Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Pirfenidone, UIP, IPF, FVC
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 60
Healthy volunteers: no

Brief summary:
This study is a national, multicenter, interventional, non-randomized, non-controlled, open-label study to assess the effectiveness of pirfenidone in participants with IPF in Russian clinical practice.

Detailed description:

Arms:
arm 1: Participants will be administered pirfenidone 2403 milligram per day (mg/d) orally for 26 weeks in participants with IPF.

Interventions: intervention 1: Pirfenidone
Intervention descriptions: intervention 1: Pirfenidone 2403 mg/d capsules orally will be given in divided doses (TID) after titration period of 14 days.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
Local Open-label Multicenter Study to Assess the Effectiveness of 
Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis in Russian 
Clinical Practice 
NCT Number: 
NCT03208933 
Document Date: 
Protocol Version 2: 01-02-2019 
 
 






 
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the patients.    
Inclusion criteria modified accordingly. 
The window ± 1 week for the end of the treatment with 
pirfenidone is set in the Protocol. 
Section 3.1 
Section 4.3.2 
Figure 1 has been revised by addition of the text box to show 
when FVC and 6MWT will be performed according to the 
Schedule of Activities (Appendix 1). 
Figure 1 in Section 3.1 
The duration of participation in the study for an individual 
patient have been re-calculated taking in account windows for 
the visits and corrected from 27-30 weeks to 31-35 weeks as 
well as the duration of participation for the patients continuing 
in the rollover study (from up to maximum 56 weeks to 
maximum 58 weeks). 
Section 3.2 
Change in FVC in patients who will proceed with treatment in 
clinical practice over the more prolonged periods will not be 
evaluated after study completion because this is out of scope 
of this study. Text revised accordingly.  
Section 3.3.5 
Inclusion criteria 3 have been corrected so patients should 
have both “confident” or “consistent” with UIP diagnosis of IPF
Section 4.1.1 
It has been clarified that patients must discontinue all 
prohibited medications at least 28 days before the start of 
treatment (instead of Screening). 
Section 4.1.1 
Exclusion criteria 3 revised so that if patient has relevant 
airways obstruction he will be excluded from the participation 
in the study 
Section 4.1.2 
Wording of exclusion criteria 7 revised. Patients with positive 
biomarker tests associated with the diseases mentioned in the 
exclusion criteria 7 also to be excluded from the participation 
in the study. 
Section 4.1.2 
The use of bronchodilator test at FVC measurement has been 
revised. It is obligatory only at screening. During further visits, 
bronchodilator test is not necessary to perform. Changes to 
Section 4.5.7 


 
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the description of DLco measurement have been made 
accordingly. 
It has been clarified that ECG recordings must be performed 
before bronchodilator test (if scheduled). 
Section 4.5.9 
If any value of QTcF parameter during ECG recording is 
> 500 ms and/ or  > 60 ms longer than the baseline value, 
another ECG must be recorded. Description of ECG recording 
revised. 
Section 4.5.9 
Description of the Borg Scale has been unified in accordance 
with the information provided in Appendix 4. 
Section 4.5.11.1 
Protocol 
has 
been 
revised 
to 
replace 
EuroQoL-5D 
Questionnaire by more detailed EuroQoL-5D-5L Questionnaire 
Section 4.5.11.2 
Section 6.4.2 
Appendix 5 
The sentence “Multidisciplinary team in each local centre must 
expect “confident” or “working” diagnose of IPF” has been 
removed because the use of such team is not to be performed 
during the study. 
Section 4.5.13 
In the Screening Period description has been clarified that In 
case of rescreening, the patient must be reconsented. 
Section 4.5.13.2 
Mistake in the text regarding the maximal duration of the 
screening  has been corrected (it should be up to  28 days in 
accordance with Description of the Study and Schedule of 
Activities). 
Section 4.5.13.2 
Section 4.5.13.3 
 
Information about when ECG should be done during the visits 
has been added to corresponding visit description. 
Section 4.5.13.2 
Section 4.5.13.3 
Section 4.5.13.5 
Section 4.5.13.8 
Section 4.5.13.10 


 
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The obligation that all results of the Screening assessments 
and eligibility documentation will be submitted to the Sponsor 
or designee for approval has been removed from the protocol. 
Eligibility will be assessed by the investigator. 
Section 4.5.13.2 
 
Review of compliance and dispense supply of study treatment
is not planned at certain visits (Week 12, 16 and 20). Text 
revised accordingly. 
Section 4.5.13.6 
Section 4.5.13.7 
Section 4.5.13.8 
 
It has been clarified that worsening of IPF (i.e. IPF 
progression) is considered as an AE only in case of fatal 
outcome attributed to this progression. In other cases 
exacerbation or worsening of IPF will not be recorded as AE. 
Section 5.2.1 
Section 6.4.3 
Emergency Medical Contacts have been updated in the 
protocol. 
Section 5.4.1 
The subject samples of interest (populations) for the statistical 
analysis have been revised. One more sets added: the ‘Full 
analysis’ set (FAS).  
Section 6 
The level of confidence interval used for determination of 
sample size have been specified. 
Section 6.1 
Expected rate of screen failures (about 45%) have been 
specified in the protocol, so up to 109 patients will be screened 
for eligibility to include 60 subjects in the study. 
Section 6.1 
As in the study there is not specified ‘safety’ set a subject will 
be considered at risk if the subject is in the Treated set. 
Section 6.2 
Section 6.5 
It has been clarified that the FAS set will be used for efficacy 
analysis.  
Section 6.4 
The distribution of primary outcome variable by patients will be 
provided in frequency table across three categories intead of 
two (category Decline of < 10% to 0% added).  
Section 6.4.1 


 
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Discrepancy in the timelines for HRCT fibrosis score analysis 
and assessment of sign ‘lung opacity’ has been corrected. 
Optional HRCT is not planned to be done at Week 39, but at 
Week 26. 
Section 6.4.3 
In the study is not planned to include patients that are not able 
to sign the Consent Forms. Information about patient’s legally 
authorized representative removed from the Protocol. 
Section 8.2 
Administrative structure information has been updated. 
Section 9.4 
List of the references has been updated. One reference 
moved from the text of the Protocol. Reference to EuroQol-5D
Questionnaire 
removed. 
Reference 
to 
EuroQol-5D-5L 
Questionnaire added instead. 
Section 10 
The schedule of activities has been revised to reflect the 
changes to the protocol. 
Appendix 1 
Minor changes have been made to the text of HRCT Protocol 
(spelling mistakes and reference corrected) 
Appendix 2 
IPF Care Program has been revised to reflect the changes to 
the protocol. The scheme of IPF Care Program has been 
corrected accordingly. 
Appendix 7 
 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
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PROTOCOL AMENDMENT, VERSION 2: 
SUMMARY OF CHANGES 
 
PROTOCOL SYNOPSIS  
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS: 
 
DMC 
Data Monitoring Committee 
ERS 
European Respiratory Society 
EP 
European Pharmacopeia 
ERS 
European Respiratory Society 
EQ-5D/ EuroQol-5D 
European Quality of Life 5-Dimension Questionnaire 
FAS 
Full analysis set 
FEV 
Forced expiratory volume 
SOC 
System огпфн organ class 
TNF 
Tumor necrosis factor inhibitors  
USP 
United States Pharmacopeia 
 
SECTION 1.2  BACKGROUND ON PIRFENIDONE 
Pirfenidone was first approved in Japan in 2008 under the trade name Pirespa. In 2011, 
Esbriet (pirfenidone) grabted marketing authorization in European Union (EU) as an 
orphan medicinal product for the treatment of adults with mild to moderate IPF. In 2014, 
the product was approved by the US FDA. Under different trade names pirfenidone is 
also approved for the treatment of IPF in many countries, including Argentina, China, 
India, Mexico and South Korea (Esbriet EMA 2010). Pirfenidone was also registered in 
Russia, marketing authorization number DP (drug product) - 004030. Pirfenidone 
(commercial product name Esbriet) was approved by the Misnistry of Healthcare of the 
Russian Federation for treatment of idiopathic pulmonary fibrosis. 
SECTION  1.3.1 Study Rationale 
Pirfenidone is currently approved for the treatment of patients with IPF in many countries 
worldwide, including Registration in Russia is also expected. Despite the lack of 
epidemiological data on IPF in Russia, the number of patients diagnosed with the 
disease is expected to be large. The only available in Russia specific treatment of IPF 








 
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Q 
An Independent Data Monitoring Committee (IDMC) will be implemented in the study. 
The IDMC will conduct regular review of the trial safety data, with the focus on death 
cases, serious adverse events, unexpected adverse events, adverse events leading to 
treatment or study discontinuation, liver enzyme increases, reported as adverse events, 
and other AEs immediately reported to the Sponsor (see Section 5.2.3Section 5.2.3.2) 
SECTION 3.2  End of Study and Length of Study 
Q 
The total length of the study, from recruiting of the first patient to the end of the study, is 
expected to be approximately 2 years. Duration of participation in the study for an 
individual patient is between 2731 and 3035 weeks (excluding long-term follow-up). For 
patients continuing in the rollover study the duration of participation in the study extends 
up to 5658 weeks. 
SECTION 3.3.1 Rationale for Pirfenidone Dose and Schedule 
Posology and schedule of administration, including dose titration, of pirfenidone in the 
current study are those recommended in the official Russian instruction for use of the IMP. 
unanimously by health authorities of countries where the product is approved for medical 
use, particularly in EU and the USA.  
SECTION 3.3.3 Rationale for Control Group 
The study is non-controlled by design. The choice of the non-controlled design is 
supported by the following positions: 
• Enrolment of patients with rare disease in a clinical study is challenging and 
presumes ethical issues to be addressed in the design. Pirfenidone has been 
granted an orphan designation in Europe and the USA. Idiopathic pulmonary fibrosis 
is listed in the Russian Ministry of Healthcare registry of rare (orphan) diseases, so 
pirfenidone is expected to get obtained the status of an orphan drug in Russia, too. 
• Efficacy of pirfenidone has been previously demonstrated in a number of placebo-
controlled studies and meta-analyses, therefore, additional placebo-controlled study 
in patients with poor prognosis is deemed unethical. 
• There is no adequate literature data to design a comparative active-controlled study 
of pirfenidone; non-inferiority study is merely feasible. 
 


 
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SECTION 3.3.5 Rationale for Endpoint Selection 
Q 
In patients who will proceed with treatment in clinical practice after study completion, 
change in FVC over the more prolonged period of 12 months (52 weeks) will be 
evaluated. Thus, design features of the planned local clinical trial support the study 
objectives and are deemed to provide new insights in this modified study population. 
... 
The 2011 IPF guidelines provide updated and simplified IPF diagnostic criteria proposed 
by the ATS/ERS/JRS/ALAT, which may result in HRCT scanning playing a central role in 
the diagnosis of IPF. Technological advances in HRCT have brought an opportunity of 
HRCT as an accurate, sensitive and objective technique for evaluating IPF. 
SECTION 4.1.1 Inclusion Criteria 
Q 
3. Patients could should have both “confident” or “consistent” with UIP diagnosis of 
IPF based on clinical, radiologic or and pathologic data according to 2011 
ATS/ERS guidelines at the Screening. HRCT scan performed within 24 months 
before the start of the Screening may be used, if it meets all image acquisition 
guidelines. 
Q 
8. Eligible patients must discontinue all prohibited medications at least 28 days 
before the Screening start of treatment. 
 
SECTION 4.1.2 Exclusion Criteria 
Q 
3. Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC < 0.7) at the 
Screening. 
Q 
7. Clinical diagnosis of any connective tissue disease, including but not limited to 
scleroderma, polymyositis/ dermatomyositis, systemic lupus erythematosus, and 
rheumatoid arthritis, or patients with positive biomarker tests associated with these 
diseases (rheumatoid factor, anticyclic citrullinated peptide and antinuclear antibodies) 
at the Screening. 


 
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Q 
15. History of unstable or deteriorating cardiac or pulmonary disease (other than IPF) 
within the previous 6 months, including but not limited to the following:  
a. 
d.  unstable angina pectoris or myocardial infarction 
b. 
e. congestive heart failure requiring hospitalization 
c. 
f. uncontrolled clinically significant arrhythmias 
Q 
21. Use of any of the following therapies within 28 days before the start of treatment 
period:  
a. f. investigational therapy, defined as any drug that has not been approved 
for marketing for any indication in Russia 
b. g. any cytotoxic, immunosuppressive, cytokine modulating, or receptor 
antagonist agent including but not limited to azathioprine, bosentan, 
ambrisentan, 
cyclophosphamide, 
cyclosporine, 
etanercept, 
iloprost, 
infliximab, leukotriene antagonists, methotrexate, mycophenolate mofetil, 
tacrolimus, montelukast, tetrathiomolybdate, tumor necrosis factor (TNF)-α 
inhibitors, N-acetylcysteine (NAC), imatinib mesylate, interferon gamma-1b 
(IFN γ-1b), and tyrosine kinase inhibitors 
c. h. medications that are specifically used for the treatment of IPF including 
but not limited to angiotensin converting enzyme (ACE) inhibitors, 
colchicine, corticosteroids (prednisolone at doses exceeding 15 mg/day or 
equivalents), heparin, warfarin, and 3-hydroxy-3-methyl-glutaryl-coenzyme 
A (HMG-CoA) reductase inhibitors. These drugs may be used if given for a 
non-IPF indication if there is no clinically acceptable alternative therapy for 
the same indication 
d. i. fluvoxamine 
e. j. sildenafil (chronic use for pulmonary arterial hypertension). Note: 
intermittent use for erectile dysfunction is allowed. 
Q 
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a. d. total bilirubin above the upper limit of normal (ULN);  
b. e. aspartate or alanine aminotransferase (AST or ALT) > 3 × ULN;  
c. f. alkaline phosphatase > 2.5 × ULN 
23.  Creatinine clearance < 30 mL/min, calculated using the Cockcroft-Gault formula 
(see Section 4.5.7 Section 4.5.8)  
SECTION 4.3.1 Formulation, Packaging, and Handling 
Q 
Storage 
Study treatment will be shipped to the investigational sites at room temperature and 
should be stored between 15 and 30oC. Study drug must not be refrigerated or frozen!  
Shelf life is 3 years. Study drug must not be used beyond the expiration date. 
Investigator is responsible for appropriate storage of the study drug. Investigator should 
maintain temperature in the room of storage and fill out temperature log on regular basis. 
The study drug must be stored as prescribed in the official Russian instruction for use of 
pirfenidone (Esbriet). Do not store above 30°C. 
Shelf life is indicated on label. Study drug must not be used beyond the expiration date. 
Handling 
Study treatment will be dispensed by the responsible investigator or investigational site 
pharmacist only to the participants of this clinical study. Drug accountability must be 
confirmed in written by the responsible employee of the site (see Section 4.3.3). Detailed 
Instructions for handling and reconstitution of the study drug will be provided to 
investigational sites as appropriate. 
For further information on the formulation and handling of pirfenidone, see the latest 
version of the Investigator's Brochure or the pharmacy manual, if applicable. 
SECTION 4.3.2 Dosage, Administration, and Compliance 
Study treatment will be initiated on Day 1 in patients who completed Screening period 
successfully and fully comply for the study. Study treatment will continue until visit at Week 
26 (± 1 week), unless terminated earlier for reasons indicated in Section 4.6.2, or patient is 
proceeding in the rollover study. 
… 


 
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Any overdose or incorrect administration of the study drug should be noted on the Study 
Drug Administration electronic Case Report Form (eCRF). Adverse events associated 
with an overdose or incorrect administration of the study drug should be recorded on the 
Adverse Event eCRF. Section 5.3.5.11 Section 5.3.5.10 summarizes available safety data 
related to overdosing of pirfenidone. 
SECTION 4.3.3 Investigational Medicinal Product Accountability 
Q 
Study treatment will be dispensed to the patient every 12 weeks, but may be dispensed 
at other visits, as needed. Patients will be instructed to store study treatment at room 
temperature. Patients will be instructed to use study treatments as prescribed by the 
investigator and to keep and return to the investigator all used and unused bottles of the 
study drug treatment upon completion of the study treatment. 
SECTION 4.4.1 Permitted Therapy 
Q 
An acute IPF exacerbation is defined in updated publication (Collard HR et al., 2016) 
Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group 
Report. Am J Respir Crit Care Med. 2016 Aug 1). 
SECTION 4.5.6.1 High-Resolution Computed Tomography 
HRCT scans should be obtained before the Screening period as part of the routine 
practice for a patient. It may be used to confirm eligibility, if they meet all of the image 
acquisition and quality criteria required by the central expert readers and separately for 
semiquantitative analysis of CT scans. 
SECTION 4.5.7 Spirometry and DLCO Measurements 
FVC  
Q 
At screening, Sspirometry measurements of FVC will be performed before and after 
administration of albuterol (or salbutamol) from a metered dose inhaler. Four separate 
doses of 100 mg should be used when given by metered dose inhaler using a spacer. 
Tests should be repeated after a 15-min delay. During further visits, bronchodilator test is 
not necessary to perform. 
DLCO 
DLCO will be measured by determining the diffusing capacity of the lung for carbon 
monoxide corrected to hemoglobin. DLCO measurement should be performed before or 


 
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at least 30 min after the last bronchodilator puff, in case bronchodilator test has been 
performed. It is measured by a single breath technique where helium and carbon 
monoxide are rapidly inspired, held for several seconds and then expired with the 
measurement of the remaining carbon monoxide. Comparison of the inspired and 
expired CO fractions allows calculation of DLCO (Ranu et al. 2011). 
SECTION 4.5.9 Electrocardiograms 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements. 
Lead placement should be as consistent as possible. ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes. 
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws, bronchodilator test) and should not be 
obtained within 3 hours after any meal. Circumstances that may induce changes in heart 
rate, including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording. 
Q 
If at a particular postdose timepoint the mean QTcF is  > 500 ms and/ or  > 60 ms 
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes or in the utmost 24 hours, and ECG monitoring should continue until QTcF 
has stabilized on two successive ECGs. The Medical Monitor should be notified. 
Standard-of-care treatment may be instituted per the discretion of the investigator. A 
decision on study drug discontinuation should be made, as described in Section 5.1.2. 
The investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval, severe 
bradycardia). 
SECTION 4.5.10 6-Minute Walk Test 
The 6MWT measures the distance in meters that a patient can walk at his/her own pace 
on a measured, flat hard surface in a period of 6 min. The 6MWT assesses the global 
and integrated responses of all body systems involved during walking. The 6MWT based 
on ATS recommendations (ATS 2002) will be performed as outlined in the Reference 
Guide. 
SECTION 4.5.11 Patient-Reported and Clinician-Reported Outcomes 
SECTION 4.5.11.1 Borg Scale 
The Borg Scale is an instrument to be self-administered by the patient as part of the 
6MWT procedure (Borg 1982) (see Appendix 4). The Borg scale should be printed on 
heavy paper (11 inches high and perhaps laminated) in 20-point type size. At the 
beginning of the 6-minute exercise, the patient should tick the answer to the questions: 
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on the following scale.” “Please grade your level of shortness of breath using this scale.” 
and: “Please grade your level of fatigue using this scale.” At the end of the exercise, the 
patient should grade his breathing level and level of fatigue again. 
SECTION 4.5.11.2 
EuroQol 5-Dimension Questionnaire 
The European Quality of Life (EuroQol) 5-Dimension Questionnaire, 3 5-level version 
(EQ-5D-5L), is a self-report health status questionnaire that consists of six questions 
used to calculate a health utility score for use in health economic analysis (EuroQol 
Group, 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013; Jindal et al. 2011; 
Behr J et al.  2013). 
Q 
EQ-5D-5L questionnaire (Self-completed version on paper 1.0) will be used in the study. A 
sample of the validated questionnaire in English (for UK) is provided in Appendix 5. A validated 
version (Self-completed version on paper 1.0) in a local (Russian) language will be given to the 
patients for completion. 
SECTION  4.5.13 Detalization of Details on the Study Visits 
Before starting any study specific procedures, investigator must have  HRCT and 
surgical biopsy (if applicable) performed in routine practice confirming diagnose of IPF to 
assess eligibility of patient. Multidisciplinary team in each local centre must expect 
"confident" or "working" diagnose of IPF. 
SECTION 4.5.13.1 
Informed Consent Visit   
Written informed consent must be obtained before initiating any study-associated 
procedures or changes to a pre-existing treatment regimen for purposes of this study. 
Informed Consent Visit is performed for explaining the study, collecting Informed 
Consent,   handing out the Patient Information, collecting and  sending HRCT or surgical 
biopsy (if applicable) and also for starting the washout medication prior 28 days to start 
of treatment. Any identified patient identified for the study, must discontinue all prohibited 
medications and stop smoking at least 28 days before the start of treatment. This is the 
Washout Period. If a medication must be tapered, tapering must start early enough that 
the patient has discontinued the drug 28 days before the start of treatment. Written 
informed consent must be obtained before withdrawing or tapering the patient off 
prohibited therapies. 
After signing of the Informed consent, the investigator must review and transfer for 
central review HRCT scans, surgical lung biopsies (if available), which were performed 
in routine practice, to assess eligibility. (HRCT must be no older than 24 months. Results 
of the surgical lung biopsy must be no older than 4 years). 


 
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SECTION 4.5.13.2 
Screening Period (Day -28 to Day -1) 
Procedures conducted during Screening will be used to determine the eligibility of each 
patient for study enrollment before initiation of treatment and to establish patient 
baseline status. If patients fail Screening due to a condition that subsequently resolves 
(e.g., infection), they may be considered for rescreening; however, these patients must 
be discussed with the study Mmedical Mmonitor or designee before rescreening. In case 
of rescreening, the patient must be reconsented. 
The Screening period is defined as the time between the date of the first Screening 
procedure and Day -1 and may last up to 49 28 days. Screening procedures may be 
conducted on different days within the Screening period, if convenient. The order of 
procedures is not strict; however, basic requirements to be followed are given in gaps 
below. 
The following procedures will be performed during Screening:  
• 
Demographic data 
• 
Review and update medical history and concomitant medications  
• 
EQ5D questionnaire (should be performed before any other non-PRO assessments) 
• 
ECGs (obtained before bronchodilator administration or on a separate day) All ECGs are to 
be obtained prior to other procedures scheduled at that same time (e.g., vital sign 
measurements, blood draws) and should not be obtained within 3 hours after any meal. 
• 
Physical examination, vital signs, weight, and height  
• 
Clinical laboratory assessments, including hematology, serum chemistries, serologic 
tests, and pregnancy test for women of childbearing capacity (blood samples must 
be drawn in fasted state) 
• 
HRCT scan for baseline assessment (for patients with HRCT scans performed more 
than 2 months before the treatment period or with scans not meeting  the imaging 
acquisition criteria outlined in Appendix 2)  
• 
Review transbronchial lung biopsy/ BAL; 
• 
Unique triplicate ECGs (obtained before bronchodilator administration or on a 
separate day) 
• 
Spirometry (FVC) (before and after bronchodilator administration with a 15 min 
delay). Сollection and recording of the retrospective FVC values obtained in clinical 
practice over the last year. 
• 
6MWT and Borg Scale    
• 
DLCO (obtained before or 30 min after bronchodilator administration) 
• 
GAP assessment  
• 
Eliciting AEs  


 
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All results of the Screening assessments and eligibility documentation will be submitted 
to the Sponsor or designee for approval. 
SECTION 4.5.13.3  Start of Treatment (Day 1) 
Treatment must be initiated no more than 49 28 days after the start of screening. All Day 
1 procedures must be performed before administration of the study treatment. This study 
has no Day 0.  
The following procedures will be performed on Day 1: 
• 
Directed history (including review of AEs/SAEs, concomitant medications, oxygen 
use, and hospitalizations)  
• 
EQ5D questionnaire (should be performed before any other non-PRO assessments) 
• 
ECGs. All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours after 
any meal. 
• 
Physical examination, vital signs, and weight  
• 
Clinical laboratory assessments, including hematology, serum chemistries, 
pregnancy test for women of childbearing capacity (blood samples must be taken in 
fasted state). 
• 
Unique triplicate ECGs (obtained before bronchodilator administration or on a 
separate day) 
• 
Spirometry (FVC)  
• 
6MWT and Borg Scale  
• 
Confirmation of patient eligibility for study participation  
• 
Instruct the patient on how to titrate the dose of study treatment  
• 
Dispense 12-week supply of study treatment. Dosing should start on the Dday 1  
• 
Dispense patient diary and instruct patients on how to properly record information 
using the diary. 
SECTION 4.5.13.5  Weeks 2, 4, and 8 (± 2 Days) 
The following procedures will be performed at Weeks 2, 4, and 8:  
• 
Directed history (including review of AEs/SAEs, concomitant medications, oxygen 
use, hospitalizations, dosing)  
• 
ECG (at Weeks 4 and 8 only)/ All ECGs are to be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws) and should not be 
obtained within 3 hours after any meal. 
• 
Physical examination, vital signs, and weight  
• 
ECG (at Weeks 4 and 8 only) 


 
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• 
Clinical laboratory assessments, including hematology, serum chemistries, and 
pregnancy test for women of childbearing capacity (pregnancy test at Weeks 4 and 
8 only) 
• 
Review patient’s diary  
SECTION 4.5.13.6 Weeks 12 (± 2 Days) 
The following procedures will be performed at Week 12:  
• 
Directed history (including review of AEs/SAEs, concomitant medications, oxygen 
use, hospitalizations, dosing) 
• 
EQ5D questionnaire (should be performed before any other non-PRO assessments)  
• 
Physical examination, vital signs, and weight  
• 
Clinical laboratory assessments, including hematology, serum chemistries, and 
pregnancy test for women of childbearing capacity 
• 
Spirometry (FVC)  
• 
6MWT and Borg Scale  
• 
Review patient’s diary  
• 
Review compliance and dispense 12 week supply of study treatment 
 
SECTION 4.5.13.7 
Weeks 16 and 20 (± 1 Week) 
The following will be performed at Weeks 16 and 20:  
• 
Directed history (including review of AEs/SAEs, concomitant medications, oxygen 
use, hospitalizations, dosing)  
• 
Physical examination, vital signs, and weight  
• 
Clinical laboratory assessments, including hematology, serum chemistries, 
pregnancy test for women of childbearing capacity (pregnancy test at Week 20 only) 
• 
Collection of any unused study treatment, review compliance and dispensing of 
supply of study treatment, as needed  
• 
Review and dispense new diary, if required.  
SECTION 4.5.13.8 
Week 26 (± 1 Week) 
The following will be performed at Week 26 (on two separate days):  
1st day at Week 26: 
• 
Physical examination, vital signs 
• 
Spirometry (FVC)  
• 
6MWT and Borg Scale  
2nd day at Week 26: 


 
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• 
Directed history (including review of AEs/SAEs, concomitant medications, oxygen 
use, and hospitalizations)  
• 
EQ5D questionnaire (should be performed before any other non-PRO assessments) 
• 
ECG. All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours after 
any meal. 
• 
Physical examination, vital signs, and weight  
• 
Clinical laboratory assessments, including hematology, serum chemistries, 
pregnancy test for women of childbearing capacity  
• 
HRCT 
• 
ECG   
• 
Spirometry (FVC) (before and after bronchodilator administration with a 15 min 
delay) 
• 
6MWT and Borg Scale  
• 
Collect patient’s diary 
• 
Assessment of compliance 
SECTION 4.5.13.10  Long-Term Follow-Up/ Rollover Study 
Week 39 (± 2 weeks) 
The following will be performed at Week 39: 
• 
Physical examination, vital signs 
• 
Clinical laboratory assessments (hematology, serum chemistries) 
• 
Spirometry (FVC)  
• 
6MWT and Borg Scale  
• 
Review AEs 
Week 52 (± 2 weeks) 
The following will be performed at Week 52: 
• 
EQ5D questionnaire (should be performed before any other non-PRO assessments) 
• 
ECG. All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours after 
any meal. 
• 
Physical examination, vital signs 
• 
ECG   
• 
Clinical laboratory assessments (hematology, serum chemistries) 


 
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• 
HRCT 
• 
Spirometry (FVC)  
• 
6MWT and Borg Scale  
• 
Review AEs 
SECTION 5.1 
SAFETY PLAN 
Pirfenidone is currently approved for medical use in many countries of the world (see 
Section 1.2). The safety plan for patients in this study is based on clinical experience 
with pifenidone in completed and ongoing clinical studies and in post-marketing use. The 
anticipated important safety risks for pirfenidone are outlined below. Please refer to the 
pirfenidone Investigator's Brochure instruction for medical use of the medicinal product for a 
complete summary of safety information. 
SECTION 5.2.1 Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An adverse event can therefore 
be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except exacerbation or 
worsening of IPF as described in Section 5.3.5.10. Worsening of IPF (i.e. IPF 
progression) is considered as an AE only in case of fatal outcome attributed to this 
progression (as described in Section 5.3.5.7). 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
• 
Lack of efficacy is not considered as AE 
SECTION 5.2.2 Serious Adverse Events (Immediately Reportable to the Sponsor) 
Q 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10 Section 5.3.5.9) 
 


 
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SECTION 5.2.3.2 Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be implemented in the study. All 
adverse events immediately reported to the Sponsor will be expeditely reviewed by the 
IDMC. The IDMC will also review every death case from the point of relationship to the 
study drug.  
 
SECTION 5.4.1 Emergency Medical Contacts 
Medical Monitor Contact Information for all sites  
Medical Monitor :   
 
 
 
 
 
 
, MD, PhD  
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Roche Medical Responsible: 
 
 
Telephone No.: 
 
 
Mobile Telephone No.: 
 
 
 
SECTION 5.7 
EXPEDITED 
REPORTING 
TO 
HEALTH 
AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS COMMITTEES 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
Pirfenidone Local Instruction for Use Investigator's Brochure 
• 
Pirfenidone Core Data Sheet 
 
SECTION  6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Q 
The main subject samples of interest are defined as follows. 
The ‘Allocated to treatment’ set will consist of all subjects who: 
• 
Gave their Informed Consent and  
• 
Has successfully completed Screening procedures. 
The ‘Treated’ set (TS) will consist of all subjects who: 
• 
Were in the ‘Allocated to treatment’ set and 


 
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• 
Received any dose of the study treatment. 
The ‘Full analysis’ set (FAS) will consist of all subjects who:   
• 
Were included in the ‘Treated’ set and  
• 
Had data for at least one post-baseline assessment of any efficacy measurement.  
 
SECTION 6.1 
DETERMINATION OF SAMPLE SIZE 
The required sample size for two-sided 95% confidence level can be calculated using the 
following formula: 
 
Assuming previous calculations, 60 subjects included in the study will be sufficient for 
study parameters estimation.  Taking into account study goals and the notion that the 
study drug is a product for the treatment of an orphan drug, margin of error of 0.125 is 
considered sufficient for parameter estimation. For precision-based sample size justification, 
with a sample size of 60 patients, an expected mean value of 2.5% and standard deviation of 20, 
distance from the mean to limit of the two-sided 95% confidence interval for the mean Change 
from Baseline to Week 26 (Percent Predicted FVC) will extend about 5 (margin of error). The SD 
for change from baseline at week 26 is conservatively estimated based on the results of the 
ASCEND study as standard deviation for Percent Predicted FVC in pirfenidone group at week 
26 (14.52) multiplied by √2 (Machin et al., 1997).  This is also in line with the results of 
CAPACITY programme (Noble et al. 2011) in which the SD of changes from baseline was 17 - 20 
at week 72. 
 
Taking into account an expected rate of screening failures about 45%, up to 109 patients will be 
screened for eligibility. 
SECTION 6.2 SUMMARIES OF CONDUCT OF STUDY 
Q 
Default Frequency Tabulations 
For qualitative variables, per category the numbers and frequencies of subjects with 
non-missing data (n, %) will be the default summary presentation. 


 
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For AEs and medical history, however, the denominator for the percentage calculation 
will be the number of subjects at risk. A subject will be considered at risk if the subject is 
in the Treated safety set sample. 
Q 
Handling missing values 
For missing FVC data imputation, patients will be classified into different patterns 
depending on the availability of data:  
Patients with a 26 week FVC value:  
1. those who received trial study drug until 26 weeks;  
2. those, who prematurely discontinued trial study drug, but who were followed up 
until Week 26.  
SECTION 6.3 
SUMMARIES 
OF 
DEMOGRAPHIC 
AND 
BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race and ethnicity, height, 
weight, medical history, concomitant medication, serology etc) will be summarized using 
means, SD standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate.   
SECTION 6.4 
EFFICACY ANALYSES 
The Treated FAS set will be used for the efficacy analysis.  
All efficacy parameters and will be summarized with descriptive statistics (mean, SD 
standard deviation, median, minimum maximum, 95% CI) for each measurement time 
point. 
SECTION 6.4.2 Primary Efficacy Endpoint 
Q 
The distribution (number and percentage) of primary outcome variable by patients 
across two three categories of change from Baseline (Decline of ≥10% or death before 
Week 26; Decline of < 10% to 0%; Improvement of ≥ 0%) will be provided in frequency 
table. 
 
SECTION 6.4.2 Secondary Efficacy Endpoints 
Q 


 
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Change from Baseline to Week 26 in patients’ quality of life as measured with EQ-5D-5L 
Results of EQ-5D-5L questionnaire will be summarized in two ways: 
• 
Cross tabulation for each of five dimensions (Mobility, Self-Care, Usual Activities, 
Pain / Discomfort, Anxiety / Depression) by response and study week. 
• 
VAS score, including changes from baseline, will be summarized with descriptive 
statistics (mean, standard deviation, median, minimum and maximum) for study 
week.  
Additionally, a single summary Index score will be provided, if necessary.    
 
SECTION 6.4.3 Exploratory Efficacy Endpoints 
HRCT fibrosis score 
The HRCT findings will be evaluated using HRCT scoring system. One ILD radiologist 
will make assessments of 4 main findings in three zones of each lung. The six zone 
scores will be averaged to determine the total score for each patient. Score will be 
recorded at the initial diagnosis and after six and 12 months in a similar manner for 
further comparison. The mean ± standard deviation (SD) of HRCT fibrosis score like 
continuous variable will be determined obligatory at baseline, 6 months and optional at 
12 months.  
The values of HRCT fibrosis score at baseline, at Week 39 26 (optional) and Week 52 
(optional) will be summarized in table with standard descriptive statistics for continuous 
variables and 95% CI for the mean. 
Additionally, the absolute change of HRCT fibrosis score from baseline at Week 39 26 
(optional) and Week 52 (optional) will be summarized in table with standard descriptive 
statistics for continuous variables and 95% CI for the mean. 
The paired t-test will be performed to evaluate the changes in the variable from the 
baseline to Week 39 26 (optional) and Week 52 (optional), respectively. The type I error 
rate will be set to 5%. 
Lung opacity (ground-glass attenuation) 
The sign ‘lung opacity’ will be qualified separately using methodology described above 
for other signs, and its change over time will be assessed outside the framework of a 
total summed index of fibrosis (HRCT fibrosis score). Lung opacity should be graded as 


 
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reticular abnormality to calculate the score for each zone, i.e. the percentage (%) area of 
opacity in a zone should be multiplied by the score of 2. 
The percentage area of opacity at Baseline, at Week 39 26 (optional) and Week 52 
(optional) will be summarized in table with standard descriptive statistics for continuous 
variables and 95% CI for the mean. 
Additionally, the absolute change of percentage area of opacity from Baseline at Week 
39 26 (optional) and Week 52 (optional) will be summarized in table with standard 
descriptive statistics for continuous variables and 95% CI for the mean. 
Exacerbations 
An exacerbation will be defined as an AE with special criteria, i.e. only in case the 
exacerbation has led to death of a patient (see Section 5.2.1). Rate of exacerbation will be 
reported in three following tables: 
SECTION 6.5 
SAFETY ANALYSES 
The safety Treated set sample will be used for the analysis of the safety and tolerability 
data. 
Study treatment is defined as pirfenidone 2403 mg/d administered in divided doses three 
times per day (TID) with food. Study treatment will be titrated over 14 days to the full 
dose of 9 capsules per day (three 267-mg capsules taken orally TID with food). Patients 
will remain on a stable maintenance dose for the duration of the treatment period unless 
the dose is reduced to manage an AE or titrated again when restarting study treatment 
after a 28-day or greater interruption in treatment. 
AEs will be reported on a per-subject basis, i.e. counting subjects rather than events. 
Only treatment emergent AEs will be reported. In the listings, however, all occurrences 
of the AEs will be presented. 
Treatment emergent AEs will be summarized per primary SOC system organ class and 
PT per preferred term. Severity and drug-event relationship of treatment emergent AEs 
will be summarized separately. 
Vital signs, including changes from baseline will be listed and summarized with 
descriptive statistics (mean, SD standard deviation, median, minimum and maximum) for 
each measurement time point. Out-of-range values with assessment of clinical 
significance will be provided in frequency tables. 
Results of ECG, including changes from baseline will be listed and summarized with 
descriptive statistics (mean, SD standard deviation, median, minimum and maximum) for 


 
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each measurement time point. Out-of-range values with assessment of clinical 
significance will be provided in frequency tables. 
Laboratory variables, including changes from baseline will be listed and summarized 
with descriptive statistics (mean, SD standard deviation, median, minimum and 
maximum) for each measurement time point. Additionally, shift tables summarizing the 
frequencies of patients below, within, and above the normal ranges at each time point 
will be provided. 
SECTION 8.2 INFORMED CONSENT 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 






 
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Ichikado K, Suga M, Müller NL et al. Acute interstitial pneumonia: Ccomparison of high-
resolution computed tomography findings between survivors and nonsurvivors. Am 
J Respir Crit Care Med. 2002, 165:1551–6 
Q 
Machin D., Campbell M., Fayers P., Pinol A. “Sample size tables for clinical studies”// Second 
edition Blackwell Science Ltd, 1997 
Q 
 
APPENDIX 1:  Schedule of Activities 
The schedule of activities has been revised to reflect the changes to the protocol, 
including changes in Section 4.5.13 Detalization of the Study Visits. 
Revised Appendix 1 provided below. 
 
