and are entered into the clinical database. 
For further safety-related disposition analyses please see Section 4.7.1. 
An overview on patients’ enrolment by country and center will be provided. 
4.4.2 
Major Protocol Deviations 
A Per-Protocol population will not be defined; however, major protocol deviations and 
eligibility violations will be summarized by frequency tables and all patients with protocol 
deviations will be listed. 
Protocol deviations will be assessed by Clinical Science and will be provided in a 
spreadsheet. All deviations provided in that spreadsheet will be considered as major 
protocol deviations.  
4.4.3 
Demographic and Baseline Characteristics 
Baseline and disease characteristics such as demographics, medical history, tobacco 
and substance use history will be summarized by descriptive statistics or frequency 
tables. 
Demographics 
The following demographic characteristics will be summarized:  
 
Age (years): as entered in the eCRF at the screening visit 
 
Age categories:18 – 64 years, 65 - 84 years, ≥85 years 
 
Gender (male/female)  
 
Race: White, American Indian or Alaska Native, Asian (Indian subcontinent, 
Other than Indian subcontinent), Black or African American, Native Hawaiian or 
Other Pacific Islander, Unknown. In case that more than one race will be ticked, a 
concatenated variable, containing all races will be presented (e.g. Asian/White). 
 
Ethnicity: Hispanic (Latino), Non-Hispanic (Non-Latino) 
 
Weight (kg) at baseline 
 
Height (cm) at baseline 
 
BMI (kg/m2) at baseline. BMI will be calculated as weight in kg / (height in cm)2 
10000 
Data on female reproductive status will be presented descriptively; methods of 
contraception will only be listed. 


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Tobacco use history and substance use 
The history of tobacco use will be summarized with the following characteristics:  
 
Tobacco use history (never, current, previous) 
 
Pack-years, smokers only 
Numbers and percentages of patients for following characteristics will be presented to 
specify substance use:  
 
Current substance use (yes/no) 
 
Substance use (cannabinoids, amphetamines, opiates, caffeine, 
benzodiazepines, barbiturates, cocaine) 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®), version 19.0 or higher and will be summarized presenting numbers and 
frequencies by primary System Organ Class (SOC) and Preferred Term (PT). If patients 
have more than one disease within a SOC or PT they will be counted only once for the 
respective SOC or PT. 
Historical Pulmonary Function Test 
The number and percentage of patients who performed the respective pulmonary 
function test 
 (calculated)) in the past will be 
provided. This assessment was planned to be performed closest to 6 months before the 
Screening visit. These historical pulmonary function test parameters will be summarized 
using descriptive statistics. Both, absolute and percent predicted values will be 
presented. The time from assessment of the historical value to Screening will be 
summarized and defined as follows: 
Time from assessment to Screening = (Date of Screening – Date of historical 
assessment) + 1. 
4.5 
EFFICACY ANALYSIS 
The efficacy measures of this study will only be analyzed in an exploratory manner. A 
replacement of missing values is not planned. 
4.5.1 
Primary Efficacy Endpoints 
Not applicable. 
4.5.2 
Secondary Efficacy Endpoints 
Not applicable. 


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4.5.3 
Exploratory Efficacy Endpoints 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.5.4 
Analyses of Patient-Reported Outcomes 
 
 
 


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4.5.5 
Sensitivity Analyses 
No sensitivity analyses are planned. 
4.5.6 
Subgroup Analyses 
Subgroup analyses will be conducted for selected endpoints. The following subgroups 
will be based on: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.6 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
No pharmacokinetic or pharmacodynamic analyses are planned for this study. 
4.7 
SAFETY ANALYSES 
The primary objective for this study is to investigate safety and tolerability of adding 
nintedanib to treatment with pirfenidone. Consequently, safety endpoints related to 
patient disposition, early discontinuations and adverse events are of main interest.  
Analyses will be descriptive. No confirmatory analyses are defined and no comparative 
statistics will be generated.  
The main and final time point for safety assessments is at the final analysis. However, 
decisions at the different stages of this study (such as during iDMCs) may require 
deeper insight into safety data. Therefore, a selection or all of the specified safety 
evaluations of this section will be conducted at each analysis time point. 


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Patients’ safety will be assessed further through analyses of treatment exposure, 
laboratory tests, vital signs, and ECGs. 
4.7.1 
Treatment Completion/Early Discontinuation 
A summary of the number and proportion of patients who complete 24 weeks of 
combination treatment (with 95% CI) will be presented. A patient is considered to have 
completed 24 weeks of combination treatment, if the eCRF question “Did the subject 
complete the treatment?” is ticked “Yes” (eCRF form “Study Drug Completion/Early 
Discontinuation”). It is expected that these patients have completed the Week 24 visit 
within expected time window (see Section 4.9), but patients performing the Week 24 visit 
outside of these windows will also be considered for this analysis. 
The number and proportion of patients who complete 24 weeks of combination treatment 
(with 95% confidence interval (CI)) on pirfenidone at a dose of 1602-2403 mg/d and 
nintedanib at a dose of 200-300 mg/d will be presented. Average daily dose information 
as defined in Section 4.7.2 will be used to assess whether a patient completed 24 weeks 
on target dose. 
The number and percentage of patients who discontinued combination treatment 
because of an adverse event (with 95% CI) will also be presented. This summary 
comprises patients who have reported “Adverse Event” as main reason for treatment 
discontinuation. 
The duration of combination treatment (weeks) and duration of participation in the study 
(weeks) (incl. follow-up) will be summarized descriptively. Duration of combination 
treatment will be defined as the time from combination treatment start date (see Section 
4.2.2) to the date subject completed or early discontinued from combination treatment 
period as per eCRF (Study Drug Completion/Early discontinuation form). Duration of 
participation in the study will be defined as the time from date of Screening to date of 
Follow-up visit.  
Kaplan-Meier (KM) plots for time to treatment discontinuation will be provided, based on 
the date subject completed or early discontinued from combination treatment period, as 
per eCRF (see Section 4.2.5). Separate lines by drug that is considered to be the 
primary reason for discontinuation (i.e. pirfenidone, nintedanib, both or ‘not applicable’) 
will be added to this presentation. The date of last administration of the respective study 
drug as per the eCRF drug logs will be used for these presentations. 
Details on treatment and study discontinuations will be listed. 
Logistic regression analysis will be used to assess the influence of baseline covariates 
on the discontinuation rate in an exploratory manner. The following parameters will be 
used to explain early treatment discontinuation: 


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 
Age (years) at baseline,  
 
Sex (female = 0, male = 1), 
 
FVC % predicted at baseline, 
 
DLco % predicted at baseline. 
 
Region (US vs non-US) 
Further parameters will be analyzed on an exploratory basis.  
The regression coefficients for each covariate, together with the standard error and p-
value will be presented. Further, odds ratios and 95% confidence intervals will also be 
given. In addition, a model including all covariates will be investigated in order to assess 
the consistency of the results. 
4.7.2 
Exposure of Study Medication 
Summaries of dosing, treatment duration, dose interruptions or reductions will be 
provided for each treatment separately, as well as for combination treatment, if 
applicable. 
The overall treatment duration (weeks), including and excluding dose interruptions, will 
be summarized descriptively. Also the days with dose interruptions will be given in this 
presentation.  
The overall treatment duration including dose interruptions will be defined as follows: 
 
Overall duration of combination treatment including dose interruptions = 
(Maximum date of last dose of pirfenidone or nintedanib received – date of 
initiation of combination treatment) + 1. 
The date of first administration of nintedanib or pirfenidone at or after the Baseline visit 
(Day 1) will be considered as initiation date of combination treatment (see Section 4.2.1).  
 
Overall treatment duration of pirfenidone/nintedanib including dose interruptions 
= (Date of last dose of treatment received – date of initiation of combination 
treatment) + 1. 
The overall treatment duration excluding dose interruptions will be derived from the 
treatment administration panels, considering only days on treatment. When calculating 
duration of combination treatment, only days where both, pirfenidone and nintedanib, 
were interrupted will be excluded. 
Dose interruptions will be calculated by summing all days where dose (pirfenidone or 
nintedanib) was interrupted. Combination treatment will only be considered to be 
interrupted if both, pirfenidone and nintedanib, were interrupted. 


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The total number of patient days on treatment, including and excluding dose 
interruptions, and the total number of patient days with dose interruptions, will be 
presented. 
The total dose (mg), the last dose administered (mg/d) and the average daily dose 
for each of the study treatments will be presented descriptively. The average daily dose 
will be calculated by summing up the number of capsules taken, divided by the number 
of days on combination treatment including treatment interruptions, as defined above. 
Further, frequencies for categories of average daily doses (e.g. <1602, 1602 – 
2403, >2403 mg/d for pirfenidone, and <200, 200 – 300, >300 for nintedanib, as well as 
combinations of both) will be presented. 
Dose modifications will be investigated for any modification, as well as for dose 
reductions and drug interruptions separately. Numbers and proportions of patients with 
at least one dose modification, dose reduction or drug interruption will be presented for 
each treatment separately. Numbers and proportions of patients with 1, 2, 3 or more 
dose modifications, dose reductions or drug interruptions will be given. 
Numbers of dose modifications, reductions or interruptions will be presented together 
with numbers and frequencies of reasons for dose modification, reduction or interruption. 
Dose modifications, defined as dose reductions or drug interruptions will be derived from 
the drug log information on dose strength and number of capsules taken.  
4.7.3 
Adverse Events 
Verbatim descriptions of adverse events (AEs) will be mapped to a preferred term (PT) 
and system organ class (SOC) using the Medical Dictionary for Regulatory Agencies 
(MedDRA®). MedDRA version 19.0 or higher and related SMQ lists (see below) will be 
used for coding. 
AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03. For AEs of varying severity, the 
most severe grade as documented on the eCRF will be used in the summaries. 
According to the protocol, after informed consent has been obtained but prior to initiation 
of combination treatment on Day 1, only SAEs caused by a protocol-mandated 
intervention should be reported. 
After initiation of combination treatment at or after the ‘Baseline (Day 1)’ visit, all adverse 
events will be reported until 28 days after the last dose of study drug.  After this period, 
the Investigator should report any SAEs that are believed to be related to prior study 
drug treatment. 


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An AE that started or worsened on the day of initiation of combination treatment through 
28 days after the last dose of combination treatment, i.e. the maximum date of 
nintedanib or pirfenidone treatment, will be considered treatment emergent.  
The analysis of AEs will focus on treatment-emergent AEs (TEAE), but all AEs will be 
listed. This also includes AEs that might occur after initiation of investigational 
pirfenidone, but prior to Baseline (Day 1). For these AEs a separate listing will be 
provided. 
Classifications of seriousness, severity and causality are described in the protocol 
sections 5.2 and 5.3. 
An overview of patient safety profile will present the number and proportion of patients 
experiencing  
 
 all and related treatment-emergent adverse events (TEAE),  
 
all and related serious treatment-emergent adverse events (serious TEAE),  
 
all and related severe TEAE,  
 
all and related  TEAE of special interest (AESI) (MedDRA Preferred term for 
STIAMP -  ‘Suspected transmission of an infectious agent via product’ or SMQ: 
‘Drug related hepatic disorders – severe events only (SMQ)’),  
 
all and related gastrointestinal (GI) (SOC: Gastrointestinal disorders),  
 
hepatic side effects (MedDRA AEGT: Esbriet  - Potential Hy’s Law AEGT’ see 
Appendix 4), 
 
any (related) clinical significant vascular event (as angina pectoris, myocardial 
infarction, transient ischaemic attack (TIA), stroke) (Defined as any AE included 
in the MedDRA SMQs Ischemic heart disease, Central nervous system vascular 
disorders, Haemorrhages, Embolic and thrombotic events), 
o all and related ischemic heart disease (MedDRA SMQ: Ischemic heart 
disease) 
o all and related cerebrovascular event (MedDRA SMQ: Central nervous 
system vascular disorders),  
o all and related bleeding event (MedDRA SMQ: Haemorrhages), 
o all and related  thromboembolic event (MedDRA SMQ: Embolic and 
thrombotic events),  
 
all and related major adverse cardiac event (MACE), (any CV death, non-fatal 
myocardial infarction, nonfatal stroke, acute coronary syndrome (ACS)/ unstable 
angina (UA)) 


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 
all and related photosensitivity or rash (MedDRA Preferred terms Nodular rash, 
Photodermatosis, Photosensitivity reaction, Pruritus, Pruritus generalized, Rash, 
Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, 
Rash popular, Rash pruritic, Retching, Solar dermatitis, Solar urticarial, 
Somnolence, Sunburn, Erythema, Dry skin),  
 
all and related gastrointestinal (GI) perforation (MedDRA SMQ: Gastrointestinal 
perforation, ulceration, haemaorrhage or obstruction: sub-category 
Gastrointestinal perforation), 
 
all and related TEAEs  leading to death, 
 
all and related TEAEs leading to treatment discontinuation, 
 
all and related elevated liver test results leading to treatment discontinuation, 
 
all and related TEAE resulting in hospitalization or prolonged hospitalization 
together with the number of events in each of these event categories. For related TEAEs 
the relationship to pirfenidone, nintedanib or both investigational drugs will be assessed. 
The number and percentage of patients with CTCAE grade 3-4 laboratory liver test 
results will also be included in this overview.  
If relationship to study drug is missing, the event will be presented in the ‘All TEAEs’ 
column. A listing presenting all AEs with missing relationship will be added. 
All categories of (all and related) TEAEs as presented in the overview will be 
summarized by system organ class (SOC) and preferred term (PT). Frequencies and 
percentages of patients experiencing (at least) one event in the respective category will 
be presented by decreasing frequencies. If patients have more than one AE within a 
SOC or PT they will be counted only once for the respective SOC or PT. Total numbers 
of TEAEs will be provided for each SOC and overall. 
Similar summary presentations will be provided for patients with TEAEs leading to dose 
reduction and drug interruption and TEAEs leading to hospitalization. 
Special interest in this study will be on assessment of treatment discontinuation. 
Therefore, TEAEs leading to treatment discontinuation will be summarized for TEAEs 
leading to discontinuation of any drug, and for TEAEs leading to discontinuation of both 
treatments, to pirfenidone alone or to nintedanib alone. These presentations will be 
provided for all AEs by most extreme NCI CTCAE grade. Additional presentations for the 
following categories of (all and related) TEAEs leading to treatment discontinuation will 
be presented: 
 
Seriousness (serious, non-serious). 
 
GI event, 


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 
Photosensitivity reaction/rash. 
All TEAEs indicating “Action taken with pirfenidone/nintedanib due to SAE/AE” = “Drug 
withdrawn” in the eCRF will be included in these summaries. 
Numbers and frequencies of patients with TEAEs by most extreme CTCAE Grade will be 
provided for any TEAEs and for each SOC and PT. In case the most extreme intensity is 
missing, it will be replaced by the initial intensity. If both most extreme and initial intensity 
are missing, AE will be included in the summaries for grade 3 to 5 AEs (i.e. in the total 
column) and a column for “missing” will be added.  
All adverse event data will be listed by patient number and study day of onset. Separate 
listings will be provided for AEs leading to treatment discontinuation, serious adverse 
events (SAEs), adverse events of special interest (AESIs) and deaths. 
Non-treatment-emergent AEs (i.e. AEs that start prior to first administration of 
combination treatment and do not worsen at/after combination treatment, or AEs that 
start more than 28 days after last dose of combination treatment) will be listed separately. 
The following additional analyses will be performed for the purpose of fulfilling the 
Clinical Trial Registry (CTR) requirements:  
 
Both Serious Adverse Events and ‘Other’ Adverse Events will be summarized by 
MedDRA preferred term. 
An adverse event is considered ‘Serious’ whether or not it is a TEAE. An adverse event 
is considered in the ‘Other’ category if it is both, a TEAE and is not serious. 
For each Serious AE and ‘Other’ AE, and for each term the following are provided: 
 
The number of subjects at risk of an event; 
 
The number of subjects who experienced each event term; 
 
The number of events experienced. 
4.7.4 
Deaths 
Numbers and frequencies of deaths and of deaths occurring within 28 days after the last 
dose of combination treatment will be presented. The primary cause of death and the 
information on whether an autopsy was performed will be given. All information on 
deaths will be collected from the eCRF panel on study discontinuation. 
4.7.5 
Pregnancies 
Pregnancy test results will be listed, presenting the visit, date and study day of 
pregnancy test and test result. 


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4.7.6 
Laboratory Data 
All laboratory parameters will be assessed by a central laboratory, with the exception of 
the results of urine pregnancy tests, which will be determined locally and will be 
recorded in the eCRF. 
All parameters will be graded according to NCI CTCAE (CTEP 2010), version 4.03, if 
applicable. Laboratory parameters that cannot be graded according to NCI CTCAE 
version 4.03 will be assessed with respect to normal range (low, normal, high). 
The following laboratory parameters will be collected: 
 
Hematology: complete blood count with platelet count and automated differential, 
i.e. hemoglobin, hematocrit, platelet count, red blood cell count, RBC morphology, 
white blood cell count, absolute differential count (neutrophils, bands, eosinophils, 
lymphocytes, monocytes, basophils), 
MCH, MCHC, MCV, 
 
Serum chemistry:  albumin, alkaline phosphatase, ALT, AST, direct bilirubin*, 
total bilirubin, calcium, cholesterol, creatine kinase, creatinine, triglycerides, 
gamma-glutamyl transferase, glucose, lactic dehydrogenase*, magnesium, 
phosphorus*, potassium, sodium, urea nitrogen, serum uric acid*, and amylase, 
C-reactive protein (N HS)-PS* (CRP), Creatinine clearance rate*, calculated 
using the Cockcroft-Gault formula 
 
Serum pregnancy test*, 
 
Urine dipstick for pregnancy testing*(local). 
* = for these parameters no grading as per NCI CTCAE, version 4.03 is possible. 
Hemoglobin A1c (HbA1c) was planned to be collected according to the initial version of 
the Clinical Study Protocol (CSP), but was removed in Amendment 3 of the CSP as not 
specifically relevant for this patient population. HbA1c values are continuously reported 
by the central laboratory, but will not be presented in any summary presentations. 
HbA1c values will only be listed. 
Clinical laboratory values will be presented separately for CTCAE-gradable and non-
CTCAE gradable parameters by laboratory panel (hematology, serum chemistry).  
Serum or urine pregnancy data will only be listed.  
For laboratory analyses, visits will be assigned to visit windows as described in Section 
4.9. This will also be valid for possible unscheduled visits. In case that multiple evaluable 
assessments occur within the same visit, the most extreme value will be used for 
analyses. 


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The following summaries will be prepared: 
For each laboratory parameter, descriptive statistics of laboratory values at each 
scheduled visit (derived as described above), and absolute changes from baseline to 
post-baseline will be presented.  
Shift tables presenting changes from baseline to worst CTCAE grade, in the indicated 
direction, will be provided for CTCAE-gradable parameters. These changes will also be 
expressed as shifts of 1 to 4 grades, 3 to 4 grades and 4 grades. If no CTCAE grade is 
available for a specific laboratory variable, shift tables will present worst changes with 
respect to normal range category (low, normal, high). 
For CTCAE-gradable parameters, numbers and percentages of patients with laboratory 
values of Grade 3 and 4 will presented over time. Further, the total number of visits with 
Grade 3/4 elevations, as well as the number and percentages of patients with Grade 3/4 
elevations for each parameter will be provided. 
Liver abnormalities (total bilirubin, alkaline phosphatase, ALAT (SGPT), ASAT (SGOT)) 
of Grade 3 and 4 will be presented showing numbers and percentages of patients for 
each parameter separately, as well as in combination with at least one of the other 
parameters elevated post-baseline. 
All laboratory data will be listed. 
4.7.7 
Vital Signs 
Vital signs, body weight and body temperature assessments will be assigned to visit 
windows as per Section 4.9. Descriptive statistics will be used to summarize vital signs 
data at baseline, at each scheduled post-baseline visit, and for the absolute change from 
baseline to each scheduled post-baseline visit. The body mass index (BMI) will only be 
calculated for the BMI at baseline and presented with the demographic data. 
4.7.8 
ECG 
QTcF values will be assigned to the following intervals: < 500 ms, 500–550 ms, and > 
550 ms.  Numbers and proportions of patients with their maximum QTcF interval 
category will be summarized at Baseline, Week 24 or early discontinuation, EOT and 
Follow-up. Absolute changes from the Baseline to each post-baseline visit in QTcF 
values will be categorized to ≤ 30 ms, 31–60 ms, and > 60 ms. Numbers and proportions 
of patients in each category will be presented for each post-baseline visit. Planned visits 
will be used for presentations. 
At each visit, the ECG result is to be assessed as being normal, abnormal - not clinically 
significant, abnormal - clinically significant, or unable to evaluate. Changes from baseline 
to each post-baseline visit will be presented showing numbers and proportions of 
patients in each combination of categories. 


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Descriptive statistics for heart rate and changes from baseline for each visit will be 
presented. 
4.7.9 
Previous and Concomitant Medication 
Previous and concomitant medications are non-study medications. Different from the 
description in the Clinical Study Protocol, which describes that the non-study 
medications will be coded using the World Health Organization (WHO) Drug Dictionary, 
the previous and concomitant medication will be coded using the Genentech (GNE) drug 
dictionary. This is a proprietary Roche Dictionary which is used to code concomitant 
medications in the Trial Management System (TMS) coding tool. The Standardized 
Medication Name (CMDECOD), which is the medication generic or combination generic 
as defined by the Drug Thesaurus (proprietary Genentech/Roche dictionary), and the 
Medication Class (CMCLAS), which is the primary medication class as defined by the 
Drug Thersaurus, will be used for the analyses. 
Therapies will be classified as previous or concomitant as follows: 
 
Previous: If the medication end date is prior to start of combination treatment, 
 
Concomitant: If medication is taken anytime between the start of combination 
treatment (Day 1) and 28 days after last dose of combination treatment.  
The number and frequency of previous and concomitant medications will be given per 
Medication Class and Standardized Medication Name. If patients receive more than one 
drug within an Medication Class or Standardized Medication Name they will be counted 
only once for the respective Medication Class or Standardized Medication Name.  
All medications will be listed. Medication that starts after the end of study treatment will 
be considered as post-treatment. This medication will be identified by a flag in the data 
listing. 
4.8 
MISSING DATA 
In general, missing data will not be imputed. Exceptions will be made for the data related 
to adverse events and concomitant medications as described below. 
For adverse events, missing start or end dates will only be imputed for determination of 
whether the adverse event is considered to be treatment-emergent or not by using the 
following principles: 
Incomplete or missing onset dates will be imputed to the earliest date possible (using 
any reliable portions of the onset date that are available and the eCFR flag on 
whether the event/medication occurred prior to study drug administration) following 
the first dose of combination treatment. Note that the onset day is considered 
unreliable if the month or year portions of the date are missing, and the onset month 
is considered unreliable if the year portion of the date is missing. If, given the 


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completed portions of the adverse event onset date and the known first combination 
treatment start date, the event could not have started after the first dose of 
combination treatment, then the adverse event will be considered non-treatment-
emergent and the onset date will be left as an incomplete date. 
If the stop date is completely missing, then the event will be assumed to be ongoing and 
a stop date will not be imputed.  
For imputation and handling of missing intensity or relationship to study medication, 
please see Section 4.7.3. 
All other missing or incomplete adverse event data will be left as missing. 
For concomitant medications, missing start or end dates will only be imputed for 
determination of whether the concomitant medication is considered to be prior, on-
treatment, post-treatment. The eCRF flag ‘Select if (medication) taken prior to study’ will 
be used in addition.  
4.9 
VISIT WINDOWS 
Visit windows will be applied to vital signs and laboratory data and the derived visits will 
be used in the by-visit summarizations. If multiple observations fall within the same visit 
window, the observation with the most extreme value will be used in the analysis, if not 
stated otherwise.  
For presentation of vital signs, laboratory tests, exposure and pulmonary function test 
results, an end of treatment (EOT) visit will be defined. This will include Week 24 data for 
patients who completed 24 weeks of combination treatment and data from the early 
discontinuation visit for patients who prematurely discontinued from combination 
treatment. 
Table 5 
Visit Windows for vital signs and laboratory data 
Analysis Visit [AVISITN] 
Target Day 
Window (Study Days) 
 
 
 
Baseline [0] 
1 
Last valid assessment prior to 
start of combination treatment 
Week 1 [1] – lab data only 
7 
2 to 10 
Week 2 [2] 
14 
11 to 17 (2 to 21 vital signs) 
Week 3 [3] – lab data only 
21 
18 to 24 
Week 4 [4] 
28 
25 to 42 (22 to 42 vital signs) 
Week 8 [8] 
56 
43 to 70 
Week 12 [12] 
84 
71 to 98 
Week 16 [16] 
112 
99 to 126 
Week 20 [20] 
140 
127 to 154  
Week 24 [24] 
168 
155 to 174 
Early discontinuation [25] 
Not applicable 
As occurred 
End of treatment (EOT) [26] 
Not applicable 
As occurred 




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5. 
REFERENCES 
Respiratory Medicine 
 
 
 
Thorax 
 
 
 


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Appendix 1  
Protocol Synopsis 
PROTOCOL SYNOPSIS 
TITLE: 
AN EXPLORATORY MULTICENTER, OPEN-LABEL, SINGLE ARM 
STUDY OF THE SAFETY AND TOLERABILITY OF PIRFENIDONE 
(ESBRIET®) IN COMBINATION WITH NINTEDANIB (OFEV®) IN 
PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS 
PROTOCOL NUMBER: 
MA29895 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2015-003280-11 
IND NUMBER: 
67,284 
TEST PRODUCT: 
Pirfenidone (Esbriet®) and nintedanib (Ofev®) 
PHASE: 
IV 
INDICATION: 
Idiopathic Pulmonary Fibrosis 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
The primary objective for this study is to investigate the safety and tolerability of adding 
nintedanib to treatment with pirfenidone in patients with Idiopathic Pulmonary Fibrosis (IPF). 
Eligible patients must be receiving chronic treatment with pirfenidone for at least 16 weeks and on 
a stable dose (1602–2403 mg/d) for at least 28 days. In patients eligible for this study, nintedanib 
will be added as an additional treatment for IPF (combination treatment) for 24 weeks. 
STUDY OBJECTIVES 
Primary Safety Objective 
• Proportion of patients who complete 24 weeks of combination treatment on pirfenidone at a 
dose of 1602–2403 mg/d and nintedanib at a dose of 200–300 mg/d 
Secondary Safety Objectives 
Secondary Safety Objectives are: 
• Proportion of patients who discontinue pirfenidone, nintedanib, or both study treatments 
because of adverse events before the Week 24 Visit  
• Total number of patient days of combination treatment with pirfenidone at a dose of 1602–
2403 mg/d and nintedanib at a dose of 200–300 mg/d 
• Total number of days from the initiation of combination treatment to discontinuation of 
pirfenidone, nintedan b, or both study treatments 
• Frequency and timing of adverse events (AE) and Serious Adverse Events (SAEs)  


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1769
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
35 
Exploratory Efficacy Objectives 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
Patient-Reported Outcome Objective 
 
 
 
 
 
 
Biomarker Study 
 
Blood samples will be collected for the purposes of assessing the pharmacodynamics effect 
of nintedanib on pirfenidone or IPF-related biomarkers.  
STUDY DESIGN 
DESCRIPTION OF THE STUDY 
This is a multicenter, international, open-label, single-arm safety and tolerability study of 
pirfenidone/nintedan b combination treatment in patients with IPF who have been on a stable 
dose of pirfenidone with demonstrated tolerability. In this study, a stable pirfenidone dose will be 
defined as 1602–2403 mg/d (801 mg twice daily [BID] or three times daily [TID]). Up to 
approximately 60 clinical centers in the US, Europe, and Canada are expected to enroll up to 
approximately 80 patients. Patients who are withdrawn from the study will not be replaced. The 
study design is presented in the figure below. 
At the start of Screening, patients will have been on pirfenidone for at least 16 weeks and on a 
stable dose (1602–2403 mg/d) for at least 28 days; also, the dose must be expected to remain 
within that range throughout the study. In addition, in the 28 days before the start of Screening, 
patients must not have experienced either a new or ongoing moderate or severe adverse reaction 
considered by the Investigator to be related to pirfenidone, or an interruption of pirfenidone 
treatment for > 7 days for any reason. 
After providing informed consent and discussing the risks and benefits of the study with the 
Investigator, patients will be required to.taper and/or discontinue all prohibited medications 
(Section 4.4.2) at least 28 days before the start of Screening; this is the Washout Period. Patients 
will be instructed to continue their commercial pirfenidone during the Washout Period. If a 
proh bited medication must be tapered, tapering must start early enough that the patient has 
discontinued the medication 28 days before the start of Screening. After completing Washout, 
patients will enter Screening, which lasts up to 21 days; during Screening, patients will be 
evaluated for eligibility based on the inclusion and exclusion criteria. Patients not taking a 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1770
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
36 
proh bited medication will forgo Washout and directly enter Screening. At screening, after 
eligibility criteria have been met, patients may be provided pirfenidone for the study and will be 
instructed on proper use. In this case, patients will be instructed to stop taking their commercial 
pirfenidone and start taking the study provided pirfenidone.  
During Screening, patients on a stable dose of pirfenidone may return for the Baseline Visit 
(Study Day 1) as soon eligibility has been confirmed.  At this visit, they will have nintedanib added 
to the ongoing pirfenidone treatment.  Nintedanib dosing will start at 100 mg once daily (QD) and 
be titrated to 150 mg BID over 15 days, as tolerated, according to the schedule provided in 
protocol Error! Reference source not found..  
The Sponsor will supply pirfenidone and nintedanib for use in the study; nintedanib will be 
supplied in 100 mg and 150 mg capsules to facilitate temporary dose reduction if required for the 
management of AEs.  
Combination treatment will continue through Week 24, with monitoring by office visits and 
telephone contacts. Blood samples will be obtained from all patients for analysis of clinical 
laboratory values. 
Patients will be encouraged to remain on stable doses of pirfenidone (1602–2403 mg/d) and 
nintedanib (200–300 mg/d) throughout the combination-treatment period, unless dosing is 
modified to manage an AE.  Patients will return to the clinic for a final Follow-up Visit 28–35 days 
after the completion of combination treatment.  
If 
one 
or 
both 
study 
treatments 
are 
prematurely 
discontinued 
or 
interrupted 
for  
≥ 28 consecutive days, nintedanib treatment will end as will the patient’s participation in the study; 
whether commercial pirfenidone treatment continues will be left to the judgment of the 
Investigator. The patient will then return to the clinic as soon as possible (≤ 7 days after the 
decision to discontinue nintedan b) for an Early Discontinuation Visit. 
In addition, 28–35 days after the decision to discontinue nintedanib, the patient will return for a 
final Follow-up Visit.  
A patient diary will be used to record AEs, daily dosing adherence for both pirfenidone and 
nintedanib, and concomitant medication use from the screening visit to the final Follow-up Visit. 
Also, patients will receive a wallet card that provides important information relevant to 
study participation. 
On completion of study participation, patients may be prescr bed appropriate IPF treatment at 
the discretion of the treating physician. 
An independent Data Monitoring Committee (iDMC) will review safety data and advise on study 
conduct at least three times during the study: when the first approximately 20 patients have 
completed 8 weeks of combination treatment or permanently discontinued study treatments, 
when approximately 50% of the total patient group has completed 12 weeks of combination 
treatment or permanently discontinued study treatments and when approximately 75% of the total 
patient group has completed 24 weeks of combination treatment or permanently discontinued 
study treatments. Additional ad hoc meetings or data reviews can be requested at any time by the 
iDMC or the Sponsor, if warranted.  