 


 
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Appendix 1  
Schedule of Activities 
Study period 
IC visit  
Screening 
(Washout, 
if 
applicable) 
Treatment period 
Follow-Up 
Long-Term 
Follow-Up16 
Week/ 
Day 
(Window) 
 
- 
 
–4 to –1 W  
Day 1 
W1 
(± 1 d) 
 
W2 
(± 2 d) 
W4 
(± 2 d) 
W8 
(± 2 d) 
W12 
(± 2 d) 
 
W16 
(± 1 
w) 
 
W20 
(± 1 
w) 
 
W26 (± 1 w) 
14–28 days 
after last 
dose 
W39 
(± 2 w) 
W52 
(± 2 w) 
Informed consent1 
х 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Call Assessment2 
 
 
 
х 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, concomitant medication3 
x3 
x3 
х 
 
х 
х 
х 
х 
x 
x 
 
х 
х 
 
 
Vital signs, physical exam4 
 
х 
х 
 
х 
х 
х 
х 
x 
x 
x 
х 
х 
x 
x 
Height, weight5 
 
х 
х 
 
х 
х 
х 
х 
x 
x 
 
х 
x 
 
 




 
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Serologic tests1112 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
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1 Written informed consent must be obtained prior to any study-associated procedure, including discontinuing any prohibited medications.  
2  Safety-related information (AEs) and adherence to treatment is collected. 
3 Complete medical history is collected at an IC visit, washout and screening only. Thereafter, directed history (including review of AEs/SAEs, concomitant medications, oxygen use, 
hospitalizations, dosing, and diary) is only collected.  
4 Complete physical examination is performed at the Screening only (head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems). At subsequent visits (or as clinically indicated), only limited, symptom-directed physical examinations should be performed. 
5 Height is assessed at the Screening only. 
6 ECG should be performed after patient’s resting in a supine position for at least 10 min, prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood 
draws), bronchodilator administration and within 3 hours after any meal) 
7   Study treatment is dispensed to the patient every 12 weeks, but may be dispensed at other visits, as needed. 
78 To confirm IPF will be applicable to use previously performed HRCT, if it is meets image acquisition guidelines and performed not earlier than 24 months before the Screening. 
Review of the SLB samples obtained within 4 years before the Screening should be performed centrally for eligibility confirmation. Histopathological evaluation, if not available, is not 
repeated at the Screening.  
89 Transbroncheal biopsy or BAL are not mandatory and will only be reviewed at the Screening, if available, to exclude other causes of PF. 
910  HRCT should be performed at the Screening only for patients having no validated procedure within 2 months prior initiation of treatment.  
1011 OnAt screening, spirometry measurements of FVC should be performed before and after administration of albuterol (or salbutamol) from a metered dose inhaler (4 separate doses 
of 100 mg). Tests should be repeated after a 15-min delay. During further visits, bronchodilator test is not necessary to perform. Collection and recording of the retrospective FVC 
values obtained in clinical practice over the last year will be performed only on at the screening visit. 
1112 Blood samples must be drawn in fasted state. Serologic tests: rheumatoid factor, anticyclic citrullinated peptide and antinuclear antibody titer. 
1213 Pregnancy test must be performed before first dosing on Day 1 and must be negative. If the urine test is positive, serum pregnancy test must be performed. 
1314  Questionnaires should be self-administered before the patient or clinician receives any information on disease status, prior to the performance of non-PRO assessments, and prior 
to the administration of study treatment, with the exception for Borg scale administered in conjunction with the 6MWT. 
1415 Patient diary should be filled out on daily basis by the patient and reviewed by the investigator at in-clinic visits. Patient diary captures information on compliance and AEs occurance 


 
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and is dispensed as needed. 
1516 Schedule of calls in IPF Care Program you can see in Appendix 7   
16 Only in patients continuing treatment with pirfenidone in real clinical practice. 


 
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APPENDIX 2:  HRCT Protocol 
Minor changes have been made to the text of Appendix 2 (spelling mistakes and 
reference corrected). 
Q 
HRCT scans are usually obtained with the patient in supine position, with hands on the 
nape, in a single unforced breath hold. Scanning is normally directed upward (from feet 
to the head) in order to attenuate breathing artefacts in the basal parts of lungs. The key 
technical requirements are acquisition collimation is < 1 mm (opposite regular 0.65-0.8 
mm), reconstruction parameters: 1 mm-slices, reconstruction interval 1 mm, high 
resolution imaging, lung window, imaginfg field is adjusted to the chest volume. Dose 
detection software should be utilized to decrease radiation exposure of the patients. Key 
technical requirements for spiral HRCT are summarized in the Table 1-1. 
Q 
References 
Ichikado K, Suga M, Müller NL et al. Acute interstitial pneumonia: Ccomparison of high-
resolution computed tomography findings between survivors and nonsurvivors. Am 
J Respir Crit Care Med 2002, 165:1551–6.  
APPENDIX 5:  EuroQol-5D-5L Questionnaire 
Appendix 5 has been revised to replace EuroQoL-5D Questionnaire by more detailed 
EuroQoL-5D-5L Questionnaire (correct reference also provided accordingly). 
Below samples of deleted EuroQoL-5D and introduced EuroQoL-5D-5L Questionnaire 
are presented. 


 
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EuroQol-5D Questionnaire 
Questionnaire deleted 
 


 
 
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References 
EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of 
life. Health Policy 1990;16:199−208. 


 
 
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EuroQol-5D-5L Questionnaire 
Questionnaire added 
Under each heading, please tick the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems in walking about 

I have slight problems in walking about 

I have moderate problems in walking about 

I have severe problems in walking about 

I am unable to walk about 

SELF-CARE 
 
I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself 

I am unable to wash or dress myself 

USUAL ACTIVITIES (e.g. work, study, housework, family or leisure 
activities) 
 
I have no problems doing my usual activities 

I have slight problems doing my usual activities 

I have moderate problems doing my usual activities 

I have severe problems doing my usual activities 

I am unable to do my usual activities 

PAIN / DISCOMFORT 
 
I have no pain or discomfort 

I have slight pain or discomfort 



 
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I have moderate pain or discomfort 

I have severe pain or discomfort 

I have extreme pain or discomfort 

ANXIETY / DEPRESSION 
 
I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 

 
 


 
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References 
EuroQol Group. EuroQol: a new facility for the measurement of health related quality of 
life. Health Policy 1990;16:199−208. 
EuroQol Group. Web-source [Available at:https://euroqol.org/eq-5d-instruments/eq-5d-5l-
available-modes-of-administration/self-complete-on-paper/] 


 
 
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APPENDIX 7: 7 IPF Care Program 
Appendix 7 has been revised to reflect the changes to the protocol. The scheme of IPF 
Care Program has been corrected accordingly. 
Previous version and revised version of the scheme of IPF Care Program are presented 
below. 
 
 
 
 
 
 
 
 


 
 
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Appendix 7 
IPF Care Program 
IPF Care Program by F. Hoffmann-La Roche Ltd (Switzerland) 
Guidance for telephone calls to the patients participating in the clinical trial of pirfenidone 
Telephone calls are scheduled at Weeks 3, 5, 7, 13 and 24. Optional calls can be performed at Weeks 8 and 10, if necessary.   
A total number of calls is 5 to 7. Schedule of telephone calls and topics for discussion are detailed in the Figure below. 
 
 


 
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A full version of the IPF Care Program will be supplied by the Sponsor to the investigators or other designated staff. 


 
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Scheme  of IPF Care Program (current version) introduced 
A full version of the IPF Care Program will be supplied by the Sponsor to the investigators or other designated staff.


 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ...................................................... 50 


 
 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
LOCAL 
OPEN-LABEL 
MULTICENTER 
STUDY 
TO 
ASSESS THE  EFFECTIVENESS OF PIRFENIDONE IN 
PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS 
IN RUSSIAN CLINICAL PRACTICE 
PROTOCOL NUMBER: ML39355 
VERSION NUMBER: 
2 
TEST PRODUCT: 
Esbriet / Pirfenidone  (RO0220912) 
MEDICAL MONITOR: 
MD, PhD 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy 
{as instructed by XX [e.g., your local study monitor, the CRO]} [or] {to the contact 
provided below}. 
{Name}  
{Address} 


 
 
FINAL PROTOCOL APPROVAL 
Name: 
, 
                                   Date:  
Signature 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
Protocol ML39355, Final  Version 2 dated 09-Jun-2018 
PROTOCOL 
TITLE: 
LOCAL 
OPEN-LABEL 
MULTICENTER 
STUDY 
TO 
ASSESS THE  EFFECTIVENESS OF PIRFENIDONE IN 
PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS 
IN RUSSIAN CLINICAL PRACTICE  
PROTOCOL NUMBER: 
ML39355 
VERSION NUMBER: 
2 
TEST PRODUCT: 
Esbriet / Pirfenidone  (RO0220912) 
MEDICAL MONITOR: 
MD, PhD 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
09 June 2018 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ...................................................... 50 
PROTOCOL ACCEPTANCE FORM .............................................................................. 59 
PROTOCOL SYNOPSIS ............................................................................................... 60 
1. 
BACKGROUND ..................................................................................................... 72 
1.1 
Background on Idiopathic Pulmonary Fibrosis ................................ 72 
1.2 
Background on Pirfenidone ............................................................ 73 
1.3 
Study Rationale and Benefit-Risk Assessment ............................... 77 
1.3.1 
Study Rationale .............................................................................. 77 
1.3.2 
Risk-Benefit Assessment ................................................................ 77 
2. 
OBJECTIVES AND ENDPOINTS .......................................................................... 78 
3. 
STUDY DESIGN ................................................................................................... 79 
3.1 
Description of the Study ................................................................. 79 
3.2 
End of Study and Length of Study .................................................. 82 
3.3 
Rationale for Study Design ............................................................. 83 
3.3.1 
Rationale for Pirfenidone Dose and Schedule ................................ 83 
3.3.2 
Rationale for Patient Population ..................................................... 83 
3.3.3 
Rationale for Control Group ............................................................ 83 
3.3.4 
Rationale for Open-Label Design ................................................... 84 
3.3.5 
Rationale for Endpoint Selection .................................................... 84 
4. 
MATERIALS AND METHODS ............................................................................... 85 
4.1 
Patients .......................................................................................... 85 
4.1.1 
Inclusion Criteria ............................................................................ 85 
4.1.2 
Exclusion Criteria ........................................................................... 86 
4.2 
Method of Treatment Assignment and Blinding .............................. 89 
4.3 
Study Treatment ............................................................................. 90 
4.3.1 
Formulation, Packaging, and Handling ........................................... 90 
4.3.2 
Dosage, Administration, and Compliance ....................................... 91 
4.3.3 
Investigational Medicinal Product Accountability ............................ 92 


 
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4.3.4 
Post-Trial Access to Pirfenidone ..................................................... 92 
4.4 
Concomitant 
Therapy, 
Prohibited 
Food, 
and 
Additional Restrictions .................................................................... 93 
4.4.1 
Permitted Therapy .......................................................................... 93 
4.4.2 
Prohibited Therapy ......................................................................... 94 
4.4.3 
Prohibited Food .............................................................................. 95 
4.4.4 
Additional Restrictions .................................................................... 95 
4.5 
Study Assessments ........................................................................ 95 
4.5.1 
Informed Consent Forms and Screening Log ................................. 96 
4.5.2 
Medical History and Demographic Data ......................................... 96 
4.5.3 
Physical Examinations ................................................................... 96 
4.5.4 
Weight and Height .......................................................................... 97 
4.5.5 
Vital Signs ...................................................................................... 97 
4.5.6 
HRCT and Surgical Lung Biopsy .................................................... 97 
4.5.6.1 High-Resolution Computed Tomography ....................................... 97 
4.5.6.2 Surgical Lung Biopsy ..................................................................... 98 
4.5.7 
Spirometry and DLCO Measurements .............................................. 99 
4.5.8 
Laboratory, Biomarker, and Other Biological Samples ................. 100 
4.5.9 
Electrocardiograms ...................................................................... 102 
4.5.10 
6-Minute Walk Test ...................................................................... 102 
4.5.11 
Patient-Reported and Clinician-Reported Outcomes ....................... 103 
4.5.11.1 Borg Scale ................................................................................. 103 
4.5.11.2 EuroQol 5-Dimension Questionnaire .......................................... 103 
4.5.11.3 GAP Risk Assessment System .................................................. 104 
4.5.12 
IPF Care Program ........................................................................ 104 
4.5.13 
Details on the Study Visits ............................................................. 105 
4.5.13.1 Informed Consent Visit ............................................................... 106 
4.5.13.2 Screening Period (Day -28 to Day -1) ........................................ 106 
4.5.13.3 Start of Treatment (Day 1) ......................................................... 107 
4.5.13.4 Week 1 Telephone Assessment (± 1 Day) ................................. 108 
4.5.13.5 Weeks 2, 4, and 8 (± 2 Days) ..................................................... 108 
4.5.13.6 Weeks 12 (± 2 Days) ................................................................. 108 


 
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4.5.13.7 Weeks 16 and 20 (± 1 Week) ..................................................... 109 
4.5.13.8 Week 26 (± 1 Week) .................................................................. 109 
4.5.13.9 Follow-up Visit (14-28 Days after Last Dosing) .......................... 110 
4.5.13.10 Long-Term Follow-Up/ Rollover Study ..................................... 110 
4.5.14 
Samples for Research Biosample Repository ............................... 111 
4.6 
Patient, Treatment, Study, and Site Discontinuation ..................... 111 
4.6.1 
Patient Discontinuation ................................................................. 111 
4.6.2 
Study Treatment Discontinuation .................................................. 111 
4.6.3 
Study and Site Discontinuation ..................................................... 112 
4.6.3.1 Study Discontinuation .................................................................. 112 
4.6.3.2 Site Discontinuation ..................................................................... 112 
5. 
ASSESSMENT OF SAFETY ............................................................................... 113 
5.1 
Safety Plan ................................................................................... 113 
5.1.1 
Risks Associated with Pirfenidone ................................................ 113 
5.1.1.1 Gastrointestinal Adverse Events .................................................. 113 
5.1.1.2 Skin-Related Adverse Events ...................................................... 114 
5.1.1.3 Effects on Liver Function Tests .................................................... 114 
5.1.1.4 Cardiovascular Safety .................................................................. 114 
5.1.1.5 Other Adverse Events .................................................................. 115 
5.1.2 
Management of Patients Who Experience Specific 
Adverse Events ................................................................................................ 115 
5.2 
Safety Parameters and Definitions ............................................... 117 
5.2.1 
Adverse Events ............................................................................ 117 
5.2.2 
Serious Adverse Events (Immediately Reportable to 
the Sponsor) .................................................................................................... 118 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .............................................................................. 119 
5.2.3.1 Adverse Events of Special Interest .............................................. 119 
5.2.3.2 Independent Data Monitoring Committee ..................................... 119 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ........................................................................ 120 
5.3.1 
Adverse Event Reporting Period .................................................. 120 
5.3.2 
Eliciting Adverse Event Information .............................................. 121 


 
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5.3.3 
Assessment of Severity of Adverse Events .................................. 121 
5.3.4 
Assessment of Causality of Adverse Events ................................. 122 
5.3.5 
Procedures for Recording Adverse Events ................................... 123 
5.3.5.1 Diagnosis versus Signs and Symptoms ....................................... 123 
5.3.5.2 Adverse Events That Are Secondary to Other Events .................. 124 
5.3.5.3 Persistent or Recurrent Adverse Events ...................................... 124 
5.3.5.4 Abnormal Laboratory Values ........................................................ 125 
5.3.5.5 Abnormal Vital Sign Values .......................................................... 125 
5.3.5.6 Abnormal Liver Function Tests .................................................... 126 
5.3.5.7 Deaths ......................................................................................... 126 
5.3.5.8 Preexisting Medical Conditions .................................................... 127 
5.3.5.9 Hospitalization or Prolonged Hospitalization ................................ 127 
5.3.5.10 Adverse Events Associated with an Overdose or 
Error in Drug Administration ....................................................................... 128 
5.3.5.11 Patient-Reported Outcome Data ................................................ 128 
5.4 
Immediate Reporting Requirements from Investigator 
to Sponsor .................................................................................... 129 
5.4.1 
Emergency Medical Contacts ....................................................... 129 
5.4.2 
Reporting Requirements for Serious Adverse Events 
and Adverse Events of Special Interest ............................................................ 130 
5.4.2.1 Events That Occur prior to Study Drug Initiation .......................... 130 
5.4.2.2 Events That Occur after Study Drug Initiation .............................. 130 
5.4.3 
Reporting Requirements for Pregnancies ..................................... 131 
5.4.3.1 Pregnancies in Female Patients................................................... 131 
5.4.3.2 Pregnancies in Female Partners of Male Patients ........................ 131 
5.4.3.3 Abortions ..................................................................................... 131 
5.4.3.4 Congenital Anomalies/Birth Defects ............................................. 132 
5.5 
Follow-Up of Patients after Adverse Events.................................. 132 
5.5.1 
Investigator Follow-Up .................................................................. 132 
5.5.2 
Sponsor Follow-Up ....................................................................... 132 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .......................................................................... 132 


 
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5.7 
Expedited 
Reporting 
to 
Health 
Authorities, 
Investigators, Institutional Review Boards, and Ethics 
Committees .................................................................................. 133 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ................................ 133 
6.1 
Determination of Sample Size ...................................................... 134 
6.2 
Summaries of Conduct of Study ................................................... 135 
6.3 
Summaries 
of 
Demographic 
and 
Baseline 
Characteristics ............................................................................. 137 
6.4 
Efficacy Analyses ......................................................................... 137 
6.4.1 
Primary Efficacy Endpoint ............................................................ 137 
6.4.2 
Secondary Efficacy Endpoints ...................................................... 138 
6.4.3 
Exploratory Efficacy Endpoints ..................................................... 139 
6.5 
Safety Analyses ........................................................................... 140 
6.6 
Interim Analysis ............................................................................ 141 
7. 
DATA COLLECTION AND MANAGEMENT ........................................................ 141 
7.1 
Data Quality Assurance ................................................................ 141 
7.2 
Electronic Case Report Forms...................................................... 141 
7.3 
Electronic Patient- and Observer-Reported Outcome 
Data ............................................................................................. 142 
7.4 
Source Data Documentation ........................................................ 142 
7.5 
Use of Computerized Systems ..................................................... 142 
7.6 
Retention of Records .................................................................... 143 
8. 
ETHICAL CONSIDERATIONS ............................................................................ 143 
8.1 
Compliance with Laws and Regulations ....................................... 143 
8.2 
Informed Consent ......................................................................... 144 
8.3 
Institutional Review Board or Ethics Committee ........................... 145 
8.4 
Confidentiality ............................................................................... 145 
8.5 
Insurance ..................................................................................... 146 
8.6 
Financial Disclosure ..................................................................... 146 
9. 
STUDY 
DOCUMENTATION, 
MONITORING, 
AND 
ADMINISTRATION .............................................................................................. 146 
9.1 
Study Documentation ................................................................... 146 


 
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9.2 
Protocol Deviations ...................................................................... 146 
9.3 
Site Inspections ............................................................................ 146 
9.4 
Administrative Structure ............................................................... 147 
9.5 
Publication of Data and Protection of Trade Secrets .................... 149 
9.6 
Protocol Amendments .................................................................. 150 
10. REFERENCES .................................................................................................... 151 


 
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LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints .............................................. 8 
Table 2 
 Summary of Select Criteria for Diagnosis of IPF ................................. 99 
Table 3 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events .................................................................................. 116 
Table 4 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE ......................................................................... 122 
Table 5 
Causal Attribution Guidance ............................................................... 123 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ...................................................................................... 10 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities .......................................................................... 32 
Appendix 2 
 HRCT Protocol .................................................................................. 157 
Appendix 3 
Histopathologic Criteria for UIP Pattern .............................................. 165 
Appendix 4 
Borg Scale ......................................................................................... 167 
Appendix 5 
EuroQol-5D Questionnarie ................................................................... 41 
Appendix 6 
GAP Risk Assessment ....................................................................... 172 
Appendix 7 
IPF Care Program .............................................................................. 174 


 
Pirfenidone—F. Hoffmann-La Roche Ltd 
59/Protocol ML39355, Version 2 dated 09-Jun-2018 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
LOCAL 
OPEN-LABEL 
MULTICENTER 
STUDY 
TO 
ASSESS THE  EFFECTIVENESS OF PIRFENIDONE IN 
PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS 
IN RUSSIAN CLINICAL PRACTICE 
PROTOCOL NUMBER: ML39355 
VERSION NUMBER: 
2 
TEST PRODUCT: 
Esbriet / Pirfenidone  (RO0220912) 
MEDICAL MONITOR: 
MD, PhD 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
Please retain the signed original of this form for your study files. Please return a copy 
of this form to the Sponsors or their designee. Contact details will be provided to the 
investigator prior to study start. 


 
Pirfenidone—F. Hoffmann-La Roche Ltd 
60/Protocol ML39355, Version 2 dated 09-Jun-2018 
PROTOCOL SYNOPSIS 
TITLE: 
LOCAL OPEN-LABEL MULTICENTER STUDY TO ASSESS 
THE  EFFECTIVENESS OF PIRFENIDONE IN PATIENTS 
WITH IDIOPATHIC PULMONARY FIBROSIS IN RUSSIAN 
CLINICAL PRACTICE 
PROTOCOL NUMBER: 
ML39355 
VERSION NUMBER: 
2 
TEST PRODUCT: 
Esbriet / Pirfenidone  (RO0220912) 
PHASE: 
III 
INDICATION: 
Idiopathic Pulmonary Fibrosis (IPF) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
Objectives and Endpoints 
This is an interventional, open-label study to estimate effectiveness of pirfenidone in patients with 
idiopathic pulmonary fibrosis. Specific objectives and corresponding endpoints for the study are 
outlined below. 
Objectives and Corresponding Endpoints 
Objectives 
Corresponding Endpoints 
Primary Efficacy Objective: 
Primary Efficacy Endpoint: 
To estimate the treatment effect of 
pirfenidone 2403 mg/d on lung function  
Change from Baseline to Week 26 in absolute mL 
forced vital capacity (FVC) and % FVC.  
Secondary Efficacy Objective: 
Secondary Efficacy Endpoints: 
To 
estimate 
the 
effectiveness 
of 
pirfenidone on IPF patients’ functional 
capability and quality of life 
• Change from baseline to Week 26 in 6-minute walk 
test (6MWT) distance 
• Change from baseline to Week 26 in patients’ 
quality of life as measured with European Quality of 
Life 5-Dimension Questionnaire (EQ-5D) 
Exploratory Efficacy Objective: 
Exploratory Efficacy Endpoints: 
To 
estimate 
the 
effectiveness 
of 
pirfenidone on the frequency and number 
of acute exacerbations of IPF and on 
features of HRCT 
• Frequency and number of IPF exacerbations  
• CT scan evaluation (semiquantitative assessment 
"HRCT 
fibrosis 
score". 
The 
high-resolution 
computed tomography (HRCT) findings will be 
evaluated using HRCT scoring system. Interstitial 
lung disease (ILD) radiologist will make assessment 
of 4 main findings in three zones of each lung. The 
six zone scores will be averaged to determine the 


 
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total score for each patient at baseline and at 
Weeks 26 and 52)  
Safety Objective: 
Safety Endpoints 
To evaluate the safety of pirfenidone  
• Treatment-emergent adverse events (AEs) 
• Treatment-emergent serious adverse events 
(SAEs) 
• Change from baseline in clinical laboratory 
parameters 
and 
electrocardiogram 
(ECG) 
parameters 
 
Study Design 
Description of Study 
This is a national, multicenter, interventional, non-randomized, non-controlled, open-label study to 
assess the effectiveness of pirfenidone in patients with IPF in Russian clinical practice. 
Approximately 60 patients will be enrolled to receive pirfenidone 2403 mg/d for 26 weeks. The 
primary endpoint will be the absolute change from Baseline to Week 26 in FVC (both in mL and % 
predicted). Eligible patients aged 40–80 years must have a “confident” clinical and radiographic/or 
histological diagnosis of IPF according to 2011 ATS/ERS IPF guidelines. Patients with “possible” 
usual interstitial pneumonia (UIP) on HRCT and without surgical lung biopsy (SLB) are also 
eligible for the trial in case the multidisciplinary team (MDT) of the investigator’s site agrees on a 
“working diagnosis” of IPF. Patients with various degrees of lung function impairment can be 
included (%FVC ≥ 40; %DLCO ≥ 30% and 6MWT ≥ 100 m). All chest HRCTs, and histopathology 
slides of surgical lung biopsies (the latter if available) will be centrally reviewed by experienced 
experts.  
The study treatment will be initiated on Day 1 and continued until Week 26 (± 1). The dose of 
study treatment will be titrated over 14 days. Patients will have a telephone assessment at Week 
1 and an in-clinic assessment at Weeks 2, 4, 8, 12, 16, 20, 26. Patients should complete an 
adverse event and dosing compliance diary between all visits. If patients discontinue study 
treatment early for any reason, they should continue with all scheduled study procedures through 
week 26. 
Patients who will pass 26 (± 1) weeks in the trial and continue treatment with pirfenidone in real 
clinical practice will have two follow-up assessments of FVC and 6MWD at Weeks 39 and 52 and 
CT scans evaluation at Week 52. 
Number of Patients 
Approximately 60 eligible patients with IPF will be enrolled into the study. Expected rate of screening 
failure patients is about 45% which accounts for 109 patients to be screened. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 


 
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1. Male and female patients aged 40–80 years, inclusive.  
2. Clinical symptoms consistent with IPF of ≥ 6 months duration.  
3. Patients should have both “confident” or “consistent” with UIP diagnosis of IPF based on 
clinical, radiologic or pathologic data according to 2011 ATS/ERS guidelines at the 
Screening. HRCT scan performed within 24 months before the start of the Screening may 
be used. 
4. No features supporting an alternative diagnosis on transbronchial biopsy, bronchoalveolar 
lavage (BAL), or surgical lung biopsy, if performed. Results of the surgical lung biopsy 
performed within the last 4 years must be confirmed by central review. 
5. Patients with %FVC ≥ 40 % at the Screening.  
6. Patients with %DLCO ≥ 30 % at the Screening. 
7. Ability to walk ≥ 100 m during the 6-minute walk test at the Screening. 
8. Eligible patients must discontinue all prohibited medications at least 28 days before the 
start of treatment. 
9. Female patients of childbearing potential must have negative urine pregnancy test at the 
Screening and before first dosing on Day 1. 
10. Patients able to conceive must agree to use safe contraceptive methods for the whole 
duration of the study and 28 days after the last dosing.  
11. Ability to understand and sign Informed Consent Form. 
12. Ability to comply with the study protocol, in the investigator’s judgment (e.g. ability to fill out 
patient diary and other patient-reported outcome tools). 
13. Able to understand the importance of adherence to study treatment and the study protocol 
and willing to follow all study requirements.  
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Disease-Related Exclusions:  
1. Significant clinical worsening of IPF between the Screening and Day 1, in the opinion of 
the investigator. 
2. Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC < 0.7) at the Screening. 
3. In the opinion of the investigator patients with predicted life expectancy <12 months or 
those who are on an active transplant waiting list. 
4. Cigarette smoking within 28 days before the start of treatment or unwilling to avoid 
tobacco products throughout the study.  
5. History of clinically significant environmental exposure known to cause pulmonary fibrosis 
(PF), including but not limited to drugs (such as amiodarone), asbestos, beryllium, 
radiation, and domestic birds.  


 
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6. Known explanation for interstitial lung disease, including but not limited to radiation, drug 
toxicity, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans organizing 
pneumonia, human immunodeficiency virus (HIV), viral hepatitis, and cancer. 
7. Clinical diagnosis of any connective tissue disease, including but not limited to 
scleroderma, polymyositis/ dermatomyositis, systemic lupus erythematosus, and 
rheumatoid arthritis, or patients with positive biomarker tests associated with these diseases 
(rheumatoid factor, anticyclic citrullinated peptide and antinuclear antibodies) at the Screening.  
8. During baseline analysis of HRCT, significant coexistent emphysema (emphysema extent 
greater than extent of fibrosis) confirmed by central review. 
9. Planned lung transplantation during the study. 
10. Clinical evidence of active infection, including but not limited to bronchitis, pneumonia, 
sinusitis, urinary tract infection, or cellulitis.  
Medical Exclusions:  
11. Unable to perform 6MWT or to undergo pulmonary function test. 
12. Any history of malignancy likely to result in significant disability or likely to require 
significant medical or surgical intervention within the next 1 years. This does not include 
minor surgical procedures for localized cancer (e.g., basal cell carcinoma).  
13. History of severe hepatic impairment or end-stage liver disease.  
14. History of end-stage renal disease requiring dialysis. 
15. History of unstable or deteriorating cardiac or pulmonary disease (other than IPF) within 
the previous 6 months, including but not limited to the following:  
a. 
unstable angina pectoris or myocardial infarction 
b. 
congestive heart failure requiring hospitalization 
c. 
uncontrolled clinically significant arrhythmias 
16. Pregnancy or lactation, or intention to become pregnant during the study. Women of 
childbearing capacity are required to have a negative urine pregnancy test before 
treatment and must agree to maintain highly effective contraception.   
17. History of alcohol or substance abuse in the past 1 year.  
18. History of gastrointestinal (GI) tract perforation or history of peptic ulcer within six months. 
19. Family or personal history of long QT Syndrome.  
20.  Known hypersensitivity to prior used pirfenidone or any excipient of the study treatment.  
21. Use of any of the following therapies within 28 days before the start of treatment period:  
a. investigational therapy, defined as any drug that has not been approved for 
marketing for any indication in Russia 
b. any cytotoxic, immunosuppressive, cytokine modulating, or receptor antagonist 
agent including but not limited to azathioprine, bosentan, ambrisentan, 
cyclophosphamide, cyclosporine, etanercept, iloprost, infliximab, leukotriene 


 
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antagonists, methotrexate, mycophenolate mofetil, tacrolimus, montelukast, 
tetrathiomolybdate, tumor necrosis factor (TNF)-α inhibitors, N-acetylcysteine 
(NAC), imatinib mesylate, interferon gamma-1b (IFN γ-1b), and tyrosine kinase 
inhibitors 
c. medications that are specifically used for the treatment of IPF including but not 
limited 
to 
angiotensin 
converting 
enzyme 
(ACE) 
inhibitors, 
colchicine, 
corticosteroids (prednisolone at doses exceeding 15 mg/day or equivalents), 
heparin, warfarin, and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) 
reductase inhibitors. These drugs may be used if given for a non-IPF indication if 
there is no clinically acceptable alternative therapy for the same indication. 
d. fluvoxamine 
e. sildenafil (chronic use for pulmonary arterial hypertension). Note: intermittent use 
for erectile dysfunction is allowed. 
Laboratory Exclusions:  
22. Any of the following liver function test outside specified limits at the Screening:  
a. 
total bilirubin above the upper limit of normal (ULN);  
b. 
aspartate or alanine aminotransferase (AST or ALT) > 3 × ULN;  
c. 
alkaline phosphatase > 2.5 × ULN.  
23. Creatinine clearance < 30 mL/min, calculated using the Cockcroft-Gault formula.  
24. Electrocardiogram (ECG) with a QT interval corrected according to Fridericia’s formula 
(QTcF) > 500 msec at the Screening. 
Other Exclusions: 
25. Inability to return for follow-up visits or obtain follow-up data required to assess study 
therapy, or presence of other reasons for anticipated non-compliance to therapy or 
procedures, in the opinion of the investigator. 
End of Study 
The end of study is defined as the date when the last patient, last visit (LPLV) occurs or the date 
at which the last data point required for statistical analysis or long-term follow-up is received from 
the last patient, whichever occurs later. LPLV is expected to occur after 12 months after the last 
patient is enrolled. 
Length of Study 
The total length of the study, from recruiting of the first patient to the end of the study, is expected 
to be approximately 2 years. Duration of participation in the study for an individual patient is 
between 31 and 35 weeks (excluding long-term follow-up). For patients continuing in the rollover 
study the duration of participation in the study extends up to 58 weeks. 
Investigational Medicinal Product 
An investigational medicinal product (IMP) for this study is Pirfenidone (RO0220912) (INN: 
pirfenidone, ATC code L04AX05) 267 mg capsules, manufactured by Catalent Pharma Solutions 


 
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LLC, Winchester, USA. Pirfenidone is the medicinal product, immunodepressant, which has anti-
inflamatory and antifibrotic effects. Pirfenidone is registered in Russia, marketing authorization 
number DP (drug product) - 004030. Pirfenidone (commercial product name Esbriet) was 
approved by the Ministry of Healthcare of the Russian Federation for treatment of idiopathic 
pulmonary fibrosis on 22-Dec-2016. 
Permitted Therapy 
Permitted therapy in the study include the use of corticosteroids either permanently at the 
discretion of the investigator as a part of routine management of IPF (at a maximum daily dose of 
15 mg of prednisolone or equivalents), or temporally for the management of the IPF 
exacerbations without dose restriction for a period of up to 21 days.  
Statistical Methods 
Primary Analysis 
The primary outcome variable will be analyzed in the Full Analysis Set (FAS) sample (patients who 
were included in the ‘Treated’ set and had data for at least one post-baseline assessment of any efficacy 
measurement). The primary outcome variable is the absolute change in FVC from baseline to 
Week 26 (both in mL and % predicted). Baseline FVC will be the average of the highest FVC 
measurements recorded at the Screening and Day 1 visits. The FVC at Week 26 will be the 
average of the highest FVC measurements recorded on two separate days at week 26. Data will 
be analyzed using a standard descriptive statistics for continuous variables and 95% CI for the 
means. 
For missing FVC data imputation, patients will be classified into different patterns depending on 
the availability of data. Patients with a 26-week FVC value will be classified into those who 
received study drug until Week 26 and those who prematurely discontinued but who were 
followed up until Week 26. Patients without a 26-week FVC value will be classified into those who 
were alive at Week 26 and those who died before Week 26. Missing data at other visits before 
Week 26 (primary outcome variable) will not be imputed.  
Methods for handling missing data due to death will include replacement with the worst possible 
value (FVC = 0 mL or 0%) (primary analysis), replacement with worst observed FVC value at 
week 26 (sensitivity analysis), and replacement with an intermediate value (FVC =1500 mL or 
50%) (sensitivity analysis). 
Missing data due to reasons other than death will be replaced with imputed values based on the 
average measurements for “similar” patients at that time point (primary analysis). Similar patients 
are those without missing data before that time point and whose data have the smallest sum of 
squared deviations (SSD) from that patient for all visits prior to the one with the missing data. 
Missing data due to lung transplant will be imputed using the SSD method even if the patient dies 
after lung transplant. A sensitivity analysis will use the data imputed with last observation carried 
forward method (LOCF). Complete case analysis will also be performed as a sensitivity analysis.  
The distribution (number and percentage) of primary outcome variable by patients across two 
categories of change from Baseline (Decline of ≥ 10% or death before Week 26; Decline of < 10% 
to 0%; Improvement of ≥ 0%) will be provided in frequency table. Absolute change in FVC from 
baseline at Weeks 12, 39 (optional) and 52 (optional) and mean FVC change through all time 
endpoints (both in mL and % predicted) will be summarized with standard descriptive statistics for 
continuous variables and 95% CI for means. 








 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
ATS 
American Thoracic Society  
AV 
Atrioventricular 
BAL 
Bronchoalveolar lavage 
CI 
Confidence interval 
CK 
Creatine kinase  
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
Carbon monoxide diffusing capacity  
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EP 
European Pharmacopeia 
ERS 
European Respiratory Society 
EU 
European Union 
EQ-5D/ EuroQol-5D 
European Quality of Life 5-Dimension Questionnaire 
FAQ 
Facts, Answers, Questions 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FEV 
Forced expiratory volume 
FOV 
Field of vision 
(F)VC 
(Forced) Vital capacity of the lungs 
GAP 
Gender, Age, Physiology (multidimensional index and staging 
system for IPF) 
GGT 
Gamma-glutamyl transferase  
GI 
Gastrointestinal 
Hb 
Hemoglobin 
hERG 
Potassium ion channel of myocytes, coded with hERG gene 
HIV 
Human immunodeficiency virus 


 
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Abbreviation 
Definition 
HMG-CoA 
3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A 
(HR)CT 
(High-resolution) Computer Tomography 
HU 
Hounsfield unit 
IC50 
Half inhibitory concentration  
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee  
IFN γ 
Interferon gamma  
IMP 
Investigational Medicinal Product 
ILD 
Interstitial lung disease 
IND 
Investigational New Drug (application) 
INN 
International non-proprietary name 
IPF 
Idiopathic Pulmonary Fibrosis  
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IWRS 
Interactive Web Response System 
kV 
Kilovolt 
LDH 
Lactic dehydrogenase 
LL 
Left lung 
LOCF 
Last observation carried forward 
LPLV 
Last patient, last visit 
LPS 
Lipopolysaccharide 
(n)MET 
N-minute exercise test 
MDT 
Multidisciplinary team 
mEq/L 
Milliequivalents per liter, equivalent to mmol/L 
(n)MWT 
N-minute walk test 
NAC 
N-acetylcysteine  
NCI 
National Cancer Institute 
NOAEL 
No Observed Adverse Effect Level  
PBRER 
Periodic Benefit-Risk Evaluation Report  
PFS 
Progression-free survival 
PFT 
Pulmonary function test 
PK 
Pharmacokinetic 
PRO 
Patient-reported outcome 
PT 
Preferred term 
QTc(F) 
QT interval corrected (using Fridericia’s formula) 
RBC 
Red blood cells 


 
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Abbreviation 
Definition 
RL 
Right lung 
RR 
Risk ratio 
SAE 
Serious Averse Event 
SD 
Standard deviation 
SOC 
System organ class 
SSD 
Sum of squared deviations  
SLB 
Surgical lung biopsy 
SpO2 
Oxygen saturation 
TID 
Three times per day 
TGF 
Transforming growth factor  
Tmax 
Time to reach maximal concentration of the drug in plasma  
TNF 
Tumor necrosis factor   
TS 
Treated set 
UIP 
Usual interstitial pneumonia 
ULN 
Upper limit of normal 
US 
United States of America 
USP 
United States Pharmacopeia 
UV 
Ultraviolet 
VAS 
Visual Analogue Scale 
WBC 
White blood cells 
yr 
Year 


 
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1. BACKGROUND 
1.1 BACKGROUND ON IDIOPATHIC PULMONARY FIBROSIS 
Idiopathic Pulmonary Fibrosis (IPF) is a chronic disease of unknown etiology that is 
characterized by progressive fibrotic destruction of the lung (predominantly of the 
lung interstitium), resulting in disabling dyspnea, poor gas exchange, decrease in 
lung volume, progressive pulmonary insufficiency typically leading to death. IPF is 
recognized by the American Thoracic Society (ATS) and European Respiratory 
Society (ERS) as a specific form of chronic, progressive fibrosing interstitial 
pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, 
and associated with the histopathologic and/or radiologic pattern of usual interstitial 
pneumonia (UIP) (ATS 2011). 
IPF is a rare disease, it is estimated to affect about 1-5 in 10,000 persons in the 
European population (Orphanet). IPF is most prevalent in middle aged and elderly 
patients, and usually presents between the ages of 40 and 70 years (Esbriet EMA 
2010); the mean age at presentation is 66 years (Orphanet). Although the disease is 
idiopathic by its nature, several potential risk factors have been identified. They 
include cigarette smoking, environmental exposures (metal, wood dust and other 
dusts), microbial agents (Epstein-Barr virus, cytomegalovirus, human herpesvirus), 
gastroesophageal reflux and genetic factors (ATS 2011). 
Usual clinical findings of IPF include slowly increasing dyspnea and a nonproductive 
cough with progressive loss of lung volumes, i.e. decreased forced vital capacity 
(FVC), and decline in exercise tolerance. On high-resolution computed tomography 
(HRCT) 
scan, 
there 
are 
peripheral 
(subpleural), 
bibasilar, 
reticulonodular 
abnormalities with architectural distortion, honeycomb change, and traction 
bronchiectasis (ATS 2011; ATS 2015).  
The diagnosis of IPF carries a bleak prognosis, the median survival for IPF patients is 
about 3 years from the time of diagnosis. However, the course of the disease varies 
from patient to patient. Slow progression of respiratory insufficiency is interspersed 
with episodes of acute exacerbation that accelerate decline and may be fatal (Collard 
et al. 2007).  
For the long period of time no preventive approach or globally accepted treatment 
other than lung transplantation and enrolment in clinical trials was available. There is 
no good evidence to suggest the efficacy of therapies often administered to patients 
with IPF, such as corticosteroids and azathioprine (ATS 2015; Walter et al. 2006). 
ATS/ERS/JRS/ALAT guidelines updated in 2015 gave conditional positive 
recommendations for two antifibrotic drugs for the treatment of IPF - nintedanib and 
pirfenidone (ATS 2015). 