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1771
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
37 
 
Design of Study  
 
 
 
 
 
 
 
 
 
 
 
 
 
NUMBER OF PATIENTS 
Number of patients to be enrolled: approximately 80 
TARGET POPULATION 
Inclusion Criteria 
Eligible patients for this study must meet the following criteria for study entry: 
1. Written informed consent to participate in the study 
2. Male or female, and age 40 through 80 years old at the start of Screening (inclusive). 
3. At the start of Screening, on pirfenidone for at least 16 weeks and on a stable dose for at 
least 28 days (in this study, a stable dose will be defined as 1602–2403 mg/d); the dose 
must be expected to remain in that range throughout the study. 
4. Documented diagnosis of IPF, per the Investigator per using the criteria of the 2011 
American Thoracic Society / European Respiratory Society / Japanese Respiratory 
Society / Latin American Thoracic Association guidelines 
5. The value from pulmonary function test results (from documented pulmonary function 
laboratory reports) measured at the screening visit as follows:  
- Percent predicted FVC ≥ 50%. 
-  Percent predicted DLco (or carbon monoxide transfer capacity converted to DLco)  
 ≥ 30% 
6. Able to understand the importance of adherence to the study treatment regimen and the 
study protocol, and willing to follow all study requirements, including the concomitant 
medication restrictions, throughout the study. 
7. For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including at 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1772
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
38 
least one method with a failure rate of  < 1% per year, during the treatment period and for 
at least 3 months after the final Follow-up Visit. 
- A woman is considered to be of childbearing potential if she is post-menarcheal, has 
not reached a post-menopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
- Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, established, proper use of hormonal contraceptives that 
inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine 
devices. 
- The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
- Barrier methods must always be supplemented with the use of a spermicide. 
8. For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below: 
- With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
< 1% per year during the treatment period and for at least for at least 4 months after the 
final Follow-up Visit.  Men must refrain from donating sperm during this same period. 
- With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for at least for at least 4 months after the final Follow-up Visit. 
- The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
2. Clinical evidence of any active infection which according to the judgment of the 
investigator may interfere with study conduct, measurement of pulmonary function, or 
impact the course of IPF.  
3. In the 28 days before the start of Screening, any new or ongoing moderate or severe 
adverse reaction considered by the Investigator to be related to pirfenidone, or an 
pirfenidone treatment interruption > 7 days for any reason.  
4. Any condition that is likely to result in death in the 12 months after the start of Screening. 
5. Lung transplantation anticipated in the 12 months after the start of Screening. 
6. Any planned significant surgical intervention from the start of Screening through the final 
Follow-up Visit. This does not include minor surgical procedures (e.g., excision of a 
localized basal cell carcinoma). 
7. Known hypersensitivity to the active substance or any excipient of either pirfenidone or 
nintedanib.  
8. Any condition that, in the Investigator’s judgment, might be significantly exacerbated by 
the known side effects associated with the administration of pirfenidone or nintedanib. 
9. Mild (Child Pugh A), moderate (Child Pugh B) or severe (Child Pugh C) hepatic 
impairment. 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1773
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
39 
10. Severe renal impairment (creatinine clearance < 30 mL/min by the Cockcroft-Gault 
calculation), including end-stage renal disease requiring dialysis.  
11. History or risk of gastrointestinal (GI) tract perforation. 
12. History of unstable or deteriorating cardiac or pulmonary disease (other than IPF) in the 6 
months before the start of Screening, including but not limited to, the following:  
- Unstable angina pectoris or myocardial infarction. 
- Congestive heart failure expected to require hospitalization during the study. 
- Uncontrolled clinically significant arrhythmias. 
13. Electrocardiogram (ECG) with a heart-rate–corrected QT interval (corrected using 
Fridericia’s formula, QTcF) ≥ 500 ms at Screening, or a family or personal history of long 
QT syndrome. 
14. Bleeding risk: genetic predisposition to bleeding, a hemorrhagic event in the 12 months 
before the start of Screening, or abnormal laboratory coagulation parameters. Patients 
who require fibrinolysis, full-dose therapeutic anticoagulation (e.g., vitamin K antagonists, 
dabigatran, heparin, hirudin), high-dose antiplatelet therapy, or other therapy that may 
substantially increase bleeding risk are excluded.  
Note:  the following are permitted: prophylactic low-dose heparin or heparin flush as needed for 
maintaining an indwelling intravenous device (e.g., enoxaparin 4000 IU SC per day), as well as 
prophylactic use of antiplatelet therapy (e.g., acetylsalicylic acid up to 325 mg/d, clopidogrel at 75 
mg/d, or equivalent doses of other antiplatelet therapy). 
15. Use of strong CYP1A2 inhibitors (e.g., fluvoxamine, enoxacin) in the 28 days before the 
start of Screening. 
16. Use of inhibitors of P-glycoprotein (e.g., ketoconazole, erythromycin) or CYP3A4 (e.g., 
ketoconazole, erythromycin) or their inducers (e.g., rifampicin, carbamazepine, phenytoin, 
St John’s wort) in the 28 days before the start of Screening.  
17. History of alcohol or substance abuse in the 2 years before the start of Screening. 
18. Use of any tobacco product in the 12 weeks before the start of Screening, or an 
unwillingness to abstain from their use through the final Follow-up Visit. 
19. In the judgment of the Investigator, not a suitable candidate for enrollment, or unlikely or 
unable to comply with the requirements of this study.  
20. Use of any investigational therapy in a clinical study protocol in the 28 days before the 
start of Screening 
21. Pregnancy or lactation. 
22. Hypersensitivity to peanuts. 
23. Hypersensitivity to soy. 
END OF STUDY AND LENGTH OF STUDY 
Length of Study 
The expected study length is up to 21 months 
End of Study 
January 2018 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number
1774
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
40 
INVESTIGATIONAL MEDICINAL PRODUCTS 
PIRFENIDONE 
Pirfenidone is approved in a 267 mg capsule dosage form.  
The recommended dose is 801 mg (i.e., three 267 mg capsules) TID, at the same times each day, 
taken with food (total dose, 2403 mg/d). At the beginning of the study, patients will be on a stable 
pirfenidone dose, as defined in the inclusion criteria. 
NINTEDANIB 
Nintedan b is approved in 100 mg and 150 mg capsule dosage forms.  
The recommended dose is 150 mg BID, approximately 12 hours apart, at the same times each 
day, taken with food (total dose, 300 mg/d). Both 100 mg and 150 mg capsules will be supplied to 
facilitate temporary dose reduction if required to manage AEs.  
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The analysis population will be the Safety Population. It will consist of all patients who received at 
least one dose of nintedanib or pirfenidone at the Baseline Visit (Day 1). 
AEs will be coded to a preferred term and system organ class using the Medical Dictionary for 
Regulatory Activities (MedDRA). Laboratory abnormalities will be graded using the Common 
Terminology Criteria for Adverse Events (CTCAE). Prior and concomitant medications will be 
coded using the World Health Organization (WHO) Drug Dictionary. 
Because this is a safety and tolerability study that is not designed to assess efficacy, no formal 
statistical hypotheses for efficacy will be assessed. The efficacy analyses will be limited to 
descriptive statistics.  
Data summaries will be provided for baseline characteristics; patient disposition; extent of 
exposure; the number and proportion of patients who complete 24 weeks on pirfenidone at a 
dose of 1602–2403 mg/d and nintedanib at a dose of 200–300 mg/d (with 95% confidence 
interval [CI]); the numbers and proportions of patients with a dose reduction or a dose interruption; 
the number and proportion of patients who discontinued combination treatment because of a AE 
(with 95% CI); the total number of days on combination treatment at an pirfenidone dose of 1602–
2403 mg/d and a nintedan b dose of 200–300 mg/d; the total number of days from the start of 
combination treatment to discontinuation of one or both study treatments; the final prescribed 
doses of pirfenidone and nintedanib; and the reasons for premature discontinuation of 
combination treatment. 
AEs and SAEs leading to discontinuation will be summarized by incidence, severity, seriousness, 
and relationship to treatment. Additional summaries will be provided for the numbers and 
proportions of patients with a Major Adverse Cardiac Event (MACE), a cerebrovascular event, 
a bleeding event, or a thromboembolic event; the numbers and proportions of patients 
discontinuing combination treatment for a liver test abnormality, a GI event, or a photosensitivity 
reaction/rash; the numbers and proportions of patients with an emergency department visit or 
hospitalization; and deaths. 
Observed and change values for clinical laboratory and vital signs data will be summarized. 
Grade 3 and 4 laboratory abnormalities will be summarized by CTCAE grade, and shift tables by 
CTCAE grade will be provided. 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1775
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
41 
ECG data will be summarized, presenting the numbers and proportions of patients with a 
maximum QTcF interval < 500 ms, 500–550 ms, and > 550 ms; with a maximum change from the 
baseline QTcF interval of ≤ 30 ms, 31–60 ms, and > 60 ms; and with ECG changes considered 
by the Investigator to be clinically significant.  
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 80 patients was selected based on the AE discontinuation rates 
after one year observed in the randomized Phase 3 pirfenidone studies and the randomized 
Phase 2 and 3 nintedanib studies (pirfenidone 14.6%, nintedanib 21%; per the 2014 US labels). 
Given that for pirfenidone the discontinuation rate after 24 weeks was 6%-8% in studies PIPF-004 
and PIPF-006 it is a reasonable assumption that the nintedanib discontinuation rate was around 
10% - 11%. As in this study of combination treatment, it is possible that the addition of nintedanib 
to ongoing pirfenidone treatment could increase the proportion of patients who discontinue 
because of an AE, given the overlap in the GI and hepatic effects of the two medications.  
Assuming 85% of the patients complete 24 weeks of combination treatment, a sample size of 80 
patients would be expected to yield an actual completion rate of 77.2% to 92.8% using a 95% CI 
Number of Patients who 
completed 24 weeks 
Proportion of 
Patients who 
completed 24 
weeks 
Lower 
Bound of 
95% CI 
Upper 
Bound of 
95% CI 
76 
95.0% 
90.2% 
99.8% 
72 
90.0% 
84.4% 
96.6% 
68 
85.0% 
77.2% 
92.8% 
64 
80.0% 
71.2% 
88.8% 
60 
75.0% 
65.5% 
84.5% 
CI = confidence interval 
 
. 




Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1777
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
43 
If 
Study Period 
Follow-
up 
Early d/c 
 
W/O 
[a] 
Screen
-ing 
[a] 
Combination Treatment 
 
 
 
Visit Window, ± 3 d 
Visit Window, ± 7 d 
Refer to 
foot note 
for 
timing 
[b] 
ASAP 
≤ 7 d after 
decision to 
d/c 
nintedanib 
[c] 
Study Day: 
-50 
to 
-22 
-21 to 
-1 
1 
(BL) 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 
126 
140 
168 
Study Week: 
 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
24 
Type of 
Contact: 
O 
O 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
O 
O 
O 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
physical 
examination, 
including vital 
signs [i] 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Body weight 
(kg) 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Height (cm) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG [j] 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Spirometry 
(FVC), and 
DLco [k] 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Spirometry 
(FEV1) [k] 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, 
serum chemistry 
[l], CRP 
 
X 
X 
[m] 
X 
[m] 
X 
[m] 
X 
[m] 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1778
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
44 
If 
Study Period 
Follow-
up 
Early d/c 
 
W/O 
[a] 
Screen
-ing 
[a] 
Combination Treatment 
 
 
 
Visit Window, ± 3 d 
Visit Window, ± 7 d 
Refer to 
foot note 
for 
timing 
[b] 
ASAP 
≤ 7 d after 
decision to 
d/c 
nintedanib 
[c] 
Study Day: 
-50 
to 
-22 
-21 to 
-1 
1 
(BL) 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 
126 
140 
168 
Study Week: 
 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
24 
Type of 
Contact: 
O 
O 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
O 
O 
O 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test [n] 
 
 
 
 
 
 
X 
[r] 
 
X 
[r] 
 
X 
[r] 
 
X 
[r] 
 
X 
[r] 
X 
[r] 
 
 
Serum 
pregnancy test 
[n] 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Biomarker 
sample 
collection [o] 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Review patient 
diary 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Review AEs [p] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review 
pirfenidone 
dosing 
adherence [p] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1779
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
45 
If 
Study Period 
Follow-
up 
Early d/c 
 
W/O 
[a] 
Screen
-ing 
[a] 
Combination Treatment 
 
 
 
Visit Window, ± 3 d 
Visit Window, ± 7 d 
Refer to 
foot note 
for 
timing 
[b] 
ASAP 
≤ 7 d after 
decision to 
d/c 
nintedanib 
[c] 
Study Day: 
-50 
to 
-22 
-21 to 
-1 
1 
(BL) 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 
126 
140 
168 
Study Week: 
 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
24 
Type of 
Contact: 
O 
O 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
O 
O 
O 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
nintedanib 
dosing 
adherence [p] 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Review 
concomitant 
medications [p] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review 
inclusion / 
exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain historical 
FEV1, FVC and 
DLco data [q] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Dispense/collect 
patient diary 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number
1780
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
46 
If 
Study Period 
Follow-
up 
Early d/c 
 
W/O 
[a] 
Screen
-ing 
[a] 
Combination Treatment 
 
 
 
Visit Window, ± 3 d 
Visit Window, ± 7 d 
Refer to 
foot note 
for 
timing 
[b] 
ASAP 
≤ 7 d after 
decision to 
d/c 
nintedanib 
[c] 
Study Day: 
-50 
to 
-22 
-21 to 
-1 
1 
(BL) 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 
126 
140 
168 
Study Week: 
 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
24 
Type of 
Contact: 
O 
O 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
O 
O 
O 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense wallet 
card 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense 
pirfenidone and 
explain dosing  
 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Dispense 
nintedanib and 
explain dosing 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Instruct to 
resume 
commercial 
pirfenidone and 
explain dosing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Collect unused 
pirfenidone and 
empty bottles 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1781
 
Pirfenidone and nintedanib —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 1.0, final, 21 November 2016 
 
47 
If 
Study Period 
Follow-
up 
Early d/c 
 
W/O 
[a] 
Screen
-ing 
[a] 
Combination Treatment 
 
 
 
Visit Window, ± 3 d 
Visit Window, ± 7 d 
Refer to 
foot note 
for 
timing 
[b] 
ASAP 
≤ 7 d after 
decision to 
d/c 
nintedanib 
[c] 
Study Day: 
-50 
to 
-22 
-21 to 
-1 
1 
(BL) 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 
126 
140 
168 
Study Week: 
 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
24 
Type of 
Contact: 
O 
O 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
O 
O 
O 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect unused 
nintedanib and 
empty bottles 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
AE = adverse event; ASAP = as soon as possible; BL = Baseline; d = day; d/c = discontinue; DLco = carbon monoxide diffusing capacity; ECG = 
electrocardiogram; FVC = forced vital capacity; IPF = idiopathic pulmonary fibrosis; 
 
; O = office visit; P 
= telephone contact; SAE = serious adverse event; W/O = Washout 
a. Patients taking prohibited medications enter Washout; if prohibited medication must be tapered, patient must be off that medication 28 days 
before start of Screening. Other patients directly enter Screening.  
b. For patients who complete 24 weeks of study treatment, visit should occur 28–35 days after completion of combination treatment.  For patients 
who prematurely discontinue study treatment or have a treatment interruption of ≥ 28 consecutive days, visit should occur 28–35 days after 
decision to discontinue nintedan b. 
c. If a patient cannot return in ≤ 7 days, study center is to call patient to review medical history and to send laboratory kit and shipping supplies to 
patient so that blood samples can be drawn at another study center, commercial laboratory or by home nursing agency; Early Discontinuation 
Visit should then be scheduled as soon as possible. 
d. Written informed consent must be obtained before any study-mandated assessment or procedure, including tapering and/or discontinuing 
prohibited medication. If written informed consent was not obtained at Washout, it must be obtained at start of Screening. 
e. Including systems review, and review of concomitant medications, events in 28 days before start of Screening, and historical data (including 
prior high-resolution computed tomography scans, pulmonary function tests, and surgical lung biopsy data, if available). If complete medical 




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Appendix 4  
MedDRA Browser Basket: Esbriet – Potential Hy’s Law AEGT 
Project: Esbriet 
 
Title: Esbriet - Potential Hy's Law AEGT 
 
Description 
AEGT to identify cases of potential Hy's Law: 49 Terms 
 
Created Date 11-May-2016  
 
By User 
 
Last Modified Date 03-Nov-2016  
 
By User 
 
Last Reviewed Date 04-Nov-2016  
 
By User 
 
 
Included MedDRA Preferred Terms 
 
 
 
Liver injury 
 
Bilirubin conjugated increased 
 
Urine bilirubin increased 
 
Hepatobiliary disease 
 
Jaundice 
 
Transaminases abnormal 
 
Subacute hepatic failure 
 
Aspartate aminotransferase increased 
 
Cholestatic liver injury 
 
Bilirubin conjugated abnormal 
 
Mixed liver injury 
 
Hyperbilirubinaemia 
 
Drug-induced liver injury 
 
Hepatic enzyme abnormal 
 
Blood a kaline phosphatase abnormal 
 
Gamma-glutamyltransferase increased 
 
Hepatic failure 
 
Acute hepatic failure 
 
Blood a kaline phosphatase increased 
 
Hepatic enzyme increased 
 
Aspartate aminotransferase abnormal 
 
Biopsy liver abnormal 
 
Liver function test increased 
 
Liver function test abnormal 
 
Blood bilirubin increased 
 
Jaundice hepatocellular 
 
Hepatitis 
 
Alanine aminotransferase abnormal 
 
Hepatitis fulminant 
 
Hepatitis cholestatic 
 
Hepatitis acute 
 
Acute yellow liver atrophy 
 
Cholestasis 
 
Blood bilirubin unconjugated increased 
 
Prothrombin time ratio increased 
 
Chronic hepatitis 
 
Prothrombin time abnormal 
 
Hepatic infiltration eosinophilic 
 
Hepatic function abnormal 
 
Prothrombin time prolonged 
 
Hepatotoxicity 
 
Hepatitis toxic 
 


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Transaminases increased 
 
Blood bilirubin abnormal 
 
Prothrombin time ratio abnormal 
 
Liver disorder 
 
Alanine aminotransferase increased 
 
Hepatic necrosis 
 
Gamma-glutamyltransferase abnormal 
 
Hepatocellular injury 
 
 
 
Excluded MedDRA Terms 
 
Nested Baskets 
 
 
End of Esbriet - Potential Hy's Law AEGT definition 
 
MedDRA Version 19.1 
Language English 
 


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1 
STATISTICAL ANALYSIS PLAN 
TITLE: 
AN EXPLORATORY MULTICENTER, OPEN-LABEL, SINGLE 
ARM STUDY OF THE SAFETY AND TOLERABILITY OF 
PIRFENIDONE (ESBRIET®) IN COMBINATION WITH 
NINTEDANIB (OFEV®) IN PATIENTS WITH IDIOPATHIC 
PULMONARY FIBROSIS  
 
PROTOCOL NUMBER: 
MA29895 
STUDY DRUG: 
Pirfenidone (Esbriet®) and nintedanib (Ofev®) 
VERSION NUMBER: 
Version 2.0 Final 
IND NUMBER: 
67,284 
EUDRACT NUMBER: 
2015-003280-11 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
 
 (F. Hoffmann-La Roche Ltd)  
DATE FINAL: 
17 May 2017 
 
 
 




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STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
This SAP update was necessary to reflect ongoing discussions with respect to statistical 
analysis. Please see the following summary for details. 


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SAP section 
Change 
Rationale for 
Change 
4.2.2 Baseline and 
Screening 
Observations 
Combination Treatment Start Date is the date of first 
administration of nintedanib and pirfenidone on or after 
the Baseline visit.  
Drug log 
contains 
pirfenidone 
entries during 
screening 
period 
4.4.3 Demographic 
and Baseline 
Characteristics 
Description of analyses of previous pirfenidone 
treatment added. 
Not included in 
previous 
version. 
4.7.1 Treatment 
Completion/Early 
Discontinuation 
KM-plots presenting separate lines by treatment which 
is primary reason for treatment discontinuation are 
deleted. 
Cannot be 
derived.  
4.7.2 Exposure to 
Study Medication 
Clarify dose modifications and treatment interruptions 
Decision to 
only rely on the 
information as 
provided by the 
investigator on 
the drug-log 
CRF page. 
4.7.2 Exposure to 
Study Medication 
Treatments administered from combination treatment 
start date up to the ‘Date subject completed or early 
discontinued from combination treatment period’ as per 
eCRF ‘Study drug completion/Early Discontinuation’ will 
be considered for exposure analyses. 
Drug log 
contains 
pirfenidone 
entries during 
screening 
period or after 
end of 
combination 
treatment. 
4.7.3 Adverse Events 
Updated definition of ‘treatment-emergent: “An AE that 
started or worsened on the day of initiation of 
combination treatment through 28 days after the date 
subject completed or early discontinued from 
combination treatment period as per eCRF (eCRF form 
Study Drug Completion/Early discontinuation), will be 
considered treatment emergent.” 
Need to 
account for  
cases of 
pirfenidone IMP 
intake after the 
date of 
completion of 
combination 
treatment (up 
to Follow-up 
visit) 
4.7.3 Adverse Events 
Updated definition for major adverse cardiac event 
(MACE): Specific terms from SMQs Arrhythmia related 
investigations, signs and symptoms, Cardiac arrhythmia 
terms (incl bradyarrhythmias and tachyarrthythmias), 
Cardiac arrhythmias, Cardiac failure:  Cardiac arrest, 
Cardiac death, Cardio-respiratory arrest, Sudden 
cardiac death, Sudden death, Ventricular asystole, 
Agonal rhythm, Sinus arrest, Pulseless electrical 
Need to specify  
terms. 


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activity, Torsade de pointes, Ventricular fibrillation, 
Ventricular flutter, Ventricular tachycardia, Cardiac 
fibrillation, Cardiac flutter 
 
Retching and Somnolence were deleted from the 
basket for photosensitivity reaction or rash 
Terms also 
belong to other 
AE baskets 
 
‘All and related elevated liver test results leading to 
treatment discontinuation’ was deleted from the safety 
summary output. 
The link 
between liver 
test results and 
respective AEs 
not established. 
 
‘Number of events’ was removed from the safety 
overview table. 
Numbers of 
events are 
presented with 
the ‘by SOC 
and PT’ outputs 
 
Categories of TEAEs that are presented separately by 
SOC and PT specified in detail. 
Description 
was not 
specific.  
 
Categories of TEAEs leading to treatment 
discontinuation specified in detail. 
Description 
was not 
specific 
 
Analysis of timing of TEAEs added. 
Not included in 
previous 
version. 
4.7.6 Laboratory data 
Paragraph added describing grading of laboratory 
values as per NCI CTCAE, when criteria for grading 
conflict with normal ranges as per central laboratory. 
Safety assessment of creatinine values changed from 
NCI-CTC grading to non-NCI-CTC grading. 
Not included in 
previous 
version. 
 
4.7.6 Laboratory data 
Paragraph added on handling of values below the limit 
of quantification 
Not included in 
previous 
version. 
4.7.9 Previous and 
Concomitant 
medication 
Note added that previously administered Pirfenidone 
will be presented separately. 
Presented with 
previous/conco
mitant 
medications, 
previously. 
4.8 Missing Data 
Description added for imputation of missing start dates 
for previously administered Pirfenidone. 
Presented with 
previous/conco
mitant 
medications, 
previously. 
Appendix 5 
Calculation of GAP 
Index Categories 
Description of derivation of GAP Index added. 
Not included in 
previous 
version. 
   


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TABLE OF CONTENTS 
SIGNATURE PAGE .............................................................................................. 2 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 3 
1. 
BACKGROUND .......................................................................................... 11 
2. 
STUDY DESIGN ......................................................................................... 11 
2.1 
Protocol Synopsis .................................................................. 12 
2.2 
Outcome Measures ............................................................... 12 
2.2.1 
Primary Efficacy Outcome Measures .................................... 12 
2.2.2 
Secondary Efficacy Outcome Measures ................................ 12 
2.2.3 
Exploratory Efficacy Outcome Measures ............................... 12 
2.2.4 
Patient-Reported Outcome Measures ................................... 12 
2.2.5 
Safety Outcome Measures .................................................... 13 
2.3 
Determination of Sample Size ............................................... 13 
2.4 
Analysis Timing ..................................................................... 14 
3. 
STUDY CONDUCT ..................................................................................... 14 
3.1 
Randomization Issues ........................................................... 14 
3.2 
Independent Review Facility .................................................. 14 
3.3 
Data Monitoring ..................................................................... 14 
4. 
STATISTICAL METHODS .......................................................................... 15 
4.1 
Analysis Populations ............................................................. 15 
4.1.1 
Full Analysis Set .................................................................... 15 
4.1.2 
Per Protocol Population ......................................................... 15 
4.1.3 
Pharmacokinetic-Evaluable Population ................................. 16 
4.1.4 
Safety Population .................................................................. 16 
4.2 
Trial Periods, Observation and analysis times ....................... 16 
4.2.1 
Study Days ............................................................................ 16 
4.2.2 
Baseline and Screening Observations ................................... 16 
4.2.3 
On-treatment Assessments ................................................... 17 
4.2.4 
Post-treatment Assessments ................................................. 17 
4.2.5 
Treatment Start and Stop Dates ............................................ 17 
4.2.6 
Cut-off points ......................................................................... 18 


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4.3 
Analysis of Treatment Group Comparability .......................... 18 
4.4 
Analysis of Study Conduct ..................................................... 19 
4.4.1 
Patient Disposition ................................................................. 19 
4.4.2 
Major Protocol Deviations ...................................................... 19 
4.4.3 
Demographic and Baseline Characteristics ........................... 19 
4.5 
Efficacy Analysis .................................................................... 21 
4.5.1 
Primary Efficacy Endpoints .................................................... 21 
4.5.2 
Secondary Efficacy Endpoints ............................................... 21 
4.5.3 
Exploratory Efficacy Endpoints .............................................. 21 
4.5.4 
Analyses of Patient-Reported Outcomes ............................... 22 
4.5.5 
Sensitivity Analyses ............................................................... 22 
4.5.6 
Subgroup Analyses ............................................................... 22 
4.6 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 23 
4.7 
Safety Analyses ..................................................................... 24 
4.7.1 
Treatment Completion/Early Discontinuation ......................... 24 
4.7.2 
Exposure of Study Medication ............................................... 25 
4.7.3 
Adverse Events ..................................................................... 27 
4.7.4 
Deaths ................................................................................... 30 
4.7.5 
Pregnancies ........................................................................... 30 
4.7.6 
Laboratory Data ..................................................................... 31 
4.7.7 
Vital Signs .............................................................................. 32 
4.7.8 
ECG ....................................................................................... 33 
4.7.9 
Previous and Concomitant Medication .................................. 33 
4.8 
Missing Data .......................................................................... 34 
4.9 
Visit Windows ........................................................................ 35 
4.10 
Interim Analyses .................................................................... 35 
4.11 
Biomarker Analyses ............................................................... 36 
5. 
REFERENCES ........................................................................................... 37 
 




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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
%FVC  
Percent predicted forced vital capacity  
ACS  
Acute coronary syndrome  
AE  
Adverse event  
AEGT  
Standard Adverse Event  Group Terms 
ALT  
Alanine aminotransferase  
AST  
Aspartate aminotransferase  
BCE  
Biostatistical Computing Environment  
BID  
Twice daily  
BMI  
Body mass index  
BP  
Blood pressure  
CI  
Confidence interval  
CTCAE  
Common Terminology Criteria for Adverse Events  
d  
Day  
DLco  
Carbon monoxide diffusing capacity  
ECG  
Electrocardiogram  
eCRF  
Electronic Case Report Form  
EOT 
End of Treatment  
FVC 
Forced vital capacity  
GCP  
Good clinical practice  
GI  
Gastrointestinal  
HR  
Heart rate  
ICF  
Informed consent form  
ICH  
International Conference on Harmonisation  
iDMC  
Independent Data Monitoring Committee  
IPF  
Idiopathic pulmonary fibrosis  
IRB  
Institutional Review Board  
  
  
LPLV  
Last patient, last visit  
MACE  
Major Adverse Cardiac Event  
MedDRA  
Medical Dictionary for Regulatory Activities  
ms  
Millisecond  
PDMS  
Protocol Deviation Management System 
PRO  
Patient-reported outcome  
QD  
Once daily  


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QTcF  
QT interval corrected using Fridericia’s formula  
SAE  
Serious adverse event  
TEAE  
Treatment-emergent adverse event  
TESAE  
Treatment-emergent serious adverse event  
TID  
Three times daily  
TMS 
Trial Management System 
UA  
Unstable angina 
ULN  
Upper limit of normal  
WHO  
World Health Organization  
 
 


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1. 
BACKGROUND 
As described in the Clinical Study Protocol (CSP) (Section 1.3), the mechanism of action 
of pirfenidone in Idiopathic Pulmonary Fibrosis (IPF) has not been established (Esbriet® 
EU SmPc and US label 2014), while nintedanib is thought to act by inhibiting multiple 
RTKs and nRTKs (Esbriet® US label 2014). Because multiple co-activated pathways are 
involved in the pathogenesis of IPF, experts have suggested that targeted therapies may 
work better in combination (Wuyts et al. 2014). Furthermore, experience in other 
pulmonary diseases (e.g., asthma, chronic obstructive pulmonary disease, and 
pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 18 / Protocol MA29895, 
Version 2 pulmonary hypertension) has demonstrated the value of moving from 
monotherapy to combination therapy.  
The positive benefit risk assessment of both drugs have been established in respective 
Phase II and Phase III programs which led to approval in the EU, the US, Japan and 
many other countries worldwide. Both drugs demonstrated that pulmonary function could 
be significantly improved in IPF patients, while the safety and tolerability profile was 
considered acceptable.  
Considering the overlap in the gastrointestinal (GI) and hepatic Adverse Events (AEs) 
associated with these two drugs, it is worthwhile to characterize the safety and 
tolerability of nintedanib when added to pirfenidone as a combination treatment using the 
doses recommended in the respective pirfenidone and nintedanib labels.  
This prospective study will evaluate the safety and tolerability of 24 weeks of nintedanib 
combination treatment in patients with IPF who are on a stable dose of pirfenidone with 
demonstrated tolerability. The study is not designed to evaluate the efficacy of 
combination treatment, nor is it designed to assess the safety and tolerability of adding 
pirfenidone to ongoing nintedanib treatment. 
 
2. 
STUDY DESIGN 
This is a multicenter, international, open-label, single-arm safety and tolerability study of 
pirfenidone/nintedanib combination treatment in patients with IPF who have been on a 
stable dose of pirfenidone with demonstrated tolerability. In this study, a stable 
pirfenidone dose will be defined as 1602–2403 mg/d (801 mg twice daily [BID] or three 
times daily [TID]). Up to approximately 60 clinical centers in the US, Europe, and 
Canada are expected to enroll up to approximately 80 patients. Patients who are 
withdrawn from the study will not be replaced.  
At the start of Screening, patients will have been on pirfenidone for at least 16 weeks 
and on a stable dose (1602–2403 mg/d) for at least 28 days; also, the dose must be 
expected to remain within that range throughout the study. In addition, in the 28 days 
before the start of Screening, patients must not have experienced either a new or 


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ongoing moderate or severe adverse reaction considered by the Investigator to be 
related to pirfenidone, or an interruption of pirfenidone treatment for > 7 days for any 
reason. 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2. For additional details, please see the Protocol Amendment 
Version 3, 21 June 2016 (and its Appendices). 
2.2 
OUTCOME MEASURES 
The primary objective for this study is to investigate the safety and tolerability of adding 
nintedanib to treatment with pirfenidone in patients with IPF. Consequently, the primary 
objectives of this study focus on safety and tolerability and not efficacy. 
2.2.1 
Primary Efficacy Outcome Measures 
Not applicable. 
2.2.2 
Secondary Efficacy Outcome Measures 
Not applicable. 
2.2.3 
Exploratory Efficacy Outcome Measures 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
2.2.4 
Patient-Reported Outcome Measures 
 
 
 
 
  
 


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2.2.5 
Safety Outcome Measures 
The primary safety outcome measure is: 
 
Proportion of patients who complete 24 weeks of combination treatment on 
pirfenidone at a dose of 1602–2403 mg/d and nintedanib at a dose of 200–300 
mg/d. 
Secondary safety outcome measures are: 
 
Proportion of patients who discontinue pirfenidone, nintedanib, or both study 
treatments because of adverse events before the Week 24 visit, 
 
Total number of patient days of combination treatment with pirfenidone at a dose 
of 1602–2403 mg/d and nintedanib at a dose of 200–300 mg/d, 
 
Total number of days from the initiation of combination treatment to 
discontinuation of pirfenidone, nintedanib, or both study treatments, 
 
Frequency and timing of Adverse Events (AEs) and Serious Adverse Events 
(SAEs). 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 80 patients was selected based on the AE 
discontinuation rates after one year observed in the randomized Phase 3 pirfenidone 
studies and the randomized Phase 2 and 3 nintedanib studies (pirfenidone 14.6% AE 
discontinuation [Esbriet® US label 2014]; nintedanib 21% AE discontinuation [Ofev® US 
label 2014]). Given that for pirfenidone the discontinuation rate after 24 weeks was 6%-
8% in studies PIPF-004 and PIPF-006 it is a reasonable assumption that the nintedanib 
discontinuation rate was around 10%-11%. As in this study of combination treatment, it 
is possible that the addition of nintedanib to ongoing pirfenidone treatment could 
increase the proportion of patients who discontinue because of an AE, given the overlap 
in the GI and hepatic effects of pirfenidone and nintedanib.  
Assuming 85% of the patients complete 24 weeks of combination treatment, a sample 
size of 80 patients would be expected to yield an actual completion rate of 77.2% - 
92.8% using a 95% confidence interval (CI). Table 1 shows the 95% CIs associated with 
projected completion rates of 75%, 80%, 85%, 90% or 95%, assuming an 80-patient 
sample size. 