 
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1.2 BACKGROUND ON PIRFENIDONE  
Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) is a small non-peptide molecule of 
low molecular weight (185.2 daltons). Pirfenidone belongs to immunosuppressants 
group (ATC code L04AX05). The mechanism of action of pirfenidone has not been 
fully established, but existing data suggest that it exerts both antifibrotic and anti-
inflammatory properties (Esbriet EMA 2010). Pirfenidone attenuates fibroblast 
proliferation, production of fibrosis-associated proteins and cytokines, and the 
increased biosynthesis and accumulation of extracellular matrix in response to 
cytokine growth factors. 
Pirfenidone was first approved in Japan in 2008 under the trade name Pirespa. In 
2011, Esbriet (pirfenidone) grabted marketing authorization in European Union (EU) 
as an orphan medicinal product for the treatment of adults with mild to moderate IPF. 
In 2014, the product was approved by the US FDA. Under different trade names 
pirfenidone is also approved for the treatment of IPF in many countries, including 
Argentina, China, India, Mexico and South Korea (Esbriet EMA 2010). Pirfenidone 
was also registered in Russia, marketing authorization number DP (drug product) - 
004030. Pirfenidone (commercial product name Esbriet) was approved by the Ministry 
of Healthcare of the Russian Federation for treatment of idiopathic pulmonary fibrosis. 
Nonclinical development 
In the in vitro experiments pirfenidone suppressed the proliferation of fibroblasts, 
inhibited lipopolysaccharide (LPS)-stimulated release of platelet-derived growth factor 
AB and of transforming growth factor (TGF)-β1, inhibited collagen synthesis in 
fibroblast cultures and promoted the release of collagenase from fibroblasts over the 
concentration range 5.5 to 185 µg/mL. These in vitro effects were observed at clinical 
concentrations or low multiples of clinical concentrations. In vivo studies were 
conducted in relevant models of fibrosis in mice, rats, hamsters and dogs. 
Pharmacodynamic activity was demonstrated particularly in bleomycin-induced lung 
fibrosis in mice, rats and hamsters (Esbriet EMA 2010).  
In safety pharmacology studies pirfenidone demonstrated minimal hERG inhibition 
(16%) at concentration of 185 µg/mL, with a half inhibitory concentration (IC50) of 925 
µg/mL (5000 µM). Other cardiovascular effects in rats included decreased blood 
pressure and increased heart rate observed at doses 30-300 mg/kg. Premature 
ventricular contractions and atrioventricular (AV) block occurred at submaximal and 
maximal doses. In dogs prolongation of QT and corrected QT (QTc) intervals was 
seen at 100 mg/kg, shortening of QT interval and increase in heart rate were 
observed at 300 mg/kg (Esbriet EMA 2010).  
Pharmacokinetics of pirfenidone was similar in mice, rats, guinea pigs and dogs. The 
compound was rapidly absorbed after oral administration with time to maximal 


 
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concentration (tmax) of 0.5 hour. Terminal elimination half-life ranged between 1.6 to 
4.8 hours in mice, rats and dogs, and was similar to that in humans. Bioavailability 
was 97% in rats and 79% in dogs. In mice and rats pirfenidone showed an 
approximately dose-proportional increase in absorption in the dose range 30 to 2000 
mg/kg. In humans serum protein binding, predominantly to albumin, ranged from 54% 
to 62% (Esbriet EMA 2010).  
There is little evidence to suggest accumulation of pirfenidone and its metabolites in 
any tissues. Metabolism of pirfenidone was rapid in rats and dogs and was mediated 
mostly by CYP1A2 enzymes in humans. The major circulating metabolite was 5-CA 
pirfenidone, its plasma levels approximated a half of parent compound levels in dogs 
and humans. The elimination of pirfenidone was rapid and occurred primarily via the 
urine as the 5-CA pirfenidone metabolite. About 5 to 15% of the metabolite was 
excreted faecally. No meaningful changes in pharmacokinetics were seen with 
repeated dosing (Esbriet EMA 2010). 
Toxicity of pirfenidone was studied after single dosing in mice, rats and dogs, and 
after multiple dosing in mice and rats. Toxic effects were more pronounced in fasted 
animals than in fed. In rodents, effects on the central nervous system, including 
hypoactivity, respiratory effects, abnormal gait and recumbency, were noted. Emesis, 
salivation and vocalisation were observed in dogs. These signs developed after 
administration of high doses (1000 mg/kg). The main target organ was liver, however, 
the changes were considered to be adaptive. There was no irreversible or delayed 
toxicity (Esbriet EMA 2010).  
The main signs in the oral subchronic and chronic toxicology studies of pirfenidone 
lasting up to 6-9 months were similar to those seen acutely. The exposure at the 
highest doses in rats and dogs were 6- and 12-fold, respectively, the Cmax in IPF 
patients. Animals developed altered posture, hypoactivity, altered gait and sedation. 
The main systemic effect was an increase in liver weight, often in conjunction with 
hepatic centrilobular hypertrophy. There was no increase in alanine aminotransferase 
(ALT), aspartate aminotransferase (AST) or bilirubin, suggesting that the hepatic 
effects were not a manifestation of toxicity, but the result of enzyme induction. All 
findings were completely or partially reversible. There was no evidence of delayed 
toxicity. The no observed adverse effect level (NOAEL) in the 3- and 9-month studies 
was established as 200 mg/kg/day (Esbriet EMA 2010). 
Pirfenidone was shown to cause phototoxicity and photoirritation when dosed 
concomitantly with exposure to ultraviolet (UV) light in hairless mice. Pirfenidone was 
not antigenic in guinea pigs and was not immunotoxic. Pirfenidone had no harmful 
effect on fertility of rats of either gender, but there was an effect on the oestrous cycle 
in females. There were also a prolongation of gestation and reduction in viability in 


 
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the neonates in animals dosed in the perinatal period. The NOAEL for fertility and 
fetal development was 900 mg/kg/day (Esbriet EMA 2010). 
Pirfenidone and its 5-CA main metabolite were not genotoxic in a standard battery of 
tests. Tumours were found in the carcinogenicity studies after oral administration via 
diet to mice at doses of 800, 2000 or 5000 mg/kg/day for 104 weeks. However, 
tumors in the liver were deemed to result from the adaptive changes and not 
indicative of a risk for humans. Hormonally-mediated mechanisms were proposed for 
tumours in the uterus of rats; but the findings were not considered to represent a risk 
to patients (Esbriet EMA 2010). 
Clinical studies 
Efficacy, safety and tolerability of pirfenidone were studied in four phase III, 
multicentre, randomized, double-blind, placebo-controlled studies in patients with IPF 
(King et al. 2014; Noble et al. 2011; Taniguchi et al. 2010). 
SP3 study  
275 Japanese patients with IPF and mild to moderate impairment in pulmonary 
function tests (PFT) were randomized in 2:1:2 ratio to pirfenidone 1800 mg/day, 1200 
mg/day or placebo, respectively, for 52 weeks. The primary end-point was the change 
in vital capacity (VC) from baseline to week 52. Other end-points were progression-
free survival (PFS) time and the change in the lowest oxygen saturation (SpO2) 
during the 6-minute steady-state exercise test (6MET). The progression of disease 
was defined by death and/ or ≥ 10% decline in VC from baseline. The trial 
demonstrated a benefit to both doses of pirfenidone in terms of a reduction in VC 
decline (-0.09 L vs. -0.16 L; P = 0.0416). Significant improve in PFS was observed for 
the high-dose group (P = 0.028). Marginally significant difference with placebo was 
found for the low-dose group (P = 0.066). There were no significant differences in the 
mean changes of the lowest SpO2 and incidence of acute exacerbation during the 
study or within 28 days after the termination of the study among the three groups 
(Taniguchi et al. 2010).  
CAPACITY -004 and -006 studies 
In two concurrent trials (CAPACITY-004 and -006) patients with IPF were randomly 
assigned to pirfenidone or placebo for a minimum of 72 weeks in 110 centres in 
Australia, Europe, and North America. In study 004, 435 patients were assigned in a 
2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo. In study 
006, patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo. The 
primary endpoint was change in percentage predicted forced vital capacity (FVC) at 
week 72.  


 
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In study 004, pirfenidone significantly reduced decline in FVC with mean change at 
week 72 -8.0% (standard deviation [SD] 16.5) in the pirfenidone 2403 mg/day group 
and -12.4% (18.5) in the placebo group (difference 4.4%, 95% CI 0.7 to 9.1). 35 (20%) 
versus 60 (35%) patients, respectively, had a decline of at least 10%. Mean change 
in FVC in the lower dose pirfenidone group was intermediate to that in the higher 
dose pirfenidone and placebo groups.  
In study 006, the difference between groups in FVC change at week 72 was not 
significant (P = 0.501). Mean change in FVC at week 72 was -9.0% (SD 19.6) in the 
pirfenidone group and -9.6% (19.1) in the placebo group (difference 0.6%, 95% CI -
3.5 to 4.7). However, a consistent pirfenidone effect was apparent until week 48 and 
in an analysis of all study timepoints. Fewer overall deaths and fewer deaths related 
to IPF occurred in the pirfenidone 2403 mg/day groups than in the placebo groups 
(Noble et al. 2011). 
ASCEND study 
555 patients were randomized in 1:1 ratio to receive pirfenidone 2403 mg/day or 
placebo for 52 weeks (King et al. 2014). The primary endpoint was the change in 
FVC or death at week 52. In the pirfenidone group, as compared with the placebo, 
there was a relative reduction of 47.9% in the proportion of patients who had an 
absolute decline of 10% or more in the percentage of FVC or who died. There was 
also a relative increase of 132.5% in the proportion of patients with no decline in FVC 
(P < 0.001). Pirfenidone significantly reduced the decline in the 6-minute walk 
distance (6MWT) (P = 0.04) and improved PFS (P < 0.001). There was no significant 
difference in dyspnea scores or in rates of death from any cause or from IPF. 
However, in a prespecified pooled analysis incorporating results from CAPACITY 
trials, the between-group difference favoring pirfenidone was significant for death 
from any cause (P = 0.01) and from IPF (P = 0.006). Pooled results suggested 
improved mortality with pirfenidone (risk ratio [RR], 0.70; 95% CI, 0.47–1.02; 
moderate confidence). Pirfenidone reduced the rate of FVC decline (standardized 
mean difference, 0.23; 95% CI, 0.06–0.41; high confidence) (King et al. 2014). 
Pirfenidone, as compared with placebo, reduced disease progression, as reflected by 
lung function, exercise tolerance, and PFS in patients with IPF (King et al. 2014). 
In addition, an open-label long-term extension RECAP study enrolled patients, who 
completed CAPACITY and ASCEND trials (Costabel et al. 2014). The primary 
objective of RECAP study was to assess safety and tolerability of pirfenidone in the 
long-term treatment of IPF. Secondary objective was to obtain additional efficacy data 
for pirfenidone 2403 mg/day in patients who previously were allocated to placebo in 
CAPACITY and ASCEND trials and received pirfenidone in RECAP study for the first 
time. Preliminary results of the study demonstrated that patients newly treated with 


 
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pirfenidone in RECAP had similar FVC and survival outcomes to those in the 
CAPACITY pirfenidone group (Costabel et al. 2014). 
Refer to the latest version of the Investigator's Brochure for details on nonclinical and 
clinical studies. 
On the basis of evidence from the Phase III ASCEND and CAPACITY studies, joint 
clinical guidelines published in 2015 by ATS/ERS/JRS/ALAT recommendation put a 
high value on the potential benefit of pirfenidone on patient-reported outcomes 
(PROs), disease progression, as measured by rate of forced vital capacity decline, 
and mortality, and a lower value on potentially significant adverse events. 
1.3 STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 Study Rationale 
IPF is a life-threatening and severely debilitating disease characterized by poor 
survival. Results from five controlled clinical trials, as described above, suggest that 
treatment with pirfenidone results in clinically meaningful benefits in a variety of 
domains, including lung volume (FVC/VC), exercise tolerance (change in 6MWT 
distance), PFS and risk of mortality.  
Pirfenidone is currently approved for the treatment of patients with IPF in many 
countries worldwide, including Russia. Despite the lack of epidemiological data on IPF 
in Russia, the number of patients diagnosed with the disease is expected to be large. 
The only available in Russia specific treatment of IPF recommended by international 
guidelines is an antitumor agent nintedatib. At the stage of clinical development of 
pirfenidone, none of Russian clinical centers were ever involved in the programme of 
global clinical trials of the medicinal product, and experience with pirfenidone in 
clinical practice is absent. Therefore, there is a great unmet medical need for a local 
trial to estimate the effectiveness of pirfenidone in the Russian population suffering 
from IPF. 
1.3.2 Risk-Benefit Assessment 
The estimated cumulative exposure to pirfenidone in clinical trials is from 3536 
individuals. Up to the end of the most recent reporting period (27 February 2016), the 
majority of pirfenidone-treated patients are from the international phase III studies, 
mentioned in the Section 1.2. Cumulative post-marketing exposure to pirfenidone is 
estimated to be over 30 475 patient-years. A revised Periodic Benefit-Risk Evaluation 
Report (PBRER) submitted in 2016 updated the figure. 
Results from five controlled clinical trials suggest that treatment with pirfenidone is 
generally safe and well tolerated. Patients from both CAPACITY studies who were 
assigned to receive high-dose pirfenidone reported increased rates of nausea, 


 
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dyspepsia, vomiting, anorexia, photosensitivity, and rash compared with placebo 
(Noble et al. 2011). Similar results were observed in the ASCEND trial in regards to 
gastrointestinal (GI) and skin-related adverse events. Pooled analysis showed 
increased rates of photosensitivity (high confidence), fatigue (moderate confidence), 
stomach discomfort (moderate confidence), and anorexia (high confidence) in 
patients treated with pirfenidone. However, those events rarely led to treatment 
discontinuation (King et al. 2014).  
According to RECAP study interim data, 603 patients were exposed to pirfenidone. 
Mild to moderate gastrointestinal (nausea, dyspepsia and diarrhoea) and skin-related 
events (rash, photosensitivity reaction) were among the most commonly reported 
adverse events. The incidence of nausea was 16.8 per 100 patient-years and of rash 
8.2 per 100 patient-years (Costabel et al. 2014). 
The data show that treatment with pirfenidone is associated with acceptable adverse 
events profile, and the benefit in patients with IPF outweighs the potential risks. Thus, 
pirfenidone represents an appropriate treatment option for patients with idiopathic 
pulmonary fibrosis.  
2. OBJECTIVES AND ENDPOINTS 
This study will estimate effectiveness of pirfenidone in patients with idiopathic 
pulmonary fibrosis. Specific objectives and corresponding endpoints for the study are 
outlined in Table 1 below. 




 
 
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Study sites will be specialized  centres experienced in the management of IPF, and their 
work will be coordinated  by a Leading Specialist-- Investigator, chosen among experts in 
the field (see Section 9.4).  
For enrolment into the study, the diagnosis of IPF must be confirmed by central review of 
HRCT scans and of the surgical lung biopsy (SLB) samples, if available (if performed prior 
enrolment in routine clinical practice). The HRCT scans will be reviewed by one or two 
central readers who are radiologists with expertise in IPF. If the first expert (central 
reader-1) agrees with the local opinion, the second expert (central reader-2) will not 
review scans. If the first expert disagrees with the local opinion, the second expert 
should review scans. Histopathological (SLB) samples will be reviewed by the one 
central reader who is a pathologist with expertise in IPF. Information on central 
reviewers and other administrative aspects of the study is provided in Section 9.4. All 
other diagnostic procedures will be performed and assessed at a local level.  
Eligible patients aged 40–80 years must have a confident clinical and radiographic/ or 
histological diagnosis of IPF according to 2011 IPF guidelines (ATS 2011). Patients with 
possible UIP on high-resolution computed tomography and without SLB in case of 
“working diagnose” of IPF during multidisciplinary team (MDT) discussion, are also 
eligible for the trial (see Table 2).  
Patients will be required to have a relative %FVC ≥ 40 %, percent predicted carbon 
monoxide diffusing capacity (%DLCO) ≥ 30 %, and able to walk ≥ 100 meters during the 
6-minute walk test at the Screening.  
All assessments in the study will be initiated only after signed Informed Consent is 
obtained from the patient. For this purpose, an additional visit may be perfomed prior to 
the start of the Screening procedures and an appropriate review of the patient’s clinical 
data relevant to the IPF diagnosis is done (see Appendix 1). 
Any patient identified for the study must discontinue all prohibited therapies including 
therapy targeted to treat IPF for at least 28 days before the start of the treatment period. 
Other than permanent use of corticosteroids (prednisolone at a maximum daily dose of 
15 mg or equivalents) and brief periods of corticosteroid use for acute IPF exacerbation, 
patients will not receive any other therapy for the treatment of IPF (see Section 4.4). 
After central review of HRCT and SLB, patients will enter the Screening period, which 
may last up to 28 days (4 weeks). 
After the Screening, eligible patients will enter the Treatment period lasting 26 (± 1) 
weeks. All patients will receive pirfenidone 2403 mg/d administered orally in divided 
doses three times per day (TID) with food. Dose of the study treatment will be titrated 


 
 
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over 14 days to the full dose of 9 capsules per day (three 267 mg capsules taken orally 
TID with food). Patients will remain on a stable maintenance dose for the duration of the 
treatment period unless the dose is reduced to manage adverse events or titrated again 
when restarting study treatment after an appropriate interruption in treatment (see 
Section 5.1.2).  
The primary efficacy endpoint in the study is the change from baseline to Week 26 in 
absolute (mL) FVC and relative (%) FVC as measured by spirometry procedure. 
Spirometry will be performed at the Screening, on Day 1 of treatment, at Week 12, Week 
26 and in the extended Follow-up period (Weeks 39 and 52), if applicable. At screening, 
spirometry measurements will be performed before and after administration of albuterol 
(or salbutamol) from a metered dose inhaler. During further visits, bronchodilator test is 
not necessary to perform. Spirometry data collected throughout the study will be 
evaluated by local readers.  
Patients will have a telephone assessment at Week 1, when safety-related information 
and adherence to treatment is collected. Subsequently patients will have in-clinic visits at 
Weeks 2, 4, 8, 12, 16, 20 and 26. Patients should complete an adverse event and 
dosing compliance diary between all visits. Additionally, telephone calls to patients will 
be scheduled at Weeks 3, 5, 7, 13 and 24 as a part of IPF care program. A total of 5-7 
calls are scheduled in the study, including extra-calls at Weeks 8 and 10 as needed. 
Treatment with pirfenidone will continue until Week 26 (± 1). Patients will be followed 
through the Follow-up visit scheduled 2-4 weeks after treatment completion or until entry 
into the long-term follow-up (rollover study), whichever occurs earlier. Patients who 
undergo lung transplantation or who chose to withdraw from study procedures early will 
be followed for vital status until Week 26. If patients discontinue study treatment early for 
any reason, they should continue with all scheduled study procedures through Week 26.  
Patients who complete participation in the study prematurely due to any reasons (drop-
outs) will not be replaced. 
Patients who proceed until Week 26 in the study and are compliant with the study 
treatment, may continue treatment with commercially available pirfenidone after study 
completion in real clinical practice (long-term follow-up or rollover study). In this case, 
patients will have two follow-up assessments of FVC and 6MWT at Weeks 39 and 52 
and CT scans evaluation at Week 52. Information on AEs occurance will also be 
collected during the rollover part of the study. 
If a patient cannot participate in the rollover part of the study for any reason, a follow-up 
visit will be performed 14-28 days after the last dose of pirfenidone is taken. 




 
 
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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Pirfenidone Dose and Schedule 
Posology and schedule of administration, including dose titration, of pirfenidone in the 
current study are those recommended in the official Russian instruction for use of the IMP.   
These dose and schedule of administration of pirfenidone were evaluated in previous 
controlled clinical trials (CAPACITY-004, -006, ASCEND), which demonstrated favorable 
efficacy and safety results compared with placebo. 
3.3.2 
Rationale for Patient Population 
Based on results from the previous studies, the eligibility criteria have been modified/ 
broadened (including a confident and “working” diagnosis of IPF, patients with %FVC 
≥ 40% and %DLCO ≥ 30%) to ensure that appropriate population will be enrolled to more 
closely correspond to real clinical practice in Russia. This would support estimating 
findings, which were observed in previously conducted studies of pirfenidone. It is 
expected, that studied population diagnosed IPF with mild to moderate deterioration of 
lung function would benefit from the treatment with pirfenidone. 
3.3.3 
Rationale for Control Group  
The study is non-controlled by design. The choice of the non-controlled design is 
supported by the following positions: 
• Enrolment of patients with rare disease in a clinical study is challenging and 
presumes ethical issues to be addressed in the design. Pirfenidone has been 
granted an orphan designation in Europe and the USA. Idiopathic pulmonary fibrosis 
is listed in the Russian Ministry of Healthcare registry of rare (orphan) diseases, so 
pirfenidone obtained the status of an orphan drug in Russia, too. 
• Efficacy of pirfenidone has been previously demonstrated in a number of placebo-
controlled studies and meta-analyses, therefore, additional placebo-controlled study 
in patients with poor prognosis is deemed unethical. 
• There is no adequate literature data to design a comparative active-controlled study 
of pirfenidone; non-inferiority study is merely feasible. 
Taking into consideration all the mentioned above, non-controlled design is considered 
acceptable for the current study from the regulatory and ethical positions.  


 
 
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3.3.4 
Rationale for Open-Label Design 
Open-label design is chosen resulting from the absence of the control group. 
3.3.5 
Rationale for Endpoint Selection 
Primary endpoint rationale 
Decline of FVC over 6 months was convincingly shown to be associated with overall 
prognosis in patients with IPF. Pathophysiologically, fibrotic remodelling of the lung 
interstitium, with a subsequent restrictive ventilatory defect represents the core element 
of the histopathology of IPF. Consequently, any intervention which can slow the fibrosis 
leading to lung restriction is expected to be determined by a reduction in FVC decline. 
This reduction has the potential to ultimately improve prognosis in IPF.  
The primary endpoint of the study, change in FVC from baseline to Week 26, represents 
a clinically meaningful outcome measure that has been demonstrated to be reliable, 
valid, and predictive of changes in other important clinical endpoints in patients with IPF 
(du Bois et al. 2009). Many researchers reported previously that a decrement in %FVC 
over 6 months, particularly if ≥ 10% in magnitude, is both clinically significant and highly 
predictive of mortality (Collard et al. 2007; Flaherty et al. 2003; Zappala et al. 2010). 
Therefore, 6 months’ timeframe for the assessment of the primary outcome is sufficient 
to estimate treatment effect.  
Secondary endpoints rationale 
In addition to a poor prognosis for life expectancy, patients with IPF suffer from dyspnea 
and decrease of tolerability to physical activity. This substantially reduces the quality of 
life and cause major restriction in everyday activity and incapacity in many patients with 
IPF. It is therefore considered valuable to estimate potential influence of the study 
treatment on patient-reported outcomes (Borg scale, EQ-5D). 
Exploratory endpoints rationale 
The 2011 IPF guidelines provide updated and simplified IPF diagnostic criteria proposed 
by the ATS/ERS/JRS/ALAT, which may result in HRCT scanning playing a central role in 
the diagnosis of IPF. Technological advances in HRCT have brought an opportunity of 
HRCT as an accurate, sensitive and objective technique for evaluating IPF.  
In addition, physicians often observe patients who exhibit worsening of HRCT findings 
associated with a poor prognosis in clinical practice. Additional exploratory objective of 


 
 
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this study is to assess the changes in HRCT findings using a new HRCT scoring system 
based on the grading scale.  
Evaluation of the number of exacerbations is a clinically significant outcome but can only 
serve as an exploratory additional outcome, due to the low frequency of such events, 
and low number of patients in the trial. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The study population consists of approximately 60 male and female patients with IPF 
diagnosis aged 40–80 years. Eligible patients must meet the inclusion and exclusion 
criteria outlined below. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Male and female patients aged 40–80 years, inclusive.  
2. Clinical symptoms consistent with IPF of ≥ 6 months duration.  
3. Patients should have both “confident” or “consistent” with UIP diagnosis of IPF 
based on clinical, radiologic or pathologic data according to 2011 ATS/ERS 
guidelines at the Screening. HRCT scan performed within 24 months before the 
start of the Screening may be used. 
4. No features supporting an alternative diagnosis on transbronchial biopsy, 
bronchoalveolar lavage (BAL), or surgical lung biopsy, if performed. Results of 
the surgical lung biopsy performed within the last 4 years must be confirmed by 
central review. 
5. Patients with %FVC ≥ 40 % at the Screening.  
6. Patients with %DLCO ≥ 30 % at the Screening. 
7. Ability to walk ≥ 100 m during the 6-minute walk test at the Screening. 
8. Eligible patients must discontinue all prohibited medications at least 28 days 
before the start of treatment. 
9. Female patients of childbearing potential must have negative urine pregnancy 
test at the Screening and before first dosing on Day 1. 


 
 
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10. Patients able to conceive must agree to use safe contraceptive methods for the 
whole duration of the study and 28 days after the last dosing.  
a. For women of childbearing potential: agreement to remain abstinent (refrain 
from heterosexual intercourse) or use a highly effective contraceptive method 
with a failure rate of  < 1% per year during the treatment period and for at least 
28 days after the last dose of pirfenidone. A woman is considered to be of 
childbearing potential if she is postmenarcheal, has not reached a 
postmenopausal 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 highly effective 
contraceptive methods with a failure rate of < 1% per year include bilateral tubal 
ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices (IUD), and copper intrauterine devices.  
b. 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 or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 28 days after the last dose of pirfenidone to avoid exposing the embryo. 
Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence of patients of both sexes 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 postovulation methods) and withdrawal are not acceptable 
methods of contraception. 
11. Ability to understand and sign Informed Consent Form. 
12. Ability to comply with the study protocol, in the investigator’s judgment (e.g. 
ability to fill out patient diary and other patient-reported outcome tools). 
13. Able to understand the importance of adherence to study treatment and the study 
protocol and willing to follow all study requirements.  
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
Disease-Related Exclusions:  


 
 
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1. Significant clinical worsening of IPF between Screening and Day 1, in the opinion 
of the investigator. 
2. Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC < 0.7) at the 
Screening. 
3. In the opinion of the investigator patients with predicted life expectancy <12 
months or those who are on an active transplant waiting list. 
4. Cigarette smoking within 28 days before the start of treatment or unwilling to 
avoid tobacco products throughout the study.  
5. History of clinically significant environmental exposure known to cause 
pulmonary fibrosis (PF), including but not limited to drugs (such as amiodarone), 
asbestos, beryllium, radiation, and domestic birds.  
6. Known explanation for interstitial lung disease, including but not limited to 
radiation, drug toxicity, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis 
obliterans organizing pneumonia, human immunodeficiency virus (HIV), viral 
hepatitis, and cancer. 
7. Clinical diagnosis of any connective tissue disease, including but not limited to 
scleroderma, polymyositis/ dermatomyositis, systemic lupus erythematosus, and 
rheumatoid arthritis, or patients with positive biomarker tests associated with these 
diseases (rheumatoid factor, anticyclic citrullinated peptide and antinuclear antibodies) 
at the Screening.  
8. During baseline analysis of HRCT, significant coexistent emphysema 
(emphysema extent greater than extent of fibrosis) confirmed by central review. 
9. Planned lung transplantation during the study. 
10. Clinical evidence of active infection, including but not limited to bronchitis, 
pneumonia, sinusitis, urinary tract infection, or cellulitis.  
Medical Exclusions:  
11. Unable to perform 6MWT or to undergo pulmonary function test. 
12. Any history of malignancy likely to result in significant disability or likely to 
require significant medical or surgical intervention within the next 1 years. This 


 
 
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does not include minor surgical procedures for localized cancer (e.g., basal cell 
carcinoma).  
13. History of severe hepatic impairment or end-stage liver disease.  
14. History of end-stage renal disease requiring dialysis. 
15. History of unstable or deteriorating cardiac or pulmonary disease (other than IPF) 
within the previous 6 months, including but not limited to the following:  
a. 
unstable angina pectoris or myocardial infarction 
b. 
congestive heart failure requiring hospitalization 
c. 
uncontrolled clinically significant arrhythmias 
16. Pregnancy or lactation, or intention to become pregnant during the study. 
Women of childbearing capacity are required to have a negative urine pregnancy 
test before treatment and must agree to maintain highly effective contraception.   
17. History of alcohol or substance abuse in the past 1 year.  
18. History of gastrointestinal (GI) tract perforation or history of peptic ulcer within six 
months. 
19. Family or personal history of long QT Syndrome.  
20. Known hypersensitivity to pirfenidone during prior treatment or any excipient of 
the study treatment.  
21. Use of any of the following therapies within 28 days before the start of treatment 
period:  
a. investigational therapy, defined as any drug that has not been approved for 
marketing for any indication in Russia 
b. any cytotoxic, immunosuppressive, cytokine modulating, or receptor 
antagonist agent including but not limited to azathioprine, bosentan, 
ambrisentan, 
cyclophosphamide, 
cyclosporine, 
etanercept, 
iloprost, 
infliximab, leukotriene antagonists, methotrexate, mycophenolate mofetil, 
tacrolimus, montelukast, tetrathiomolybdate, tumor necrosis factor (TNF)-α 


 
 
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inhibitors, N-acetylcysteine (NAC), imatinib mesylate, interferon gamma-1b 
(IFN γ-1b), and tyrosine kinase inhibitors 
c. medications that are specifically used for the treatment of IPF including but 
not limited to angiotensin converting enzyme (ACE) inhibitors, colchicine, 
corticosteroids (prednisolone at doses exceeding 15 mg/day or equivalents), 
heparin, warfarin, and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) 
reductase inhibitors. These drugs may be used if given for a non-IPF 
indication if there is no clinically acceptable alternative therapy for the same 
indication 
d. fluvoxamine 
e. sildenafil (chronic use for pulmonary arterial hypertension). Note: 
intermittent use for erectile dysfunction is allowed. 
Laboratory Exclusions:  
22. Any of the following liver function test outside specified limits at the Screening:  
a. total bilirubin above the upper limit of normal (ULN);  
b. aspartate or alanine aminotransferase (AST or ALT) > 3 × ULN;  
c. alkaline phosphatase > 2.5 × ULN.  
23. Creatinine clearance < 30 mL/min, calculated using the Cockcroft-Gault formula 
(see Section 4.5.8).  
24. Electrocardiogram (ECG) with a QT interval corrected according to Fridericia’s 
formula (QTcF) > 500 msec at the Screening. 
Other Exclusions: 
25. Inability to return for follow-up visits or obtain follow-up data required to assess 
study therapy, or presence of other reasons for anticipated non-compliance to 
therapy or procedures, in the opinion of the investigator. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
The study is a single-arm, open-label by design. All patients will receive pirfenidone 
2403 mg/d orally in divided doses TID after titration period of 14 days (Section 4.3.2). 


 
 
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Therefore, treatment allocation methods and blinding/ unblinding procedures are not 
applicable in the study. 
4.3 
STUDY TREATMENT  
The investigational medicinal product (IMP) for this study is Pirfenidone (trade name 
Esbriet, drug code RO0220912) (INN: pirfenidone, ATC code L04AX05) 267 mg 
capsules, manufactured by Catalent Pharma Solutions, Winchester, USA. 
The terms "study drug" and "study treatment" are used throughout the protocol and refer 
to the test product pirfenidone.  
4.3.1 
Formulation, Packaging, and Handling 
Pirfenidone will be supplied to the study sites by the Sponsor (F. Hoffmann-La Roche 
Ltd., Switzerland) as needed. 
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and will bear labeling with identification required by law, the protocol number, drug 
identification, and dosage. The packaging and labeling of the study medication will be in 
accordance with Roche standard and local regulations. 
Formulation 
Pharmaceutical form: hard capsules (capsules). 
Composition: each capsule contains: active substance - 267 mg pirfenidone (82.15%); 
excipients - croscarmellose sodium 8.15%, microcrystalline cellulose 7.39%, povidone, 
USP, EP 1.85%, magnesium stearate 0.46%.  
Appearance: two piece hard capsules with a white to off-white opaque body and white to 
off-white opaque cap imprinted with “PFD 267 mg” in brown ink and containing a white to 
pale yellow powder.  
Packaging and labelling 
Study treatment will be supplied in bottles, 270 capsules per bottle.  
Bottles will be labeled for investigational use only according to applicable regulations of 
the Russian Federation. 


 
 
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Storage 
Investigator is responsible for appropriate storage of the study drug. Investigator should 
maintain temperature in the room of storage and fill out temperature log on regular basis. 
The study drug must be stored as prescribed in the official Russian instruction for use of 
pirfenidone (Esbriet). Shelf life is indicated on label. Study drug must not be used beyond the 
expiration date. 
Handling 
Study treatment will be dispensed by the responsible investigator or investigational site 
pharmacist only to the participants of this clinical study. Drug accountability must be 
confirmed in written by the responsible employee of the site (see Section 4.3.3). Detailed 
Instructions for handling of the study drug will be provided to investigational sites as 
appropriate. 
 
4.3.2 
Dosage, Administration, and Compliance 
Study treatment will be initiated on Day 1 in patients who completed Screening period 
successfully and fully comply for the study. Study treatment will continue until visit at Week 
26 (± 1 week), unless terminated earlier for reasons indicated in Section 4.6.2, or patient is 
proceeding in the rollover study.Pirfenidone will be taken orally in a daily dose of 2403 mg 
in divided doses three times per day with food. Study treatment should be titrated over 
14 days, as tolerated, to the full dose of 9 capsules per day (three capsules TID), as 
follows:  
• 
Days 1 to 7: one capsule TID (801 mg/day) 
• 
Days 8 to 14: two capsules TID (1602 mg/day) 
• 
Day 15 and continuing: three capsules TID (maximum of 9 capsules daily equal 
to 2403 mg/day). 
Each dose should be taken with food, with a drink of water, at the same time each day. 
Patients will remain on a stable maintenance dose for the duration of the study period 
unless the dose is reduced to manage AEs. Guidelines for dosage modification and 
treatment interruption or discontinuation are provided in Section 5.1.2. 
Any overdose or incorrect administration of the study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF). Adverse events 


 
 
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associated with an overdose or incorrect administration of the study drug should be 
recorded on the Adverse Event eCRF. Section 5.3.5.10 summarizes available safety data 
related to overdosing of pirfenidone. 
4.3.3 
Investigational Medicinal Product Accountability 
IMP required for completion of this study will be provided by the Sponsor as required by 
the local health authority regulations. The study site will acknowledge receipt of the IMP, 
using the Interactive Web Response System (IWRS) for Patient Randomization and Trial 
Supply Management or by returning the appropriate documentation form, to confirm the 
shipment condition and content. Any damaged shipments will be replaced. 
IMP either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation. The site’s method of IMP destruction must be agreed to by the Sponsor. 
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Study treatment will be dispensed to the patient every 12 weeks, but may be dispensed 
at other visits, as needed. Patients will be instructed to store study treatment at room 
temperature. Patients will be instructed to use study treatments as prescribed by the 
investigator and to keep and return to the investigator all used and unused bottles of the 
study drug upon completion of the study treatment.  
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. After drug accountability 
has been verified, sites will return all used and unused study treatment bottles to the 
Sponsor in accordance with applicable standard operating procedures. 
4.3.4 
Post-Trial Access to Pirfenidone 
Roche is committed to a high standard of quality and ethical conduct in all aspects of 
conducting clinical trials. As part of this commitment and in accordance with the 
Declaration of Helsinki, Roche offers patients who participate in Roche-sponsored 
clinical trials continued access to IMP. However, in this trial Roche is not obliged to 
provide pirfenidone to patients who have completed the 26-week study, due to the fact 
that investigational medicinal product will be commercially marketed in Russia and 
reasonably accessible to the patient. Also, there is availability of appropriate alternative 
treatment to the patient on Russian market. 
The patients can continue treatment with pirfenidone in routine clinical practice 
according to the local label. 


 
 
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4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND ADDITIONAL 
RESTRICTIONS 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to initiation of study drug to the study completion/ 
discontinuation visit. All such medications should be reported to the investigator and 
recorded on the Concomitant Medications eCRF. Collection of concomitant medication 
data is ceased if a patient enters the rollover study. 
4.4.1 
Permitted Therapy  
Corticosteroids may be used permanently at the discretion of the investigator as a part of 
routine management of IPF (at a maximum daily dose of 15 mg of prednisolone or 
equivalents). Corticosteroids may also be used without dose restriction for a period of up 
to 21 days in patients experiencing an episode of acute IPF exacerbation. The study 
drug should be continued during exacerbations, if possible. If study treatment 
interruption or discontinuation is considered, it must be immediately reported by 
telephone to Sponsor’s Medical Monitor or designee. 
An acute IPF exacerbation is defined in updated publication (Collard HR et al., 2016).  
The diagnostic criteria:  
 
• 
Previous or concurrent diagnosis of IPF; 
• 
Acute worsening or development of dyspnea typically <1 mo duration; 
• 
Computed tomography with new bilateral ground-glass opacity and/or 
consolidation superimposed on a background pattern consistent with usual 
interstitial pneumonia pattern; 
• 
Deterioration not fully explained by cardiac failure or fluid overload. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 


 
 
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4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study and for at least 28 days prior 
the start of treatment period: 
• 
investigational therapy, defined as any drug that has not been approved for 
marketing for any indication in the country of the participating site; 
• 
corticosteroids at a daily doses exceeding 15 mg/ day of prednisolone or 
equivalents when used for the treatment of IPF (except for durations of up to 21 
days for acute IPF exacerbation, see Section 4.4.1). No restrictions apply to 
corticosteroids used for reasons other than IPF therapy (e.g., allergic reactions, 
sepsis); however, the specific reason for use must be recorded; 
• 
cytotoxic, immunosuppressive, cytokine-modulating, or receptor antagonist 
agents including, but not limited to, azathioprine, bosentan, ambrisentan, 
cyclophosphamide, cyclosporine, 
D-penicillamine, 
colchicines, etanercept, 
iloprost, infliximab, leukotriene antagonists, methotrexate, mycophenolate mofetil, 
tacrolimus, montelukast, tetrathiomolybdate, TNF-α inhibitors, NAC, IFN-γ1b, and 
tyrosine kinase inhibitors; 
• 
concomitant medications used for the treatment of IPF including but not limited to 
ACE inhibitors, warfarin, heparin, and HMG-CoA reductase inhibitors. These 
drugs may be used if given for a non-IPF indication, if there is no clinically 
acceptable alternative therapy for the same indication; however, the specific 
reason for use must be recorded; 
• 
sildenafil (daily use). Note: intermittent use for erectile dysfunction is allowed. 
In vitro data suggest that pirfenidone is metabolized by CYP1A2 without apparent 
inhibitory activity on the enzyme, however, there is a potential for drug-drug interaction 
with any medication that is metabolized by or strongly inhibits or induces this enzyme. 
Therefore, the medications listed below should be avoided. If use of one of these 
medications is necessary, the risks and benefits should be discussed with the Medical 
Monitor prior to concomitant administration with pirfenidone: 
• 
strong CYP1A2 inhibitors, including, but not limited to, fluvoxamine and enoxacin 
(a 2- to 4-fold increase in exposure to pirfenidone); 
• 
moderate CYP1A2 inhibitors, including, but not limited to, ciprofloxacin, 
amiodarone, propafenone. 


 
 
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The above lists of medications are not necessarily comprehensive. Thus, the 
investigator should consult the prescribing information for any concomitant medication 
as well as the Internet references provided below when determining whether a certain 
medication is metabolized by or strongly inhibits or induces CYP1A2. In addition, the 
investigator should contact the Medical Monitor if questions arise regarding medications 
not listed above. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM292362.pdf 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
4.4.3 
Prohibited Food  
Consumption of grapefruit juice is associated with inhibition of CYP1A2 and should be 
avoided during treatment with pirfenidone. 
No special diet or dietary restrictions are otherwise designated in the study, unless 
recommended by the investigator for the treatment of adverse events. 
 
4.4.4 
Additional Restrictions  
Patients should stop smoking at entering the treatment period (not less than 28 days 
before the start of treatment) as smoking is known to induce metabolism of the study 
drug and thus attenuate treatment effect. Smoking patients will not be enrolled in the 
study. 
All participants will be warned of the potential photosensitivity skin adverse reactions and 
will be advised to use sunscreens during exposure to direct sunlight. 
4.5 
STUDY ASSESSMENTS  
Study procedures are defined as laboratory tests, spirometry, DLCO measurement, ECG, 
HRCT scan, directed medical history, physical examination, vital signs, height, weight, 
GAP risk assessment, 6MWT and Borg Scale, EQ-5D questionnaire, procedures for 
eliciting AEs and any changes to existing treatment regimens.  
Patients will be followed through the Follow-up visit scheduled 2-4 weeks after treatment 
completion on Week 26 (± 1) or until entry into the long-term follow-up (rollover study), 
whichever occurs earlier. Patients who undergo lung transplantation or who choose to 
withdraw from study procedures early will be followed for vital status until Week 26.  
Please see Appendix 1 for the schedule of activities to be performed during the study. 


 
 
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4.5.1 
Informed Consent Forms and Screening Log 
Written Informed Consent for participation in the study must be obtained before 
performing any study-related procedures. Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
An additional Informed Consent visit may be perfomed prior to the start of the Screening 
procedures and an appropriate review of the patient’s clinical data relevant to the IPF 
diagnosis is done (see Appendix 1). 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria within 4 weeks before enrollment. The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
All patients should be notified of the necessity to use safe contraceptive methods during 
participation in the study and 28 days after its completion or discontinuation (see Section 
4.1.1). 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
use of alcohol, and drugs of abuse. In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 28 days prior to treatment period will be 
recorded. 
Demographic data will include age, sex, and self-reported race and ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination should be performed at an IC visit, the Screening 
(Washout) and should include an evaluation of the head, eyes, ears, nose, and throat, 
the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems. Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in patient notes. New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 


 
 
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4.5.4 
Weight and Height 
Weight and height will be measured as outlined in Appendix 1. Height will be assessed 
at the Screening only. 
4.5.5 
Vital Signs  
Vital signs will be measured by the investigator at the Screening and subsequent visits 
and include measurements of respiratory rate (breaths/ minute), pulse rate (beats/ 
minute), and systolic and diastolic blood pressure (mmHg), and axillary temperature (ºC). 
Respiratory rate will be measured in patient’s resting position by counting chest 
movements per minute. Blood pressure and pulse rate will be measured in the supine/ 
sitting position. All recordings should be made using the same blood pressure recording 
instrument. Pulse rate is defined as radial pulse counted for 30 seconds in the supine/ 
sitting position. Body temperature is defined as axillary temperature (ºC). 
4.5.6 
HRCT and Surgical Lung Biopsy 
4.5.6.1 
High-Resolution Computed Tomography 
HRCT scans should be obtained before the Screening period as part of the routine 
practice for a patient. It may be used to confirm eligibility. For eligibility confirmation 
acceptable HRCT scans should be dated not earlier than 2 years before the Screening.  
Baseline HRCT scans will be performed only in those patients who have no acceptable 
scans within 2 months before the start of treatment period (Day 1) and had no IPF 
exacerbations within this period. Semiquantitative analysis of CT scans with HRCT 
fibrosis score calculation should be performed in each timepoint as outlined in the 
schedule of study assessments (see Appendix 1).  
All HRCT images are to be read by the site’s local radiologist reader at first. Additionally, 
for eligibility confirmation the HRCT scans will be reviewed by two central readers who 
are radiologists with expertise in IPF. If the first expert (central reader-1) agrees with the 
local opinion, the second expert (central reader-2) will not review scans. If the first expert 
disagrees with the local opinion, the second expert should review scans.  
HRCT acquisition in the study will be performed using the same scanning protocol. 
Images in a particular site should be read by the same local specialist. Further 
semiquantitative assessments of CT scans for fibrosis scores will be performed by one 
central reader. Detailed HRCT acquisition protocol and fibrosis scoring system are 
described in Appendix 2. 


 
 
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All HRCT digital scans should be stored on a dedicated disk or tape at each study center. 
The images will be transferred electronically to the central readers responsible for 
interpretation of the images.  
Data regarding the HRCT interpretation will be entered electronically into the vendor’s 
database and incorporated into the clinical database.  
4.5.6.2 
Surgical Lung Biopsy 
Histopathological assessment of the lung tissue samples obtained within 4 years before 
the Screening should be performed centrally for eligibility confirmation. Histopathological 
evaluation, if not available, is not repeated at the Screening.  
Transbroncheal biopsy or BAL are not mandatory and will only be reviewed at the 
Screening, if available, to exclude other causes of PF. 
Histopathologic criteria for UIP are outlined in Appendix 3. Samples will be submitted 
and reviewed by one of the two central readers who are pathologists with expertise in 
IPF. Data regarding the pathology findings will be entered directly into the electronic 
case report form (eCRF).  
The observations of the central readers in radiology and pathology will be stored in the 
clinical database. Based on the algorithm detailed in Table 2, patient eligibility will be 
communicated to the study site by the Sponsor’s designated vendor.  


 
 
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Table 2 
Summary of Select Criteria for Diagnosis of IPF 
 
Surgical 
Lung 
Biopsy Not 
Available 
Pathology 
Panel: 
Definite 
UIP 
Pathology 
Panel: 
Probable 
UIP 
Pathology 
Panel: 
Possible 
UIP 
Pathology Panel: 
Inconsistent with 
UIP or Not 
Classifiable 
Radiology 
Panel: Definite 
UIP  
Eligible 
Eligible 
Eligible 
Eligible 
NOT Eligible 
Radiology 
Panel: 
Possible UIP  
Eligible 
Eligible 
Eligible 
NOT Eligible 
NOT Eligible 
Radiology 
Panel: 
Inconsistent 
with IPF  
NOT 
Eligible 
NOT 
Eligible 
NOT 
Eligible 
NOT Eligible 
NOT Eligible 
 
4.5.7 
Spirometry and DLCO Measurements 
Spirometry and PFT will be standardized and performed as described in ATS 
recommendations (ATS 2005). 
FVC  
FVC is the maximal volume of air exhaled with maximally forced effort from a maximal 
inspiration, i.e. vital capacity performed with a maximally forced expiratory effort, 
expressed in litres at body temperature and ambient pressure saturated with water 
vapour (ATS 2005). 
At screening, spirometry measurements of FVC will be performed before and after 
administration of albuterol (or salbutamol) from a metered dose inhaler. Four separate 
doses of 100 mg should be used when given by metered dose inhaler using a spacer. 
Tests should be repeated after a 15-min delay. During further visits, bronchodilator test is 
not necessary to perform.  
DLCO 
DLCO will be measured by determining the diffusing capacity of the lung for carbon 
monoxide corrected to hemoglobin. DLCO measurement should be performed before or 
at least 30 min after the last bronchodilator puff, in case bronchodilator test has been 


 
 
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performed. It is measured by a single breath technique where helium and carbon 
monoxide are rapidly inspired, held for several seconds and then expired with the 
measurement of the remaining carbon monoxide. Comparison of the inspired and 
expired CO fractions allows calculation of DLCO (Ranu et al. 2011). 
Results of DLCO measurements should be corrected to patients’ hemoglobin (Hb) using 
one of the formulas (Cotes et al. 1979):  
Hb-corrected DLCO for men: DLCO × (10.22 + Hb)/(1.7 × Hb) 
Hb-corrected DLCO for women: DLCO × (9.38 + Hb)/(1.7 × Hb) 
where Hb indicates the value of hemoglobin, in g/dL. If the Hb value is reported in g/L, 
then the Hb value is divided by 10. If the Hb value is reported in mmol/L, then the Hb 
value is divided by 0.6206.  
Use the hemoglobin value available on the same day if possible; otherwise, the closest 
hemoglobin value before or after the actual DLCO assessment date should be used. If the 
two values are equidistant, the value before the actual DLCO assessment should be used 
(Cotes et al. 1979). 
Lung fuction assessments in one patient during the study should be performed using the 
same equipment and by the same investigator. All spirometry and DLCO data collected 
throughout the study will be evaluated by local readers. Data for FVC and DLCO will be 
entered by the study staff into the eCRF electronically.  
4.5.8 
Laboratory, Biomarker, and Other Biological Samples  
All samples for laboratory tests (hematology, blood chemistry, serologic tests) will be 
analyzed in the study site's local laboratory. 
 
Blood samples should be obtained in fasted patients and handled appropriately. The 
following parameters will be utilized in the study: 
• 
hematology (plasma): white blood cells (WBC) count, red blood cells (RBC) 
count, hemoglobin, hematocrit, platelet count, (relative) differential WBC count 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes); 
• 
blood chemistry panel (serum or plasma): albumin, alkaline phosphatase (AP), 
ALT, AST, direct bilirubin, total bilirubin, total protein, albumin, cholesterol, 
creatine kinase (CK), creatinine, triglycerides, gamma-glutamyl transferase 


 
 
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(GGT), glucose, lactic dehydrogenase (LDH), calcium, phosphorus, magnesium, 
potassium, sodium, urea nitrogen, uric acid; 
• 
serologic tests (at screening only, exclusion tests): rheumatoid factor, anticyclic 
citrullinated peptide and antinuclear antibody titer. 
Creatinine clearance  
Creatinine clearance should be assessed at the Screening for eligibility confirmation 
using the following formula by Cockcroft-Gault (Cockcroft DW et al, 1976): 
For serum creatinine concentration in mg/dL: 
CrCl (mL/min) = (140 – age (years)) × weight (kg) × 1.0 / 72 × serum creatinine (mg/dL) 
For serum creatinine concentration in µmol/L: 
CrCl (mL/min) 
= (140 – age 
(years)) × weight 
(kg) × 1.0 / 0.81 × serum 
creatinine 
(µmol/L) 
Pregnancy test 
All women of childbearing potential will have a urine pregnancy test at the Screening and 
on Day 1 before start of treatment. Only women with negative pregnancy test will be 
included in the study. Urine pregnancy tests will be performed repeatedly at specified 
subsequent visits as scheduled in the Appendix 1.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
Women with confirmed positive pregnancy test should be immediately withdrawn from 
the study treatment (see Section 5.4.3). Urine pregnancy test will be performed by the 
investigator using test-strips with least sensitivity to human chorionic gonadotropin (hCG) 
of 10 mLU/mL.  
The investigator can perform clinical laboratory assessments more frequently, if it is 
clinically indicated. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. Biological samples will be destroyed immediately after analyzing.  
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples. 


 
 
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Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.9 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements. 
Lead placement should be as consistent as possible. ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes. 
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws, bronchodilator test) and should not be 
obtained within 3 hours after any meal. Circumstances that may induce changes in heart 
rate, including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings. Paper and digital copies of ECG tracings will be kept as part of the patient's 
permanent study file at the site. The following should be recorded in the appropriate 
eCRF: heart rate, RR interval, QRS interval, PR duration, uncorrected QT interval, and 
QT interval corrected for heart rate using Fridericia’s method (QTcF) based on the 
machine readings of the individual ECG tracings. Any morphologic waveform changes or 
other ECG abnormalities must be documented on the eCRF. If considered appropriate 
by the Sponsor, ECGs may be analyzed retrospectively at a central laboratory. 
If at a particular postdose timepoint the QTcF is  > 500 ms and/ or  > 60 ms longer than 
the baseline value, another ECG must be recorded, ideally within the next 5 minutes or 
in the utmost 24 hours, and ECG monitoring should continue until QTcF has stabilized 
on two successive ECGs. The Medical Monitor should be notified. Standard-of-care 
treatment may be instituted per the discretion of the investigator. A decision on study 
drug discontinuation should be made, as described in Section 5.1.2. The investigator 
should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia). 
4.5.10 
6-Minute Walk Test  
The 6MWT measures the distance in meters that a patient can walk at his/her own pace 
on a measured, flat hard surface in a period of 6 min. The 6MWT assesses the global 
and integrated responses of all body systems involved during walking. The 6MWT based 


 
 
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on ATS recommendations (ATS 2002) will be performed as outlined in the Reference 
Guide. 
4.5.11 
Patient-Reported and Clinician-Reported Outcomes 
PRO data will be collected via questionnaires to document the treatment benefit of 
pirfenidone. ClinRO data will be collected using a scale for patient clinical assessment at 
baseline. The validated scales and questionnaires, translated into the local language as 
required, will be completed in their entirety at specified timepoints during the study.  
To ensure instrument validity and that data standards meet health authority 
requirements, questionnaires will be self-administered before the patient or clinician 
receives any information on disease status, prior to the performance of non-PRO 
assessments, and prior to the administration of study treatment, unless otherwise 
specified. 
4.5.11.1 
Borg Scale  
The Borg Scale is an instrument to be self-administered by the patient as part of the 
6MWT procedure (Borg 1982) (see Appendix 4). The Borg scale should be printed on 
heavy paper (11 inches high and perhaps laminated) in 20-point type size. At the 
beginning of the 6-minute exercise, the patient should tick the answer to the question: 
“Please rate the current severity of your breathlessness by circling the most appropriate number 
on the following scale.” At the end of the exercise, the patient should grade his breathing 
level again.  
Study staff will enter the 6MWT data into the eCRF. 
4.5.11.2 
EuroQol 5-Dimension Questionnaire 
The European Quality of Life (EuroQol) 5-Dimension Questionnaire, 5-level version (EQ-
5D-5L), is a self-report health status questionnaire that consists of six questions used to 
calculate a health utility score for use in health economic analysis (EuroQol Group, 1990; 
Brooks 1996; Herdman et al. 2011; Janssen et al. 2013; Jindal et al. 2011; Behr J et al.  
2013).   
There are two components to the EuroQol EQ-5D: a five-item health state profile that 
assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as 
well as a visual analogue scale (VAS) that measures health state. Published weighting 
systems allow for creation of a single summary score. Overall scores range from 0 to 1, 
with low scores representing a higher level of dysfunction. The EQ-5D will be utilized in 
this study for economic modeling.  


 
 
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EQ-5D-5L questionnaire (Self-completed version on paper 1.0) will be used in the study. A 
sample of the validated questionnaire in English (for UK) is provided in Appendix 5. A validated 
version (Self-completed version on paper 1.0) in a local (Russian) language will be given to the 
patients for completion.The questionnaire will be administered on the visits as outlined in 
the schedule of activities (see Appendix 1) and prior to any interventions. The patients 
will be provided with a hard copy of a questionnaire and a pen. Patients should be given 
ample time for questionnaire completion. 
4.5.11.3 
GAP Risk Assessment System 
The GAP (Gender, Age, Physiology) risk assessment system is a validated clinical 
prediction tool for estimating prognosis in patients with IPF. It consists of two 
complimentary prognostic tools intended to inform, but not replace clinical judgment.  
First, the GAP index and staging system provides a simple screening method for 
determining the average risk of mortality of patients by GAP stage. Second, the GAP 
calculator provides an estimation of individual risk of mortality for those patients in whom 
a more precise estimation of risk may further inform patient care (see Appendix 6). 
The GAP risk assessment system is utilized at baseline only. Points for each variable of 
the scoring system will be entered by the investigator directly into the eCRF. GAP index 
and an estimation of individual risk of mortality will be calculated automatically by the 
system (Ley et al. 2012). 
GAP risk assessment is utilized on the basis of predicted DLCO values. The formulas for 
computing predicted DLCO are as follows (Crapo and Morris 1971):  
Predicted DLCO for men 0.410 × height (cm) − 0.210 × age (yr) − 26.31  
Predicted DLCO for women 0.282 × height (cm) − 0.157 × age (yr) − 10.89. 
4.5.12 
IPF Care Program  
IPF Care Program is a program developed by the Sponsor to support patients with the 
debilitating lung disease, who are enrolled in the study. The program is implemented to 
improve patients’ compliance to the study treatment and reduce number of drop-outs. 
The program consists of telephone calls to the patient scheduled at specific timepoints 
and voluntary information materials for patients. 


 
 
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Telephone calls 
Telephone calls to patients will be scheduled at Weeks 3, 5, 7, 13 and 24. Additional 
calls can be performed at Weeks 8 and 10 as needed. A total of 5-7 calls are scheduled 
in the study. Topics for discussion will include the following: 
• 
Explanation of the IPF disease nature 
• 
Pirfenidone titration and dosing 
• 
Management of side effects 
• 
Everyday life 
• 
Answering questions 
• 
Necessity of additional calls. 
A detailed schedule of calls and topics for discussion at each timepoint is presented in 
Appendix 7. 
Investigator should record in the eCRF the date and time of the IPF Care Program calls. 
Information materials 
The following materials will also be provided to all patients participating in the trial: 
• 
Patient information brochure (information on treatment with pirfenidone) 
• 
Pocket guide (brief information on treatment with pirfenidone) 
The materials will be supplied by the Sponsor and dispensed by the investigators or 
other designated staff. Samples of the IPF Care Program will be provided to the study 
sites as separate documents. 
4.5.13 
Details on the Study Visits 
Before starting any study specific procedures, investigator must have  HRCT and 
surgical biopsy (if applicable) performed in routine practice confirming diagnose of IPF to 
assess eligibility of patient.. 


 
 
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4.5.13.1 
Informed Consent Visit   
Written informed consent must be obtained before initiating any study-associated 
procedures or changes to a pre-existing treatment regimen for purposes of this study. 
Informed Consent Visit is performed for explaining the study, collecting Informed 
Consent,   handing out the Patient Information, collecting and  sending HRCT or surgical 
biopsy (if applicable) and also for starting the washout medication prior 28 days to start 
of treatment. Any patient identified for the study, must discontinue all prohibited 
medications and stop smoking at least 28 days before the start of treatment. This is the 
Washout Period. If a medication must be tapered, tapering must start early enough that 
the patient has discontinued the drug 28 days before the start of treatment. Written 
informed consent must be obtained before withdrawing or tapering the patient off 
prohibited therapies. 
After signing the Informed consent, the investigator must review and transfer for central 
review HRCT scans, surgical lung biopsies (if available), which were performed in 
routine practice, to assess eligibility. (HRCT must be no older than 24 months. Results of 
the surgical lung biopsy must be no older than 4 years). 
The investigator must explain to the patient that entry into the study is not guaranteed. 
4.5.13.2 
Screening Period (Day -28 to Day -1)  
Procedures conducted during Screening will be used to determine the eligibility of each 
patient for study enrollment before initiation of treatment and to establish patient 
baseline status. If patients fail Screening due to a condition that subsequently resolves 
(e.g., infection), they may be considered for rescreening; however, these patients must 
be discussed with the study Medical Monitor or designee before rescreening. In case of 
rescreening, the patient must be reconsented. 
The Screening period is defined as the time between the date of the first Screening 
procedure and Day -1 and may last up to 28 days. Screening procedures may be 
conducted on different days within the Screening period, if convenient. The order of 
procedures is not strict; however, basic requirements to be followed are given in gaps 
below. 
The following procedures will be performed during Screening:  
• 
Demographic data 
• 
Review and update medical history and concomitant medications  
• 
EQ5D questionnaire (should be performed before any other non-PRO assessments) 


 
 
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• 
ECGs (obtained before bronchodilator administration or on a separate day) All ECGs are to 
be obtained prior to other procedures scheduled at that same time (e.g., vital sign 
measurements, blood draws) and should not be obtained within 3 hours after any meal. 
• 
Physical examination, vital signs, weight, and height  
• 
Clinical laboratory assessments, including hematology, serum chemistries, serologic 
tests, and pregnancy test for women of childbearing capacity (blood samples must 
be drawn in fasted state) 
• 
HRCT scan for baseline assessment (for patients with HRCT scans performed more 
than 2 months before the treatment period or with scans not meeting  the imaging 
acquisition criteria outlined in Appendix 2)  
• 
Review transbronchial lung biopsy/ BAL; 
• 
Spirometry (FVC) (before and after bronchodilator administration with a 15 min 
delay).Сollection and recording of the retrospective FVC values obtained in clinical 
practice over the last year. 
• 
6MWT and Borg Scale    
• 
DLCO (obtained before or 30 min after bronchodilator administration) 
• 
GAP assessment  
• 
Eliciting AEs  
 
4.5.13.3 
 Start of Treatment (Day 1)  
Treatment must be initiated no more than 28 days after the start of screening. All Day 1 
procedures must be performed before administration of the study treatment. This study 
has no Day 0.  
The following procedures will be performed on Day 1:  
• 
Directed history (including review of AEs/SAEs, concomitant medications, oxygen 
use, and hospitalizations)  
• 
EQ5D questionnaire (should be performed before any other non-PRO assessments) 
• 
ECGs. All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours after 
any meal. 
• 
Physical examination, vital signs, and weight  


 
 
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• 
Clinical laboratory assessments, including hematology, serum chemistries, 
pregnancy test for women of childbearing capacity (blood samples must be taken in 
fasted state) 
• 
Spirometry (FVC)  
• 
6MWT and Borg Scale  
• 
Confirmation of patient eligibility for study participation  
• 
Instruct the patient on how to titrate the dose of study treatment  
• 
Dispense 12-week supply of study treatment. Dosing should start on the Day 1  
• 
Dispense patient diary and instruct patients on how to properly record information 
using the diary. 
4.5.13.4 
Week 1 Telephone Assessment (± 1 Day)  
A telephone interview will be conducted to determine vital status and to assess 
tolerability of study treatment, patient compliance with dosing, and titration of study 
treatment.  
4.5.13.5 
Weeks 2, 4, and 8 (± 2 Days)  
 
The following procedures will be performed at Weeks 2, 4, and 8:  
• 
Directed history (including review of AEs/SAEs, concomitant medications, oxygen 
use, hospitalizations, dosing)  
• 
ECG (at Weeks 4 and 8 only)/ All ECGs are to be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws) and should not be 
obtained within 3 hours after any meal. 
• 
Physical examination, vital signs, and weight  
• 
Clinical laboratory assessments, including hematology, serum chemistries, and 
pregnancy test for women of childbearing capacity (pregnancy test at Weeks 4 and 
8 only) 
• 
Review patient’s diary  
4.5.13.6 
Weeks 12 (± 2 Days)  
 
The following procedures will be performed at Week 12:  
• 
Directed history (including review of AEs/SAEs, concomitant medications, oxygen 
use, hospitalizations, dosing) 
• 
EQ5D questionnaire (should be performed before any other non-PRO assessments)  


 
 
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• 
Physical examination, vital signs, and weight  
• 
Clinical laboratory assessments, including hematology, serum chemistries, and 
pregnancy test for women of childbearing capacity 
• 
Spirometry (FVC)  
• 
6MWT and Borg Scale  
• 
Review patient’s diary  
4.5.13.7 
Weeks 16 and 20 (± 1 Week)  
The following will be performed at Weeks 16 and 20:  
• 
Directed history (including review of AEs/SAEs, concomitant medications, oxygen 
use, hospitalizations, dosing)  
• 
Physical examination, vital signs, and weight  
• 
Clinical laboratory assessments, including hematology, serum chemistries, 
pregnancy test for women of childbearing capacity (pregnancy test at Week 20 only) 
• 
Review and dispense new diary, if required.  
4.5.13.8 
Week 26 (± 1 Week)  
The following will be performed at Week 26 (on two separate days):  
1st day at Week 26: 
• 
Physical examination, vital signs 
• 
Spirometry (FVC)  
• 
6MWT and Borg Scale  
2nd day at Week 26: 
• 
Directed history (including review of AEs/SAEs, concomitant medications, oxygen 
use, and hospitalizations)  
• 
EQ5D questionnaire (should be performed before any other non-PRO assessments) 
• 
ECG. All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours after 
any meal. 
• 
Physical examination, vital signs, and weight  
• 
Clinical laboratory assessments, including hematology, serum chemistries, 
pregnancy test for women of childbearing capacity  


 
 
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• 
HRCT 
• 
Spirometry (FVC) 6MWT and Borg Scale  
• 
Collect patient’s diary 
4.5.13.9 
Follow-up Visit (14-28 Days after Last Dosing) 
The following will be performed at follow-up: 
• 
Directed history (including review of AEs/SAEs, concomitant medications, oxygen 
use, and hospitalizations)  
• 
Physical examination, vital signs, and weight  
• 
Clinical laboratory assessments (hematology, serum chemistries) 
• 
Estimating patient’s further participation in the rollover study 
4.5.13.10 
Long-Term Follow-Up/ Rollover Study  
Week 39 (± 2 weeks) 
The following will be performed at Week 39: 
• 
Physical examination, vital signs 
• 
Clinical laboratory assessments (hematology, serum chemistries) 
• 
Spirometry (FVC)  
• 
6MWT and Borg Scale  
• 
Review AEs 
Week 52 (± 2 weeks) 
The following will be performed at Week 52: 
• 
EQ5D questionnaire (should be performed before any other non-PRO assessments) 
• 
ECG. All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours after 
any meal. 
• 
Physical examination, vital signs 
• 
Clinical laboratory assessments (hematology, serum chemistries) 
• 
HRCT 
• 
Spirometry (FVC)  


 
 
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• 
6MWT and Borg Scale  
• 
Review AEs 
4.5.14 
Samples for Research Biosample Repository 
Not applicable as no samples will be stored in the study. All blood samples drawn for 
safety assessments will be destroyed immediately after analyzing.  
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the investigator has the right to withdraw a patient from the study at any time 
if it is considered to meet patients’ interests best and approved by the Sponsor.   
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient for other 
reasons 
• 
Protocol deviation (at Sponsor’s discretion) (e.g. refusal to follow study requirements) 
Generally poor compliance in the study will not be treated as a sufficient reason for 
patient’s early discontinuation from the study. However, non-compliant patients cannot 
proceed in the rollover part of the study, where treatment with pirfenidone is continued in 
a routine clinical setting.  
Every effort should be made to obtain information on patients who withdraw from the 
study. The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. However, patients will not be followed for any reason after consent 
has been withdrawn. Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Unacceptable tolerability and personal safety profile (e.g. adverse events listed in 
Section 5.1.2, or serious adverse events related to study treatment)  


 
 
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• 
Patient request or withdrawal of consent  
• 
Patient’s early discontinuation from the study (see Section 4.6.1) 
• 
Termination of the whole study by the Sponsor  
• 
Lung transplantation 
 
Patients who receive a lung transplant during the study will discontinue study treatment 
and the study itself. 
If study treatment is discontinued, patients will complete a Follow-up Visit 14-28 days 
after the last dose of the study treatment. If applicable, discontinued patients should 
complete all scheduled study assessments and procedures through Week 26. 
If early discontinuation of study treatment is being considered, it must be immediately 
reported by telephone to the Sponosr medical monitor or designee.  
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patients who discontinue study treatment prematurely will not be 
replaced. 
4.6.3 
Study and Site Discontinuation 
4.6.3.1 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other ongoing studies of 
pirfenidone indicates a potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
• 
Administrative and regulatory reasons. 
 
The Sponsor will notify the investigator if a decision to discontinue the study is made.   
4.6.3.2 
Site Discontinuation 
The Sponsor has the right to close a site at any time. Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 


 
 
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• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Pirfenidone is currently approved for medical use in many countries of the world (see 
Section 1.2). The safety plan for patients in this study is based on clinical experience 
with pifenidone in completed and ongoing clinical studies and in post-marketing use. The 
anticipated important safety risks for pirfenidone are outlined below. Please refer to the 
pirfenidone instruction for medical use of the medicinal product  for a complete summary of 
safety information.  
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events. In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below. 
5.1.1 
Risks Associated with Pirfenidone 
Pirfenidone has a favourable benefit-risk profile with a well-characterized long-term 
safety and tolerability profile and manageable side-effects. Pirfenidone does not appear 
to be associated with unexpected serious adverse events, which could be considered to 
be life-threatening. Guidelines for management of patients who develop the most 
common adverse events are provided in Table 3 (see Section 5.1.2).  
5.1.1.1 
Gastrointestinal Adverse Events 
Pirfenidone is associated with a dose response effect regarding gastro-intestinal side-
effects notably nausea, vomiting, diarrhoea, dyspepsia. There is a correlation between 
the maximal plasma concentration of pirfenidone and the incidence of GI adverse events, 
suggesting that food may reduce the incidence of certain adverse events associated with 
pirfenidone.  
Patients with clinically significant GI symptoms or disease will be excluded from this 
study (see Section 4.1.2).  


 
 
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5.1.1.2 
Skin-Related Adverse Events 
Common skin-related adverse events associated with pirfenidone are rash and 
photosensitivity. The seasonal variation in frequency of skin reactions suggests an 
association with sun exposure. The underlying mechanism of photosensitivity reactions 
is likely to be phototoxic and related to the drug ability to absorb both ultraviolet B and A. 
Pre-clinical data supports that pirfenidone-induced skin reactions are proportional to both 
light and drug exposure. 
Exposure to direct sunlight (including sunlamps) should be avoided or minimised during 
treatment with pirfenidone. Patients should be instructed to use a sunblock daily, to wear 
clothing that protects against sun exposure, and to avoid other medicinal products 
known to cause photosensitivity. Patients should be instructed to report symptoms of 
photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are 
uncommon. 
5.1.1.3 
Effects on Liver Function Tests 
Elevations of ALT and AST > 3 × ULN have been reported in patients receiving therapy 
with pirfenidone. Rarely these have been associated with concomitant elevations in total 
serum bilirubin. Liver function tests (ALT, AST and bilirubin) should be conducted prior to 
the initiation of treatment with pirfenidone and subsequently as indicated in the schedule 
of assessments (see Appendix 1). Patients with significant signs of hepatic impairment 
will be excluded from the study (see Section 4.1.2).  
In case of significant elevation of liver aminotransferases the dose of pirfenidone should 
be adjusted or treatment discontinued according to the guidelines provided in Table 3. 
For patients with confirmed elevations in ALT, AST or bilirubin during treatment, the 
following dose adjustments may be necessary. 
5.1.1.4 
Cardiovascular Safety 
The incidence of major cardiovascular events were similar between pirfenidone and 
placebo groups in pooled population of two clinical studies (ASCEND and CAPACITY). 
There is no evidence of pirfenidone having a significant effect on QT interval, incidence 
of arrhythmias and ischemia events. However, pirfenidone should be used with caution 
in patients treated with other moderate inhibitors of CYP1A2, such as amiodarone and 
propafenone. 
Cardiac function should be monitored with ECG prior to the initiation of treatment with 
pirfenidone and subsequently as indicated in the schedule of assessments (see 
Appendix 1). Patients with clinically significant symptoms of cardiac disease will be 
excluded from the study (see Section 4.1.2).  


 
 
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5.1.1.5 
Other Adverse Events 
Dizziness 
Dizziness has been reported in patients receiving pirfenidone. Patients should know how 
they react to the study drug before they engage in activities requiring mental alertness or 
coordination. In clinical studies, most patients who experienced dizziness had a single 
event, and most events resolved, with a median duration of 22 days.  
Fatigue 
Fatigue has been reported in patients receiving pirfenidone. Patients should know how 
they react to the study drug before they engage in activities requiring mental alertness or 
coordination. 
Weight loss 
Weight loss has been reported in patients treated with pirfenidone. There was an 
increase in anorexia and poor appetite but this was not consistently dose related. 
Investigator should monitor patients’ weight, and when appropriate encourage increased 
caloric intake if weight loss is considered to be of clinical significance. 
Risks which, were observed in the post-authorization setting: 
• 
Angioedema  
• 
Agranulocytosis 
5.1.2 
Management of Patients Who Experience Specific Adverse Events 
Guidelines for management of specific adverse events are outlined in Table 3.   


 
 
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Table 3 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events 
Event 
Action to Be Taken 
Gastrointestinal 
adverse 
events 
(nausea, vomiting, 
diarrhoea, 
dyspepsia) 
Confirm that the study drug is administered with food.   
If symptoms persist when the drug is taken with food, the dose of 
pirfenidone should be reduced to 1-2 capsules (267-534 mg) 2-3 times/ day 
with food.  
If symptoms resolve, the dose can be re-escalated to the recommended 
daily dose as tolerated.  
If symptoms continue, treatment should be interrupted for 1-2 weeks to 
allow symptoms to resolve.  
If symptoms continue after temporal interruption, treatment should be 
permanently discontinued. 
Skin-related 
adverse 
events 
(photosensitivity 
reaction and rash) 
 
Mild to moderate photosensitivity reaction or rash - the dose of pirfenidone 
should be reduced to 801 mg (3 capsules) per day (267 mg (1 capsule) 3 
times a day). Confirm that the patient uses a sunblock daily and avoids sun 
exposure.  
If the rash persists after 7 days, pirfenidone should be discontinued for 15 
days, with re-escalation to the recommended daily dose in the same 
manner as the dose escalation period.  
Severe photosensitivity reaction or rash - treatment should be interrupted 
and medical advice is sought.  
If the rash has resolved, pirfenidone may be re-introduced and re-escalated 
up to the recommended daily dose at the discretion of the investigator. 
Elevations of ALT 
and AST 
ALT/ AST elevation > 3 to ≤ 5 × ULN - confounding medicinal products 
should be discontinued, other causes excluded, and the patient monitored 
closely. If clinically appropriate, the dose of pirfenidone should be reduced 
or interrupted. Once liver function tests are within normal limits the dose 
may be re-escalated to the recommended daily dose if tolerated. 
ALT/ AST elevation to ≤ 5 × ULN accompanied by symptoms or 
hyperbilirubinaemia (> 2 × ULN) - treatment should be permanently
discontinued.  
ALT/ AST elevation to > 5 × ULN - treatment should be permanently
discontinued. 
 


 
 
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Table 3 
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.) 
Event 
Action to Be Taken 
Increased 
QT 
Interval 
QTcF interval is > 500 ms and/ or  > 60 ms longer than the baseline value, 
another ECG must be recorded, ideally within the next 5 minutes or in the 
utmost 24 hours, verified by a study site or local cardiologist.  
If increase of QT Interval is confirmed, ECG monitoring should continue 
until QTcF has stabilized on two successive ECGs within 24 h, verified by a 
study site or local cardiologist. In this case study drug should be interrupted 
and the patient should be discontinued from study treatment.  
If QTcF interval is between 500 and 550 msec, confirmed by a repeat ECG 
within 24 hours, and verified by a study site or local cardiologist, study 
treatment should be interrupted.  
If an alternative explanation is identified (e.g., electrolyte abnormality or 
concomitant medication), re-initiation of study treatment may be considered 
by the investigator in consultation with the study medical monitor. 
Dizziness 
If dizziness does not improve within 3-4 weeks or worsens in severity, dose 
adjustment or even discontinuation of treatment may be warranted. 
Fatigue 
No action required.  
Weight loss 
If considered to be of clinical significance, increased caloric intake should 
be recommended to the patient. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An adverse event can therefore 
be any of the following: 


 
 
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• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except exacerbation or 
worsening of IPF. Worsening of IPF (i.e. IPF progression) is considered as an AE only in 
case of fatal outcome attributed to this progression (as described in Section 5.3.5.7). 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
• 
Lack of efficacy is not considered as AE 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.9) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug or the female partner of a male patient exposed to study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/ surgical intervention to prevent one of the outcomes 
listed above) 
 


 
 
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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) 
5.2.3.1 
Adverse Events of Special Interest 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions). Adverse events of special interest for this study 
include the following: 
• Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6) 
• Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term applies only 
when a contamination of the study drug is suspected. 
5.2.3.2 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be implemented in the study. All 
adverse events immediately reported to the Sponsor will be reviewed by the IDMC. The 
IDMC will also review every death case from the point of relationship to the study drug.  
The IDMC will conduct regular review of the trial safety data, with the focus on the 
following safety information: 


 
 
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• 
Death cases 
• 
Serious adverse events 
• 
Adverse events leading to treatment or study discontinuation 
• 
Unexpected adverse events 
• 
Liver enzyme increases, reported as adverse events 
On the basis of the safety data aggregated from different study sites and investigators, 
the IDMC can recommend discontinuation of the study due to safety concerns.  
IDMC members and detailed working regulations are provided in a separate document.  
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4−5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 28 days after the 
last dose of study drug. 
For patients continuing in the rollover part of the study adverse events will be reported 
until Week 52. 


 
 
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Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints. Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit/ telephone call?" 
"Have you had any new or changed health problems since you were last here/ we talked 
by the phone?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity. Table 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
 
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Table 4 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
a 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b 
Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are not 
bedridden. 
c 
If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious adverse 
event in Section 5.2.2. 
d 
Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly. The following guidance should be taken into consideration (see also 
Table 5): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 


 
 
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• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 5 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting 
medical 
condition, 
underlying 
disease, 
intercurrent 
illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
For adverse events, a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice and elevated transaminases). However, if a constellation 
of signs and/or symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded on the 
Adverse Event eCRF. If a diagnosis is subsequently established, all previously reported 
adverse events based on signs and symptoms should be nullified and replaced by one 
adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 


 
 
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5.3.5.2 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF. For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints. Such events should only be recorded once on the Adverse 
Event eCRF. The initial severity (intensity or grade) of the event will be recorded at the 
time the event is first reported. If a persistent adverse event becomes more severe, the 
most extreme severity should also be recorded on the Adverse Event eCRF. If the event 
becomes serious, it should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions). The Adverse Event eCRF should be updated by changing the event from 
"non-serious" to "serious," providing the date that the event became serious, and 
completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs. Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 


 
 
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5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
It is the investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium"). If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event. For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be 
reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  


 
 
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It is the investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law). Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). This 
includes death attributed to progression of IPF. 
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported.  
The term "sudden death" should be used only for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without 


 
 
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preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF. If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
replaced by the established cause of death. 
If the death is attributed to progression of IPF, "IPF progression" should be recorded on 
the Adverse Event eCRF.   
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.9 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., to perform protocol required 
procedures) 


 
 
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• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
• 
Cases when medical aid was provided to the patient in the hospital reception ward 
 
5.3.5.10 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied. An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event. All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
There is limited clinical experience with pirfenidone overdose. Multiple doses of 
pirfenidone up to a dose of 4806 mg/day were administered as six 267 mg capsules 
three times daily to healthy adult volunteers over a 12-day dose escalation period. 
Adverse reactions were mild, transient, and consistent with the most frequently reported 
adverse reactions for pirfenidone (Esbriet EMA 2010). 
5.3.5.11 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data. However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 


 
 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR TO 
SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event. The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for all sites  
Medical Monitor:   
 
 
 
 
 
 
, MD, PhD  
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Roche Medical Responsible: 
 
Telephone No.: 
  
Mobile Telephone No.: 
 
 


 
 
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To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week. Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and Adverse 
Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the last dose of study drug (including rollover 
study). Investigators should record all case details that can be gathered immediately (i.e., 
within 24 hours after learning of the event) on the Adverse Event eCRF and submit the 
report via the electronic data capture (EDC) system. A report will be generated and sent 
to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators. Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting serious adverse events that occur  >  28 days after the last dose 
of study treatment are provided in Section 5.6. 


 
 
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5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 28 days after the last 
dose of study drug. A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators. Pregnancy should not be 
recorded on the Adverse Event eCRF. The investigator should discontinue study drug 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus. Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 
defect in the child) should be reported on the Adverse Event eCRF. In addition, the 
investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.   
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 28 
days after the last dose of study drug. A Clinical Trial Pregnancy Reporting Form should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug. The pregnant partner 
will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy. After the authorization has been 
signed, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
5.4.3.3 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 


 
 
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reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).   
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, or the event is assessed as stable by the investigator, the 
patient is lost to follow-up, or the patient withdraws consent. Every effort should be made 
to follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE EVENT 
REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment. These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 


 
 
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emailing the Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to investigators. 
5.7 
EXPEDITED 
REPORTING 
TO 
HEALTH 
AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
Pirfenidone Local Instruction for Use   
• 
Pirfenidone Core Data Sheet 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
Additionally, the IDMC will conduct regular review of the trial safety data, as described in 
Section 5.2.3.2.  
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Data handling will be the responsibility of Data Matrix. The data will be inspected for 
inconsistencies by performing validation checks. Any inconsistencies found will be 
resolved by the monitor after contacting the Investigator. When the data in the database 
are considered clean and the subjects allocated to subject samples in a data review, the 
database will be locked to prevent unauthorized access. Next, the database will be 
made available as SAS® files for statistical analysis. 
All details regarding the statistical analysis and the preparation of tables, listings and 
figures will be described in the Statistical Analysis Plan prepared by Data Matrix and 
approved by F. Hoffmann-La Roche Ltd. before database lock. 
The statistical analysis will be performed by Data Matrix. 