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Table 1 
Confidence Limits for Sample Size Determination 
Number of Patients who 
completed 24 weeks  
Proportion of Patients 
who completed 24 weeks  
Lower Bound 
of 95% CI  
Upper Bound 
of 95% CI  
76 
95.0% 
90.2% 
99.8% 
72 
90.0% 
84.4% 
96.6% 
68 
85.0% 
77.2% 
92.8% 
64 
80.0% 
71.2% 
88.8% 
60 
75.0% 
65.5% 
84.5% 
CI = confidence interval 
Patients who are withdrawn from the study will not be replaced. 
2.4 
ANALYSIS TIMING 
The following analyses will be performed for this study: 
Table 2 
Analysis Timing 
Analysis 
Timing of Analysis 
First iDMC 
When the first approximately 20 patients have completed 8 weeks of 
combination treatment or permanently discontinued study treatments 
Second iDMC 
When approximately 50% of the total patient group has completed 12 
weeks of combination treatment or permanently discontinued study 
treatments 
Third iDMC 
When approximately 75% of the total patient group has completed 24 
weeks of combination treatment or permanently discontinued study 
treatments 
Final 
All patients completed 24 weeks of combination treatment or 
permanently discontinued study treatments, and have performed the 
Follow-up visit. 
 
3. 
STUDY CONDUCT 
The study conduct is described in Section 2 (Study design).  
3.1 
RANDOMIZATION ISSUES 
This will be an open-label trial involving only one treatment arm. 
3.2 
INDEPENDENT REVIEW FACILITY 
Not applicable. 
3.3 
DATA MONITORING 
An independent Data Monitoring Committee (iDMC) will review safety data and advise 
on study conduct at least three times during the study. For details on timing of the safety 


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reviews please see Table 2 above. Efficacy data will only be provided if requested by the 
iDMC. For details please see Section 4.10. 
4. 
STATISTICAL METHODS 
This is a safety and tolerability study, not designed to assess efficacy, comprising only 
one treatment group. There are no formal statistical hypothesis tests to be performed, 
and there will be no adjustments for multiplicity of endpoints or within-subgroups 
comparisons. Efficacy analyses will be limited to descriptive statistics.  
Categorical data will be summarized using frequencies and percentages (including a 
category for missing, if appropriate).  
Continuous endpoints will be summarized using descriptive statistics (mean, standard 
deviation, minimum, 25th and 75th quartiles, median, and maximum).  
Where data will be presented over time, e.g. Baseline, Week 12, Week 24, and early 
discontinuation visit, an end of treatment visit (EOT) will be added. This will include 
Week 24 data for patients who completed 24 weeks of combination treatment and data 
from the early discontinuation visit for patients who prematurely discontinued from 
combination treatment. 
Other analysis methods will be specified below, where applicable. All data recorded in 
the electronic Case Report Form (eCRF), as well as derived data that will be used in 
analyses, will be listed.  
Analyses will be presented for the total population, together with geographic region, i.e.  
US and non-US patients. Results for US and non-US will be presented as additional 
columns or additional blocks within the outputs of the total population. 
Percentages will be based on the total population or on the number of patients in the 
respective geographic region, if not otherwise specified. 
4.1 
ANALYSIS POPULATIONS 
Only one analysis population, the Safety Population, has been defined as per CSP. No 
further analysis populations will be assessed.  
4.1.1 
Full Analysis Set 
Not applicable. 
4.1.2 
Per Protocol Population 
Not applicable. 


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4.1.3 
Pharmacokinetic-Evaluable Population 
Not applicable. 
4.1.4 
Safety Population 
The Safety Population will consist of all patients who received at least one dose of 
nintedanib or pirfenidone on or after the Baseline visit. 
Analyses will be produced for the Safety Population, if not otherwise specified. 
4.2 
TRIAL PERIODS, OBSERVATION AND ANALYSIS TIMES 
In case that durations are to be calculated (e.g. treatment duration), these will be derived 
based on days and converted to months and years if needed, using 30.4375 and 365.25, 
respectively, as denominator if not otherwise specified.  
4.2.1 
Study Days 
Study day is defined as the number of days since combination treatment start date, and 
is calculated as: 
 
For assessments on or after the day of start of combination treatment: 
Study day = Assessment date – Date of start of combination treatment + 1. 
 
For assessments before the day of start of combination treatment: 
Study day = Assessment date – Date of start of combination treatment 
The day of the first dose of combination treatment is defined as Day 1.  
4.2.2 
Baseline and Screening Observations 
 
Table 3 
Definition of Baseline and Screening Observations 
 
Definition 
Combination 
Treatment 
Start Date 
Combination Treatment Start Date is the date of first administration of 
nintedanib and pirfenidone on or after the Baseline visit.  
Combination treatment start date will be used for all safety 
assessments and for the calculation of study days. 
Baseline data 
Baseline is defined as the last valid assessment prior to start of 
combination treatment. This may not be the same as the Baseline visit 
as per eCRF.  
Generally, it is assumed that measurements referring to the Baseline  
visit have been performed before study drug was given. This applies 


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for laboratory values, vital signs, ECG, pulmonary function tests and 
 
Adverse events occurring on the combination treatment start date will 
not be considered baseline, but treatment-emergent. 
Screening 
data 
Screening measurements are all the measurements performed before 
the combination treatment start date and not respecting the “baseline” 
criteria. 
 
4.2.3 
On-treatment Assessments 
On-treatment assessments will be the assessments performed on or after the 
combination treatment start date until the date of the Follow-up visit, which is planned to 
be performed 28 - 35 days after the date the subject discontinued from/completed 
combination treatment (see Section 4.2.5 for details).  
However, treatment emergent adverse events are defined as adverse events with an 
onset date  on or after the day of initiation of combination treatment up to 28 days after 
the date subject completed or early discontinued from combination treatment period as 
per eCRF (eCRF form Study Drug Completion/Early discontinuation).  
4.2.4 
Post-treatment Assessments 
Post-treatment evaluations will be the evaluations performed later than the Follow-up 
visit. Post-treatment evaluations are not expected to occur. If there should be any, the 
data of assessments falling into this time-window will only be listed. 
In addition adverse events, reporting more than 28 days after early 
discontinuation/completion of combination treatment will be considered as post-
treatment. 
4.2.5 
Treatment Start and Stop Dates 
As this is a combination treatment study, different assessments with respect to study 
treatment are possible: Pirfenidone alone, nintedanib alone, and combination treatment. 
To account for this, the following definitions will be made: 


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Table 4 
Definition of Treatment/Combination Treatment Start and Stop 
Dates 
 
Treatment start date 
Treatment end date 
Combination 
treatment 
Date of first administration of 
nintedanib and pirfenidone on 
or after the Baseline visit 
= Start date of combination 
treatment 
Date subject completed or early 
discontinued from combination 
treatment period as per eCRF 
(eCRF form Study Drug 
Completion/Early discontinuation). 
= Date of completion or 
discontinuation from 
combination treatment 
Pirfenidone 
Start date of combination 
treatment 
Date of last administration of 
pirfenidone as recorded in the 
study drug log for pirfenidone, until 
the date of completion or 
discontinuation from combination 
treatment. 
Nintedanib 
Start date of combination 
treatment 
Date of last administration of 
nintedanib as recorded in the study 
drug log for nintedanib, until the 
date of completion or 
discontinuation from combination 
treatment. 
 
4.2.6 
Cut-off points 
Clinical cut-off for final analysis is defined as the date of last patient last visit (LPLV). A 
description of data cleaning activities and a date for database lock will be provided by 
Data Management in a separate document. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
This is an open-label single arm phase IV study that will assess the combination 
treatment of pirfenidone and nintedanib. Consequently, no formal assessment of 
treatment group comparability can be conducted. 


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4.4 
ANALYSIS OF STUDY CONDUCT 
4.4.1 
Patient Disposition 
An overview on patient disposition, showing number and percentages of patients 
screened (as per IxRS), enrolled, treated and completed the study will be provided. For 
patients who have early discontinued study treatment or the study, frequencies of 
reasons for early discontinuation will be provided. Patients enrolled are all patients that 
have signed informed consent and are entered into the clinical database. 
For further safety-related disposition analyses please see Section 4.7.1. 
An overview on patients’ enrolment by country and center will be provided. 
4.4.2 
Major Protocol Deviations 
A Per-Protocol population will not be defined; however, major protocol deviations and 
eligibility violations will be summarized by frequency tables and all patients with protocol 
deviations will be listed. 
Protocol deviations will be collected in PDMS, reviewed by the medical monitors, and will 
be provided in a SAS dataset via the Biometrics Computing Environment (BCE). All 
deviations provided in that spreadsheet will be considered as major protocol deviations.  
4.4.3 
Demographic and Baseline Characteristics 
Baseline and disease characteristics such as demographics, medical history, tobacco 
and substance use history will be summarized by descriptive statistics or frequency 
tables. 
Demographics 
The following demographic characteristics will be summarized:  
 
Age (years): as entered in the eCRF at the screening visit 
 
Age categories:18 – 64 years, 65 - 84 years, ≥85 years 
 
Gender (male/female)  
 
Race: White, American Indian or Alaska Native, Asian (Indian subcontinent, 
Other than Indian subcontinent), Black or African American, Native Hawaiian or 
Other Pacific Islander, Unknown. In case that more than one race will be ticked, a 
concatenated variable, containing all races will be presented (e.g. Asian/White). 
 
Ethnicity: Hispanic (Latino), Non-Hispanic (Non-Latino) 
 
Weight (kg) at baseline 
 
Height (cm) at baseline 


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 
BMI (kg/m2) at baseline. BMI will be calculated as weight in kg / (height in cm)2 
10000 
Data on female reproductive status will be presented descriptively; methods of 
contraception will only be listed. 
Tobacco use history and substance use 
The history of tobacco use will be summarized with the following characteristics:  
 
Tobacco use history (never, current, previous) 
 
Pack-years, smokers only 
Numbers and percentages of patients for following characteristics will be presented to 
specify substance use:  
 
Current substance use (yes/no) 
 
Substance use (cannabinoids, amphetamines, opiates, caffeine, 
benzodiazepines, barbiturates, cocaine) 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®), version 19.0 or higher and will be summarized presenting numbers and 
frequencies by primary System Organ Class (SOC) and Preferred Term (PT). If patients 
have more than one disease within a SOC or PT they will be counted only once for the 
respective SOC or PT. 
Historical Pulmonary Function Test 
The number and percentage of patients who performed the respective pulmonary 
function test (FVC, DLco, FEV1, and FEV1/FVC ratio (calculated)) in the past will be 
provided. This assessment was planned to be performed closest to 6 months before the 
Screening visit. These historical pulmonary function test parameters will be summarized 
using descriptive statistics. Both, absolute and percent predicted values will be 
presented. The time from assessment of the historical value to Screening will be 
summarized and defined as follows: 
Time from assessment to Screening = (Date of Screening – Date of historical 
assessment) + 1. 
Previous Pirfenidone Treatment 
The number and percentage of patients with previous pirfenidone treatment and the 
duration of previous pirfenidone treatment will be summarized descriptively. 
 


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4.5 
EFFICACY ANALYSIS 
The efficacy measures of this study will only be analyzed in an exploratory manner. A 
replacement of missing values is not planned. 
4.5.1 
Primary Efficacy Endpoints 
Not applicable. 
4.5.2 
Secondary Efficacy Endpoints 
Not applicable. 
4.5.3 
Exploratory Efficacy Endpoints 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.5.4 
Analyses of Patient-Reported Outcomes 
The 
) 
 
 
 
 
 
 
  
 
4.5.5 
Sensitivity Analyses 
No sensitivity analyses are planned. 
4.5.6 
Subgroup Analyses 
Subgroup analyses will be conducted for selected endpoints. The following subgroups 
will be based on: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.6 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
No pharmacokinetic or pharmacodynamic analyses are planned for this study. 


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4.7 
SAFETY ANALYSES 
The primary objective for this study is to investigate safety and tolerability of adding 
nintedanib to treatment with pirfenidone. Consequently, safety endpoints related to 
patient disposition, early discontinuations and adverse events are of main interest.  
Analyses will be descriptive. No confirmatory analyses are defined and no comparative 
statistics will be generated.  
Patients’ safety will be assessed further through analyses of treatment exposure, 
laboratory tests, vital signs, and ECGs. 
4.7.1 
Treatment Completion/Early Discontinuation 
A summary of the number and proportion of patients who complete 24 weeks of 
combination treatment (with 95% CI) will be presented. A patient is considered to have 
completed 24 weeks of combination treatment, if the eCRF question “Did the subject 
complete the treatment?” is ticked “Yes” (eCRF form “Study Drug Completion/Early 
Discontinuation”). It is expected that these patients have completed the Week 24 visit 
within expected time window (see Section 4.9). 
The number and proportion of patients who complete 24 weeks of combination treatment 
(with 95% confidence interval (CI)) on pirfenidone at a dose of 1602-2403 mg/d and 
nintedanib at a dose of 200-300 mg/d will be presented. Average daily dose information 
as defined in Section 4.7.2 will be used to assess whether a patient completed 24 weeks 
on target dose. 
The number and percentage of patients who discontinued combination treatment 
because of an adverse event (with 95% CI) will also be presented. This summary 
comprises patients who have reported “Adverse Event” as the main reason for treatment 
discontinuation. 
The duration of combination treatment will be summarized descriptively. Duration of 
combination treatment will be defined as the time (days) from combination treatment 
start date (see Section 4.2.2) to the date subject completed or early discontinued from 
combination treatment period as per eCRF (Study Drug Completion/Early 
discontinuation form).  
Kaplan-Meier (KM) plots for time to treatment discontinuation will be provided, based on 
the date subject completed or early discontinued from combination treatment period, as 
per eCRF (see Section 4.2.5).  
Details on treatment and study discontinuations will be listed. 


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Logistic regression analysis will be used to assess the influence of baseline covariates 
on the discontinuation rate in an exploratory manner. The following parameters will be 
used to explain early treatment discontinuation: 
 
Age (years) at baseline,  
 
Sex (female = 0, male = 1), 
 
FVC % predicted at baseline, 
 
DLco % predicted at baseline. 
 
Region (US vs non-US) 
Further parameters will be analyzed on an exploratory basis.  
The regression coefficients for each covariate, together with the standard error and p-
value will be presented. Further, odds ratios and 95% confidence intervals will also be 
given. In addition, a model including all covariates will be investigated in order to assess 
the consistency of the results. 
4.7.2 
Exposure of Study Medication 
Summaries of dosing, treatment duration, dose interruptions or reductions will be 
provided for each treatment separately, as well as for combination treatment, if 
applicable.  
Generally, treatments administered from combination treatment start date up to the ‘Date 
subject completed or early discontinued from combination treatment period’ as per eCRF 
‘Study drug completion/Early Discontinuation’ will be considered for exposure analyses.  
All drug records before or after these dates reported in the drug-log will be disregarded. 
The below definitions are to be interpreted within this time window. 
The overall treatment duration (weeks), including and excluding dose interruptions, will 
be summarized descriptively. Also the days with dose interruptions will be given in this 
presentation.  
The overall treatment duration including dose interruptions will be defined as follows: 
 
Overall duration of combination treatment including dose interruptions = [(Date of 
discontinuation/completion of combination treatment – date of initiation of 
combination treatment) + 1]/7. 
The date of first administration of nintedanib and pirfenidone on or after the Baseline visit 
will be considered as initiation date of combination treatment (see Section 4.2.1).  
 