 
 
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The main subject samples of interest are defined as follows. 
The ‘Allocated to treatment’ set will consist of all subjects who: 
• 
Gave their Informed Consent and  
• 
Has successfully completed Screening procedures. 
The ‘Treated set’ (TS) will consist of all subjects who: 
• 
Were in the ‘Allocated to treatment’ set and 
• 
Received any dose of the study treatment. 
The ‘Full analysis’ set (FAS) will consist of all subjects who:   
• 
Were included in the ‘Treated’ set and  
• 
Had data for at least one post-baseline assessment of any efficacy measurement.  
6.1 
DETERMINATION OF SAMPLE SIZE 
Taking into account study design (single group prospective study), sample size was 
estimated based on feasibility of subject enrollment with precision-based approach. In 
the ASCEND study primary efficacy endpoint (Percent Predicted FVC) in pirfenidone 
group changed from 67.8 (11.24) (denoted as mean (SD)) at baseline to 65.3 (14.52) at 
week 26, with stable disease (decline in FVC < 10 % to 0 %) in 60.1 % of study subjects. 
The required sample size for two-sided 95% confidence level can be calculated using the 
following formula: 
 
Assuming previous calculations, 60 subjects included in the study will be sufficient for 
study parameters estimation. Taking into account study goals and the notion that the 
study drug is a product for the treatment of an orphan drug, margin of error of 0.125 is 
considered sufficient for parameter estimation. For precision-based sample size justification, 
with a sample size of 60 patients, an expected mean value of 2.5% and standard deviation of 20, 
distance from the mean to limit of the two-sided 95% confidence interval for the mean Change 
from Baseline to Week 26 (Percent Predicted FVC) will extend about 5 (margin of error). The SD 
for change from baseline at week 26 is conservatively estimated based on the results of the 
ASCEND study as standard deviation for Percent Predicted FVC in pirfenidone group at week 


 
 
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26 (14.52) multiplied by √2 (Machin et al., 1997).  This is also in line with the results of 
CAPACITY programme (Noble et al. 2011) in which the SD of changes from baseline was 17 - 20 
at week 72. 
Taking into account an expected rate of screening failures about 45%, up to 109 patients will be 
screened for eligibility. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Time-Related Definitions 
The baseline period will be defined as the period from Informed Consent to the first 
study drug administration. The baseline value for a variable in common cases (except 
efficacy analysis) is defined as the last non-missing value collected before the first study 
drug administration.  
All variables planned to be measured at one or more time points, and supposed to be 
time-related will be windowed.  
Coding Systems 
AEs and medical history Investigator terms will be assigned to a lowest level term (LLT) 
and a preferred term (PT) and will be classified by high level term (HLT) and primary 
system organ class (SOC) according to the Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus. 
Prior and concomitant medications will be classified according to active drug substance 
using the WHO drug dictionary. The generic name, the preferred name and the WHO 
name will be assigned. 
In addition, the Anatomical Therapeutic Chemical (ATC) classes will be assigned to the 
drug ID. ATC codes are defined to the 4th level. For each medication, the primary ATC 
class will be assigned manually based on the generic name and the reason for use. 
Default Summary Statistics 
The default summary statistics for quantitative and ordinal variables will be the number 
of observations (n), mean, standard deviation (SD), median, minimum (Min) and 
maximum (Max) for subjects with data. For efficacy data 95% CI will be provided 
additionally. 
Default Frequency Tabulations 
For qualitative variables, per category the numbers and frequencies of subjects with 
non-missing data (n, %) will be the default summary presentation. 


 
 
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For AEs and medical history, however, the denominator for the percentage calculation 
will be the number of subjects at risk. A subject will be considered at risk if the subject is 
in the Treated set. 
Subject Listings 
Individual subject listings will be produced for all raw data. 
Handling missing values 
For missing FVC data imputation, patients will be classified into different patterns 
depending on the availability of data:  
Patients with a 26 week FVC value:  
1. those who received study drug until 26 weeks;  
2. those, who prematurely discontinued study drug, but who were followed up until 
Week 26.  
Patients without a 26 Week FVC value:  
1. those who were alive at 26 weeks;  
2. those, who died before 26 weeks.  
Missing data at other visits before Week 26 (primary outcome variable) will not be 
imputed.  
The following imputation methods including sensitivity analyses will be applied for 
patients with pattern 3 - 4:  
Assuming that deaths of the patients (pattern 4) is likely to be related to worsening of 
IPF, these unobserved FVC values should be lower than those in patients who did not 
die prior to Week 26. Methods for handling missing data due to death will include the 
following: 
• 
Replacement with the worst possible value (FVC= 0 mL or 0%) (Primary 
analysis). 
• 
Replacement with worst observed FVC value at week 26 (Sensitivity analysis).  


 
 
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• 
Replacement with an intermediate value (FVC =1500 mL or 50%) (Sensitivity 
analysis). 
Missing data due to reasons other than death (pattern 3) will be replaced with imputed 
values based on the average measurements for “similar” patients at that time point 
(Primary analysis). Similar patients are those without missing data before that time point 
and whose data have the smallest sum of squared deviations (SSD) from that patient for 
all visits prior to the one with the missing data. Missing data due to lung transplant will be 
imputed using the SSD method even if the patient dies after lung transplant. A sensitivity 
analysis will use the data imputed with last observation carried forward method (LOCF). 
Complete case analysis will also be performed as a sensitivity analysis.  
6.3 
SUMMARIES 
OF 
DEMOGRAPHIC 
AND 
BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race and ethnicity, height, 
weight, medical history, concomitant medication, serology etc) will be summarized using 
means, SD, medians, and ranges for continuous variables and proportions for 
categorical variables, as appropriate.   
The assignment of subjects to subject samples, the disposition of subjects with respect 
to premature termination, reason for premature termination, drug exposure will be 
summarized.  
Medical history, including coding data will be summarized per primary SOC by PT. 
Additionally medical history will be listed. Protocol deviations will be listed. 
Prior/concomitant medications will be summarized per Therapeutic or chemical group 
and preferred WHO name. Additionally prior/concomitant medications will be listed. 
6.4 
EFFICACY ANALYSES 
The FAS set will be used for the efficacy analysis. All efficacy parameters will be 
summarized with descriptive statistics (mean, SD, median, minimum maximum, 95% CI) 
for each measurement time point. 
6.4.1 
Primary Efficacy Endpoint 
The primary outcome variable is the absolute change in FVC from Baseline to Week 26 
(both in mL and % predicted). Baseline FVC will be the average of the highest FVC 
measurement recorded at the Screening and Day 1 visits. The FVC at Week 26 will be 
the average of the highest FVC measurement recorded on two separate days at Week 


 
 
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26. Data will be analyzed using a standard descriptive statistics for continuous variables 
and 95% CI for the mean.   
The data imputation methods for primary endpoint are described in Section 6.2. 
The distribution (number and percentage) of primary outcome variable by patients 
across three categories of change from Baseline (Decline of ≥10% or death before Week 
26; Decline of < 10% to 0%; Improvement of ≥ 0%) will be provided in frequency table.  
Additionally, the absolute change in FVC from Baseline at Week 12, 39 (optional) and 52 
(optional) and mean FVC change through all time endpoints (both in mL and % predicted) 
will be summarized in tables with standard descriptive statistics for continuous variables 
and 95% CI for mean. 
6.4.2 
Secondary Efficacy Endpoints 
Change in 6MWT distance from Baseline to Week 26 
Baseline 6MWT distance will be the average of the measurements recorded at the 
Screening and Day 1 visits. The 6MWT distance at Week 26 will be defined as the 
average of the 6MWT distance recorded on two separate days at Week 26. Data will be 
analyzed using a standard descriptive statistics for continuous variables and 95% CI for 
mean.  
The distribution (number and percentage) of 6MWT distance by patients across two 
categories of change from Baseline (Decline of ≥ 50 m or death before Week 26; 
Improvement of ≥ 0 m) will be provided in frequency table.  
Additionally, the absolute change in 6MWT from Baseline at Week 39 (optional) and 
Week 52 (optional) will be summarized in table with standard descriptive statistics for 
continuous variables and 95% CI for mean. 
Change from Baseline to Week 26 in patients’ quality of life as measured with EQ-5D-5L 
Results of EQ-5D-5L questionnaire will be summarized in two ways: 
• 
Cross tabulation for each of five dimensions (Mobility, Self-Care, Usual Activities, 
Pain / Discomfort, Anxiety / Depression) by response and study week. 
• 
VAS score, including changes from baseline, will be summarized with descriptive 
statistics (mean, standard deviation, median, minimum and maximum) for study 
week.  


 
 
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Additionally, a single Index score will be provided, if necessary.    
6.4.3 
Exploratory Efficacy Endpoints 
HRCT fibrosis score 
The HRCT findings will be evaluated using HRCT scoring system. One ILD radiologist 
will make assessments of 4 main findings in three zones of each lung. The six zone 
scores will be averaged to determine the total score for each patient. Score will be 
recorded at the initial diagnosis and after six and 12 months in a similar manner for 
further comparison. The mean ± SD of HRCT fibrosis score like continuous variable will 
be determined obligatory at baseline, 6 months and optional at 12 months.  
The values of HRCT fibrosis score at baseline, at Week 26 (optional) and Week 52 
(optional) will be summarized in table with standard descriptive statistics for continuous 
variables and 95% CI for the mean. 
Additionally, the absolute change of HRCT fibrosis score from baseline at Week 26 
(optional) and Week 52 (optional) will be summarized in table with standard descriptive 
statistics for continuous variables and 95% CI for the mean. 
The paired t-test will be performed to evaluate the changes in the variable from the 
baseline to Week 26 (optional) and Week 52 (optional), respectively. The type I error rate 
will be set to 5%. 
Lung opacity (ground-glass attenuation) 
The sign ‘lung opacity’ will be qualified separately using methodology described above 
for other signs, and its change over time will be assessed outside the framework of a 
total summed index of fibrosis (HRCT fibrosis score). Lung opacity should be graded as 
reticular abnormality to calculate the score for each zone, i.e. the percentage (%) area of 
opacity in a zone should be multiplied by the score of 2. 
The percentage area of opacity at Baseline, at Week 26 (optional) and Week 52 (optional) 
will be summarized in table with standard descriptive statistics for continuous variables 
and 95% CI for the mean. 
Additionally, the absolute change of percentage area of opacity from Baseline at 
Week 26 (optional) and Week 52 (optional) will be summarized in table with standard 
descriptive statistics for continuous variables and 95% CI for the mean. 
Exacerbations 


 
 
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An exacerbation will be defined as an AE with special criteria, i.e. only in case the 
exacerbation has led to death of a patient (see Section 5.2.1). Rate of exacerbation will be 
reported in three following tables: 
• 
Exacerbation cases during treatment period (until Week 26). 
• 
Exacerbation cases during long-term follow-up period (from Week 26 to Week 
52). 
• 
Exacerbation cases during whole study period (from Day 1 to Week 52, 
applicable only for subjects continuing in the rollover study). 
Exacerbation cases will be listed. 
6.5 
SAFETY ANALYSES 
The Treated set will be used for the analysis of the safety and tolerability data. 
Study treatment is defined as pirfenidone 2403 mg/d administered in divided doses TID 
with food. Study treatment will be titrated over 14 days to the full dose of 9 capsules per 
day (three 267-mg capsules taken orally TID with food). Patients will remain on a stable 
maintenance dose for the duration of the treatment period unless the dose is reduced to 
manage an AE or titrated again when restarting study treatment after a 28-day or greater 
interruption in treatment. 
AEs will be reported on a per-subject basis, i.e. counting subjects rather than events. 
Only treatment emergent AEs will be reported. In the listings, however, all occurrences 
of the AEs will be presented. 
Treatment emergent AEs will be summarized per primary SOC and PT. Severity and 
drug-event relationship of treatment emergent AEs will be summarized separately. 
Vital signs, including changes from baseline will be listed and summarized with 
descriptive statistics (mean, SD, median, minimum and maximum) for each 
measurement time point. Out-of-range values with assessment of clinical significance 
will be provided in frequency tables. 
Results of ECG, including changes from baseline will be listed and summarized with 
descriptive statistics (mean, SD, median, minimum and maximum) for each 
measurement time point. Out-of-range values with assessment of clinical significance 
will be provided in frequency tables. 


 
 
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Laboratory variables, including changes from baseline will be listed and summarized 
with descriptive statistics (mean, SD, median, minimum and maximum) for each 
measurement time point. Additionally, shift tables summarizing the frequencies of 
patients below, within, and above the normal ranges at each time point will be provided. 
Results of physical examinations will be summarized in corresponding frequency table 
and listing. 
6.6 
INTERIM ANALYSIS 
No interim analysis is planned in the study.  
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
Data Matrix will be responsible for the data management of this study, including quality 
checking of the data. Data entered manually will be collected via EDC through use of 
eCRFs. Sites will be responsible for data entry into the EDC system. In the event of 
discrepant data, the data manager will request data clarification from the sites, which the 
sites will resolve electronically in the EDC system.   
The Sponsor will perform oversight of the data management of this study. The Sponsor 
will produce an EDC Study Specification document that describes the quality checking to 
be performed on the data. Central laboratory data and HRCT data will be sent directly to 
the Sponsor, using the Sponsor’s or vendor's standard procedures to handle and 
process the electronic transfer of these data as appropriate. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites will 
receive training and have access to a manual for appropriate eCRF completion. eCRFs 
will be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 


 
 
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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
ELECTRONIC PATIENT- AND OBSERVER-REPORTED OUTCOME 
DATA  
PRO data will be collected on paper questionnaires. The data from the questionnaires 
will be entered into the EDC system by site staff. ObsRO data will be entered directly 
into the eCRF. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review. The study site must also allow 
inspection by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 


 
 
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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO and ObsRO data (if applicable), Informed 
Consent Forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for at least 15 years after completion or 
discontinuation of the study or for the length of time required by relevant national or local 
health authorities, whichever is longer. After that period of time, the documents may be 
destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, and the laws and 
regulations of the country in which the research is conducted. The study will comply with 
the requirements of the ICH E2A guideline (Clinical Safety Data Management:  
Definitions and Standards for Expedited Reporting).  
The study will be conducted in accordance to the following local regulations of the 
Russian Federation as ammended: FL #323-FZ “On fundamental principles of 
healthcare in the Russian Federation” dated 21-Nov-2011; FL #61-FZ “On drug 
circulation” dated 12-Apr-2014; Government resolution of the Rusian Federation #714 
“On the approval of model rules of mandatory health and safety insurance for patients 
participating in clinical studies” dated 13-Sep-2010; Decree of the Ministry of Healthcare 
#774n “On Ethics Committee” dated 31-Aug-2010; Decree of the Ministry of Healthcare 
#200n “On the approval of the rules of Good Clinical Practice” dated 01-Apr-2016; 
National Standard “Good Clinical Practice”. GOST P 52379-2005 dated 27-Sep-2005. 


 
 
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8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site. It will be provided in a certified 
translation of the local language. The Sponsor or its designee must review and approve 
any proposed deviations from the Sponsor's sample Informed Consent Forms or any 
alternate consent forms proposed by the site (collectively, the "Consent Forms") before 
IRB/EC submission. The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures. The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason. A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures. Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 


 
 
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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC. Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor. Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patients’ confidentiality will be observed in accordance with the relevant Russian 
regulations. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will be 
available in accordance with the effective Roche policy on study data publication 
(see Section 9.5). 


 
 
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Data generated by this study must be available for inspection upon request by 
representatives 
of 
national 
and 
local 
health 
authorities, 
Sponsor 
monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
INSURANCE 
Patient insurance in the study will be performed in accordance with the Russian 
regulatory requirements. All patients will be provided with personal insurance policies as 
participants of the clinical study. All patients will be informed about health insurance at 
the signing the Informed Consent procedure and will be issued with the personal policy 
as soon as the identification number is attributed to an individual patient. Details on 
patient insurance will be provided in the Informed Consent Form. 
8.6 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval. In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs. The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 


 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
147/Protocol ML39355, Version 2 dated 09-Jun-2018 
9.4 
ADMINISTRATIVE STRUCTURE 
Administrative structure of the study is presented below. 






 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
150/Protocol ML39355, Version 2 dated 09-Jun-2018 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
151/Protocol ML39355, Version 2 dated 09-Jun-2018 
10. 
REFERENCES 
American Thoracic Society. ATS statement: guidelines for the six-minute walk test. Am J 
Resp Crit Care Med. 2002, 166:111–117. 
American 
Thoracic 
Society/European 
Respiratory 
Society. 
American 
Thoracic 
Society/European Respiratory Society international multidisciplinary consensus 
classification of the idiopathic interstitial pneumonias. Am J Resp Crit Care Med. 
2002, 165:277–304. 
ATS/ERS task force: standardisation of lung function testing. No. 2 in this Series 
Standardisation of spirometry. Eur Respir J. 2005, 26:319–38. 
American Thoracic Society/European Respiratory Society/Japanese Respiratory Society 
(JRS)/ Latin American Thoracic Association (ALAT). An official ATS/ERS/ 
JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence based guidelines for 
diagnosis and management. Am J Respir Crit Care Med. 2011, 183:1–38. 
American Thoracic Society/European Respiratory Society/Japanese Respiratory Society 
(JRS)/ 
Latin 
American 
Thoracic 
Association 
(ALAT). 
An 
Official 
ATS/ERS/JRS/ALAT Clinical Practice Guideline: treatment of idiopathic pulmonary 
fibrosis: an update of the 2011 clinical practice guideline. Am J Respir Crit Care 
Med. 2015, 192(2):e3–e19. 
Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, et al. Double blind, placebo-
controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J 
Respir Crit Care Med. 2005, 171:1040–1047. 
Behr J, Hoeper MM, Kreuter M et al. Investigating significant health trends in idiopathic 
pulmonary fibrosis (INSIGHTS-IPF): rationale, aims and design of a nationwide 
prospective registry BMJ Open Resp Res. 2013,1:e000010. 
Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 1982, 
14:377–381. 
Brooks R, Rabin R, de Charro F, editors. The measurement and valuation of health 
status using EQ-5D: a European perspective. Kluwer Academic Publishers 2003 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41. 


 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
152/Protocol ML39355, Version 2 dated 09-Jun-2018 
Collard HR, Moore BB, Flaherty KR et al. Acute exacerbations of idiopathic pulmonary 
fibrosis. Am J Respir Crit Care Med. 2007, 176:636–643. 
Collard HR, Ryerson CJ, Corte TJ et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. 
An International Working Group Report. Am J Respir Crit Care Med. 2016;194(3):265-
275. 
Committee for Medicinal Products for Human Use (CHMP): Esbriet (pirfenidone) 
(assessment 
report). 
EMA/CHMP/115147/2011. 
2010, 
London: 
European 
Medicines Agency (EMA), Ref Type: Report   
Costabel U, Albera C, Fagan E et al. Long-term safety of pirfenidone in RECAP, an 
open-label extension study in patients with idiopathic pulmonary fibrosis, interim 
results. Eur Respir J. 2014, 44:1903. 
Cotes JE, Dabbs JM, Elwood PC et al. Iron-deficiency anaemia: its effects on transfer 
factor for the lung (diffusing capacity) and ventilation and cardiac frequency during 
submaximal exercise. Clin Sci. 1972, 42:325-33. 
Crapo RO, Morris AH. Standardized single breath normal values for carbon monoxide 
diffusing capacity. Am Rev Respir Dis. 1981,123;2:185-9. 
du Bois RM, Albera C, Bradford WZ, et al. Predictors of mortality in patients with 
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009, 179:A1114. 
EuroQol Group [Web-source]. Available at: https://euroqol.org/eq-5d-instruments/eq-5d-5l-
available-modes-of-administration/self-complete-on-paper/ 
 Flaherty KR, Mumford JA, Murray S et al. Prognostic implications of physiologic and 
radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care 
Med. 2003, 168:543–548. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011, 20:1727−36. 
Ichikado K, Suga M, Müller NL et al. Acute interstitial pneumonia: comparison of high-
resolution computed tomography findings between survivors and nonsurvivors. Am 
J Respir Crit Care Med. 2002, 165:1551–6.  
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. 
Qual Life Res. 2013, 22:1717−27. 


 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
153/Protocol ML39355, Version 2 dated 09-Jun-2018 
Jindal S. K. et al. Textbook of Pulmonary and Critical Care Medicine Vols 1 and 2. – JP 
Medical Ltd, 2011.  
King TE, Bradford WZ, Castro-Bernardini S et al. A phase 3 trial of pirfenidone in 
patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014, 370:2083-92. 
Ley B, Collard HR, King TE. Clinical course and prediction of survival in idiopathic 
pulmonary fibrosis. Am J Respir Crit Care Med. 2011,183:431–40  
Ley B, Ryerson CJ, Vittinghoff E et al. A multidimensional index and staging system for 
idiopathic pulmonary fibrosis. Ann Intern Med. 2012,156:684-91 
Machin D., Campbell M., Fayers P., Pinol A. “Sample size tables for clinical studies”// 
Second edition Blackwell Science Ltd, 1997 
Noble PW, Albera C, Bradford WZ et al. CAPACITY Study Group. Pirfenidone in patients 
with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011, 
377:1760–1769 
Oda K, Ishimoto H, Yatera K et al. High-resolution CT scoring system-based grading 
scale predicts the clinical outcomes in patients with idiopathic pulmonary fibrosis. 
Respir Res. 2014,15:10. 
Orphanet: the portal for rare diseases and orphan drugs. [Electronic source] Access: 
http://www.orpha.net/consor/cgi-bin/index.php?lng=EN. Date 10-Oct-2016 
Ranu H, Wilde M, Madden B. Pulmonary function tests. Ulster Med J. 2011, 80(2):84-90. 
Taniguchi H, Ebina M, Kondoh Y et al. for Pirfenidone Clinical Study Group in Japan.  
Pirfenidone in idiopathic pulmonary fibrosis: A phase III clinical trial in Japan. Eur 
Respir J. 2010, 35:821-829. 
Walter N, Collard HR, King TE Jr. 2006. Current perspectives on the treatment of 
idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006, 3(4):330–338. 
Zappala CJ, Latsi PI, Nicholson AG et al. Marginal decline in forced vital capacity is 
associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J. 
2010, 35(4):830–6. 






Appendix 1  
Schedule of Activities (cont.) 
Pirfenidone—F. Hoffmann-La Roche Ltd 
156/Protocol ML39355, Version 2 dated 09-Jun-2018 
15 Schedule of calls in IPF Care Program you can see in Appendix 7   
16 Only in patients continuing treatment with pirfenidone in real clinical practice. 


 
 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
157/Protocol ML39355, Version 2 dated 09-Jun-2018 
Appendix 2  
HRCT Protocol 
For IPF assessment in the current clinical trial a spiral CT scanning (continuous, or 
volumetric scanning) should be utilized. HRCT acquisition should only be performed with 
multidetector CT scanners with at least 16 slices per gantry rotation capacity.  
HRCT scans are usually obtained with the patient in supine position, with hands on the 
nape, in a single unforced breath hold. Scanning is normally directed upward (from feet 
to the head) in order to attenuate breathing artefacts in the basal parts of lungs. The key 
technical requirements are acquisition collimation < 1 mm (opposite regular 0.65-0.8 
mm), reconstruction parameters: 1 mm-slices, reconstruction interval 1 mm, high 
resolution imaging, lung window, imaging field is adjusted to the chest volume. Dose 
detection software should be utilized to decrease radiation exposure of the patients. Key 
technical requirements for spiral HRCT are summarized in the Table 1-1. 
Expiratory CT scanning 
Expiratory CT scanning aims to refine the differential diagnosis of IPF with 
hypersensitivity pneumonitis and obstructive lung diseases. Expiratory CT scanning is 
performed after forced expiration and breath hold. Other scanning parameters remain 
unchanged. Expiratory CT scanning is utilized to disclose coexisting air trapping 
resulting from impaired expiration air flow in small bronchi. Expiratory CT scanning is 
performed only after inspiratory CT acquisition when existing obstructive changes are 
similar to restrictive respiratory signs. Expiratory CT scanning is performed with the 
same technical parameters. 
Prone CT scanning  
Prone CT scanning is utilized to repair functional hypoventilation of the lower lung lobes 
at inspiration. It causes development of the ground-glass opacities along the dorsal 
surface of the chest. This manoeuvre is of high importance in patients with suspected 
IPF, as absent or insignificant ground-glass opacities distinguish IPF from other UIPs. 
Prone CT acquisition must be performed only after basic HRCT and at presence of the 
ground-glass opacities along the dorsal surface of the lung as revealed with the supine 
scan.  


 Appendix 2 
HRCT Protocol (cont.) 
 
 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
158/Protocol ML39355, Version 2 dated 09-Jun-2018 
HRCT for response assessment and follow-up 
Besides diagnosic purposes, HRCT is utilized in the study for response assessment and 
follow-up. HRCT is perfomed at initiation of the participation in the study and at the end 
of treatment. Adherence to the same technical parameters of acquisition, including 
posture, inspiration volume, imaginfg field, tube current and collimation, reconstruction 
interval, is the main requirement for repeated scanning in the course of the study. HRCT 
readings must not be assessed against X-ray scans. If the patient does not have X-ray 
scan at disease onset or at certain relevant timepoints the subsequent assessments 
should be performed with HRCT. HRCT frequency in the study is not strictly regulated. 


 Appendix 2 
HRCT Protocol (cont.) 
 
 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
159/Protocol ML39355, Version 2 dated 09-Jun-2018 
Table 1-1. Spiral scanning. 
Parameter 
< 16 slices 
per gantry 
rotation 
≥ 16 slices 
per gantry 
rotation 
< 16 slices 
per gantry 
rotation 
≥ 16 slices per 
gantry rotation 
Collimation (slice 
thickness) 
1.25 mm 
0.6-0.8 mm 
1-1.5 mm 
0.6-0.8 mm 
Slice interval 
1 mm 
0.6-0.8 mm 
10 mm 
0.6-0.8 mm 
Reconstruction 
algorithm 
High resolution (bony) 
High resolution, high spatial 
resolution algorithm, bony 
algorithm 
Spot reconstruction 
(field of vision, FOV) 
Total lung volume 
Total lung volume 
Level of inspiration 
Unforced breath hold 
End inspiration 
 
Physical parameters 
120 kV/ automatical 
exposure 
120 kVp / care dose 
 
Scanning time  
As low as practicable for 
the scan (< 0.75 sec) 
< 0.75 sec 
Window (level/ width) 
-500Q-700/1500 HU 
(Hounsfield unit) lung 
window 
Pleural (lung) window 
Possible windows 
(level/ width) 
-850/900 HU emphysema 
and cystic airspaces 
assessment 
+35Q+45/400 HU 
mediastinal window 
Lung window 
 
Soft window 
Recording/ archiving  
CD/ DVD record in DICOM formate and imagery viewer 
software 
Link to the cloud archive storage 
High-Resolution Computed Tomography Criteria for UIP Pattern 
Morphologically IPF is based on the lung abnormalities typical for UIP. X-ray/ CT scans 
of patients with IPF are characterized by morphological abnormalities in lungs, i.e. UIP. 
The picture is characterized by various signs, typical or not typical for UIP (see Table 1-


 Appendix 2 
HRCT Protocol (cont.) 
 
 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
160/Protocol ML39355, Version 2 dated 09-Jun-2018 
2). These signs may a) be of different severity (varying from apparent to unlikely, 
marginally detectable) and b) be present in a variety of combinations. The main 
diagnostic role is hardly played by separate signs but by their clinically significant 
combinations. Radiological conclusion is always based on probability: typical, possible or 
inconsistent UIP picture.  
Table 1-2. HRCT Criteria for UIP Pattern  
Typical (apparent) UIP 
pattern (all 5 features) 
•
Possible UIP 
Pattern (All 3 
Features) 
•
Inconsistent with UIP Pattern (Any of 
the 7 Features) 
•
Cortical, 
basal 
predominance 
• 
Diffuse 
reticular 
abnormality 
• 
Honeycombing  
• 
Traction 
bronchiectasis 
• 
Absence 
of 
any 
features 
contradictory to this 
pathology 
• 
 
•
Cortical, 
basal 
predominance 
• 
Diffuse reticular 
abnormality 
• 
Absence of any 
features 
contradictory 
to 
this pathology 
• 
 
•
Upper or mid-lung predominance
• 
Peribronchovascular predominance 
• 
Extensive ground-glass abnormality 
(extent 
greater 
than 
reticular 
abnormality) 
• 
Profuse 
micronodules 
(bilateral, 
predominantly upper lobes) 
• 
Discrete cysts (multiple, bilateral, 
away from areas of honeycombing) 
• 
Diffuse 
mosaic 
attenuation/air-
trapping (bilateral, away from areas 
of honeycombing) 
• 
Consolidation in bronchopulmonary 
segment(s)/lobe(s) 
Typical (definite) UIP pattern implies combination of the following HRCT signs: 
• cortical and basal predominance of abnormalities in the lungs; 
• diffuse bilateral reticular abnormalities with 
o small subpleural air cysts (honeycombing);  
o traction bronchiectasis; 
• absence of untypical HRCT features of the pathology. 


 Appendix 2 
HRCT Protocol (cont.) 
 
 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
161/Protocol ML39355, Version 2 dated 09-Jun-2018 
Revealing all four sings listed above with great probability supports the presence of UIP. 
In case the key signs – honeycombing and traction bronchiectasis - are absent HRCT 
pattern of UIP is only possible (probable) and further management of the patient, 
primarily indication for lung biopsy and initiation of treatment, should be discussed by the 
MDT members.  
Typical UIP patern on HRCT is not specific for IPF only. It can be observed in patients 
with other diseases, particularly of known etiology, when lung abnormalities form UIP 
pattern. Examples are systemic connective tissue diseases, various environmental 
exposures and domestic factors (e.g. chronic hypersensitive pneumonitis), drug toxicity. 
It is impossible to ascertain these diseases on the basis of X-ray or HRCT examination 
only. Therefore, it is not recommended to use the term “idiopathic” in the description of 
the investigation procedure and conclusion. The main responsibility of the radiologist is 
to reveal or rule out typical UIP pattern, which should be stated in the conclusion. 
Disposition of abnormalities in the lungs 
Cortical predominance of lung abnormalities with amplificatiom from upper lungs to 
diaphragm is typical for IPF. The most prominent changes localize subcortically along 
the costal and diaphragmal pleura. Basal predominance forms the so called 
anteroposterior gradient when lung changes amplify from the front to the back of the 
chest. Abnormal parts of the lungs are independent from lobar or segmental margins. As 
a result, typical disposition of abnormalities in IPF is cortical and basal which can be 
distinctly observed on the series of axial tomograms and multiplanar reformation. 
Approximately 10 to 15% of patients with IPF have abnormalities in the upper lungs 
which makes the pattern not typical and complicate diagnostics. 
Honeycombing 
Honeycombing is a group of subpleural air cysts, usually similar in diameter of about 2-3 
to 10 mm, sometimes more than 2.5 cm. These cysts are round-shaped, with closed 
cavity and distinct demarcation, which differs them from bronchiectasis. Cyst diameter 
and wall thickness may vary significantly; however, the cavities look typical. 
Honeycombing symptom is the main, one of the most significant, CT signs of the lung 
fibrosis of any etiology. But predominance of the cysts along the visceral pleura, 


 Appendix 2 
HRCT Protocol (cont.) 
 
 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
162/Protocol ML39355, Version 2 dated 09-Jun-2018 
especially their multilayer location, diaphragm-oriented increment of abnormality are 
typical specifically for UIP.   
Traction bronchiectases 
Traction bronchiectases are uneven dilation of the bronchi and bronchioles as a result of 
the fibrotic shrinkage of the lung. Dilated bronchi may look like air strips with thin uneven 
(wavy) walls. Transversal dimension may show bronchi as cysts and bronchiole as 
microcysts in the peripheral parts of the lung. Location of the multiple air cysts around 
dilated bronchi may confound differentiation with the honeycombing symptom. 
Multidimensional reformations should be used for proper understanding of the 
morphological substrate. 
Reticular abnormality 
Reticular abnormality is a net of relatively thin lines, round- or polygon-shaped, on 
unchanged lung tissue or moderate lung opacity. Anatomically these lines represent 
abnormal interstitial lung elements resulting from intralobular interstitial tissue (less than 
2 cm in size) thickening in UIP. These structures are usually presented with the 
fragments of acini septa. Septal lines (acini septa of a larger size), 1-2 cm in diameter, 
can also be involved in reticular abnormalities; however, they are usually less affected 
than smaller reticular elements. 
Lung opacity (or ground-glass attenuation) 
Lung opacity (or ground-glass attenuation) is a HRCT scialogical phenomenon 
characterized with mid-enhanced density of lung tissue, with lumina and walls of the 
bronchi, lung vessels, as well as foci and reticular abnormalities, if present. 
Morphological substrate of the lung opacity symptom is formed by the changes in the 
lung tissue with unaffected airness which are not captured by the CT acquisition. These 
changes may include thickening of the alveolar septa of any etiology, partial alveolar 
filling with different contents, alveolar shrinkage due to hypoventilation, enhanced lung 
perfusion and lung congestion. When honeycombing and traction bronchiectasis are not 
revealed, lung opacity may be one of the signs of active inflammation. When 
honeycombing and traction bronchiectasis are present, lung opacity is usually a sign of 
interstitial lung fibrosis. 


 Appendix 2 
HRCT Protocol (cont.) 
 
 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
163/Protocol ML39355, Version 2 dated 09-Jun-2018 
IPF exacerbations and complications  
IPF exacerbation is characterized with appearance of new sites of lung opacity-like 
density and/ or sites of consolidation, or abrupt and fast exaggeration of the present 
alike abnormalities. Infiltration overlaps cortically on reticular abnormalities and 
honeycombing. In some cases honeycombing reduces partially or completely due to 
effusion in the cysts.   
Assessment of UIP signs   
Assessment of UIP signs on HRCT will be performed using a semiquantitative method 
(see Table 1-3). Each lung will be divided vertically into three zones: upper zone, middle 
zone and lower zone. Margins between the zones on axial section are level of tracheal 
bifurcation and level of the right lower pulmonary vein. The upper lung zone is defined as 
the area of the lung above the level of the tracheal bifurcation, the lower lung zone is 
defined as the area of the lung below the level of the lower pulmonary vein and the 
middle lung zone is defined as the area of the lung between the upper and lower zones. 
The HRCT findings will be graded on a scale of 1-4 based on the classification system: 1) 
normal attenuation; 2) reticular abnormality; 3) traction bronchiectasis; and 4) 
honeycombing. The presence of each of the above four HRCT findings should be 
assessed independently in three (upper, middle and lower) zones of each lung. The 
extent of each HRCT finding will be determined by visual estimation of the percentage 
(%) (to the nearest 5%) of parenchymal involvement in each zone, from 0 to 100. A total 
sum of all abnormalities in one zone of a lung cannot exceed 400%. 
The score for each zone will be calculated by multiplying the percentage of the area by 
the mentioned above grading scale score (1-4). The zone scores for six zones of two 
lungs will be averaged to determine the total score for each patient. The overall HRCT 
score should be obtained by adding the averages for each index. The highest possible 
score is 400 points and the lowest score is 100 points using this calculation method.  
The total score will be named as the “HRCT fibrosis score”. Semiquantitative 
assessment with HRCT fibrosis score calculation will be performed at initiation of 
treatment and 6 months later. For patients continuing therapy in real clinical practice 
after study completion additional assessment will be performed in a year of therapy.  


 Appendix 2 
HRCT Protocol (cont.) 
 
 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
164/Protocol ML39355, Version 2 dated 09-Jun-2018 
Table 1-3. Assessment of HRCT UIP signs in lungs.  
Sign 
Reticular 
abnormality 
Honeycombing 
Traction 
bronchiectases 
Normal 
attenuation 
 
Lung 
opacity 
Upper zone RL1 
 
 
 
 
 
 
Middle zone RL 
 
 
 
 
 
 
Lower zone RL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Upper zone LL2 
 
 
 
 
 
 
Middle zone LL 
 
 
 
 
 
 
Lower zone LL 
 
 
 
 
 
 
1 RL – right lung. 
2 LL – left lung.  
The sign ‘lung opacity’ will be qualified separately using methodology described above 
for other signs, and its change over time will be assessed outside the framework of a 
total summed index of fibrosis (HRCT fibrosis score). Lung opacity should be graded as 
reticular abnormality to calculate the score for each zone, i.e. the percentage (%) area of 
opacity in a zone should be multiplied by the score of 2. 
References 
Ichikado K, Suga M, Müller NL et al. Acute interstitial pneumonia: comparison of high-
resolution computed tomography findings between survivors and nonsurvivors. Am 
J Respir Crit Care Med 2002, 165:1551–6.  
Oda K, Ishimoto H, Yatera K et al. High-resolution CT scoring system-based grading 
scale predicts the clinical outcomes in patients with idiopathic pulmonary fibrosis. 
Respir Res 2014,15:10. 


 
Pirfenidone—F. Hoffmann-La Roche Ltd 
165/Protocol ML39355, Version 2 dated 09-Jun-2018 
Appendix 3  
Histopathologic Criteria for UIP Pattern 
UIP Pattern 
(All 4 Criteria) 
Probable UIP Pattern 
Possible UIP Pattern 
(All 3 Criteria) 
Not UIP Pattern 
(Any of the 6 Criteria 
• Evidence of 
• marked 
fibrosis/ 
architectural 
distortion, 
± honeycombing in a 
predominantly 
subpleural/ 
paraseptal 
distribution 
• Presence of patchy 
involvement of lung 
parenchyma 
by 
fibrosis 
• Presence 
of 
fibroblast foci 
• Absence of features 
against a diagnosis 
of UIP suggesting 
an 
alternate 
diagnosis 
(see 
fourth column) 
• Evidence of marked 
fibrosis/ 
architectural 
distortion, 
± honeycombing 
• Absence of either 
patchy involvement 
or fibroblastic foci 
• Absence of features 
against a diagnosis 
of UIP suggesting 
an 
alternate 
diagnosis 
(see 
fourth column) 
or 
• Honeycomb 
changes onlyc 
• Patchy 
or 
diffuse 
involvement of lung 
parenchyma 
by 
fibrosis, 
with 
or 
without 
interstitial 
inflammation 
• Absence 
of 
other 
criteria for UIP (see 
UIP Pattern column) 
• Absence of features 
against a diagnosis 
of UIP suggesting an 
alternate 
diagnosis 
(see fourth column)  
• Hyaline 
membranesa 
• Organizing 
pneumoniaa,b 
• Granulomasb 
• Marked 
interstitial 
inflammatory 
cell 
infiltrate away from 
honeycombing 
• Predominant airway 
centered changes 
• Other 
features 
suggestive 
of 
an 
alternate diagnosis 
a Can be associated with acute exacerbation of idiopathic pulmonary fibrosis.  
b An isolated or occasional granuloma and/ or a mild component of organizing pneumonia pattern 
may rarely be coexisting in lung biopsies with an otherwise UIP pattern.   
c This scenario usually represents end-stage fibrotic lung disease where honeycombed segments 
have been sampled but where a UIP pattern might be present in other areas. Such areas are 
usually represented by overt honeycombing on HRCT and can be avoided by pre-operative 
targeting of biopsy sites away from these areas using HRCT.  
 


 
Appendix 5  
EuroQol-5D Questionnarie (cont.) 
Pirfenidone—F. Hoffmann-La Roche Ltd 
166/Protocol ML39355, Version 2 dated 09-Jun-2018 
Reference  
American Thoracic Society/European Respiratory Society/Japanese Respiratory 
Society/ Latin American Thoracic Association. 2011. An official ATS/ERS/ 
JRS/ALAT statement:  idiopathic pulmonary fibrosis:  evidence-based guidelines 
for diagnosis and management. Am J Respir Crit Care Med 183:1–38 [In press]. 


 
Pirfenidone—F. Hoffmann-La Roche Ltd 
167/Protocol ML39355, Version 2 dated 09-Jun-2018 
Appendix 4 
Borg Scale 
This instrument is to be self-administered by the patient as part of the 6MWT procedure. 
The patient will be given a paper copy of this instrument with the following instructions 
given in writing at the time the instrument is administered: 
“Please rate the current severity of your breathlessness by circling the most appropriate 
number on the following scale.” 
0 Nothing at all 
0.5 Very, very slight (just noticeable) 
1 Very slight 
2 Slight (light) 
3 Moderate 
4 Somewhat severe 
5 Severe (heavy) 
6 
7 Very severe 
8 
9 
10 Very, very severe (almost max) 
Reference 
Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982, 
14,5:377–81.


 
Pirfenidone—F. Hoffmann-La Roche Ltd 
168/Protocol ML39355, Version 2 dated 09-Jun-2018 
Appendix 5  
EuroQol-5D-5L Questionnarie 
Under each heading, please tick the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems in walking about 
 
I have slight problems in walking about 
 
I have moderate problems in walking about 
 
I have severe problems in walking about 
 
I am unable to walk about 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure 
activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 


 
Appendix 5  
EuroQol-5D Questionnarie (cont.) 
Pirfenidone—F. Hoffmann-La Roche Ltd 
169/Protocol ML39355, Version 2 dated 09-Jun-2018 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
 


 
Appendix 5  
EuroQol-5D Questionnarie (cont.) 
Pirfenidone—F. Hoffmann-La Roche Ltd 
170/Protocol ML39355, Version 2 dated 09-Jun-2018 


Appendix 5  
EuroQol-5D Questionnarie (cont.) 
 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
171/Protocol ML39355, Version 2 dated 09-Jun-2018 
 
References 
EuroQol Group. Web-source [Available at:https://euroqol.org/eq-5d-instruments/eq-5d-
5l-available-modes-of-administration/self-complete-on-paper/] 


 
Pirfenidone—F. Hoffmann-La Roche Ltd 
172/Protocol ML39355, Version 2 dated 09-Jun-2018 
Appendix 6  
GAP Risk Assessment 
 
 
Figure Legend 
The GAP index and staging system. 
Points are assigned for each variable of the scoring system to obtain a total point score 
(range, 0–8). Patients should be scored in the “Cannot perform” category for DLco if 
their symptoms or lung function prohibited performance of the DLco maneuver. If Dlco is 
unavailable because it was not ordered or not completed because of nonrespiratory 
limitations, then the model cannot be applied. The total point score is used to classify 
patients as stage I (0–3 points), stage II (4–5 points), or stage III (6–8 points). Model-


Appendix 6  
GAP Risk Assessment (cont.) 
 
 
 
Pirfenidone—F. Hoffmann-La Roche Ltd 
173/Protocol ML39355, Version 2 dated 09-Jun-2018 
predicted 1-, 2-, and 3-y mortality is shown by stage. GAP = gender, age, and 2 lung 
physiology variables (FVC and DLco). 
The formulas for computing predicted DLCO are as follows (Crapo and Morris 1971):  
Predicted DLCO for men 0.410 × height (cm) − 0.210 × age (yr) − 26.31  
Predicted DLCO for women 0.282 × height (cm) − 0.157 × age (yr) − 10.89  
References 
Crapo RO, Morris AH. Standardized single breath normal values for carbon monoxide 
diffusing capacity. Am Rev Respir Dis 1981,123;2:185-9. 
Ley B, Ryerson CJ, Vittinghoff E et al. A multidimensional index and staging system for 
idiopathic 
pulmonary 
fibrosis. 
Ann 
Intern 
Med 
2012,156:684-91.


 
Pirfenidone—F. Hoffmann-La Roche Ltd 
174/Protocol ML39355, Version 2 dated 09-Jun-2018 
Appendix 7 
IPF Care Program 
IPF Care Program by F. Hoffmann-La Roche Ltd (Switzerland) 
Guidance for telephone calls to the patients participating in the clinical trial of pirfenidone 
Telephone calls are scheduled at Weeks 3, 5, 7, 13 and 24. Optional calls can be performed at Weeks 8 and 10, if necessary.   
A total number of calls is 5 to 7. Schedule of telephone calls and topics for discussion are detailed in the Figure below. 
 
 
 
 
 
 
 
 
 
 


Appendix 7 
IPF Care Program (cont.) 
Pirfenidone—F. Hoffmann-La Roche Ltd 
175/Protocol ML39355, Version 2 dated 09-Jun-2018 
 
A full version of the IPF Care Program will be supplied by the Sponsor to the investigators or other designated staff.  

SAP_001.pdf: 
 
Official Title: 
Local Open-label Multicenter Study to Assess the Effectiveness of 
Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis in Russian 
Clinical Practice 
NCT Number: 
NCT03208933 
Document Date: 
SAP Version 2.0: 17-Jun-2020 
 
 




 
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Revision History 
№ Date 
Changes Implemented 
Version Number 
1 
22.01.2020 New document 
1.0 
2 
17.06.2020 
Section 9.2 (Adverse Events) was updated to 
include additional adverse event summaries. New 
tables (3.12.X, 3.13.X, 3.14) were added as 
requested by Roche Regulatory Disclosures and 
described in ML39355 Study Results Posting 
Requirements. The numeration of subsequent 
tables was adjusted. 
Section 7 (Summary of Study Data) was updated 
with the statement regarding summary of data 
from patients who received different Pirfenidone 
drugs during rollover study. 
Numeration of sections was adjusted according to 
the latest template version. 
Typing errors were corrected. 
 
2.0 
 
 
 
 
 
 
 


 
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Table of Contents 
1. Abbreviations and Definitions ............................................................................................................................ 4 
2. Introduction ........................................................................................................................................................ 5 
3. Study Objectives and Endpoints ......................................................................................................................... 5 
3.1. Study Objectives .......................................................................................................................................... 5 
3.2. Endpoints ..................................................................................................................................................... 5 
4. Study Design ...................................................................................................................................................... 6 
4.1. General Study Design and Plan ................................................................................................................... 6 
4.2. Randomization and Blinding ..................................................................................................................... 11 
5. Sample Size ...................................................................................................................................................... 11 
6. General Considerations ..................................................................................................................................... 11 
6.1. Timing of Analyses.................................................................................................................................... 11 
6.2. Analysis Populations ................................................................................................................................. 12 
6.3. Missing Data .............................................................................................................................................. 12 
6.4. Interim Analyses and Data Monitoring ...................................................................................................... 14 
6.5. Multi-center Studies................................................................................................................................... 14 
6.6. Multiple Testing ........................................................................................................................................ 14 
7. Summary of Study Data.................................................................................................................................... 14 
7.1. Subject Disposition .................................................................................................................................... 16 
7.2. Protocol Deviations ................................................................................................................................... 16 
7.3. Demographic and Baseline Variables  ....................................................................................................... 17 
7.4. Concurrent Illnesses and Medical Conditions ........................................................................................... 18 
7.5. Prior and Concurrent Medications ............................................................................................................. 18 
8. Efficacy Analyses ............................................................................................................................................. 19 
8.1. Primary Efficacy Analysis ......................................................................................................................... 19 
8.2. Secondary Efficacy Analyses .................................................................................................................... 21 
8.3. Exploratory Efficacy Analyses .................................................................................................................. 22 
9. Safety Analyses ................................................................................................................................................ 23 
9.1. Exposure .................................................................................................................................................... 23 
9.2. Adverse Events .......................................................................................................................................... 24 
9.3. Pregnancies ................................................................................................................................................ 25 
9.4. Clinical Laboratory Evaluations ................................................................................................................ 25 
9.5. Other Safety Measures ............................................................................................................................... 26 
10. Pharmacokinetics ............................................................................................................................................ 27 
11. Other Analyses ............................................................................................................................................... 27 
12. Reporting Conventions ................................................................................................................................... 27 
13. Technical Details ............................................................................................................................................ 27 
14. Summary of Changes to the Protocol ............................................................................................................. 27 
15. References ...................................................................................................................................................... 29 
16. Listing of Tables, Listings and Figures .......................................................................................................... 30 
16.1. Tables ...................................................................................................................................................... 30 
Patients Disposition .......................................................................................................................................... 33 
Protocol Deviations .......................................................................................................................................... 38 
Demographic and Anthropometric characteristics ............................................................................................ 39 
Baseline Variables ............................................................................................................................................ 42 
Medical history ................................................................................................................................................. 50 
Prior and concomitant medications ................................................................................................................... 53 
Efficacy Analyses ............................................................................................................................................. 55 
Primary Efficacy Endpoint ........................................................................................................................... 55 
Secondary Efficacy Endpoint ....................................................................................................................... 62 
Exploratory Efficacy Endpoint ..................................................................................................................... 77 
Safety Analyses ................................................................................................................................................ 82 
16.2. Figures ................................................................................................................................................... 116 
16.3. Listings .................................................................................................................................................. 116 


1. Abbreviations and Definitions 
The abbreviations and the definitions used in this document are listed below. 
Abbreviation 
Definition 
AE 
AESI 
Adverse event 
Adverse event of special interest 
ALT 
Alanine aminotransferase  
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
ATS 
American Thoracic Society  
BAL 
Bronchoalveolar lavage 
BMI 
Body mass index 
CCS 
Complete case set 
CS 
Clinically significant 
CI 
Confidence interval 
CK 
Creatine kinase  
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
Carbon monoxide diffusing capacity  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
CRF 
Case Report Form 
EQ-5D-5 
European Quality of Life 5-Dimension Questionnaire 
(including five levels of severity in each of the existing five EQ-
5D dimensions) 
FAS 
Full analysis set 
FEV 
Forced expiratory volume 
(F)VC 
FU 
(Forced) Vital capacity of the lungs 
Follow up 
GAP 
Gender, Age, Physiology (multidimensional index and   
staging system for IPF) 
GGT 
Gamma-glutamyl transferase  
Hb 
Hemoglobin 
(HR)CT 
(High-resolution) Computer Tomography 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee  
IMP 
Investigational Medicinal Product 
ILD 
Interstitial lung disease 
IPF 
Idiopathic Pulmonary Fibrosis  
LDH 
Lactic dehydrogenase 
LOCF 
Last observation carried forward 
MDT 
Multidisciplinary team 
(n)MWT 
N-minute wa k test 
NCS 
Not clinically significant 
PFT 
Pulmonary function test 
PRO 
Patient-reported outcome 
PT 
Preferred term 
QTC-F 
QT interval corrected (using Fridericia’s formula) 
RBC 
Red blood cells 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SOP 
Standard operating procedure 
SSD 
Sum of squared deviations  
SLB 
Surgical lung biopsy 
TEAE 
Treatment emergent adverse events  
TID 
Three times per day 
TS 
Treated set 
UIP 
Usual interstitial pneumonia 


 
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VAS 
Visual Analogue Scale 
WBC 
White blood cells 
yr 
Year 
2. Introduction 
This SAP is written according to ICH E9 Guideline [1] and Data MATRIX LLC SOP [2, 3] using 
the Protocol Final version 2.0 dated 01.02.2019 and CRF Final version 1.2 dated 08.07.2019. 
The purpose of this document is to provide a more technical and detailed elaboration of the 
principal features of the analysis, described in the Protocol, and to include detailed procedures for 
executing the statistical analysis. 
The SAP needs to be finalized and signed prior to database soft lock. Revisions to the approved 
SAP may be made prior to database soft lock. In case of deviation from the finalized SAP, 
explanation will be provided in the clinical study report (CSR). 
3. Study Objectives and Endpoints 
3.1. Study Objectives 
3.1.1. Primary Efficacy Objective 
To estimate the treatment effect of pirfenidone 2403 mg/d on lung function. 
3.1.2. Secondary Efficacy Objective 
To estimate the effectiveness of pirfenidone on IPF patients’ functional capability and quality 
of life. 
3.1.3. Exploratory Efficacy Objective 
To estimate the effectiveness of pirfenidone on the frequency and number of acute 
exacerbations of IPF and on features of HRCT. 
3.1.4. Safety Objective 
To evaluate the safety of pirfenidone. 
3.2. Endpoints 
3.2.1. Primary Efficacy Endpoint 
• Change from Baseline to Week 26 in absolute mL forced vital capacity (FVC) and 
% FVC 
3.2.2. Secondary Efficacy Endpoints 
• Change from baseline to Week 26 in 6-minute walk test (6MWT) distance 
• Change from baseline to Week 26 in patients’ quality of life as measured with 
European Quality of Life 5-Dimension Questionnaire (EQ-5D) 
3.2.3. Exploratory Efficacy Endpoints 
• Frequency and number of IPF exacerbations 


 
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• CT scan evaluation (semiquantitative assessment "HRCT fibrosis score". The high-
resolution computed tomography (HRCT) findings will be evaluated using HRCT 
scoring system. Interstitial lung disease (ILD) radiologist will make assessment of 
4 main findings in three zones of each lung. The six zone scores will be averaged 
to determine the total score for each patient at baseline and at Weeks 26 and 52) 
3.2.4. Safety Endpoints 
• Treatment-emergent adverse events (AEs) 
• Treatment-emergent serious adverse events (SAEs) 
• Change from baseline in clinical laboratory parameters and electrocardiogram 
(ECG) parameters 
4. Study Design 
4.1. General Study Design and Plan1 
This is a local, multicenter, interventional, non-randomized, non-controlled, non-comparative, 
open-label study to assess the effectiveness of pirfenidone in patients with IPF in Russian clinical 
practice. Approximately 60 patients diagnosed IPF will be enrolled to receive pirfenidone 2403 
mg/d for 26 weeks. No comparator group is implied in the study. 
For enrolment into the study, the diagnosis of IPF must be confirmed by central review of HRCT 
scans and of the surgical lung biopsy (SLB) samples, if available (if performed prior enrolment 
in routine clinical practice). The HRCT scans will be reviewed by one or two central readers who 
are radiologists with expertise in IPF. If the first expert (central reader-1) agrees with the local 
opinion, the second expert (central reader-2) will not review scans. If the first expert disagrees 
with the local opinion, the second expert should review scans. Histopathological (SLB) samples 
will be reviewed by the one central reader who is a pathologist with expertise in IPF. All other 
diagnostic procedures will be performed and assessed at a local level.  
Eligible patients aged 40–80 years must have a confident clinical and radiographic/ or histological 
diagnosis of IPF according to 2011 IPF guidelines (ATS 2011). Patients with possible UIP on 
high-resolution computed tomography and without SLB in case of “working diagnose” of IPF 
during multidisciplinary team (MDT) discussion, are also eligible for the trial (see Table 2).  
Patients will be required to have a relative %FVC ≥ 40 %, percent predicted carbon monoxide 
diffusing capacity (%DLCO) ≥ 30 %, and able to walk ≥ 100 meters during the 6-minute walk 
test at the Screening.  
All assessments in the study will be initiated only after signed Informed Consent is obtained from 
the patient. For this purpose, an additional visit may be performed prior to the start of the 
Screening procedures and an appropriate review of the patient’s clinical data relevant to the IPF 
diagnosis is done. 
Any patient identified for the study must discontinue all prohibited therapies including therapy 
targeted to treat IPF for at least 28 days before the start of the treatment period. Other than 
 
1 This section is based on the sections 3.1 “Description of the study”, 3.2 “End of study and length of study” of the 
clinical study Protocol. 


 
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permanent use of corticosteroids (prednisolone at a maximum daily dose of 15 mg or equivalents) 
and brief periods of corticosteroid use for acute IPF exacerbation, patients will not receive any 
other therapy for the treatment of IPF. After central review of HRCT and SLB, patients will enter 
the Screening period, which may last up to 28 days (4 weeks). 
After the Screening, eligible patients will enter the Treatment period lasting 26 (± 1) weeks. All 
patients will receive pirfenidone 2403 mg/d administered orally in divided doses three times per 
day (TID) with food. Dose of the study treatment will be titrated over 14 days to the full dose of 
9 capsules per day (three 267 mg capsules taken orally TID with food). Patients will remain on a 
stable maintenance dose for the duration of the treatment period unless the dose is reduced to 
manage adverse events or titrated again when restarting study treatment after an appropriate 
interruption in treatment.  
The primary efficacy endpoint in the study is the change from baseline to Week 26 in absolute 
(mL) FVC and relative (%) FVC as measured by spirometry procedure. Spirometry will be 
performed at the Screening, on Day 1 of treatment, at Week 12, Week 26 and in the extended 
Follow-up period (Weeks 39 and 52), if applicable. At screening, spirometry measurements will 
be performed before and after administration of albuterol (or salbutamol) from a metered dose 
inhaler. During further visits, bronchodilator test is not necessary to perform. Spirometry data 
collected throughout the study will be evaluated by local readers.  
Patients will have a telephone assessment at Week 1, when safety-related information and 
adherence to treatment is collected. Subsequently patients will have in-clinic visits at Weeks 2, 4, 
8, 12, 16, 20 and 26. Patients should complete an adverse event and dosing compliance diary 
between all visits. Additionally, telephone calls to patients will be scheduled at Weeks 3, 5, 7, 13 
and 24 as a part of IPF care program. A total of 5-7 calls are scheduled in the study, including 
extra-calls at Weeks 8 and 10 as needed. 
Treatment with pirfenidone will continue until Week 26 (± 1). Patients will be followed through 
the Follow-up visit scheduled 2-4 weeks after treatment completion or until entry into the long-
term follow-up (rollover study), whichever occurs earlier. Patients who undergo lung 
transplantation or who chose to withdraw from study procedures early will be followed for vital 
status until Week 26. If patients discontinue study treatment early for any reason, they should 
continue with all scheduled study procedures through Week 26.  
Patients who complete participation in the study prematurely due to any reasons (drop-outs) will 
not be replaced. 
Patients who proceed until Week 26 in the study and are compliant with the study treatment, may 
continue treatment with commercially available pirfenidone after study completion in real clinical 
practice (long-term follow-up or rollover study). In this case, patients will have two follow-up 
assessments of FVC and 6MWT at Weeks 39 and 52 and CT scans evaluation at Week 52. 
Information on AEs occurrence will also be collected during the rollover part of the study. 
If a patient cannot participate in the rollover part of the study for any reason, a follow-up visit will 
be performed 14-28 days after the last dose of pirfenidone is taken. 
A schedule of activities is provided in Table 1. 
An Independent Data Monitoring Committee (IDMC) will be implemented in the study. The 


 
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IDMC will conduct regular review of the trial safety data, with the focus on death cases, serious 
adverse events, unexpected adverse events, adverse events leading to treatment or study 
discontinuation, liver enzyme increases, reported as adverse events, and other AEs immediately 
reported to the Sponsor. 
Duration of participation in the study for an individual patient is between 31 and 35 weeks 
(excluding long-term follow-up). For patients continuing in the rollover study the duration of 
participation in the study extends up to maximum 58 weeks. 
 
 




 
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Study period 
IC 
Visit 
Screening 
(Washout, if 
applicable) 
Treatment period 
Follow-Up 
Long-Term 
Follow-Up16 
Week 
(Window) 
 
 
–4 to –1 
Day 1 
W1  
(± 1 d) 
 
W2 
( 2 d) 
W4 
( 2 d) 
W8 
( 2 d) 
W12 
( 1 w) 
 
W16 
( 1 w) 
 
W20 
( 1 w) 
 
W26  
( 1 w) 
14–28 days 
after last 
dose 
W39 
(± 2 w) 
W52 
(± 2 w) 
Borg scale13 
 
х 
х 
 
 
 
 
х 
 
 
x 
х 
 
х 
x 
EQ-5D questionnarie13 
 
x 
х 
 
 
 
 
х 
 
 
 
х 
 
 
x 
Patient diary (review, dispense)14 
 
 
x 
х 
Х 
х 
х 
x 
x 
x 
 
х 
 
 
 
Telephone calls (IPF Care program)15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Written informed consent must be obtained prior to any study-associated procedure, including discontinuing any prohibited medications.  
2  Safety-related information (AEs) and adherence to treatment is collected. 
3 Complete medical history is collected at an IC visit, washout and screening only. Thereafter, directed history (including review of AEs/SAEs, concomitant medications, oxygen use, hospitalizations, 
dosing, and diary) is only collected.  
4 Complete physical examination is performed at the Screening only (head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems). At subsequent visits (or as clinically indicated), only limited, symptom-directed physical examinations should be performed. 
5 Height is assessed at the Screening only. 
6 ECG should be performed after patient’s resting in a supine position for at least 10 min, prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws), 
bronchodilator administration and within 3 hours after any meal) 
7 To confirm IPF will be applicable to use previously performed HRCT, if it is performed not earlier than 24 months before the Screening. Review of the SLB samples obtained within 4 years before 
the Screening should be performed centrally for elig bility confirmation. Histopathological evaluation, if not available, is not repeated at the Screening.  
8 Transbroncheal biopsy or BAL are not mandatory and will only be reviewed at the Screening, if available, to exclude other causes of PF. 
9  HRCT should be performed at the Screening only for patients having no validated procedure within 2 months prior initiation of treatment.  
10 At screening, spirometry measurements of FVC should be performed before and after administration of albuterol (or salbutamol) from a metered dose inhaler (4 separate doses of 100 mg). 
Tests should be repeated after a 15-min delay. During further visits, bronchodilator test is not necessary to perform. Collection and recording of the retrospective FVC values obtained in clinical 
practice over the last year will be performed only at the screening visit. 
11 Blood samples must be drawn in fasted state. Serologic tests: rheumatoid factor, anticyclic citrullinated peptide and antinuclear antibody titer. 
12 Pregnancy test must be performed before first dosing on Day 1 and must be negative. If the urine test is positive, serum pregnancy test must be performed. 
13  Questionnaires should be self-administered before the patient or clinician receives any information on disease status, prior to the performance of non-PRO assessments, and prior to the 
administration of study treatment, with the exception for Borg scale administered in conjunction with the 6MWT. 
14 Patient diary should be filled out on daily basis by the patient and reviewed by the investigator at in-clinic visits. Patient diary captures information on compliance and AEs occurance and is 
dispensed as needed. 
15 Schedule of calls in IPF Care Program you can see in Appendix 7   
16  Only in patients continuing treatment with pirfenidone in real clinical practice. 


4.2. Randomization and Blinding2 
Randomization is not planned in the study. 
Blinding is not applicable in this open-label study. 
 
5. Sample Size3 
 
Taking into account study design (single group prospective study), sample size was 
estimated based on feasibility of patient enrollment with precision-based approach. In the 
ASCEND study primary efficacy endpoint (Percent Predicted FVC) in pirfenidone group changed 
from 67.8 (11.24) (denoted as mean (SD)) at baseline to 65.3 (14.52) at week 26, with stable 
disease (decline in FVC < 10 % to 0 %) in 60.1 % of study patients. 
The required sample size for two-sided 95% confidence level can be calculated using the 
following formula: 
 
 
Assuming previous calculations, 60 patients included in the study will be sufficient for study 
parameters estimation. Taking into account study goals and the notion that the study drug is a 
product for the treatment of an orphan drug, margin of error of 0.125 is considered sufficient for 
parameter estimation. For precision-based sample size justification, with a sample size of 60 
patients, an expected mean value of 2.5% and standard deviation of 20, distance from the mean to 
limit of the two-sided 95% confidence interval for the mean Change from Baseline to Week 26 
(Percent Predicted FVC) will extend about 5 (margin of error). The SD for change from baseline 
at week 26 is conservatively estimated based on the results of the ASCEND study as standard 
deviation for Percent Predicted FVC in pirfenidone group at week 26 (14.52) multiplied by √2 
(Machin et al., 1997).  This is also in line with the results of CAPACITY programme (Noble et al. 
2011) in which the SD of changes from baseline was 17 - 20 at week 72. 
Taking into account an expected rate of screening failures about 45%, up to 109 patients will 
be screened for eligibility. 
 
6. General Considerations 
6.1. Timing of Analyses 
No interim analysis is planned in this study. 
 
 
2 This section is based on the section 4.2 “Method of treatment assignment and blinding” of clinical study Protocol. 
3 This section is based on the section 6.1 “Determination of sample size” of clinical study Protocol. 


 
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6.2. Analysis Populations 
The main patient samples of interest are defined as follows. 
The ‘All enrolled patients’ set will consist of all patients who: 
Gave their Informed Consent.  
The ‘Allocated to treatment’ set will consist of all patients who: 
Gave their Informed Consent and  
Had successfully completed Screening procedures. 
The ‘Treated set’ (TS) will consist of all patients who: 
Were in the ‘Allocated to treatment’ set and 
Received any dose of the study treatment. 
The ‘Full analysis’ set (FAS) will consist of all patients who:   
• Were included in the ‘Treated’ set and  
• Had data for at least one post-baseline assessment of any efficacy measurement.  
The ‘Complete case set’ (CCS) will include FAS patients who  
• Provided FVC data at 26-week assessment. 
 
6.3. Missing Data4 
For missing FVC data imputation, patients will be classified into different patterns depending on 
the availability of data:  
Patients with a 26 week FVC value:  
1. those who received study drug until 26 weeks (completed the treatment period);  
2. those who prematurely discontinued study drug, but who were followed up until Week 26.  
Patients without a 26 Week FVC value:  
3. those who were alive at 26 weeks;  
4. those who died before 26 weeks.  
Missing data at other visits before Week 26 (primary outcome variable) will not be imputed.  
The following imputation methods including sensitivity analyses will be applied for patients with 
pattern 3 - 4:  
Assuming that deaths of the patients (pattern 4) is likely to be related to worsening of IPF, these 
unobserved FVC values should be lower than those in patients who did not die prior to Week 26. 
Methods for handling missing data due to death will include the following: 
• Replacement with the worst possible value (FVC= 0 mL or 0%) (Primary analysis). 
• Replacement with worst observed averaged FVC value at week 26 (Sensitivity analysis).  
 
4 This section is based on the section 6.2 “Summaries of conduct of study” of clinical study Protocol. 


 
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• Replacement with an intermediate value (FVC =1500 mL or 50%) (Sensitivity analysis). 
Missing data due to reasons other than death (e.g., missing visits, early withdrawal from the study, 
including missing values due to lung transplantations) (pattern 3) will be replaced with imputed 
values based on the average measurements for “similar” patients at that time point. Similar patients 
are those without missing data before that time point and whose data have the smallest sum of 
squared deviations (SSD) from that patient for all visits prior to the one with the missing data. 
Missing data due to lung transplant will be imputed using the SSD method even if the patient dies 
after lung transplant.  
The procedure referred to as the sum of squared deviations (SSD) is outlined as follows: 
Step 1: For post-Baseline missing value to be imputed at a visit (Visit week 26) for a particular 
patient (Patient A), a set of all patients without any missing values for visits from Baseline up to 
Visit week 26 as Patient A will be selected. 
Step 2: For the patients in this set, the SSDs between each patient selected in Step 1 and Patient 
A will be calculated across all non-missing values from Baseline up to the visit prior to Visit week 
26. 
Step 3: The 3 patients with the smallest SSDs will be identified and the average of their non-
missing value at Visit week 26 will be used to impute the missing value for Patient A at that visit. 
The number of smallest SSDs to calculate the average can be less than 3 due to availability of 
patients defined in Step 1 or more than 3 based on tied SSDs. 
 
A sensitivity analysis will use the data imputed with last observation carried forward method 
(LOCF). 
Complete case analysis will also be performed as a sensitivity analysis. 
 
If the information about end date for prior/concomitant therapy is missing or incomplete, the 
following rules (table 6.1) will be used for the classification of therapy as prior or concomitant. 
Table 6.1 – Management of partial and missing prior/concomitant therapy end date. 
Day 
Month 
Year 
Processing 
is missing 
is known 
is known 
Therapy will be classified as 
concomitant, if month and year ≥ month 
and year of the first dose of study 
therapy, else – as prior 
is missing 
is missing 
is known 
Therapy will be classified as 
concomitant, if year ≥ year of the first 
dose of study therapy, else – as prior 
is known 
is missing 
is known 
is missing 
is known 
is missing 
Therapy will be classified as 
concomitant 
is known 
is missing 
is missing 
is missing 
is missing 
is missing 
 


 
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If the information about adverse event start date and time is missing or incomplete, the 
following rules (table 6.2) will be used for the classification of adverse events as TEAEs and non-
TEAEs (occurred before the start of study treatment). 
Table 6.2 – Management of partial and missing AE start date. 
Day 
Month 
Year 
Processing 
is missing 
is known 
is known 
AE will be classified as TEAE, if month 
and year ≥ month and year of the first 
dose of study therapy  
is missing 
is missing 
is known 
AE will be classified as TEAE, if year ≥ 
year of the first dose of study therapy  
is known 
is missing 
is known 
is missing 
is known 
is missing 
AE will be classified as 
TEAE 
is known 
is missing 
is missing 
is missing 
is missing 
is missing 
 
No date imputation will be performed for listings. 
 
6.4. Interim Analyses and Data Monitoring5 
No interim analysis is planned in the study.  
6.5. Multi-center Studies 
Data from all centers will be merged and analyzed as one population for all study endpoints. 
6.6. Multiple Testing 
No adjustment for multiplicity is planned. 
7. Summary of Study Data 
Demographic and other baseline characteristics, efficacy and safety data will be summarized 
by time point of assessment and listed.        
Default Summary Statistics 
The default summary statistics for quantitative and ordinal variables will be the number of 
observations (n), mean, standard deviation (SD), median, minimum (Min) and maximum (Max). 
Default Frequency Tabulations 
For qualitative variables, the number and percentage (n, %) of patients with non-missing data per 
category and total number of patients with non-missing data where applicable (n’) will be the default 
summary presentation. 
For AEs and medical history, however, the denominator for the percentage calculation will be the 
number of patients at risk. A patient will be considered at risk if the patient is in the Treated set. 
 
5 This section is based on the section 6.6 “Interim analysis” of clinical study Protocol. 


 
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The number of decimals for each descriptive statistic will be determined by the following rules: 
− mean, median: +1 decimal symbols compared to the analysed variable values; 
− standard deviation: +2 decimal symbols compared to the analysed variable values; 
− minimum and maximum values: the same as for the analysed variable values; 
− percentages will be rounded to one decimal symbol; 
− confidence intervals will be presented with accuracy of the estimated value. 
The maximum number of decimal places in the statistical report is four. If some descriptive 
statistic has more than four decimal places after above mentioned rules application, this value will 
be rounded to four decimal places. 
Statistical Tests and Common Calculations 
Unless otherwise specified in the description of the analyses, the following arrangements will be 
applied: 
− 95% two-sided confidence intervals (CI); 
− [if appropriate] CIs for mean values will be calculated based on normal distribution (SAS 
procedure UNIVARIATE with CIBASIC option); 
− [if appropriate] CIs for proportions will be computed using the exact (Clopper-Pearson) 
method. 
− Type I error values (p-values) will be rounded to four decimal symbols. 
For descriptive statistics and analysis, the following rules will be applied: 
− “<XX” results (e.g. below the limit of quantification, BLQ) will be replaced by the “XX/2” 
values; 
For quantitative measurements, changes from baseline will be calculated as [value at post-
baseline visit X – baseline value].  
For change from baseline, the baseline value for a variable in common cases (except for 
efficacy analysis) is defined as the last non-missing value collected before the first study drug 
administration. 
Study day for each event will be calculated from the reference start date (date when patient was 
first exposed to study drug). 
If the date of the event is on or after the reference date, then 
study day = (date of event – reference date) + 1. 
If the date of the event is prior to the reference date, then 
study day = (date of event – reference  date). 
For partial dates study day will not be calculated. 
 
The following visit windows will be defined: 
 


 
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Visit 
First day of the visit 
window  
Last day of the visit 
window 
  Week 1 Telephone Assessment (+/- 1 day) 
1 
8 
  Week 2 (+/- 2 days) 
6 
16 
  Week 4 (+/- 2 days) 
20 
30 
  Week 8 (+/- 2 days) 
48 
58 
  Week 12 (+/- 2 days) 
76 
86 
  Week 16 (+/- 1 week) 
99 
119 
  Week 20 (+/- 1 week) 
127 
147 
  1st day at Week 26 (+/- 1 week) 
169 
189 
  2nd day at Week 26 (+/- 1 week) 
169 
189 
  Week 39 (+/- 2 weeks) 
253 
287 
  Week 52 (+/- 2 weeks) 
344 
378 
 
 
The data from all subjects who were treated in the rollover study will be pulled for the analysis 
irrespective of the trade name(s) of pirfenidone used by the subject (Esbriet® or other, if 
applicable). An explanatory footnote will be added to the outputs where necessary to indicate 
which pharmaceutical product was used. 
7.1. Subject Disposition 
The following patient disposition summaries will be provided: 
• A summary of the number of patients signed the Informed Consent and the number of screen 
failures with reasons for premature study termination 
• A summary of the number of screen failure patients violated any inclusion/exclusion criterion, 
by criterion 
• A summary of the number of patients allocated to treatment, the number and percentage of 
treated patients, the number and percentage of patients attended each study visit, the number 
and percentage of patients who were included into rollover study (Allocated to treatment set) 
• A summary of the number and percentage of patients included in each population for statistical 
analysis (Allocated to treatment set) 
• A summary of the number and percentage of patients completed the study and prematurely 
discontinued from the study by major reason for discontinuation (Allocated to treatment set).  
 
By-patient listings of disposition details will be provided for all patients who signed the 
Informed Consent. 
 
 
7.2. Protocol Deviations6 
Number and percentage of patients with at least one protocol deviation will be tabulated 
(Allocated to treatment set). All protocol deviations will be listed (All Enrolled patients). 
 
 
 
6 This section is based on the section 9.2 “Protocol deviations” of clinical study Protocol. 


 
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7.3. Demographic and Baseline Variables 7 
eCRF form: “DEMOGRAPHIC DATA”, “VITAL SIGNS”. 
Descriptive statistics for the following demographic and anthropometric characteristics, which 
are evaluated at screening, will be presented in accordance with section 7: 
− demographic characteristics: age, gender, race, ethnicity; 
− anthropometric characteristics: height (cm), weight (kg), body mass index (BMI, kg/m2). 
Body mass index will be calculated as weight (kg) / [height (m)]2. 
eCRF form: “SURGICAL LUNG BIOPSY”, “REVIEW TRANSBRONCHIAL LUNG 
BIOPSY/BAL”, “HRCT SCAN FOR PATIENT ELIGIBILITY CONFIRMATION”, “DL(CO)”, 
“SPIROMETRY”, “SEROLOGIC TESTS”, “GAP RISK ASSESSMENT”. 
The following parameters will be tabulated in accordance with section 7: 
− Disease Assessment and PFT: 
o Surgical lung biopsy (SLB) (if available) (UIP pattern assessment of regional 
specialist: Consistent, Probable, Possible, Inconsistent / unclassified; UIP pattern 
assessment of central specialist: Consistent, Probable, Possible, Inconsistent / 
unclassified) 
o Transbronchial lung biopsy/ Bronchoalveolar lavage (BAL) (if available) (Are 
there features supporting an alternative diagnosis? Yes/No) 
o High-resolution computed tomography (HRCT) (HRCT fibrosis score; Lung 
opacity score (Ground-glass opacity )) 
o HRCT scan for patient’s eligibility confirmation (UIP pattern assessment of 
regional CT-specialist: Typical (apparent), Possible; UIP pattern assessment of 
central CT-specialist: Typical (apparent), Possible, Inconsistent) 
o Carbon monoxide diffusing capacity (DLCO predicted) 
o Pre-, post- bronchodilator, and retrospective FVC (absolute), ml; FVC (relative), 
% predicted,  pre- post-bronchodilator FEV1/FVC,  
− Laboratory Tests: 
o Serologic tests: rheumatoid factor, anticyclic citrullinated peptide and antinuclear 
antibody titer (Positive / Negative) 
− PROs and ClinROs: 
o GAP (Gender, Age, Physiology) assessment (Stage, GAP Index (Points), Mortality 
1-yr, Mortality 2-yr, Mortality 3-yr) 
Specific calculations and/or conversions include but are not limited to the following: 
DLCO: Data for DLCO will be collected in the eCRF. Results of DLCO measurements will be 
corrected to patients’ hemoglobin (Hb) using one of the formulas (Cotes et al. 1979):  
Hb-corrected DLCO for men: DLCO × (10.22 + Hb)/(1.7 × Hb) 
 
7 This section is based on the section 6.3 “Summaries of Demographic and Baseline characteristics”, 4.5.6 “HRCT 
and Surgical Lung Biopsy”, 4.5.7 “Spirometry and DLCO Measurements”, 4.5.8 “Laboratory, Biomarker, and Other 
Biological Samples”, 4.5.11.4 “GAP Risk Assessment System” of clinical study Protocol. 


 
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Hb-corrected DLCO for women: DLCO × (9.38 + Hb)/(1.7 × Hb) 
where Hb indicates the value of hemoglobin, in g/dL. If the Hb value is reported in g/L, then the 
Hb value is divided by 10. If the Hb value is reported in mmol/L, then the Hb value is divided by 
0.6206.  
Use the hemoglobin value available on the same day if possible; otherwise, the closest 
hemoglobin value before or after the actual DLCO assessment date should be used. If the two values 
are equidistant, the value before the actual DLCO assessment should be used. 
All data will be listed. 
 
7.4. Concurrent Illnesses and Medical Conditions8 
eCRF form: “GENERAL MEDICAL HISTORY”, “HISTORY OF IDIOPATHIC 
PULMONARY FIBROSIS”. 
Medical history findings will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.0 (or further updating) according to Data MATRIX SOP [4], and will be 
presented by Primary System Organ Class (SOC) and Preferred Term (PT) within SOC. 
Medical history events marked as “Resolved” will be considered as prior diseases. Medical 
history events marked as “Ongoing” will be considered as concomitant diseases. 
Prior and concomitant diseases will be tabulated separately. 
Medical history findings will be reported on a by-patient basis. This implies that if the patient 
suffered the same event (mapped to same PT) repeatedly the event will be counted once and only 
once for appropriate SOC. Within SOC patients may have reported more than one PT. The SOCs 
and PTs within each SOC will be sorted by descending order of total incidence. 
As medical history of main disease, the following parameters: (Idiophatic Pulmonary 
Fibrosis), Duration of clinical symptoms consistent with IPF (months), Clinically significant 
environmental exposure known to cause pulmonary fibrosis (Yes/ No), Known explanation for 
interstitial lung disease (Yes/ No), Cigarette smoking within 28 days before the treatment start 
(Yes/ No) will be presented descriptively in the separate table. 
All data will be listed. 
 
7.5. Prior and Concurrent Medications9 
eCRF form: “PRIOR/ CONCOMITANT MEDICATIONS”. 
 
8 This section is based on the section 4.5.2 “Medical History and Demographic Data”, 6.3 “Summaries of 
Demographic and Baseline characteristics” of clinical study Protocol. 
9 This section is based on the section 6.2 “Summaries of conduct of study” of clinical study Protocol. 