Overall treatment duration of pirfenidone or nintedanib alone including dose 
interruptions = [(Date of last non-zero dose of treatment received until 


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discontinuation/completion of combination treatment – date of initiation of 
combination treatment) + 1]/7. 
The overall treatment duration excluding dose interruptions will be derived from the 
treatment administration panels, considering only days on treatment. When calculating 
duration of combination treatment, only days where both, pirfenidone and nintedanib, 
were interrupted will be excluded. 
Dose interruptions will be calculated by summing all days where dose (pirfenidone or 
nintedanib) was interrupted. Combination treatment will only be considered to be 
interrupted if both, pirfenidone and nintedanib, were interrupted. 
The total number of patient days on treatment, including and excluding dose 
interruptions, and the total number of patient days with dose interruptions, will be 
presented. 
The total dose (mg), the last dose administered (mg/d) and the average daily dose 
for each of the study treatments will be presented descriptively. The average daily dose 
will be calculated by summing up the number of capsules taken during the combination 
treatment period, divided by the number of days on combination treatment including 
treatment interruptions, as defined above. Further, frequencies for categories of average 
daily doses (e.g. <1602, 1602 – 2403, >2403 mg/d for pirfenidone, and <200, 200 – 
300, >300 for nintedanib, as well as combinations of both) will be presented. 
Dose modifications and dose interruptions will be analyzed for any dose modification 
or dose interruption, as well as for dose modifications and drug interruptions separately. 
Numbers and proportions of patients with at least one dose modification or dose 
interruption will be presented for each treatment separately. Numbers and proportions of 
patients with 1, 2, 3 or more dose modifications or drug interruptions will be given. 
Numbers and frequencies of reasons for dose modification or dose interruption will be 
presented. 
Analyses will be based on the information on dose modifications or dose interruptions as 
provided by the investigator on the eCRF study drug administration page for data 
collected between the time of start of combination treatment and 
discontinuation/completion of combination treatment. 


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4.7.3 
Adverse Events 
Verbatim descriptions of adverse events (AEs) will be mapped to a preferred term (PT) 
and system organ class (SOC) using the Medical Dictionary for Regulatory Agencies 
(MedDRA®). MedDRA version 19.0 or higher and related SMQ lists (see below) will be 
used for coding. 
AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03. For AEs of varying severity, the 
most severe grade as documented on the eCRF will be used in the summaries. 
According to the protocol, after informed consent has been obtained but prior to initiation 
of combination treatment on Day 1, only SAEs caused by a protocol-mandated 
intervention should be reported. 
After initiation of combination treatment at or after the Baseline visit, all adverse events 
will be reported until 28 days after the last dose of study drug.  After this period, the 
Investigator should report any SAEs that are believed to be related to prior study drug 
treatment. 
An AE that started or worsened on the day of initiation of combination treatment through 
28 days after the‘date a subject completed or early discontinued from combination 
treatment period’ as per eCRF ‘Study drug completion/Early Discontinuation’ will be 
considered treatment emergent. 
The analysis of AEs will focus on treatment-emergent AEs (TEAE), but all AEs will be 
listed. For AEs that might occur after initiation of investigational pirfenidone up to start of 
combination treatment or more than 28 days after the end of combination treatment a 
separate listing will be provided. 
Classifications of seriousness, severity and causality are described in the protocol 
sections 5.2 and 5.3. 
An overview of patient safety profile will present the number and proportion of patients 
experiencing  
 
 all and related treatment-emergent adverse events (TEAE),  
 
all and related serious treatment-emergent adverse events (serious TEAE),  
 
all and related severe TEAE,  
 
all and related  TEAE of special interest (AESI) (MedDRA Preferred term for 
STIAMP -  ‘Suspected transmission of an infectious agent via product’ or SMQ: 
‘Drug related hepatic disorders – severe events only (SMQ)’),  
 
all and related gastrointestinal (GI) disorders (SOC: Gastrointestinal disorders),  


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 
hepatic side effects (MedDRA AEGT: Esbriet  - Potential Hy’s Law AEGT’ see 
Appendix 4), 
 
all and related clinical significant vascular event (as angina pectoris, myocardial 
infarction, transient ischaemic attack (TIA), stroke) (Defined as any AE included 
in the MedDRA SMQs Ischemic heart disease, Central nervous system vascular 
disorders, Haemorrhages, Embolic and thrombotic events), 
o all and related ischemic heart disease (MedDRA SMQ: Ischemic heart 
disease) 
o all and related cerebrovascular event (MedDRA SMQ: Central nervous 
system vascular disorders),  
o all and related bleeding event (MedDRA SMQ: Haemorrhages), 
o all and related  thromboembolic event (MedDRA SMQ: Embolic and 
thrombotic events),  
 
all and related major adverse cardiac event (MACE), (Specific terms from SMQs 
Arrhythmia related investigations, Signs and symptoms, Cardiac arrhythmia 
terms (incl bradyarrhythmias and tachyarrthythmias), Cardiac arrhythmias, 
Cardiac failure:   
Cardiac arrest, Cardiac death, Cardio-respiratory arrest, Sudden cardiac death, 
Sudden death, Ventricular asystole, Agonal rhythm, Sinus arrest, Pulseless 
electrical activity, Torsade de pointes, Ventricular fibrillation, Ventricular flutter, 
Ventricular tachycardia, Cardiac fibrillation, Cardiac flutter.) 
 
all and related photosensitivity or rash (MedDRA Preferred terms Nodular rash, 
Photodermatosis, Photosensitivity reaction, Pruritus, Pruritus generalized, Rash, 
Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, 
Rash popular, Rash pruritic, Solar dermatitis, Solar urticarial, Sunburn, Erythema, 
Dry skin),  
 
all and related gastrointestinal (GI) perforation (MedDRA SMQ: Gastrointestinal 
perforation, ulceration, haemaorrhage or obstruction: sub-category 
Gastrointestinal perforation), 
 
all and related TEAEs  leading to death, 
 
all and related TEAEs leading to treatment discontinuation, 
 
all and related TEAE resulting in hospitalization or prolonged hospitalization. 
. For related TEAEs the relationship to pirfenidone, nintedanib or both investigational 
drugs will be assessed. 
The number and percentage of patients with CTCAE grade 3-4 laboratory liver test 
results will also be included in this overview.  


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If relationship to study drug is missing, the event will be presented in the ‘All TEAEs’ 
column. A listing presenting all AEs with missing relationship will be added. 
The following categories of TEAEs as presented in the overview will be summarized by 
system organ class (SOC) and preferred term (PT): 
 
all and related treatment-emergent adverse events (TEAE),  
 
all serious treatment-emergent adverse events (serious TEAE),  
 
all non-serious treatment-emergent adverse events (non-serious TEAE),  
 
all severe (Grade 3 – 5) treatment-emergent adverse events  (severe TEAE),  
 
all TEAEs resulting in hospitalization or prolonged hospitalization 
Similar summary presentations will be provided for patients with TEAEs leading to dose 
modification. 
Frequencies and percentages of patients experiencing (at least) one event in the 
respective category will be presented by decreasing frequencies. If patients have more 
than one AE within a SOC or PT they will be counted only once for the respective SOC 
or PT. Total numbers of TEAEs will be provided for each SOC and overall. 
Special interest in this study will be on assessment of treatment discontinuation. 
Therefore, TEAEs leading to treatment discontinuation will be summarized for TEAEs 
leading to discontinuation of any drug, and for TEAEs leading to discontinuation of both 
treatments, to pirfenidone alone or to nintedanib alone. Additional presentations for the 
following categories of TEAEs leading to treatment discontinuation will be presented: 
 
Serious TEAEs). 
 
GI event, 
 
Photosensitivity reaction or rash 
 
TEAEs by intensity. 
All TEAEs indicating “Action taken with pirfenidone/nintedanib due to SAE/AE” = “Drug 
withdrawn” in the eCRF will be included in these summaries. 
Numbers and frequencies of patients with TEAEs by most extreme CTCAE Grade will be 
provided for any TEAEs and for each SOC and PT. In case the most extreme intensity is 
missing, it will be replaced by the initial intensity. If both most extreme and initial intensity 
are missing, AE will be included in the summaries for grade 3 to 5 AEs (i.e. in the total 
column) and a column for “missing” will be added.  


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The timing of TEAEs will be assessed by presenting numbers of patients with TEAEs 
occurring in the first 28 days (Days 0 – 28), from Day 29 to Day 84 (Weeks >4  - 12), and 
for the total study period by SOC and PT. 
Further, Kaplan-Meier curves for time to onset of first adverse event of the most relevant 
related TEAEs will be provided. These will include the following PTs or baskets (as 
defined above): Nausea, Diarrhoea, GI disorder basket, Weight decreased, Fatigue, 
Decreased appetite, photosensitivity or rash basket. 
All adverse event data will be listed by patient number and study day of onset. Separate 
listings will be provided for TEAEs leading to treatment discontinuation, serious TEAEs 
(STEAEs), adverse events of special interest (AESIs), TEAEs leading to dose 
modification, TEAEs leading to hospitalization, severe (Grade 3 – 5) TEAEs and deaths. 
Non-treatment-emergent AEs (i.e. AEs that start prior to first administration of 
combination treatment and do not worsen at/after combination treatment, or AEs that 
start more than 28 days after last dose of combination treatment) will be listed separately. 
The following additional analyses will be performed for the purpose of fulfilling the 
Clinical Trial Registry (CTR) requirements:  
 
Both Serious Adverse Events and ‘Other’ Adverse Events will be summarized by 
MedDRA preferred term. 
An adverse event is considered ‘Serious’ whether or not it is a TEAE. An adverse event 
is considered in the ‘Other’ category if it is both, a TEAE and is not serious. 
For each Serious AE and ‘Other’ AE, and for each term the following are provided: 
 
The number of subjects at risk of an event; 
 
The number of subjects who experienced each event term; 
 
The number of events experienced. 
4.7.4 
Deaths 
Numbers and frequencies of deaths and of deaths occurring within 28 days after the last 
dose of combination treatment will be presented. The primary cause of death and the 
information on whether an autopsy was performed will be given. All information on 
deaths will be collected from the eCRF panel on study discontinuation. 
4.7.5 
Pregnancies 
Pregnancy test results will be listed, presenting the visit, date and study day of 
pregnancy test and test result. 


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4.7.6 
Laboratory Data 
All laboratory parameters will be assessed by a central laboratory, with the exception of 
the results of urine pregnancy tests, which will be determined locally and will be 
recorded in the eCRF. 
All parameters will be graded according to NCI CTCAE (CTEP 2010), version 4.03, if 
applicable. Laboratory parameters that cannot be graded according to NCI CTCAE 
version 4.03 will be assessed with respect to normal range (low, normal, high). 
For laboratory parameters and specific age ranges, the upper limit of normal provided by 
the central laboratory might be higher than the criterion for Grade 1 in NCI CTCAE. In 
such cases, the definitions provided in the NCI CTCAE, version 4.03 will be followed. 
This means that a shift of a laboratory value above the ULN that corresponds to a grade 
2 abnormality or higher will be reported as such. Grade 1 abnormalities will not be 
reported for such situations. 
Laboratory values that are reported to be below the limit of quantification (e.g. ‘<2’) will 
be considered as to be ‘LOW’ for presentation in shift tables, if the value (e.g. ‘2’) equals 
the lower limit of normal. The value as such (e.g. ‘2’) will be used for descriptive statistics. 
The following laboratory parameters will be collected: 
 
Hematology: complete blood count with platelet count and automated differential, 
i.e. hemoglobin, hematocrit, platelet count, red blood cell count, RBC morphology, 
white blood cell count, absolute differential count (neutrophils, bands, eosinophils, 
lymphocytes, monocytes, basophils), 
MCH, MCHC, MCV, 
 
Serum chemistry:  albumin, alkaline phosphatase, ALT, AST, direct bilirubin*, 
total bilirubin, calcium, cholesterol, creatine kinase, creatinine*, triglycerides, 
gamma-glutamyl transferase, glucose, lactic dehydrogenase*, magnesium, 
phosphorus*, potassium, sodium, urea nitrogen, serum uric acid*, and amylase, 
C-reactive protein (N HS)-PS* (CRP), Creatinine clearance rate*, calculated 
using the Cockcroft-Gault formula 
 
Serum pregnancy test*, 
 
Urine dipstick for pregnancy testing*(local). 
* = for these parameters no grading as per NCI CTCAE, version 4.03 is applicable. 
Hemoglobin A1c (HbA1c) was planned to be collected according to the initial version of 
the Clinical Study Protocol (CSP), but was removed in Amendment 3 of the CSP as not 
specifically relevant for this patient population. HbA1c values are continuously reported 
by the central laboratory, but will not be presented in any summary presentations. 
HbA1c values will only be listed. 


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Clinical laboratory values will be presented separately for CTCAE-gradable and non-
CTCAE gradable parameters by laboratory panel (hematology, serum chemistry).  
Serum or urine pregnancy data will only be listed.  
For laboratory analyses, visits will be assigned to visit windows as described in Section 
4.9. This will also be valid for possible unscheduled visits. In case that multiple evaluable 
assessments occur within the same visit, the most extreme value will be used for 
analyses. 
The following summaries will be prepared: 
For each laboratory parameter, descriptive statistics of laboratory values at each 
scheduled visit (derived as described above), and absolute changes from baseline to 
post-baseline will be presented.  
Shift tables presenting changes from baseline to worst CTCAE grade, in the indicated 
direction, will be provided for CTCAE-gradable parameters. These changes will also be 
expressed as shifts of 1 to 4 grades, 3 to 4 grades and 4 grades. If no CTCAE grade is 
available for a specific laboratory variable, shift tables will present worst changes with 
respect to normal range category (low, normal, high). 
For CTCAE-gradable parameters, numbers and percentages of patients with laboratory 
values of Grade 3 and 4 will presented over time. Further, the total number of visits with 
Grade 3/4 elevations, as well as the number and percentages of patients with Grade 3/4 
elevations for each parameter will be provided. 
Liver abnormalities (total bilirubin, alkaline phosphatase, ALAT (SGPT), ASAT (SGOT)) 
of Grade 3 and 4 will be presented showing numbers and percentages of patients for 
each parameter separately, as well as in combination with at least one of the other 
parameters elevated post-baseline. Line graphs will also be provided. 
All laboratory data will be listed. 
4.7.7 
Vital Signs 
Vital signs, body weight and body temperature assessments will be assigned to visit 
windows as per Section 4.9. Descriptive statistics will be used to summarize vital signs 
data at baseline, at each scheduled post-baseline visit, and for the absolute change from 
baseline to each scheduled post-baseline visit. Line graphs for systolic and diastolic 
blood pressure will be provided. The body mass index (BMI) will only be calculated for 
the BMI at baseline and presented with the demographic data. 


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4.7.8 
ECG 
QTcF values will be assigned to the following intervals: < 500 ms, 500–550 ms, and > 
550 ms.  Numbers and proportions of patients with their maximum QTcF interval 
category will be summarized at Baseline, Week 24 or early discontinuation, EOT and 
Follow-up. Absolute changes from the Baseline to each post-baseline visit in QTcF 
values will be categorized to ≤ 30 ms, 31–60 ms, and > 60 ms. Numbers and proportions 
of patients in each category will be presented for each post-baseline visit. Planned visits 
will be used for presentations. 
At each visit, the ECG result is to be assessed as being normal, abnormal - not clinically 
significant, abnormal - clinically significant, or unable to evaluate. Changes from baseline 
to each post-baseline visit will be presented showing numbers and proportions of 
patients in each combination of categories. 
Descriptive statistics for heart rate and changes from baseline for each visit will be 
presented. 
4.7.9 
Previous and Concomitant Medication 
Previous and concomitant medications are non-study medications. Different from the 
description in the Clinical Study Protocol, which describes that the non-study 
medications will be coded using the World Health Organization (WHO) Drug Dictionary, 
the previous and concomitant medication will be coded using the Genentech (GNE) drug 
dictionary. This is a proprietary Roche Dictionary which is used to code concomitant 
medications in the Trial Management System (TMS) coding tool. The Standardized 
Medication Name (CMDECOD), which is the medication generic or combination generic 
as defined by the Drug Thesaurus (proprietary Genentech/Roche dictionary), and the 
Medication Class (CMCLAS), which is the primary medication class as defined by the 
Drug Thesaurus, will be used for the analyses. 
Therapies will be classified as previous or concomitant as follows: 
 
Previous: If the medication end date is prior to start of combination treatment, 
 
Concomitant: If medication is taken anytime between the start of combination 
treatment and the Follow-up visit.  
The number and frequency of previous and concomitant medications will be given per 
Medication Class and Standardized Medication Name. If patients receive more than one 
drug within an Medication Class or Standardized Medication Name they will be counted 
only once for the respective Medication Class or Standardized Medication Name.  
Previously administered pirfenidone will be presented separately (see Section 4.4.3). For 
imputation of missing or incomplete pirfenidone start or end dates please see Section 
4.8. 