 
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1 . Prior and сoncomitant medications will be analyzed based on the information from the 
Concomitant/Prior Medications (CM) domain. 
2 . All prior and concomitant medications will coded using the World Health Organization 
Drug Dictionary (WHODD) version B2 March 2018 (or further updating) according to Data 
MATRIX SOP [4]. 
Classification of treatment as either Prior or Concomitant will be based on stop date of medication 
in “PRIOR/CONCOMITANT” eCRF form. The number (%) of patients reporting the use of any 
medications, and the number of reported medications will be presented in separate tables by 
pharmacological subgroup (3rd level) and chemical substance (5th level). 
Medications that stop prior to the date of first dose of study therapy will be classified as Prior 
medications. If a medication stops on or after the date of first dose of study therapy (or 
“ONGOING”) then the medication will be classified as Concomitant. For patients who take part 
in the rollover study, medications started on or after the date of the first dose of the study drug 
during the rollover study will be summarized separately.   
3 . If the information about stop date of medication is missing or incomplete, the rules from 
section 6.3 will be applied for classification. Medications will be assumed to be concomitant, 
unless there is clear evidence (through comparison of partial dates) to suggest that the medication 
stopped prior to the first dose of study therapy.  If there is clear evidence to suggest that the 
medication stopped prior to the first dose of study therapy, the medication will be assumed to be 
Prior. 
By-patient listings will be provided. 
8. Efficacy Analyses10 
eCRF form: “SPIROMETRY”. 
Descriptive statistics for all efficacy variables will be presented by visit. For the descriptive 
statistics, the rules presented in section 7 will be applied. 
The FAS and Complete case set will be used for the efficacy analysis. Analysis on Complete 
case set will be one of the sensitivity analyses to be performed.  
All efficacy data will be listed.  
 
8.1. Primary Efficacy Analysis 
The primary outcome variable is the absolute change in FVC from Baseline to Week 26 (both 
in mL and % predicted). Baseline FVC will be the average of the FVC measured at the Screening 
(excluding values after bronchodilator administration) and Day 1 visits, if either is missing, the 
non-missing value will be used. The FVC at Week 26 will be the average of the FVC measured on 
 
10 This section is based on the section 6.4 “Efficacy analyses” of clinical study Protocol. 


 
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two separate days at Week 26, if either is missing, the non-missing value will be used. If both 
values are missing, the data will be imputed as specified in Section 6.3.  
Data will be analyzed using standard descriptive statistics for continuous variables and 95% 
CI for the means and mean changes.   
The data imputation methods for primary endpoint are described in Section 6.3. 
For the primary analysis, missing data due to death will be replaced with the worst possible 
value (FVC= 0 mL or 0%). Missing data due to reasons other than death (pattern 3) will be replaced 
with imputed values based on the average measurements for “similar” patients at that time point 
(SSD, Primary analysis). 
As sensitivity analyses, the following imputation methods will be used: 
1. Missing data due to death will be replaced with the worst observed FVC value at week 26. 
Missing data due to reasons other than death (pattern 3) will be replaced with imputed values based 
on the average measurements for “similar” patients at that time point (SSD). 
2. Missing data due to death will be replaced with an intermediate value (FVC =1500 mL or 
50%). Missing data due to reasons other than death (pattern 3) will be replaced with imputed values 
based on the average measurements for “similar” patients at that time point (SSD). 
3. Missing data due to death will be replaced with the worst possible value (FVC= 0 mL or 
0%). Missing data due to reasons other than death (pattern 3) will be replaced with LOCF. 
4. Missing data due to death will be replaced with the worst observed FVC value at week 26. 
Missing data due to reasons other than death (pattern 3) will be replaced with LOCF. 
5. Missing data due to death will be replaced with an intermediate value (FVC =1500 mL or 
50%). Missing data due to reasons other than death (pattern 3) will be replaced with LOCF. 
6. Missing data due to death and due to reasons other than death (pattern 3) will be replaced 
with LOCF. 
Analysis of the primary efficacy endpoint will be also repeated on the Complete case set (CCS) 
without missing data imputation as the sensitivity analysis. Complete case set will include patients 
related to pattern 1 and 2 (section 6.3), results will be reported for pattern 1 and 2 separately and 
overall.  
Primary analysis with missing data imputation of the primary efficacy endpoint and analysis 
on the CCS set will also be repeated excluding all values outside of visit window based on visit 
window definitions in Section 7. 
For this analysis, if one of the observations pertaining to Week 26 visit is within the visit 
window and the other is outside the visit window, the observation which is within the visit window 
will be used for Week 26 assessment. The distribution (number and percentage) of primary 
outcome variable across three categories of change from Baseline (Decline of ≥10% or death 


 
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before Week 26; Decline of < 10% to 0%; Improvement of ≥ 0%) (absolute change in FVC % 
predicted and relative change for volume) will be provided in frequency table.  
Additionally, the absolute change in FVC from Baseline at Week 12, 39 (optional) and 52 
(optional) and mean FVC values through all time points (both in mL and % predicted) will be 
summarized (without missing value imputation) in tables with standard descriptive statistics for 
continuous variables and 95% CI for the means and mean changes. For each time point, descriptive 
analysis will be repeated for values within visit window. 
 
8.2. Secondary Efficacy Analyses 
eCRF form: “6-Minute Walk Test”, “BORG SCALE”, “EUROPEAN QUALITY OF LIFE 5-
DIMENSION 5-LEVEL QUESTIONNAIRE”. 
Change in 6MWT distance from Baseline to Week 26 
Baseline 6MWT distance will be the average of the measurements recorded at the Screening 
and Day 1 visits. The 6MWT distance at Week 26 will be defined as the average of the 6MWT 
distance recorded on two separate days at Week 26. Data will be analyzed using standard 
descriptive statistics for continuous variables and 95% CI for the means and mean absolute 
changes.  
The distribution (number and percentage) of 6MWT distance across three categories of 
change from Baseline (Decline of ≥ 50 m or death before Week 26; Decline of <50 m to 0 m 
(exclusively), Improvement of ≥ 0 m) will be provided in frequency table.  
Additionally, the absolute change in 6MWT from Baseline at Week 39 (optional) and Week 
52 (optional) will be summarized in table with standard descriptive statistics for continuous 
variables and 95% CI for the mean. 
Borg scale results will be presented descriptively by visit of assessment. Borg scale results 
(as a continuous variable) will be presented for both pre-test and post-test by visit of assessment 
and change from baseline (the average of the measurements recorded at the Screening and Day 1 
visits) at post-baseline visits for pre-test assessments only.  
The Borg scale results at Week 26 will be defined as the average of the Borg scale results 
recorded on two separate days at Week 26. If at baseline and/or at Week 26 for 6MWT distance 
or Borg scale either value is missing, the non-missing value will be used. 
Descriptive analysis for 6MWT distance and Borg scale results will be repeated excluding 
assessments outside of visit window. 
 
Change from Baseline to Week 26 in patients’ quality of life as measured with EQ-5D-5L 
• Cross tabulation for each of five dimensions (Mobility, Self-Care, Usual Activities, Pain / 
Discomfort, Anxiety / Depression) by response and study week. 


 
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• VAS score, including absolute changes from baseline, will be summarized with descriptive 
statistics by study week.  
• EQ-5D-5L index score using the UK value set, including absolute changes from baseline, 
will be summarized with descriptive statistics by study week.  
Descriptive analysis will be repeated excluding assessments outside of visit window. 
The baseline assessment is the last non-missing assessment prior to the first dose of the study 
drug.  
 
8.3. Exploratory Efficacy Analyses 
eCRF form: “HRCT SCAN”, “ADVERSE EVENTS”. 
HRCT fibrosis score 
The HRCT findings will be evaluated using HRCT scoring system. One ILD radiologist will 
make assessments of 4 main findings in three zones of each lung. The six zone scores will be 
averaged to determine the total score for each patient. Score will be recorded at the initial diagnosis 
and after six and 12 months in a similar manner for further comparison. The mean ± SD of HRCT 
fibrosis score like continuous variable will be determined obligatory at baseline, 6 months and 
optional at 12 months.  
The values of HRCT fibrosis score at baseline, at Week 26 and Week 52 (optional) will be 
summarized in table with standard descriptive statistics for continuous variables and 95% CI for 
the mean. 
Additionally, the absolute change of HRCT fibrosis score from baseline at Week 26 and Week 
52 (optional) will be summarized in table with standard descriptive statistics for continuous 
variables and 95% CI for the mean. 
The paired t-test will be performed to evaluate the changes in the variable from the baseline to 
Week 26 and Week 52 (optional), respectively. The type I error rate will be set to 5%. 
Lung opacity (ground-glass attenuation) 
The sign ‘lung opacity’ will be qualified separately using methodology described above for 
other signs, and its change over time will be assessed outside the framework of a total summed 
index of fibrosis (HRCT fibrosis score). Lung opacity should be graded as reticular abnormality 
to calculate the score for each zone, i.e. the percentage (%) area of opacity in a zone should be 
multiplied by the score of 2. 
The lung opacity score at Baseline, at Week 26 and Week 52 (optional) will be summarized 
using standard descriptive statistics for continuous variables and 95% CI for the mean. 
Additionally, the absolute change of lung opacity score from Baseline at Week 26 and Week 
52 (optional) will be summarized in table with standard descriptive statistics for continuous 
variables and 95% CI for the mean. 


 
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Exacerbations 
An exacerbation will be defined as an AE with special criteria “Is this an exacerbation of IPF?” 
= “Yes”, i.e. only in case the exacerbation has led to death of a patient. Rate of exacerbation will 
be reported in three following tables: 
• Exacerbation cases during treatment period (until Week 26). 
• Exacerbation cases during long-term follow-up period (from Week 26 to Week 52). 
• Exacerbation cases during whole study period (from Day 1 to Week 52, applicable only 
for patients continuing in the rollover study). 
Exacerbation cases will be listed. 
The treatment period and rollover period for the analysis of exacerbations will be defined 
similarly to Section 9.2. 
9. Safety Analyses 
9.1. Exposure 
Exposure will be evaluated based on the information from the “ASSESSMENT OF 
COMPLIANCE”, “STUDY DRUG ADMINISTRATION (TREATMENT PERIOD)”, 
“COMMERCIALLY AVAILABLE PIRFENIDONE ADMINISTRATION (ROLLOVER 
STUDY)” eCRF form.  
 
Pirfenidone will be taken orally in a daily dose of 2403 mg in divided doses three times per day 
with food. Study treatment should be titrated over 14 days, as tolerated, to the full dose of 9 
capsules per day (three capsules TID), as follows:  
• Days 1 to 7: one capsule TID (801 mg/day) 
• Days 8 to 14: two capsules TID (1602 mg/day) 
• Day 15 and continuing: three capsules TID (maximum of 9 capsules daily equal to 2403 
mg/day). 
Study treatment will continue until visit at Week 26 (± 1 week), unless terminated earlier for 
reasons described in Section 4.6.2 of the Protocol or patient is proceeding in the rollover study. 
 
The total duration of exposure is defined as the time interval in weeks between the first dose 
and the last dose, inclusive, of study drug based on the patient study drug dosing information. 
Total duration (weeks) of exposure to study drug in the Treated set will be summarized by study 
period using descriptive statistics.  
Exposure (duration of therapy during rollover study and overall up to 58 weeks) for patients in 
the rollover study will also be presented descriptively. 


 
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Descriptive statistics for Total number of capsules taken during the study period will also be 
presented.  
All exposure data will be listed. 
 
9.2. Adverse Events 
eCRF form: “ADVERSE EVENTS”. 
AEs will be reported on a per-patient basis, i.e. counting patients rather than events.  
After informed consent has been obtained but prior to initiation of study drug, only serious 
adverse events caused by a protocol-mandated intervention should be reported. 
After initiation of study drug, all adverse events will be reported until 28 days after the last 
dose of study drug. Additionally, for patients continuing in the rollover part of the study adverse 
events will be reported until Week 52. 
Only treatment emergent AEs will be summarized. In the listings, however, all occurrences 
of the AEs will be presented. Treatment emergent AEs will be summarized per primary SOC and 
PT. Severity of treatment emergent AEs will be summarized separately. 
Treatment-emergent AE is any reported adverse event that starts after initiation of the study 
therapy and up to 28 days after the last dose of study therapy. 
All registered AEs will be coded using the MedDRA version 22.0 (or further updating) and 
tabulated in the report with grouping by primary system organ class (SOC) and preferred term (PT). 
Number (percentage) of patients and number of AEs will be presented for the Treated Set  
in the following tables: 
− All treatment-emergent AE / SAE; 
− Treatment-emergent AE / SAE related to the study drug (“Is the adverse event suspected 
to be caused by the study drug on the basis of facts, evidence, science-based rationales, and 
clinical judgment?” = “Yes” including those events where assessment is missing); 
− TEAE by maximum severity (Severity, CTCAE v.4.0); 
− TEAE related to study drug by maximum severity  (Severity, CTCAE v.4.0); 
− TEAE leading to the permanent discontinuation of study drug (Action taken with 
IMP=“Permanently discontinued”); 
− TEAE leading to death (AE with Outcome = “Death”) including TEAE related to the study 
drug; 
− TEAE related to the study drug leading to death; 
− TEAE of special interest (“Is this an adverse event of special interest?” = “Yes”); 
− Non-serious TEAEs that occurred at a frequency of >= 5% (if no events occurred at the 
5% threshold all non-serious TEAEs will be tabulated). 


 
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This set of tables will be repeated for the following study periods: 
- 
Treatment period defined as first dose of study drug to last dose of study drug in the 
treatment period + 28 days or until the first dose in the rollover period (Treated Set).  
- 
Rollover period defined as first dose in the rollover to last dose in the rollover study + 
28 days (Treated Set, patient continuing in the rollover study). 
Tables of TEAEs by maximum severity will be prepared using the following rules: each SOC / 
PT category will include only the AEs with the worst severity for each patient. In the Overall category, 
all AEs of the patient will be presented. Each patient will be counted only once with the worst severity 
in each SOC and each PT level as well as in the Overall level. 
Number of patients who died will be tabulated. 
All AEs/SAEs will be listed. Non-treatment emergent adverse events will be identified 
accordingly in the listing. 
 
9.3. Pregnancies 
eCRF form: “URINE PREGNANCY TEST”. 
All women of childbearing potential will have a urine pregnancy test at the Screening and 
on Day 1 before start of treatment. Urine pregnancy tests will be performed repeatedly at specified 
subsequent visits as scheduled in the Table 1. 
The results of these tests and pregnancies episodes will be reported in the listing. 
 
9.4. Clinical Laboratory Evaluations 
eCRF form: “HEMATOLOGY”, “SERUM CHEMISTRY”. 
Clinical laboratory evaluations as scheduled in the Table 1 include the following parameters: 
− 
hematology (plasma): white blood cells (WBC) count, red blood cells (RBC) count, 
hemoglobin, hematocrit, platelet count, (relative) differential WBC count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes); 
− 
blood chemistry panel (serum or plasma): albumin, alkaline phosphatase (AP), ALT, AST, 
direct bilirubin, total bilirubin, total protein, cholesterol, creatine kinase (CK), creatinine, 
triglycerides, gamma-glutamyl transferase (GGT), glucose, lactic dehydrogenase (LDH), 
calcium, phosphorus, magnesium, potassium, sodium, urea nitrogen, uric acid; 
Creatinine clearance should be assessed at the Screening for eligibility confirmation using the 
following formula by Cockcroft-Gault (Cockcroft DW et al, 1976): 
For serum creatinine concentration in mg/dL: 


 
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CrCl (mL/min) = (140 – age (years)) × weight (kg) × 1.0 / 72 × serum creatinine (mg/dL) 
For serum creatinine concentration in µmol/L: 
CrCl (mL/min) = (140 – age (years)) × weight (kg) × 1.0 / 0.81 × serum creatinine (µmol/L) 
For laboratory parameters the following tables will be presented according to section 7: 
− descriptive statistics of measured values and changes from baseline (including creatinine 
clearance); 
− shift tables based on comparison with normal range (Lower/Normal/Higher); 
− frequency tables for Out of range: No/Yes clinically significant (Yes CS) / Yes non-
clinically significant (Yes NCS) for laboratory parameters. 
 
All laboratory data will be listed. 
 
9.5. Other Safety Measures 
eCRF form: “VITAL SIGNS”, “ECG”, “PHYSICAL EXAMINATION”. 
Vital signs 
Vital signs (respiratory rate (breaths/ minute), pulse rate (beats/ minute), and systolic and 
diastolic blood pressure (mmHg), and axillary temperature (ºC)), body weight (kg) and body height 
(cm) results will be presented in accordance with section 7. 
Vital signs results will be presented by visit of assessment as scheduled in the Table 1. Body 
height will be assessed only at screening. 
Vital signs and body weight results will be presented as the following outputs: 
− descriptive statistics for measured values and changes from baseline (vital signs, body 
weight, BMI); 
− frequency tables for Out of range: No/Yes clinically significant (Yes CS) / Yes non-
clinically significant (Yes NCS) (vital signs). 
All data will be listed.  
 
 
ECG 
A 12-lead electrocardiogram (ECG) results will be represented in accordance with section 7 by 
visit of assessment as scheduled in the Table 1 as the following outputs: 
− shift table by post baseline visit compared to baseline for Normal/Abnormal clinically 
significant (Abnormal CS) / Abnormal non-clinically significant (Abnormal NCS) 
evaluation for General assessment 


 
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− descriptive statistics of ECG parameters and their changes from baseline (Heart rate, 
beats/min; QT interval, ms; QTC-F interval, ms ). 
− frequency table for Out of range: No/Yes clinically significant (Yes CS) / Yes non-
clinically significant (Yes NCS) for ECG parameters. 
 
All ECG data will be listed.  
 
 
Physical examinations 
Complete physical examination is performed at the Screening only (head, eyes, ears, nose, and 
throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems). At subsequent visits, only limited, symptom-directed 
physical examinations should be performed. 
Physical examination results as scheduled in the Table 1 will be presented in accordance with 
section 7 by visit of assessment as the following output: 
− frequency table for Normal/Abnormal clinically significant (Abnormal CS) / Abnormal 
non-clinically significant (Abnormal NCS) evaluation. 
All physical examination data will be listed. 
 
10. Pharmacokinetics 
Not Applicable. 
11. Other Analyses 
Not Applicable. 
12. Reporting Conventions 
Not Applicable. 
13. Technical Details 
 
Statistical analysis will be performed using SAS 9.4. 
One (final) statistical analysis report will be prepared in the Microsoft Office Word (.docx) 
format after the end of data collection and database lock. The results of statistical analysis will be 
presented in the form of tables, figures and listings in English. 
14. Summary of Changes to the Protocol 


 
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The analyses methods in this SAP are fully consistent with the clinical study Protocol. 
 
 


 
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15. References 
1) Committee for Proprietary Medicinal Products (CPMP). International Conference 
on Harmonisation (ICH) Topic E9: Note for Guidance on Statistical Principles for Clinical 
Trials; September 1998. 
2) DataMatrix_SOP_STAT001_Statistical Principles_ver.3.0_June 2019. 
3) DataMatrix_SOP_STAT002_Statistical Analysis Plan Development_ver.2.0_July 
2017. 
4) DataMatrix_SOP_DM010_Dictionary 
Management 
and 
Data 
Coding_ver.2.0_August 2015. 
5) Machin D., Campbell M., Fayers P., Pinol A. “Sample size tables for clinical 
studies”// Second edition Blackwell Science Ltd, 1997. 
6) Noble PW, Albera C, Bradford WZ et al. CAPACITY Study Group. Pirfenidone in 
patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 
2011, 377:1760–1769. 
7) ML39355 Study Results Posting Requirements. 
 
 


 
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16. Listing of Tables, Listings and Figures 
16.1. Tables 
Patients Disposition 
Table 1.1 Patients disposition (All Enrolled patients) 
Table 1.2 Violation of eligibility criteria (Screening Failures) 
Table 1.3 Analysis populations (Allocated to treatment set) 
Table 1.4 Study visits 
Protocol Deviations 
Table 1.5 Protocol deviations / violations (Allocated to treatment set) 
Demographic and Anthropometric characteristics 
Table 1.6 Demographic characteristics (TS) 
Table 1.7 Anthropometric characteristics (TS) 
Baseline Variables 
Table 1.8 Surgical lung biopsy (TS) 
Table 1.9 HRCT for patient eligibility confirmation (TS) 
Table 1.10 Carbon monoxide diffusing capacity (DLCO) (TS) 
Table 1.11 Pre- and post-bronchodilator spirometry parameters at screening (TS) 
Table 1.12 Serologic tests (TS) 
Table 1.13 GAP assessment (TS) 
Table 1.14 Review transbronchial lung biopsy/BAL (TS) 
Medical history 
Table 1.15 Prior medical/surgical conditions/diagnoses (TS) 
Table 1.16 Concurrent medical/surgical conditions/diagnoses (TS) 
Table 1.17 History of idiopathic pulmonary fibrosis (TS) 
Prior and concomitant medications 
Table 1.18 Prior medications (TS) 
Table 1.19 Concomitant medications (TS) 
Table 1.20 Concomitant medications during rollover study (TS) 
Efficacy Analyses 
Table 2.1 Descriptive statistics for FVC by visit (FAS) 
Table 2.2 Primary efficacy endpoint (FAS) 
Table 2.3 Primary efficacy endpoint: categorical results (FAS) 
Table 2.4 Primary efficacy endpoint by pattern type (CSS) 
Table 2.5 6-Minute Walk Test (FAS) 
Table 2.6 Change in 6MWT distance at Week 26 by category (FAS) 
Table 2.7 Borg scale (FAS) 
Table 2.8 EQ-5D-5L. Descriptive statistics (FAS) 
Table 2.9 Change in EQ-5D-5L. Mobility (FAS) 
Table 2.10 Change in EQ-5D-5L. Self-Care (FAS) 
Table 2.11 Change in EQ-5D-5L. Usual Activities (FAS) 
Table 2.12 Change in EQ-5D-5L. Pain/Discomfort (FAS) 
Table 2.13 Change in EQ-5D-5L. Anxiety/Depression (FAS) 
Table 2.14 EQ-5D-5L. VAS and Index score (FAS) 
Table 2.15 HRCT. HRCT fibrosis score (FAS) 
Table 2.16 HRCT. Lung opacity score (FAS) 
Table 2.17 Exacerbation cases during treatment period (FAS) 
Table 2.18 Exacerbation cases during rollover study (FAS, patients continuing in the 
rollover study) 
Table 2.19 Exacerbation cases during whole study period (FAS, patients continuing in the 
rollover study) 
 
Safety Analyses 
Table 3.1 Duration of exposure (TS) 
Table 3.2 Total number of capsules taken (TS) 
Table 3.3.1 Treatment-emergent adverse events during treatment period (TS) 
Table 3.3.2 Treatment-emergent adverse events during rollover study (TS, patients 
continuing in the rollover study) 
Table 3.3.3 Treatment-emergent adverse events during whole study period (TS) 
 
Table 3.4.1 Treatment-emergent adverse events related to the study drug during treatment 
period (TS) 
Table 3.4.2 Treatment-emergent adverse events related to the study drug during rollover 
study (TS, patients continuing in the rollover study) 


 
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Table 3.4.3 Treatment-emergent adverse events related to the study drug during whole study 
period (TS) 
 
Table 3.5.1 Serious treatment-emergent adverse events during treatment period (TS) 
Table 3.5.2 Serious treatment-emergent adverse events during rollover study (TS, patients 
continuing in the rollover study) 
Table 3.5.3 Serious treatment-emergent adverse events during whole study period (TS) 
 
Table 3.6.1 Serious treatment-emergent adverse events related to the study drug during 
treatment period (TS) 
Table 3.6.2 Serious treatment-emergent adverse events related to the study drug during 
rollover study (TS, patients continuing in the rollover study) 
Table 3.6.3 Serious treatment-emergent adverse events related to the study drug during 
whole study period (TS) 
 
Table 3.7.1 Treatment-emergent adverse events during treatment period by maximum severity 
(TS) 
Table 3.7.2 Treatment-emergent adverse events during rollover study by maximum severity 
(TS, patients continuing in the rollover study) 
Table 3.7.3 Treatment-emergent adverse events during whole study period by maximum severity 
(TS) 
 
Table 3.8.1 Treatment-emergent adverse events related to the study drug during treatment 
period by maximum severity (TS) 
Table 3.8.2 Treatment-emergent adverse events related to the study drug during rollover 
study by maximum severity (TS, patients continuing in the rollover study) 
Table 3.8.3 Treatment-emergent adverse events related to the study drug during whole study 
period by maximum severity (TS) 
 
Table 3.9.1 Treatment-emergent adverse events of special interest during treatment period 
(TS) 
Table 3.9.2 Treatment-emergent adverse events of special interest during rollover study 
(TS, patients continuing in the rollover study) 
Table 3.9.3 Treatment-emergent adverse events of special interest during whole study period 
(TS) 
 
Table 3.10.1 Treatment-emergent adverse events leading to death during treatment period 
(TS) 
Table 3.10.2 Treatment-emergent adverse events leading to death during rollover study (TS, 
patients continuing in the rollover study) 
Table 3.10.3 Treatment-emergent adverse events leading to death during whole study period 
(TS) 
 
Table 3.11.1 Treatment-emergent adverse events leading to discontinuation of study drug 
during treatment period (TS) 
Table 3.11.2 Treatment-emergent adverse events leading to discontinuation of study drug 
during rollover study (TS, patients continuing in the rollover study) 
Table 3.11.3 Treatment-emergent adverse events leading to discontinuation of study drug 
during whole study period (TS) 
 
Table 3.12.1 Treatment-emergent adverse events related to study drug and leading to death 
during treatment period (TS) 
Table 3.12.2 Treatment-emergent adverse events related to study drug and leading to death 
during rollover study (TS, patients continuing in the rollover study) 
Table 3.12.3 Treatment-emergent adverse events related to study drug and leading to death 
during whole study period (TS) 
 
Table 3.13.1 Non-serious treatment-emergent adverse events occurred at a frequency of >=5% 
during treatment period (TS) 
Table 3.13.1 Non-serious treatment-emergent adverse events occurred at a frequency of >=5% 
during rollover study (TS, patients continuing in the rollover study) 
Table 3.13.1 Non-serious treatment-emergent adverse events occurred at a frequency of >=5% 
during whole study period (TS) 
 
Table 3.14 Deaths 
Table 3.15 Urine pregnancy test (TS, women of childbearing potential) 
Table 3.16 Hematology. Descriptive statistics (TS) 
Table 3.17 Blood chemistry. Descriptive statistics (TS) 
Table 3.18 Hematology. Shift table (TS) 
Table 3.19 Blood chemistry. Shift table (TS) 
Table 3.20 Hematology. Out of range. Frequency table 
Table 3.21 Blood chemistry. Out of range. Frequency table (TS) 


 
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Table 3.22 Vital signs. Descriptive statistics (TS) 
Table 3.23 Vital signs. Out of range. Frequency table (TS) 
Table 3.24 Weight. Descriptive statistics (TS) 
Table 3.25 ECG. Descriptive statistics (TS) 
Table 3.26 ECG. Out of range and General Assessment. Frequency table (TS) 
Table 3.27 Physical examinations. Frequency table (TS) 
 
 


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Patients Disposition 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 1.1 Patients disposition 
All Enrolled patients 
Page Х of Х 
 
 
Total 
(N = XX) 
n (%) 
 
 
Patients who signed the Informed Consent Form 
XX 
Screening Failures 
  Reasons for premature discontinuation 
    Patient request or withdrawal of consent 
    Presence or development of Inclusion/Exclusion criterion (-a) 
 
XX 
XX 
XX 
XX 
  
Allocated to treatment 
xx 
  Treated during the treatment period 
XX (XX.X) 
 
 
Patients continuing (treated) in the rollover study 
XX (XX.X) 
 
 
Completed 
XX (XX.X) 
Terminated Prematurely 
XX (XX.X) 
 
 
Reasons for premature discontinuation 
 
    Pregnancy 
XX (XX.X) 
    Unacceptable tolerability and personal safety profile (e.g. adverse events listed in Section 5.1.2 of 
XX (XX.X) 
     Protocol, or serious adverse events related to study treatment) 
    Patient request or withdrawal of consent 
XX (XX.X) 
    Any medical condition that the investigator or Sponsor determines may jeopardize the patient’s safety if he 
XX (XX.X) 
     or she continues in the study 
    Investigator or Sponsor determines it is in the best interest of the patient for other reasons 
XX (XX.X) 
    Protocol deviation (at Sponsor’s discretion) (e.g. refusal to follow study requirements) 
XX (XX.X) 
    Termination of the whole study by the Sponsor 
XX (XX.X) 
    Lung transplantation 
XX (XX.X) 
    The incidence or severity of adverse events in this or other ongoing studies of pirfenidone indicates a 
XX (XX.X) 
     potential health hazard to patients 
    Patient enrollment is unsatisfactory 
XX (XX.X) 
    Administrative and regulatory reasons 
XX (XX.X) 
    Presence or development of Inclusion/Exclusion criterion (-a) 
XX (XX.X) 
    Other 
XX (XX.X) 


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      Other reason 1 
XX (XX.X) 
      Other reason 2 
XX (XX.X) 
      ... 
XX (XX.X) 
 
 
 
N: the number of patients who signed the Informed Consent Form. 
n: the number of patients within a specific category. Percentages are calculated based on number of patients Allocated to Treatment. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


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Table 1.2 Violation of eligibility criteria 
Screening Failures 
Page Х of Х 
 
 
Total 
(N = XX) 
n 
Patients with any violation of eligibility criteria 
XX 
 
 
Patients with any violation of inclusion criteria 
XX 
  Inclusion criterion #1 
XX 
  Inclusion criterion #2 
XX 
  ... 
... 
 
 
Patients with any violation of exclusion criteria 
XX 
  Exclusion criterion #1 
XX 
  Exclusion criterion #2 
XX 
  ... 
... 
 
N: the number of Screening Failures. 
n: the number of patients within a specific category.  
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


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Table 1.3 Analysis populations 
Allocated to treatment set 
Page Х of Х 
 
 
Total 
(N = XX) 
n (%) 
Allocated to treatment 
XX (100%) 
Treated set (TS) 
XX (XX.X) 
Full analysis set (FAS) 
XX (XX.X) 
Completed case set (CCS) 
XX (XX.X) 
 
N: the number of patients in the Allocated to treatment set. 
n: the number of patients within a specific category. Percentages are calculated as (100 x n/N). 
Treated set: patients from ‘Allocated to treatment’ set, who received any dose of the study treatment. 
Full analysis set: patients from ‘Treated’ set, who had data for at least one post-baseline assessment of any efficacy measurement. 
Completed case set: patients from ‘Full analysis’ set, who provided FVC data at 26-week assessment. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


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Table 1.4 Study visits 
Allocated to treatment set 
Page Х of Х 
 
 
Total 
(N = XX) 
n (%) 
Within visit  
window 
n (%) 
Treatment period 
 
 
  Start of Treatment (Day 1) 
XX (XX.X) 
N/A 
  Week 1 Telephone Assessment (+/- 1 day) 
XX (XX.X) 
XX (XX.X) 
  Week 2 (+/- 2 days) 
XX (XX.X) 
XX (XX.X) 
  Week 4 (+/- 2 days) 
XX (XX.X) 
XX (XX.X) 
  Week 8 (+/- 2 days) 
XX (XX.X) 
XX (XX.X) 
  Week 12 (+/- 2 days) 
XX (XX.X) 
XX (XX.X) 
  Week 16 (+/- 1 week) 
XX (XX.X) 
XX (XX.X) 
  Week 20 (+/- 1 week) 
XX (XX.X) 
XX (XX.X) 
  1st day at Week 26 (+/- 1 week) 
XX (XX.X) 
XX (XX.X) 
  2nd day at Week 26 (+/- 1 week) 
XX (XX.X) 
XX (XX.X) 
Follow-up Visit (14-28 days after last dosing) 
XX (XX.X) 
XX (XX.X) 
Long Term Follow-Up/Rollover Study 
 
 
  Week 39 (+/- 2 weeks) 
XX (XX.X) 
XX (XX.X) 
  Week 52 (+/- 2 weeks) 
XX (XX.X) 
XX (XX.X) 
 
N: the number of patients in the Allocated to treatment set. 
n: the number of patients within a specific category. Percentages are calculated as (100 x n/N). 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


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Protocol Deviations 
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Table 1.5 Protocol deviations / violations 
Allocated to treatment set 
Page Х of Х 
 
 
Total 
(N = XX) 
n (%) 
Patients with at least one protocol deviation 
XX (XX.X) 
 
 
  
 
 
N: the number of patients in the Allocated to treatment set. 
n: the number of patients with at least one protocol deviation. Percentages are calculated as (100 x n/N). 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


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Demographic and Anthropometric characteristics 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 1.6 Demographic characteristics 
Treated set 
Page Х of Х 
 
 
 
Total 
(N = XX) 
Age, years 
 
 
  n 
 
XX 
  Mean 
 
XX.X 
  SD 
 
XX.XX 
  Median 
 
XX.X 
  Min 
 
XX 
  Max 
 
XX 
 
 
 
Sex  
 
 
  n 
 
XX 
  Male 
n (%) 
XX (XX.X) 
  Female 
n (%) 
XX (XX.X) 
 
 
 
Race 
 
 
  n 
 
XX 
  Caucasian 
n (%) 
XX (XX.X) 
  Asian 
n (%) 
XX (XX.X) 
  Black 
n (%) 
XX (XX.X) 
  Other 
n (%) 
XX (XX.X) 
    Other race 1 
n (%) 
XX (XX.X) 
    Other race 2 
n (%) 
XX (XX.X) 
    ... 
... 
... 
 
 
 
Ethnicity 
 
 
  n 
 
XX 
  Russian 
n (%) 
XX (XX.X) 
  Tatar 
n (%) 
XX (XX.X) 
  Ukrainian 
n (%) 
XX (XX.X) 
  Bashkir 
n (%) 
XX (XX.X) 
  Chuvash 
n (%) 
XX (XX.X) 
  Unknown 
n (%) 
XX (XX.X) 
  Other 
n (%) 
XX (XX.X) 
    Other ethnicity 1 
n (%) 
XX (XX.X) 
    Other ethnicity 2 
n (%) 
XX (XX.X) 


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    ... 
... 
... 
 
N: the number of patients in the Treated set. 
n: the number of valid measurements or the number of patients within a specific category. Percentages are calculated as (100 x n/N). 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


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Table 1.7 Anthropometric characteristics 
Treated set 
Page Х of Х 
 
 
Total 
(N = XX) 
Height, cm 
 
  N 
XX 
  Mean 
XX.X 
  SD 
XX.XX 
  Median 
XX.X 
  Min 
XX 
  Max 
XX 
 
 
Weight, kg 
 
  n 
XX 
  Mean 
XX.X 
  SD 
XX.XX 
  Median 
XX.X 
  Min 
XX 
  Max 
 
Body Mass Index (BMI), kg/m2 
  n 
  Mean 
  SD 
  Median 
  Min 
  Max 
XX 
 
XX 
XX.XX 
XX.XXX 
XX.XX 
XX.X 
XX.X 
 
 
 
N: the number of patients in the Treated set. 
n: the number of valid measurements. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


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Baseline Variables 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 1.8 Surgical lung biopsy 
Treated set 
Page Х of Х 
 
 
Total 
(N = XX) 
n (%) 
Assessment of regional specialist 
 
 
 
  UIP Pattern 
 
    n’ 
XX 
    Consistent UIP pattern 
XX (XX.X) 
    Probable UIP pattern 
XX (XX.X) 
    Possible UIP pattern 
XX (XX.X) 
    Inconsistent/unclassified UIP pattern 
XX (XX.X) 
 
 
Assessment of central specialist 
 
 
 
  UIP Pattern 
 
    n’ 
XX 
    Consistent UIP pattern 
XX (XX.X) 
    Probable UIP pattern 
XX (XX.X) 
    Possible UIP pattern 
XX (XX.X) 
    Inconsistent/unclassified UIP pattern 
XX (XX.X) 
 
N: the number of patients in the Treated set. n’ – the number of valid observations.  
n: the number of patients within a specific category. Percentages are based on the corresponding number of valid observations. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


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Table 1.9 HRCT for patient eligibility confirmation 
Treated set 
Page Х of Х 
 
 
Total 
(N = XX) 
n (%) 
Assessment of regional CT-specialist 
 
 
  UIP Pattern 
 
    n’ 
XX 
    Typical (apparent) UIP pattern 
XX (XX.X) 
    Possible UIP Pattern 
XX (XX.X) 
 
 
Assessment of central CT-specialist (1) 
 
 
 
  UIP Pattern 
 
    n’ 
XX 
    Typical (apparent) UIP pattern 
XX (XX.X) 
    Possible UIP Pattern 
XX (XX.X) 
    Inconsistent with UIP Pattern 
XX (XX.X) 
 
 
Assessment of central CT-specialist (2) 
 
 
 
  UIP Pattern 
 
    n’ 
XX 
    Typical (apparent) UIP pattern 
XX (XX.X) 
    Possible UIP Pattern 
XX (XX.X) 
    Inconsistent with UIP Pattern 
XX (XX.X) 
    Not Performed 
XX (XX.X) 
     
 
 
N: the number of patients in the Treated set. n’ – the number of valid observations.  
n: the number of patients within a specific category. Percentages are based on the corresponding number of valid observations. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 


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Table 1.10 Carbon monoxide diffusing capacity (DLCO) 
Treated set 
Page Х of Х 
 
 
Total 
(N = XX) 
Predicted DLCO, % 
 
  n 
XX 
  Mean 
XX.X 
  SD 
XX.XX 
  Median 
XX.X 
  Min 
XX 
  Max 
XX 
 
 
Hb-corrected DLCO, % 
 
  n 
XX 
  Mean 
XX.X 
  SD 
XX.XX 
  Median 
XX.X 
  Min 
XX 
  Max 
XX 
 
N: the number of patients in the Treated set. 
n: the number of valid measurements. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


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Table 1.11 Pre- and post-bronchodilator spirometry parameters at screening 
Treated set 
Page Х of Х 
 
 
Total 
(N = XX) 
Pre-bronchodilator FEV1/FVC 
 
  n 
XX 
  Mean 
XX.XX 
  SD 
XX.XXX 
  Median 
XX.XX 
  Min 
XX.XX 
  Max 
  
Post-bronchodilator FEV1/FVC 
  n 
  Mean  
  SD 
  Median 
  Min 
  Max 
... 
XX.XX 
 
 
XX 
XX.XX 
XX.XXX 
XX.XX 
XX.XX 
XX.XX 
 
N: the number of patients in the Treated set. 
n: the number of valid measurements. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<Table will be continued for Pre-, post- bronchodilator FVC (absolute), ml; FVC (relative), % predicted> 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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F. Hoffmann-La Roche Ltd 
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Table 1.12 Serologic tests 
Treated set 
Page Х of Х 
 
 
Total 
(N = XX) 
n (%) 
Rheumatoid factor 
 
  n’ 
XX 
  Positive 
XX (XX.X) 
  Negative 
XX (XX.X) 
 
 
Anticyclic citrullinated peptide 
 
  n’ 
XX 
  Positive 
XX (XX.X) 
  Negative (<= 5 U/ml) 
XX (XX.X) 
 
 
Antinuclear antibody titer 
 
  n’ 
XX 
  Positive 
XX (XX.X) 
  Negative 
XX (XX.X) 
 
N: the number of patients in the Treated set. n’: the number of valid observations.  
n: the number of patients within a specific category. Percentages are based on the corresponding number of valid observations. 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 47 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 1.13 GAP assessment 
Treated set 
Page Х of Х 
 
 
 
Total 
(N = XX) 
GAP index 
 
 
  n 
 
XX 
  Mean 
 
XX.X 
  SD 
 
XX.XX 
  Median 
 
XX.X 
  Min 
 
XX 
  Max 
 
XX 
 
 
 
Stage 
 
 
  n’ 
 
XX 
  I 
n (%) 
XX (XX.X) 
  II 
n (%) 
XX (XX.X) 
  III 
n (%) 
XX (XX.X) 
 
 
 
Individual risk of mortality 
 
 
 
 
 
  One year (1-yr) mortality 
 
 
    n 
 
XX 
    Mean 
 
XX.XX 
    SD 
 
XX.XXX 
    Median 
 
XX.XX 
    Min 
 
XX.X 
    Max 
 
XX.X 
 
 
 
  Two year (2-yr) mortality 
 
 
    n 
 
XX 
    Mean 
 
XX.XX 
    SD 
 
XX.XXX 
    Median 
 
XX.XX 
    Min 
 
XX.X 
    Max 
 
XX.X 
 
 
 
  Three year (3-yr) mortality 
 
 
    n 
 
XX 
    Mean 
 
XX.XX 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 48 out of 151 
 
    SD 
 
XX.XXX 
    Median 
 
XX.XX 
    Min 
 
XX.X 
    Max 
 
XX.X 
 
N: the number of patients in the Treated set. n’: the number of valid observations. 
n: the number of patients within a specific category. Percentages are based on the corresponding number of valid observations. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 49 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 1.14 Review transbronchial lung biopsy/BAL 
Treated set 
Page Х of Х 
 
 
Total 
(N = XX) 
n (%) 
Are there features supporting an alternative diagnosis after review transbronchial lung biopsy? 
 
  n’ 
XX 
  Yes 
XX (XX.X) 
  No 
XX (XX.X) 
  
 
Are there features supporting an alternative diagnosis after review BAL? 
XX (XX.X) 
  n’ 
XX 
  Yes 
XX (XX.X) 
  No 
XX (XX.X) 
 
N: the number of patients in the Treated set. n’ – the number of valid observations.  
n: the number of patients within a specific category. Percentages are based on the corresponding number of valid observations. 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
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Page 50 out of 151 
 
Medical history 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 1.15 Prior medical/surgical conditions/diagnoses 
Treated set 
Page Х of Х 
 
System Organ Class (SOC) 
   
    Preferred Term (PT) 
       
Total 
(N = XX) 
n (%) / E 
Overall 
XX (XX.X) / XX 
 
 
System Organ Class 1 
XX (XX.X) / XX 
  Preferred Term 1 
XX (XX.X) / XX 
  Preferred Term 2 
XX (XX.X) / XX 
      ... 
... 
System Organ Class 2 
XX (XX.X) / XX 
  Preferred Term 1 
XX (XX.X) / XX 
  Preferred Term 2 
XX (XX.X) / XX 
      ... 
... 
 