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All medications will be listed. Medication that starts after the Follow-up visit will be 
considered as post-treatment. This medication will be identified by a flag in the data 
listing. 
4.8 
MISSING DATA 
In general, missing data will not be imputed. Exceptions will be made for the data related 
to adverse events and concomitant medications as described below. 
For adverse events, missing start or end dates will only be imputed for determination of 
whether the adverse event is considered to be treatment-emergent or not by using the 
following principles: 
Incomplete or missing onset dates will be imputed to the earliest date possible (using 
any reliable portions of the onset date that are available and the eCFR flag on 
whether the event/medication occurred prior to study drug administration) following 
the first dose of combination treatment. Note that the onset day is considered 
unreliable if the month or year portions of the date are missing, and the onset month 
is considered unreliable if the year portion of the date is missing. If, given the 
completed portions of the adverse event onset date and the known first combination 
treatment start date, the event could not have started after the first dose of 
combination treatment, then the adverse event will be considered non-treatment-
emergent and the onset date will be left as an incomplete date. 
If the stop date is completely missing, then the event will be assumed to be ongoing and 
a stop date will not be imputed.  
For imputation and handling of missing intensity or relationship to study medication, 
please see Section 4.7.3. 
All other missing or incomplete adverse event data will be left as missing. 
For concomitant medications, missing start or end dates will only be imputed for 
determination of whether the concomitant medication is considered to be prior, on-
treatment, post-treatment. The eCRF flag ‘Select if (medication) taken prior to study’ will 
be used in addition.  
For previous pirfenidone treatment, recorded in the concomitant medication eCRF, 
missing month and day for the start year will be imputed with July 1st of the respective 
year. If the day is unknown, the 15th of the respective month will be imputed. Imputations 
will only be used for calculation of duration of previous pirfenidone treatment. An 
imputation will only be applied if not artificially leading to a previous treatment period of 
more than 16 weeks. 


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4.9 
VISIT WINDOWS 
Visit windows will be applied to vital signs and laboratory data and the derived visits will 
be used in the by-visit summarizations. If multiple observations fall within the same visit 
window, the observation with the most extreme value will be used in the analysis, if not 
stated otherwise.  
For presentation of vital signs, laboratory tests, exposure and pulmonary function test 
results, an end of treatment (EOT) visit will be defined. This will include Week 24 data for 
patients who completed 24 weeks of combination treatment and data from the early 
discontinuation visit for patients who prematurely discontinued from combination 
treatment. 
Table 5 
Visit Windows for vital signs and laboratory data 
Analysis Visit [AVISITN] 
Target Day 
Window (Study Days) 
 
 
 
Baseline [0] 
1 
Last valid assessment prior to 
start of combination treatment 
Week 1 [1] – lab data only 
7 
2 to 10 
Week 2 [2] 
14 
11 to 17 (2 to 21 vital signs) 
Week 3 [3] – lab data only 
21 
18 to 24 
Week 4 [4] 
28 
25 to 42 (22 to 42 vital signs) 
Week 8 [8] 
56 
43 to 70 
Week 12 [12] 
84 
71 to 98 
Week 16 [16] 
112 
99 to 126 
Week 20 [20] 
140 
127 to 154  
Week 24 [24] 
168 
155 to 174 
Early discontinuation [25] 
Not applicable 
As occurred 
End of treatment (EOT) [26] 
Not applicable 
As occurred 
Follow-up [28] 
Combination treatment end 
date + 28 
As occurred 
 
4.10 
INTERIM ANALYSES 
Throughout the study, an external independent Data Monitoring Board (iDMC) will 
review individual SAE reports and laboratory toxicities. In addition, the iDMC is 
scheduled to review safety data and advise on study conduct at least three times during 
the study: when the first approximately 20 patients have completed 8 weeks of 
combination treatment or permanently discontinued study treatments, and when 
approximately 50% of the total patient group has completed 12 weeks of combination 
treatment or permanently discontinued study treatments, when approximately 75% of the 
total patient group has completed 24 weeks of combination treatment or permanently 
discontinued study treatments. 
The iDMC may recommend that the Sponsor stop the study for safety concerns set forth 
in the iDMC Charter. Enrollment will continue during iDMC review of the 8-week data, 
unless the iDMC recommends that enrollment be paused or halted. Additional ad hoc 




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5. 
REFERENCES 
Respiratory Medicine 
 
 
 
 
 
Thorax 
 
 
 
European Respiratory Review 
Kolb M, Collard HR. Staging of idiopathic pulmonary fibrosis: past, present and future. 
Eur Resp Rev 2014, 23: 220-224. 
 


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Appendix 1  
Protocol Synopsis 
PROTOCOL SYNOPSIS 
TITLE: 
AN EXPLORATORY MULTICENTER, OPEN-LABEL, SINGLE ARM 
STUDY OF THE SAFETY AND TOLERABILITY OF PIRFENIDONE 
(ESBRIET®) IN COMBINATION WITH NINTEDANIB (OFEV®) IN 
PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS 
PROTOCOL NUMBER: 
MA29895 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2015-003280-11 
IND NUMBER: 
67,284 
TEST PRODUCT: 
Pirfenidone (Esbriet®) and nintedanib (Ofev®) 
PHASE: 
IV 
INDICATION: 
Idiopathic Pulmonary Fibrosis 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
The primary objective for this study is to investigate the safety and tolerability of adding 
nintedanib to treatment with pirfenidone in patients with Idiopathic Pulmonary Fibrosis (IPF). 
Eligible patients must be receiving chronic treatment with pirfenidone for at least 16 weeks and on 
a stable dose (1602–2403 mg/d) for at least 28 days. In patients eligible for this study, nintedanib 
will be added as an additional treatment for IPF (combination treatment) for 24 weeks. 
STUDY OBJECTIVES 
Primary Safety Objective 
• Proportion of patients who complete 24 weeks of combination treatment on pirfenidone at a 
dose of 1602–2403 mg/d and nintedanib at a dose of 200–300 mg/d 
Secondary Safety Objectives 
Secondary Safety Objectives are: 
• Proportion of patients who discontinue pirfenidone, nintedanib, or both study treatments 
because of adverse events before the Week 24 Visit  
• Total number of patient days of combination treatment with pirfenidone at a dose of 1602–
2403 mg/d and nintedanib at a dose of 200–300 mg/d 
• Total number of days from the initiation of combination treatment to discontinuation of 
pirfenidone, nintedanib, or both study treatments 
• Frequency and timing of adverse events (AE) and Serious Adverse Events (SAEs)  


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Exploratory Efficacy Objectives 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
Patient-Reported Outcome Objective 
 
 
 
 
 
Biomarker Study 
 
Blood samples will be collected for the purposes of assessing the pharmacodynamics effect 
of nintedanib on pirfenidone or IPF-related biomarkers.  
STUDY DESIGN 
DESCRIPTION OF THE STUDY 
This is a multicenter, international, open-label, single-arm safety and tolerability study of 
pirfenidone/nintedanib combination treatment in patients with IPF who have been on a stable 
dose of pirfenidone with demonstrated tolerability. In this study, a stable pirfenidone dose will be 
defined as 1602–2403 mg/d (801 mg twice daily [BID] or three times daily [TID]). Up to 
approximately 60 clinical centers in the US, Europe, and Canada are expected to enroll up to 
approximately 80 patients. Patients who are withdrawn from the study will not be replaced. The 
study design is presented in the figure below. 
At the start of Screening, patients will have been on pirfenidone for at least 16 weeks and on a 
stable dose (1602–2403 mg/d) for at least 28 days; also, the dose must be expected to remain 
within that range throughout the study. In addition, in the 28 days before the start of Screening, 
patients must not have experienced either a new or ongoing moderate or severe adverse reaction 
considered by the Investigator to be related to pirfenidone, or an interruption of pirfenidone 
treatment for > 7 days for any reason. 
After providing informed consent and discussing the risks and benefits of the study with the 
Investigator, patients will be required to.taper and/or discontinue all prohibited medications 
(Section 4.4.2) at least 28 days before the start of Screening; this is the Washout Period. Patients 
will be instructed to continue their commercial pirfenidone during the Washout Period. If a 
prohibited medication must be tapered, tapering must start early enough that the patient has 
discontinued the medication 28 days before the start of Screening. After completing Washout, 
patients will enter Screening, which lasts up to 21 days; during Screening, patients will be 
evaluated for eligibility based on the inclusion and exclusion criteria. Patients not taking a 


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prohibited medication will forgo Washout and directly enter Screening. At screening, after 
eligibility criteria have been met, patients may be provided pirfenidone for the study and will be 
instructed on proper use. In this case, patients will be instructed to stop taking their commercial 
pirfenidone and start taking the study provided pirfenidone.  
During Screening, patients on a stable dose of pirfenidone may return for the Baseline Visit 
(Study Day 1) as soon eligibility has been confirmed.  At this visit, they will have nintedanib added 
to the ongoing pirfenidone treatment.  Nintedanib dosing will start at 100 mg once daily (QD) and 
be titrated to 150 mg BID over 15 days, as tolerated, according to the schedule provided in 
protocol Error! Reference source not found..  
The Sponsor will supply pirfenidone and nintedanib for use in the study; nintedanib will be 
supplied in 100 mg and 150 mg capsules to facilitate temporary dose reduction if required for the 
management of AEs.  
Combination treatment will continue through Week 24, with monitoring by office visits and 
telephone contacts. Blood samples will be obtained from all patients for analysis of clinical 
laboratory values. 
Patients will be encouraged to remain on stable doses of pirfenidone (1602–2403 mg/d) and 
nintedanib (200–300 mg/d) throughout the combination-treatment period, unless dosing is 
modified to manage an AE.  Patients will return to the clinic for a final Follow-up Visit 28–35 days 
after the completion of combination treatment.  
If 
one 
or 
both 
study 
treatments 
are 
prematurely 
discontinued 
or 
interrupted 
for  
≥ 28 consecutive days, nintedanib treatment will end as will the patient’s participation in the study; 
whether commercial pirfenidone treatment continues will be left to the judgment of the 
Investigator. The patient will then return to the clinic as soon as possible (≤ 7 days after the 
decision to discontinue nintedanib) for an Early Discontinuation Visit. 
In addition, 28–35 days after the decision to discontinue nintedanib, the patient will return for a 
final Follow-up Visit.  
A patient diary will be used to record AEs, daily dosing adherence for both pirfenidone and 
nintedanib, and concomitant medication use from the screening visit to the final Follow-up Visit. 
Also, patients will receive a wallet card that provides important information relevant to 
study participation. 
On completion of study participation, patients may be prescribed appropriate IPF treatment at 
the discretion of the treating physician. 
An independent Data Monitoring Committee (iDMC) will review safety data and advise on study 
conduct at least three times during the study: when the first approximately 20 patients have 
completed 8 weeks of combination treatment or permanently discontinued study treatments, 
when approximately 50% of the total patient group has completed 12 weeks of combination 
treatment or permanently discontinued study treatments and when approximately 75% of the total 
patient group has completed 24 weeks of combination treatment or permanently discontinued 
study treatments. Additional ad hoc meetings or data reviews can be requested at any time by the 
iDMC or the Sponsor, if warranted.  


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Design of Study  
 
 
 
 
 
 
 
 
 
 
 
 
 
NUMBER OF PATIENTS 
Number of patients to be enrolled: approximately 80 
TARGET POPULATION 
Inclusion Criteria 
Eligible patients for this study must meet the following criteria for study entry: 
1. Written informed consent to participate in the study 
2. Male or female, and age 40 through 80 years old at the start of Screening (inclusive). 
3. At the start of Screening, on pirfenidone for at least 16 weeks and on a stable dose for at 
least 28 days (in this study, a stable dose will be defined as 1602–2403 mg/d); the dose 
must be expected to remain in that range throughout the study. 
4. Documented diagnosis of IPF, per the Investigator per using the criteria of the 2011 
American Thoracic Society / European Respiratory Society / Japanese Respiratory 
Society / Latin American Thoracic Association guidelines 
5. The value from pulmonary function test results (from documented pulmonary function 
laboratory reports) measured at the screening visit as follows:  
- Percent predicted FVC ≥ 50%. 
-  Percent predicted DLco (or carbon monoxide transfer capacity converted to DLco)  
 ≥ 30% 
6. Able to understand the importance of adherence to the study treatment regimen and the 
study protocol, and willing to follow all study requirements, including the concomitant 
medication restrictions, throughout the study. 
7. For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including at 


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least one method with a failure rate of  < 1% per year, during the treatment period and for 
at least 3 months after the final Follow-up Visit. 
- A woman is considered to be of childbearing potential if she is post-menarcheal, has 
not reached a post-menopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
- Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, established, proper use of hormonal contraceptives that 
inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine 
devices. 
- The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
- Barrier methods must always be supplemented with the use of a spermicide. 
8. For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below: 
- With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
< 1% per year during the treatment period and for at least for at least 4 months after the 
final Follow-up Visit.  Men must refrain from donating sperm during this same period. 
- With pregnant female partners, men must remain abstinent or use a condom during the 
treatment period and for at least for at least 4 months after the final Follow-up Visit. 
- The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
2. Clinical evidence of any active infection which according to the judgment of the 
investigator may interfere with study conduct, measurement of pulmonary function, or 
impact the course of IPF.  
3. In the 28 days before the start of Screening, any new or ongoing moderate or severe 
adverse reaction considered by the Investigator to be related to pirfenidone, or an 
pirfenidone treatment interruption > 7 days for any reason.  
4. Any condition that is likely to result in death in the 12 months after the start of Screening. 
5. Lung transplantation anticipated in the 12 months after the start of Screening. 
6. Any planned significant surgical intervention from the start of Screening through the final 
Follow-up Visit. This does not include minor surgical procedures (e.g., excision of a 
localized basal cell carcinoma). 
7. Known hypersensitivity to the active substance or any excipient of either pirfenidone or 
nintedanib.  
8. Any condition that, in the Investigator’s judgment, might be significantly exacerbated by 
the known side effects associated with the administration of pirfenidone or nintedanib. 
9. Mild (Child Pugh A), moderate (Child Pugh B) or severe (Child Pugh C) hepatic 
impairment. 


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10. Severe renal impairment (creatinine clearance < 30 mL/min by the Cockcroft-Gault 
calculation), including end-stage renal disease requiring dialysis.  
11. History or risk of gastrointestinal (GI) tract perforation. 
12. History of unstable or deteriorating cardiac or pulmonary disease (other than IPF) in the 6 
months before the start of Screening, including but not limited to, the following:  
- Unstable angina pectoris or myocardial infarction. 
- Congestive heart failure expected to require hospitalization during the study. 
- Uncontrolled clinically significant arrhythmias. 
13. Electrocardiogram (ECG) with a heart-rate–corrected QT interval (corrected using 
Fridericia’s formula, QTcF) ≥ 500 ms at Screening, or a family or personal history of long 
QT syndrome. 
14. Bleeding risk: genetic predisposition to bleeding, a hemorrhagic event in the 12 months 
before the start of Screening, or abnormal laboratory coagulation parameters. Patients 
who require fibrinolysis, full-dose therapeutic anticoagulation (e.g., vitamin K antagonists, 
dabigatran, heparin, hirudin), high-dose antiplatelet therapy, or other therapy that may 
substantially increase bleeding risk are excluded.  
Note:  the following are permitted: prophylactic low-dose heparin or heparin flush as needed for 
maintaining an indwelling intravenous device (e.g., enoxaparin 4000 IU SC per day), as well as 
prophylactic use of antiplatelet therapy (e.g., acetylsalicylic acid up to 325 mg/d, clopidogrel at 75 
mg/d, or equivalent doses of other antiplatelet therapy). 
15. Use of strong CYP1A2 inhibitors (e.g., fluvoxamine, enoxacin) in the 28 days before the 
start of Screening. 
16. Use of inhibitors of P-glycoprotein (e.g., ketoconazole, erythromycin) or CYP3A4 (e.g., 
ketoconazole, erythromycin) or their inducers (e.g., rifampicin, carbamazepine, phenytoin, 
St John’s wort) in the 28 days before the start of Screening.  
17. History of alcohol or substance abuse in the 2 years before the start of Screening. 
18. Use of any tobacco product in the 12 weeks before the start of Screening, or an 
unwillingness to abstain from their use through the final Follow-up Visit. 
19. In the judgment of the Investigator, not a suitable candidate for enrollment, or unlikely or 
unable to comply with the requirements of this study.  
20. Use of any investigational therapy in a clinical study protocol in the 28 days before the 
start of Screening 
21. Pregnancy or lactation. 
22. Hypersensitivity to peanuts. 
23. Hypersensitivity to soy. 
END OF STUDY AND LENGTH OF STUDY 
Length of Study 
The expected study length is up to 21 months 
End of Study 
January 2018 


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INVESTIGATIONAL MEDICINAL PRODUCTS 
PIRFENIDONE 
Pirfenidone is approved in a 267 mg capsule dosage form.  
The recommended dose is 801 mg (i.e., three 267 mg capsules) TID, at the same times each day, 
taken with food (total dose, 2403 mg/d). At the beginning of the study, patients will be on a stable 
pirfenidone dose, as defined in the inclusion criteria. 
NINTEDANIB 
Nintedanib is approved in 100 mg and 150 mg capsule dosage forms.  
The recommended dose is 150 mg BID, approximately 12 hours apart, at the same times each 
day, taken with food (total dose, 300 mg/d). Both 100 mg and 150 mg capsules will be supplied to 
facilitate temporary dose reduction if required to manage AEs.  
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The analysis population will be the Safety Population. It will consist of all patients who received at 
least one dose of nintedanib or pirfenidone at the Baseline Visit (Day 1). 
AEs will be coded to a preferred term and system organ class using the Medical Dictionary for 
Regulatory Activities (MedDRA). Laboratory abnormalities will be graded using the Common 
Terminology Criteria for Adverse Events (CTCAE). Prior and concomitant medications will be 
coded using the World Health Organization (WHO) Drug Dictionary. 
Because this is a safety and tolerability study that is not designed to assess efficacy, no formal 
statistical hypotheses for efficacy will be assessed. The efficacy analyses will be limited to 
descriptive statistics.  
Data summaries will be provided for baseline characteristics; patient disposition; extent of 
exposure; the number and proportion of patients who complete 24 weeks on pirfenidone at a 
dose of 1602–2403 mg/d and nintedanib at a dose of 200–300 mg/d (with 95% confidence 
interval [CI]); the numbers and proportions of patients with a dose reduction or a dose interruption; 
the number and proportion of patients who discontinued combination treatment because of a AE 
(with 95% CI); the total number of days on combination treatment at an pirfenidone dose of 1602–
2403 mg/d and a nintedanib dose of 200–300 mg/d; the total number of days from the start of 
combination treatment to discontinuation of one or both study treatments; the final prescribed 
doses of pirfenidone and nintedanib; and the reasons for premature discontinuation of 
combination treatment. 
AEs and SAEs leading to discontinuation will be summarized by incidence, severity, seriousness, 
and relationship to treatment. Additional summaries will be provided for the numbers and 
proportions of patients with a Major Adverse Cardiac Event (MACE), a cerebrovascular event, 
a bleeding event, or a thromboembolic event; the numbers and proportions of patients 
discontinuing combination treatment for a liver test abnormality, a GI event, or a photosensitivity 
reaction/rash; the numbers and proportions of patients with an emergency department visit or 
hospitalization; and deaths. 
Observed and change values for clinical laboratory and vital signs data will be summarized. 
Grade 3 and 4 laboratory abnormalities will be summarized by CTCAE grade, and shift tables by 
CTCAE grade will be provided. 


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ECG data will be summarized, presenting the numbers and proportions of patients with a 
maximum QTcF interval < 500 ms, 500–550 ms, and > 550 ms; with a maximum change from the 
baseline QTcF interval of ≤ 30 ms, 31–60 ms, and > 60 ms; and with ECG changes considered 
by the Investigator to be clinically significant.  
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 80 patients was selected based on the AE discontinuation rates 
after one year observed in the randomized Phase 3 pirfenidone studies and the randomized 
Phase 2 and 3 nintedanib studies (pirfenidone 14.6%, nintedanib 21%; per the 2014 US labels). 
Given that for pirfenidone the discontinuation rate after 24 weeks was 6%-8% in studies PIPF-004 
and PIPF-006 it is a reasonable assumption that the nintedanib discontinuation rate was around 
10% - 11%. As in this study of combination treatment, it is possible that the addition of nintedanib 
to ongoing pirfenidone treatment could increase the proportion of patients who discontinue 
because of an AE, given the overlap in the GI and hepatic effects of the two medications.  
Assuming 85% of the patients complete 24 weeks of combination treatment, a sample size of 80 
patients would be expected to yield an actual completion rate of 77.2% to 92.8% using a 95% CI 
Number of Patients who 
completed 24 weeks 
Proportion of 
Patients who 
completed 24 
weeks 
Lower 
Bound of 
95% CI 
Upper 
Bound of 
95% CI 
76 
95.0% 
90.2% 
99.8% 
72 
90.0% 
84.4% 
96.6% 
68 
85.0% 
77.2% 
92.8% 
64 
80.0% 
71.2% 
88.8% 
60 
75.0% 
65.5% 
84.5% 
CI = confidence interval 
 
. 


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Appendix 2  
Schedule of Assessments 
If 
Study Period 
Follow-
up 
Early d/c 
 
W/O 
[a] 
Screen
-ing 
[a] 
Combination Treatment 
 
 
 
Visit Window, ± 3 d 
Visit Window, ± 7 d 
Refer to 
foot note 
for 
timing 
[b] 
ASAP 
≤ 7 d after 
decision to 
d/c 
nintedanib 
[c] 
Study Day: 
-50 
to 
-22 
-21 to 
-1 
1 
(BL) 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 
126 
140 
168 
Study Week: 
 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
24 
Type of 
Contact: 
O 
O 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
O 
O 
O 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent [d] 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
medical history 
[e]  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Directed 
medical history 
[f] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pirfenidone 
treatment 
history 
X 
X [g] 
X [h] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document IPF 
diagnosis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number
1834
 
Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 2.0, final, 17 May 2017 
 
47 
If 
Study Period 
Follow-
up 
Early d/c 
 
W/O 
[a] 
Screen
-ing 
[a] 
Combination Treatment 
 
 
 
Visit Window, ± 3 d 
Visit Window, ± 7 d 
Refer to 
foot note 
for 
timing 
[b] 
ASAP 
≤ 7 d after 
decision to 
d/c 
nintedanib 
[c] 
Study Day: 
-50 
to 
-22 
-21 to 
-1 
1 
(BL) 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 
126 
140 
168 
Study Week: 
 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
24 
Type of 
Contact: 
O 
O 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
O 
O 
O 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
physical 
examination, 
including vital 
signs [i] 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Body weight 
(kg) 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Height (cm) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG [j] 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Spirometry 
(FVC), and 
DLco [k] 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Spirometry 
(FEV1) [k] 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, 
serum chemistry 
[l], CRP 
 
X 
X 
[m] 
X 
[m] 
X 
[m] 
X 
[m] 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number
1835
 
Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 2.0, final, 17 May 2017 
 
48 
If 
Study Period 
Follow-
up 
Early d/c 
 
W/O 
[a] 
Screen
-ing 
[a] 
Combination Treatment 
 
 
 
Visit Window, ± 3 d 
Visit Window, ± 7 d 
Refer to 
foot note 
for 
timing 
[b] 
ASAP 
≤ 7 d after 
decision to 
d/c 
nintedanib 
[c] 
Study Day: 
-50 
to 
-22 
-21 to 
-1 
1 
(BL) 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 
126 
140 
168 
Study Week: 
 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
24 
Type of 
Contact: 
O 
O 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
O 
O 
O 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test [n] 
 
 
 
 
 
 
X 
[r] 
 
X 
[r] 
 
X 
[r] 
 
X 
[r] 
 
X 
[r] 
X 
[r] 
 
 
Serum 
pregnancy test 
[n] 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Biomarker 
sample 
collection [o] 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Review patient 
diary 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Review AEs [p] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review 
pirfenidone 
dosing 
adherence [p] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1836
 
Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 2.0, final, 17 May 2017 
 
49 
If 
Study Period 
Follow-
up 
Early d/c 
 
W/O 
[a] 
Screen
-ing 
[a] 
Combination Treatment 
 
 
 
Visit Window, ± 3 d 
Visit Window, ± 7 d 
Refer to 
foot note 
for 
timing 
[b] 
ASAP 
≤ 7 d after 
decision to 
d/c 
nintedanib 
[c] 
Study Day: 
-50 
to 
-22 
-21 to 
-1 
1 
(BL) 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 
126 
140 
168 
Study Week: 
 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
24 
Type of 
Contact: 
O 
O 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
O 
O 
O 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
nintedanib 
dosing 
adherence [p] 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Review 
concomitant 
medications [p] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review 
inclusion / 
exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain historical 
FEV1, FVC and 
DLco data [q] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Dispense/collect 
patient diary 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1837
 
Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 2.0, final, 17 May 2017 
 
50 
If 
Study Period 
Follow-
up 
Early d/c 
 
W/O 
[a] 
Screen
-ing 
[a] 
Combination Treatment 
 
 
 
Visit Window, ± 3 d 
Visit Window, ± 7 d 
Refer to 
foot note 
for 
timing 
[b] 
ASAP 
≤ 7 d after 
decision to 
d/c 
nintedanib 
[c] 
Study Day: 
-50 
to 
-22 
-21 to 
-1 
1 
(BL) 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 
126 
140 
168 
Study Week: 
 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
24 
Type of 
Contact: 
O 
O 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
O 
O 
O 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense wallet 
card 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense 
pirfenidone and 
explain dosing  
 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Dispense 
nintedanib and 
explain dosing 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Instruct to 
resume 
commercial 
pirfenidone and 
explain dosing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Collect unused 
pirfenidone and 
empty bottles 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number
1838
 
Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 2.0, final, 17 May 2017 
 
51 
If 
Study Period 
Follow-
up 
Early d/c 
 
W/O 
[a] 
Screen
-ing 
[a] 
Combination Treatment 
 
 
 
Visit Window, ± 3 d 
Visit Window, ± 7 d 
Refer to 
foot note 
for 
timing 
[b] 
ASAP 
≤ 7 d after 
decision to 
d/c 
nintedanib 
[c] 
Study Day: 
-50 
to 
-22 
-21 to 
-1 
1 
(BL) 
7 
14 
21 
28 
42 
56 
70 
84 
98 
112 
126 
140 
168 
Study Week: 
 
 
 
1 
2 
3 
4 
6 
8 
10 
12 
14 
16 
18 
20 
24 
Type of 
Contact: 
O 
O 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
P 
O 
O 
O 
O 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect unused 
nintedanib and 
empty bottles 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
AE = adverse event; ASAP = as soon as possible; BL = Baseline; d = day; d/c = discontinue; DLco = carbon monoxide diffusing capacity; ECG = 
electrocardiogram; FVC = forced vital capacity; IPF = idiopathic pulmonary fibrosis; 
 
 
 O = office visit; P 
= telephone contact; SAE = serious adverse event; W/O = Washout 
a. Patients taking prohibited medications enter Washout; if prohibited medication must be tapered, patient must be off that medication 28 days 
before start of Screening. Other patients directly enter Screening.  
b. For patients who complete 24 weeks of study treatment, visit should occur 28–35 days after completion of combination treatment.  For patients 
who prematurely discontinue study treatment or have a treatment interruption of ≥ 28 consecutive days, visit should occur 28–35 days after 
decision to discontinue nintedanib. 
c. If a patient cannot return in ≤ 7 days, study center is to call patient to review medical history and to send laboratory kit and shipping supplies to 
patient so that blood samples can be drawn at another study center, commercial laboratory or by home nursing agency; Early Discontinuation 
Visit should then be scheduled as soon as possible. 
d. Written informed consent must be obtained before any study-mandated assessment or procedure, including tapering and/or discontinuing 
prohibited medication. If written informed consent was not obtained at Washout, it must be obtained at start of Screening. 
e. Including systems review, and review of concomitant medications, events in 28 days before start of Screening, and historical data (including 
prior high-resolution computed tomography scans, pulmonary function tests, and surgical lung biopsy data, if available). If complete medical 




Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1840
 
Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 2.0, final, 17 May 2017 
 
53 
Appendix 3  


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1841
 
Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 2.0, final, 17 May 2017 
 
54 
 
 
  
 
 
 
 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1842
 
Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 2.0, final, 17 May 2017 
 
55 
 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1843
 
Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 2.0, final, 17 May 2017 
 
56 
Appendix 4  
MedDRA Browser Basket: Esbriet – Potential Hy’s Law AEGT 
Project: Esbriet 
 
Title: Esbriet - Potential Hy's Law AEGT 
 
Description 
AEGT to identify cases of potential Hy's Law: 49 Terms 
 
Created Date 11-May-2016  
 
By User 
 
Last Modified Date 03-Nov-2016  
 
By User 
 
Last Reviewed Date 04-Nov-2016  
 
By User 
 
 
Included MedDRA Preferred Terms 
 
 
 
Liver injury 
 
Bilirubin conjugated increased 
 
Urine bilirubin increased 
 
Hepatobiliary disease 
 
Jaundice 
 
Transaminases abnormal 
 
Subacute hepatic failure 
 
Aspartate aminotransferase increased 
 
Cholestatic liver injury 
 
Bilirubin conjugated abnormal 
 
Mixed liver injury 
 
Hyperbilirubinaemia 
 
Drug-induced liver injury 
 
Hepatic enzyme abnormal 
 
Blood a kaline phosphatase abnormal 
 
Gamma-glutamyltransferase increased 
 
Hepatic failure 
 
Acute hepatic failure 
 
Blood a kaline phosphatase increased 
 
Hepatic enzyme increased 
 
Aspartate aminotransferase abnormal 
 
Biopsy liver abnormal 
 
Liver function test increased 
 
Liver function test abnormal 
 
Blood bilirubin increased 
 
Jaundice hepatocellular 
 
Hepatitis 
 
Alanine aminotransferase abnormal 
 
Hepatitis fulminant 
 
Hepatitis cholestatic 
 
Hepatitis acute 
 
Acute yellow liver atrophy 
 
Cholestasis 
 
Blood bilirubin unconjugated increased 
 
Prothrombin time ratio increased 
 
Chronic hepatitis 
 
Prothrombin time abnormal 
 
Hepatic infiltration eosinophilic 
 
Hepatic function abnormal 
 
Prothrombin time prolonged 
 
Hepatotoxicity 
 
Hepatitis toxic 
 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1844
 
Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 2.0, final, 17 May 2017 
 
57 
Transaminases increased 
 
Blood bilirubin abnormal 
 
Prothrombin time ratio abnormal 
 
Liver disorder 
 
Alanine aminotransferase increased 
 
Hepatic necrosis 
 
Gamma-glutamyltransferase abnormal 
 
Hepatocellular injury 
 
 
 
Excluded MedDRA Terms 
 
Nested Baskets 
 
 
End of Esbriet - Potential Hy's Law AEGT definition 
 
MedDRA Version 19.1 
Language English 


Clinical Study Report: pirfenidone - F. Hoffmann-La Roche Ltd
Protocol MA29895     Report Number 
1845
 
Pirfenidone and nintedanib — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MA29895, Version 2.0, final, 17 May 2017 
 
58 
Appendix 5  
Calculation of GAP Index Categories 
Calculation of GAP Score 
The GAP score and staging system is based on four baseline characteristics, gender, 
age, %FVC at baseline and %DLco at baseline. If any of the four baseline characteristics 
is missing then the GAP score is missing. 
Table 9  
GAP Index and Staging System 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This definition follows the descriptions used in the Pirfenidone 2014 Resubmission 
Efficacy Update (RISE). 
 
GAP Index Stage I:   Total Points: 0 to 3 
 
GAP Index Stage II:  Total Points: 4 to 5 
 
GAP Index Stage III: Total Points: 6 to 8 
 
In order to prevent possible issues with unexpected data formats, the following changes 
to the above definitions will be performed in this study: 
 
 
 
 
 
 
 
 
 
Variable name from 
ADSL 
Predictor 
Points 
Gender (G) 
SEX 
Female 
0 
Male 
1 
Age (A) 
AGERAND 
Age <=60 
0 
60<Age=<65 
1 
Age >65 
2 
Physiology (P) 
FVCBL 
FVC >75 
0 
50<=FVC<=75 
1 
FVC<50 
2 
DLCOBL 
DLCO>55 
0 
36<=DLCO<=55 
1 
DLCO<36 
2 
Cannot Perform 
3 
 
Variable name from 
ADIESL 
Predictor 
Points 
Age (A) 
AGERAND 
Age < 61 
0 
61<=Age=<65 
1 
Age >65 
2