 
... 
... 
 
N: the number of patients in the Treated set. 
n: the number of patients with at least one prior medical history event within a specific category. Percentages are calculated as (100 x n/N). 
E: total number of prior medical history events reported within a specific category. 
Medical history events are coded using MedDRA version XX.X. 
Each patient is counted only once per preferred term (РТ) and once per system organ class (SOC). 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<System organ classes (SOC) and preferred terms (PT) within each SOC are sorted in descending order of n(%).> 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 51 out of 151 
 
Similar to table 1.15, the following tables will be constructed (with corrections of underlined fragments in the note): 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 1.16 Concurrent medical/surgical conditions/diagnoses 
Treated set 
Page Х of Х 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 52 out of 151 
 
 
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ML39355 
Table 1.17 History of idiopathic pulmonary fibrosis 
Treated set 
Page Х of Х 
 
 
 
Total 
(N = XX) 
Duration of clinical symptoms consistent with IPF, months 
 
 
  n 
 
XX 
  Mean 
 
XX.X 
  SD 
 
XX.XX 
  Median 
 
XX.X 
  Min 
 
XX 
  Max 
 
XX 
 
 
 
Clinically significant environmental exposure known to cause pulmonary fibrosis 
 
 
  n’ 
 
XX 
  Yes 
n (%) 
XX (XX.X) 
  No 
n (%) 
XX (XX.X) 
 
 
 
Known explanation for interstitial lung disease 
 
 
  n’ 
 
XX 
  Yes 
n (%) 
XX (XX.X) 
  No 
n (%) 
XX (XX.X) 
 
 
 
Cigarette smoking within 28 days before the treatment start 
 
 
  n’ 
 
XX 
  Yes 
n (%) 
XX (XX.X) 
  No 
n (%) 
XX (XX.X) 
 
N: the number of patients in the Treated set. 
n: the number of patients within a specific category. n’ – the number of valid observations.  
Percentages are based on the corresponding number of valid observations. 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 53 out of 151 
 
Prior and concomitant medications 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 1.18 Prior medications 
Treated set 
Page Х of Х 
 
Pharmacological subgroup (3rd level) 
  Chemical substance (5th level) 
Total 
(N = XX) 
n (%) / E 
Overall 
XX (XX.X) / XX 
 
 
Pharmacological subgroup 1 
XX (XX.X) / XX 
  Chemical substance 1 
XX (XX.X) / XX 
  Chemical substance 2 
XX (XX.X) / XX 
  ... 
 
Pharmacological subgroup 2 
XX (XX.X) / XX 
  Chemical substance 1 
XX (XX.X) / XX 
  Chemical substance 2 
XX (XX.X) / XX 
  ... 
... 
 
N: the number of patients in the Treated set. 
n: the number of patients with at least one prior medication within a specific category. Percentages are calculated as (100 x n/N). 
E: total number of prior medications reported within a specific category. 
Medications are coded by WHO drug dictionary version XX.X. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<The pharmacological subgroups and chemical substances within each pharmacological subgroup are sorted in descending order of n (%). Each patient is 
counted only once per pharmacological subgroup and once per chemical substance.> 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
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Page 54 out of 151 
 
Similar to table 1.18, the following tables will be constructed (with corrections of underlined fragments in the note): 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 1.19 Concomitant medications 
Treated set 
Page Х of Х 
 
 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 1.20 Concomitant medications during rollover study 
Treated set (patients continuing in the rollover study) 
Page Х of Х 
 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 55 out of 151 
 
 
Efficacy Analyses 
Primary Efficacy Endpoint 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.1  Descriptive statistics for FVC by visit 
Full analysis set (FAS) 
Page Х of Х 
       Parameter: XXXXXXXXXX, <units> 
 
Total 
(N = XX) 
Change from the baseline  
 
 
 
  Screening 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Day 1 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Baseline 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Week 12 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 56 out of 151 
 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
 
  Week 12* 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
... 
 
 
  Week 52 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
  Week 52* 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
N: the number of patients in the FAS. 
n: the number of valid measurements.  
Baseline FVC is the average of the pre-bronchodilator FVC measured at the Screening and Day 1 visits. The FVC at Week 26 is the average of the FVC 
measured on two separate days at Week 26. 
*: Values assessed within the corresponding visit window. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<Report the following assessments: Screening (pre-bronchodilator), Day 1, Baseline, Week 12, Week 26 Day 1, Week 26 Day 2, Week 26, Week 39, Week 52> 
<FVC values within the visit window will also be presented descriptively for the following assessments: Week 12*, Week 26 Day 1*, Week 26 Day 2*, Week 
26*, Week 39*, Week 52*> 
<Report the following parameters: FVC (absolute), mL/ FVC (relative) predicted, %> 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 57 out of 151 
 
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ML39355 
Table 2.2  Primary efficacy endpoint 
Full analysis set (FAS) 
Page Х of Х 
       Parameter: XXXXXXXXXX, <units> 
 
Total 
(N = XX) 
Change from the baseline  
 
 
 
  Baseline 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Week 26, Primary analysis 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
  Week 26, Sensitivity analysis 1 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
  Week 26, Sensitivity analysis 2 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
... 
 
 
 
 
 
 
N: the number of patients in the FAS. 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 58 out of 151 
 
n: the number of valid measurements.  
Baseline FVC is the average of the pre-bronchodilator FVC measured at the Screening and Day 1 visits. The FVC at Week 26 is the average of the FVC 
measured on two separate days at Week 26. 
Sensitivity analyses 1 – 6 related to missing Week 26 data imputation are described in SAP Section 8.1; Sensitivity analysis 7 – Primary analysis 
excluding all FVC values outside of visit window. Sensitivity analysis 8 – Complete case set; Sensitivity analysis 9 - Complete case set excluding all 
FVC values outside of visit window.  
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<Report the following parameters: FVC (absolute), mL/ FVC (relative) predicted, %> 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 59 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.3  Primary efficacy endpoint: categorical results 
Full analysis set (FAS) 
Page Х of Х 
     Parameter: XXXXXXXXXX, <units> <[1]/[2]> 
 
Total 
(N = XX) 
n (%) 
 
 
  Week 26, Primary analysis 
 
    n’ 
 XX  
    Patients with decline of ≥10% from Baseline or death before Week 26 
XX (XX.X) 
    Decline of < 10% to 0%  
XX (XX.X) 
    Patients with improvement of ≥0% from Baseline 
XX (XX.X) 
 
 
  Week 26, Sensitivity analysis 1 
 
    n’ 
XX 
    Patients with decline of ≥10% from Baseline or death before Week 26 
XX (XX.X) 
    Decline of < 10% to 0%  
XX (XX.X) 
    Patients with improvement of ≥0% from Baseline 
XX (XX.X) 
 
 
  Week 26, Sensitivity analysis 2 
 
    n’ 
XX 
    Patients with decline of ≥10% from Baseline or death before Week 26 
XX (XX.X) 
    Decline of < 10% to 0%  
XX (XX.X) 
    Patients with improvement of ≥0% from Baseline 
XX (XX.X) 
... 
… 
 
N: the number of patients in the FAS. n: the number of patients within a specific category. n’: the number of valid observations.  
Percentages are based on the corresponding number of valid observations.  
[1] Percentage change (Week 26 FVC value – Baseline FVC)*100/ Baseline FVC; [2] Absolute change in FVC % predicted. 
Baseline FVC is the average of the pre-bronchodilator FVC measured at the Screening and Day 1 visits. The FVC at Week 26 is the average of the FVC 
measured on two separate days at Week 26. 
Sensitivity analyses 1 – 6 related to missing Week 26 data imputation are described in SAP Section 8.1; Sensitivity analysis 7 – Primary analysis 
excluding all FVC values outside of visit window. Sensitivity analysis 8 – Complete case set; Sensitivity analysis 9 - Complete case set excluding all 
FVC values outside of visit window.  
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<Report the following parameters: FVC (absolute), mL [1]/ FVC (relative) predicted, % [2]> 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 60 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.4  Primary efficacy endpoint by pattern type 
Complete case set (CCS) 
Page Х of Х 
       Parameter: XXXXXXXXXX, <units> 
 
Total 
(N = XX) 
Change from the baseline  
 
 
 
  Baseline 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Baseline Pattern 1 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Baseline Pattern 2 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Week 26 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
  Week 26, Pattern 1 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
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Page 61 out of 151 
 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
  Week 26, Pattern 2 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
 
N: the number of patients in the CCS. n: the number of valid measurements.  
Baseline FVC is the average of the pre-bronchodilator FVC measured at the Screening and Day 1 visits. The FVC at Week 26 is the average of the FVC 
measured on two separate days at Week 26. 
Pattern 1: Patients who received study drug until 26 weeks;  
Pattern 2: Patients who prematurely discontinued study drug, but who were followed up until Week 26. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 62 out of 151 
 
Secondary Efficacy Endpoint 
6-Minute Walk Test 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.5 6-Minute Walk Test 
Full analysis set (FAS) 
Page Х of Х 
 
 
Total 
(N = XX) 
Change from the baseline  
6-Minute Walk Test, m 
 
 
 
 
 
  Screening 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Day 1 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Baseline 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Week 12 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 63 out of 151 
 
    Max 
XX 
XX 
 
 
 
 
  Week 12* 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
 
 
 
... 
 
 
  Week 52 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
  Week 52* 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
 
 
 
 
N: the number of patients in the FAS. 
n: the number of valid measurements.  
Baseline 6MWT distance is the average of the measurements measured at the Screening and Day 1 visits. The 6MWT distance at Week 26 is defined as the 
average of the 6MWT distance measured on two separate days at Week 26. 
*: Values assessed within the corresponding visit window. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<The following assessments will be presented: Screening, Day 1, Baseline, Week 12, Week 26 Day 1, Week 26 Day 2, Week 26, Week 39, Week 52> 
<Values within the visit window will also be presented descriptively for the following assessments: Week 12*, Week 26 Day 1*, Week 26 Day 2*, Week 26*, 
Week 39*, Week 52*> 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 64 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.6 Change in 6MWT distance at Week 26 by category 
Full analysis set (FAS) 
Page Х of Х 
 
 
Total 
(N = XX) 
n (%) 
n’ 
 
Patients with decline of ≥ 50 m from Baseline or death before Week 26 
 
Patients with decline of < 50 m  to 0 m from Baseline  
XX 
 
XX (XX.X) 
 
XX (XX.X) 
  
 
Patients with improvement of ≥0 m from Baseline 
XX (XX.X) 
 
N: the number of patients in the Full analysis set (FAS). n’ – the number of valid observations.  
n: the number of patients within a specific category. Percentages are based on the corresponding number of valid observations. 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
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Page 65 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.7 Borg scale 
Full analysis set (FAS) 
Page Х of Х 
 
 
Total 
(N = XX) 
Change Pre-test from 
Baseline Pre-test 
Change Post-test from 
Pre-test 
Borg scale 
 
 
 
 
 
 
 
  Screening Pre-test 
 
 
 
    n 
XX 
 
 
    Mean [95% CI] 
XX.XX [XX.XX - XX.XX] 
 
 
    SD 
XX.XXX 
 
 
    Median 
XX.XX 
 
 
    Min 
XX.X 
 
 
    Max 
XX.X 
 
 
 
 
 
 
  Screening Post-test 
 
 
 
    n 
XX 
 
XX 
    Mean [95% CI] 
XX.XX [XX.XX - XX.XX] 
 
XX.XX [XX.XX - XX.XX] 
    SD 
XX.XXX 
 
XX.XXX 
    Median 
XX.XX 
 
XX.XX 
    Min 
XX.X 
 
XX.X 
    Max 
XX.X 
 
XX.X 
 
 
 
 
  Day 1 Pre-test  
 
 
 
    n 
XX 
 
 
    Mean [95% CI] 
XX.XX [XX.XX - XX.XX] 
 
 
    SD 
XX.XXX 
 
 
    Median 
XX.XX 
 
 
    Min 
XX.X 
 
 
    Max 
XX.X 
 
 
 
 
 
 
  Day 1 Post-test 
 
 
 
    n 
XX 
 
XX 
    Mean [95% CI] 
XX.XX [XX.XX - XX.XX] 
 
XX.XX [XX.XX - XX.XX] 
    SD 
XX.XXX 
 
XX.XXX 
    Median 
XX.XX 
 
XX.XX 
    Min 
XX.X 
 
XX.X 
    Max 
XX.X 
 
XX.X 
  ... 
 
 
 
    ... 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 66 out of 151 
 
 Week 26 Day 1 Pre-test 
 
 
 
    n 
XX 
XX 
 
    Mean [95% CI] 
XX.XX [XX.XX - XX.XX] 
XX.XX [XX.XX - XX.XX] 
 
    SD 
XX.XXX 
XX.XXX 
 
    Median 
XX.XX 
XX.XX 
 
    Min 
XX.X 
XX.X 
 
    Max 
XX.X 
XX.X 
 
 
 
 
 
  Week 26 Day 1 Post-test 
 
 
 
    n 
XX 
 
XX 
    Mean [95% CI] 
XX.XX [XX.XX - XX.XX] 
 
XX.XX [XX.XX - XX.XX] 
    SD 
XX.XXX 
 
XX.XXX 
    Median 
XX.XX 
 
XX.XX 
    Min 
XX.X 
 
XX.X 
    Max 
XX.X 
 
XX.X 
 
 
 
 
 Week 26* Day 1 Pre-test 
 
 
 
    n 
XX 
XX 
 
    Mean [95% CI] 
XX.XX [XX.XX - XX.XX] 
XX.XX [XX.XX - XX.XX] 
 
    SD 
XX.XXX 
XX.XXX 
 
    Median 
XX.XX 
XX.XX 
 
    Min 
XX.X 
XX.X 
 
    Max 
XX.X 
XX.X 
 
 
 
 
 
  Week 26* Day 1 Post-test 
 
 
 
    n 
XX 
 
XX 
    Mean [95% CI] 
XX.XX [XX.XX - XX.XX] 
 
XX.XX [XX.XX - XX.XX] 
    SD 
XX.XXX 
 
XX.XXX 
    Median 
XX.XX 
 
XX.XX 
    Min 
XX.X 
 
XX.X 
    Max 
XX.X 
 
XX.X 
 
 
 
 
  ... 
 
 
 
    ... 
... 
... 
... 
 
 
 
 
  Week 52* Post-test 
 
 
 
    n 
XX 
 
XX 
    Mean [95% CI] 
XX.XX [XX.XX - XX.XX] 
 
XX.XX [XX.XX - XX.XX] 
    SD 
XX.XXX 
 
XX.XXX 
    Median 
XX.XX 
 
XX.XX 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 67 out of 151 
 
    Min 
XX.X 
 
XX.X 
    Max 
XX.X 
 
XX.X 
 
N: the number of patients in the FAS. 
n: the number of valid measurements.  
Baseline Borg scale result is the average of the measurements at the Screening and Day 1 visits. The Borg scale at Week 26 is defined as the average of 
the Borg scale results measured on two separate days at Week 26. 
*: Values assessed within the corresponding visit window. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
<The following assessments will be presented: Screening, Day 1, Baseline, Week 12, Week 26 Day 1, Week 26 Day 2, Week 26, Week 39, Week 52> 
<Values within the visit window will also be presented descriptively for the following assessments: Week 12*, Week 26 Day 1*, Week 26 Day 2*, Week 26*, 
Week 39*, Week 52*> 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 68 out of 151 
 
EQ-5D-5L 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.8 EQ-5D-5L. Descriptive statistics 
Full analysis set (FAS) 
Page Х of Х 
 
       Dimension: <Mobility/ Self-Care/ Usual Activities /Pain/Discomfort/ Anxiety/Depression> 
 
Total 
(N = XX) 
n (%) 
 
 
  Baseline 
 
    n’ 
XX 
    Level 1 (no problem) 
XX (XX.X) 
    Level 2 (slight problems) 
XX (XX.X) 
    Level 3 (moderate problems) 
XX (XX.X) 
    Level 4 (severe problems) 
XX (XX.X) 
    Level 5 (unable to walk about) 
XX (XX.X) 
 
 
  Week 12 
 
    n’ 
XX 
    Level 1 (no problem) 
XX (XX.X) 
    Level 2 (slight problems) 
XX (XX.X) 
    Level 3 (moderate problems) 
XX (XX.X) 
    Level 4 (severe problems) 
XX (XX.X) 
    Level 5 (unable to walk about) 
XX (XX.X) 
 
 
  Week 12* 
 
    n’ 
XX 
    Level 1 (no problem) 
XX (XX.X) 
    Level 2 (slight problems) 
XX (XX.X) 
    Level 3 (moderate problems) 
XX (XX.X) 
    Level 4 (severe problems) 
XX (XX.X) 
    Level 5 (unable to walk about) 
XX (XX.X) 
 
 
  Week 26 
 
    n’ 
XX 
    Level 1 (no problem) 
XX (XX.X) 
    Level 2 (slight problems) 
XX (XX.X) 
    Level 3 (moderate problems) 
XX (XX.X) 
    Level 4 (severe problems) 
XX (XX.X) 
    Level 5 (unable to walk about) 
XX (XX.X) 
  ... 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 69 out of 151 
 
 
N: the number of patients in the Full analysis set (FAS). n’ – the number of valid observations.  
n: the number of patients within a specific category. Percentages are based on the corresponding number of valid observations. 
Baseline is the last non-missing assessment prior to the first dose of the study drug.  
*: Values assessed within the corresponding visit window. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 70 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.9 Change in EQ-5D-5L. Mobility 
Full analysis set (FAS) 
Page Х of Х 
 
Dimension: <Mobility/ Self-Care/ Usual Activities /Pain/Discomfort/ Anxiety/Depression> 
 
Baseline assessment 
 
Level 1 (no 
problem) 
Level 2 (slight 
problems) 
Level 3 (moderate 
problems) 
Level 4 (severe 
problems) 
Level 5 (unable to 
walk about) 
Total 
(N = XX) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
  Baseline 
 
 
 
 
 
 
    Level 1 (no problem) 
 
 
 
 
 
XX (XX.X) 
    Level 2 (slight problems) 
 
 
 
 
 
XX (XX.X) 
    Level 3 (moderate problems) 
 
 
 
 
 
XX (XX.X) 
    Level 4 (severe problems) 
 
 
 
 
 
XX (XX.X) 
    Level 5 (unable to walk about) 
 
 
 
 
 
XX (XX.X) 
    Total 
 
 
 
 
 
XX (100) 
 
 
 
 
 
 
 
  Week 12 
 
 
 
 
 
 
    Level 1 (no problem) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 2 (slight problems) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 3 (moderate problems) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 4 (severe problems) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 5 (unable to walk about) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Total 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (100) 
 
 
 
 
 
 
 
  Week 12*  
 
 
 
 
 
 
    ... 
... 
... 
... 
... 
... 
... 
 
 
 
 
 
 
 
  Week 52* 
 
 
 
 
 
 
    ... 
 
 
 
 
 
 
 
N: the number of patients in the Full analysis set (FAS). 
n: the number of patients within a specific category. Percentages are based on the number of non-missing values at baseline and at the corresponding 
visit. 
Baseline is the last non-missing assessment prior to the first dose of the study drug.  
*: Values assessed within the corresponding visit window. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 71 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.10 Change in EQ-5D-5L. Self-Care 
Full analysis set (FAS) 
Page Х of Х 
 
Dimension: <Mobility/ Self-Care/ Usual Activities /Pain/Discomfort/ Anxiety/Depression> 
 
Baseline assessment 
 
Level 1 (no 
problem) 
Level 2 
(slight 
problems) 
Level 3 (moderate 
problems) 
Level 4 (severe 
problems) 
Level 5 (unable 
to wash or 
dress myself) 
Total 
(N = XX) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
  Baseline 
 
 
 
 
 
 
    Level 1 (no problem) 
 
 
 
 
 
XX (XX.X) 
    Level 2 (slight problems) 
 
 
 
 
 
XX (XX.X) 
    Level 3 (moderate problems) 
 
 
 
 
 
XX (XX.X) 
    Level 4 (severe problems) 
 
 
 
 
 
XX (XX.X) 
    Level 5 (unable to wash or dress myself) 
 
 
 
 
 
XX (XX.X) 
    Total 
 
 
 
 
 
XX (100) 
 
 
 
 
 
 
 
  Week 12 
 
 
 
 
 
 
    Level 1 (no problem) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 2 (slight problems) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 3 (moderate problems) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 4 (severe problems) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 5 (unable to wash or dress myself) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Total 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (100) 
 
 
 
 
 
 
 
  Week 12*  
 
 
 
 
 
 
    ... 
... 
... 
... 
... 
... 
... 
 
 
 
 
 
 
 
  Week 52* 
 
 
 
 
 
 
    ... 
 
 
 
 
 
 
 
N: the number of patients in the Full analysis set (FAS). 
n: the number of patients within a specific category. Percentages are based on the number of non-missing values at baseline and at the corresponding 
visit. 
Baseline is the last non-missing assessment prior to the first dose of the study drug.  
*: Values assessed within the corresponding visit window. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
F. Hoffmann-La Roche Ltd 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 72 out of 151 
 
ML39355 
Table 2.11 Change in EQ-5D-5L. Usual Activities 
Full analysis set (FAS) 
Page Х of Х 
 
Dimension: <Mobility/ Self-Care/ Usual Activities /Pain/Discomfort/ Anxiety/Depression> 
 
Baseline assessment 
 
Level 1 (no 
problem) 
Level 2 
(slight 
problems) 
Level 3 
(moderate 
problems) 
Level 4 (severe 
problems) 
Level 5 (unable 
to do my usual 
activities) 
Total 
(N = XX) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
  Baseline 
 
 
 
 
 
 
    Level 1 (no problem) 
 
 
 
 
 
XX (XX.X) 
    Level 2 (slight problems) 
 
 
 
 
 
XX (XX.X) 
    Level 3 (moderate problems) 
 
 
 
 
 
XX (XX.X) 
    Level 4 (severe problems) 
 
 
 
 
 
XX (XX.X) 
    Level 5 (unable to do my usual activities) 
 
 
 
 
 
XX (XX.X) 
    Total 
 
 
 
 
 
XX (100) 
 
 
 
 
 
 
 
  Week 12 
 
 
 
 
 
 
    Level 1 (no problem) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 2 (slight problems) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 3 (moderate problems) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 4 (severe problems) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 5 (unable to do my usual activities) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Total 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (100) 
 
 
 
 
 
 
 
  Week 12* 
 
 
 
 
 
 
    ... 
... 
... 
... 
... 
... 
... 
 
 
 
 
 
 
 
  Week 52* 
 
 
 
 
 
 
    ... 
 
 
 
 
 
 
 
N: the number of patients in the Full analysis set (FAS). 
n: the number of patients within a specific category. Percentages are based on the number of non-missing values at baseline and at the corresponding 
visit. 
Baseline is the last non-missing assessment prior to the first dose of the study drug.  
*: Values assessed within the corresponding visit window. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 73 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.12 Change in EQ-5D-5L. Pain/Discomfort 
Full analysis set (FAS) 
Page Х of Х 
 
Dimension: <Mobility/ Self-Care/ Usual Activities /Pain/Discomfort/ Anxiety/Depression> 
 
Baseline assessment 
 
Level 1  
(no pain or 
discomfort) 
Level 2  
(slight pain or 
discomfort) 
Level 3 
(moderate pain 
or discomfort) 
Level 4  
(severe pain or 
discomfort) 
Level 5 
(extreme pain 
or discomfort) 
Total 
(N = XX) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
  Baseline 
 
 
 
 
 
 
    Level 1 (no pain or discomfort) 
 
 
 
 
 
XX (XX.X) 
    Level 2 (slight pain or discomfort) 
 
 
 
 
 
XX (XX.X) 
    Level 3 (moderate pain or discomfort) 
 
 
 
 
 
XX (XX.X) 
    Level 4 (severe pain or discomfort) 
 
 
 
 
 
XX (XX.X) 
    Level 5 (extreme pain or discomfort) 
 
 
 
 
 
XX (XX.X) 
    Total 
 
 
 
 
 
XX (100) 
 
 
 
 
 
 
 
  Week 12 
 
 
 
 
 
 
    Level 1 (no pain or discomfort) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 2 (slight pain or discomfort) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 3 (moderate pain or discomfort) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 4 (severe pain or discomfort) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 5 (extreme pain or discomfort) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Total 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (100) 
 
 
 
 
 
 
 
  Week 12* 
 
 
 
 
 
 
    ... 
... 
... 
... 
... 
... 
... 
 
 
 
 
 
 
 
  Week 52* 
 
 
 
 
 
 
    ... 
 
 
 
 
 
 
 
N: the number of patients in the Full analysis set (FAS). 
n: the number of patients within a specific category. Percentages are based on the number of non-missing values at baseline and at the corresponding 
visit. 
Baseline is the last non-missing assessment prior to the first dose of the study drug.  
*: Values assessed within the corresponding visit window. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
F. Hoffmann-La Roche Ltd 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 74 out of 151 
 
ML39355 
Table 2.13 Change in EQ-5D-5L. Anxiety/Depression 
Full analysis set (FAS) 
Page Х of Х 
 
Dimension: <Mobility/ Self-Care/ Usual Activities /Pain/Discomfort/ Anxiety/Depression> 
 
Baseline assessment 
 
Level 1  
(not anxious 
or depressed) 
Level 2  
(slight anxious 
or depressed) 
Level 3  
(moderate anxious 
or depressed) 
Level 4  
(severe anxious 
or depressed) 
Level 5  
(extremely anxious 
or depressed) 
Total 
(N = XX) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
  Baseline 
 
 
 
 
 
 
    Level 1 (not anxious or depressed) 
 
 
 
 
 
XX (XX.X) 
    Level 2 (slight anxious or depressed) 
 
 
 
 
 
XX (XX.X) 
    Level 3 (moderate anxious or depressed) 
 
 
 
 
 
XX (XX.X) 
    Level 4 (severe anxious or depressed) 
 
 
 
 
 
XX (XX.X) 
    Level 5 (extremely anxious or depressed) 
 
 
 
 
 
XX (XX.X) 
    Total 
 
 
 
 
 
XX (100) 
 
 
 
 
 
 
 
  Week 12 
 
 
 
 
 
 
    Level 1 (not anxious or depressed) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 2 (slight anxious or depressed) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 3 (moderate anxious or depressed) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 4 (severe anxious or depressed) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Level 5 (extremely anxious or depressed) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Total 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (100) 
 
 
 
 
 
 
 
  Week 12* 
 
 
 
 
 
 
    ... 
... 
... 
... 
... 
... 
... 
 
 
 
 
 
 
 
  Week 52* 
 
 
 
 
 
 
    ... 
 
 
 
 
 
 
 
N: the number of patients in the Full analysis set (FAS). 
n: the number of patients within a specific category. Percentages are based on the number of non-missing values at baseline and at the corresponding 
visit. 
Baseline is the last non-missing assessment prior to the first dose of the study drug.  
*: Values assessed within the corresponding visit window. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 75 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.14 EQ-5D-5L. VAS and Index score 
Full analysis set (FAS) 
Page Х of Х 
        Parameter: XXXXXXXXX 
 
Total 
(N = XX) 
Change from the baseline  
 
 
 
  Baseline 
 
 
    n 
XX 
 
    Mean 
XX.X 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Week 12 
 
 
    n 
XX 
XX 
    Mean 
XX.X 
XX.X 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
  Week 12* 
 
 
    n 
XX 
XX 
    Mean 
XX.X 
XX.X 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
  ... 
 
 
    ... 
 
 
 
 
 
  Week 52* 
 
 
    n 
XX 
XX 
    Mean 
XX.X 
XX.X 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 76 out of 151 
 
N: the number of patients in the FAS. 
n: the number of valid measurements.  
Baseline is the last non-missing assessment prior to the first dose of the study drug.  
*: Values assessed within the corresponding visit window. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 77 out of 151 
 
Exploratory Efficacy Endpoint 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.15 HRCT. HRCT fibrosis score 
Full analysis set (FAS) 
Page Х of Х 
 
 
Total 
(N = XX) 
Change from the baseline  
HRCT fibrosis score 
 
 
 
 
 
  Baseline 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Week 26 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
  Week 52 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
  p-value for (Week 26 – Baseline) comparison 
0.XXXX 
 
 
 
 
  p-value for (Week 52 – Baseline) comparison 
0.XXXX 
 
 
N: the number of patients in the FAS. 
n: the number of valid measurements. 
The comparison of the results is performed using the paired t-test. 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 78 out of 151 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 79 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.16 HRCT. Lung opacity score 
Full analysis set (FAS) 
Page Х of Х 
 
 
Total 
(N = XX) 
Change from the baseline  
Lung opacity score 
 
 
 
 
 
  Baseline 
 
 
    n 
XX 
 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Week 26 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 
  Week 52 
 
 
    n 
XX 
XX 
    Mean [95% CI] 
XX.X [XX.X - XX.X] 
XX.X [XX.X - XX.X] 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
N: the number of patients in the FAS. 
n: the number of valid measurements. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 80 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.17 Exacerbation cases during treatment period 
Full analysis set (FAS) 
Page Х of Х 
 
System Organ Class (SOC) 
  Preferred Term (PT) 
Total 
(N = XX) 
n (%) / E 
Overall 
XX (XX.X) / XX 
 
 
System Organ Class 1 
XX (XX.X) / XX 
  Preferred Term 1 
XX (XX.X) / XX 
  Preferred Term 2 
XX (XX.X) / XX 
  ... 
 
System Organ Class 2 
XX (XX.X) / XX 
  Preferred Term 1 
XX (XX.X) / XX 
  Preferred Term 2 
XX (XX.X) / XX 
  ... 
... 
 
N: the number of patients in the FAS. E: number of adverse events reported. 
n: the number of patients within the corresponding category. Percentages are calculated as 100 x (n/N). 
Adverse events were coded using the MedDRA version XX.X.  
Each patient is counted only once per preferred term (РТ) and once per system organ class (SOC). 
 
<System organ classes (SOC) and preferred terms (PT) within each SOC should be sorted in descending order of n(%).> 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 81 out of 151 
 
Similar to table 2.17, the following tables will be constructed: 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.18 Exacerbation cases during rollover study 
Full analysis set (FAS, patients continuing in the rollover study) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 2.19 Exacerbation cases during whole study period 
Full analysis set (FAS, patients continuing in the rollover study) 
Page Х of Х 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 82 out of 151 
 
Safety Analyses 
Exposure 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.1 Duration of exposure 
Treated set (TS) 
Page Х of Х 
 
 
Total 
(N = XX) 
Duration of exposure to Pirfenidone during treatment period, weeks 
 
 
 
    n 
XX 
    Mean 
XX.XX 
    SD 
XX.XXX 
    Median 
XX.XX 
    Min 
XX.X 
    Max 
XX.X 
 
 
Duration of exposure to Pirfenidone during rollover study, weeks  
 
 
 
    n 
XX 
    Mean 
XX.XX 
    SD 
XX.XXX 
    Median 
XX.XX 
    Min 
XX.X 
    Max 
XX.X 
 
 
  Total duration of exposure to Pirfenidone (only for patients continuing in the rollover study), weeks 
  
 
    n 
XX 
    Mean 
XX.XX 
    SD 
XX.XXX 
    Median 
XX.XX 
    Min 
XX.X 
    Max 
XX.X 
 
 
 
N: the number of patients in the Treated set (TS). 
n: the number of valid measurements. 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 83 out of 151 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 84 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.2 Total number of capsules taken 
Treated set (TS) 
Page Х of Х 
 
 
Total 
(N = XX) 
Total number of capsules taken during treatment period 
 
 
 
    n 
XX 
    Mean 
XX.X 
    SD 
XX.XX 
    Median 
XX.X 
    Min 
XX 
    Max 
XX 
 
 
Total number of capsules taken during rollover study  
 
 
 
    n 
XX 
    Mean 
XX.X 
    SD 
XX.XX 
    Median 
XX.X 
    Min 
XX 
    Max 
XX 
 
 
  Total number of capsules taken during the study (only for patients continuing in the rollover study) 
 
 
    n 
XX 
    Mean 
XX.X 
    SD 
XX.XX 
    Median 
XX.X 
    Min 
XX 
    Max 
XX 
 
 
 
N: the number of patients in the Treated set (TS). 
n: the number of valid measurements. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 85 out of 151 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 86 out of 151 
 
Adverse Events 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.3.1 Treatment-emergent adverse events during treatment period 
Treated set (TS) 
Page Х of Х 
 
System Organ Class (SOC) 
  Preferred Term (PT) 
Total 
(N = XX) 
n (%) / E 
Overall 
XX (XX.X) / XX 
 
 
System Organ Class 1 
XX (XX.X) / XX 
  Preferred Term 1 
XX (XX.X) / XX 
  Preferred Term 2 
XX (XX.X) / XX 
  ... 
 
System Organ Class 2 
XX (XX.X) / XX 
  Preferred Term 1 
XX (XX.X) / XX 
  Preferred Term 2 
XX (XX.X) / XX 
  ... 
... 
 
N: the number of patients in the Treated set (TS). 
n: the number of patients with at least one TEAE within a specific category. Percentages are calculated as (100 x n/N). 
E: total number of TEAEs reported within a specific category. 
Each patient is counted only once per preferred term (РТ) and once per system organ class (SOC). 
Adverse events are coded by MedDRA version XX.X. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<System organ classes (SOC) and preferred terms (PT) within each SOC should be sorted in descending order of n (%). > 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 87 out of 151 
 
Similar to table 3.3.1, the following tables will be constructed (with the corresponding corrections of underlined fragments in the note): 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.3.2 Treatment-emergent adverse events during rollover study 
Treated set (TS, patients continuing in the rollover study) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.3.3 Treatment-emergent adverse events during whole study period 
Treated set (TS) 
Page Х of Х 
 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.4.1 Treatment-emergent adverse events related to the study drug during treatment period  
Treated set (TS) 
Page Х of Х  
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.4.2 Treatment-emergent adverse events related to the study drug during rollover study  
Treated set (TS, patients continuing in the rollover study) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.4.3 Treatment-emergent adverse events related to the study drug during whole study period 
Treated set (TS) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.5.1 Serious treatment-emergent adverse events during treatment period 
Treated set (TS) 
Page Х of Х 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 88 out of 151 
 
 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.5.2 Serious treatment-emergent adverse events during rollover study 
Treated set (TS, patients continuing in the rollover study) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.5.3 Serious treatment-emergent adverse events during whole study period 
Treated set (TS) 
Page Х of Х 
 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.6.1 Serious treatment-emergent adverse events related to the study drug during treatment period 
Treated set (TS) 
Page Х of Х 
  
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.6.2 Serious treatment-emergent adverse events related to the study drug during rollover study 
Treated set (TS, patients continuing in the rollover study) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.6.3 Serious treatment-emergent adverse events related to the study drug during whole study period 
Treated set (TS) 
Page Х of Х 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 89 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.7.1 Treatment-emergent adverse events during treatment period by maximum severity 
Treated set (TS) 
Page Х of Х 
 
System Organ Class (SOC) 
  Preferred Term (PT) 
Severity 
 
Total 
(N = XX) 
n (%) / E 
Overall 
Grade 1 
 
XX (XX.X) / XX 
 
Grade 2 
 
XX (XX.X) / XX 
 
Grade 3 
 
XX (XX.X) / XX 
 
Grade 4 
 
XX (XX.X) / XX 
 
Grade 5 
 
XX (XX.X) / XX 
 
 
 
 
System Organ Class 1 
Grade 1 
 
XX (XX.X) / XX 
 
Grade 2 
 
XX (XX.X) / XX 
 
Grade 3 
 
XX (XX.X) / XX 
 
Grade 4 
 
XX (XX.X) / XX 
 
Grade 5 
 
XX (XX.X) / XX 
 
 
 
 
  Preferred Term 1 
Grade 1 
 
XX (XX.X) / XX 
 
Grade 2 
 
XX (XX.X) / XX 
 
Grade 3 
 
XX (XX.X) / XX 
 
Grade 4 
 
XX (XX.X) / XX 
 
Grade 5 
 
XX (XX.X) / XX 
 
 
 
 
  Preferred Term 2 
Grade 1 
 
XX (XX.X) / XX 
 
Grade 2 
 
XX (XX.X) / XX 
 
Grade 3 
 
XX (XX.X) / XX 
 
Grade 4 
 
XX (XX.X) / XX 
 
Grade 5 
 
XX (XX.X) / XX 
 
 
 
 
  ... 
... 
 
... 
 
 
 
 
System Organ Class 2 
Grade 1 
 
XX (XX.X) / XX 
 
Grade 2 
 
XX (XX.X) / XX 
 
Grade 3 
 
XX (XX.X) / XX 
 
Grade 4 
 
XX (XX.X) / XX 
 
Grade 5 
 
XX (XX.X) / XX 
 
 
 
 
  ... 
... 
 
... 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 90 out of 151 
 
N: the number of patients in the Treated set (TS). 
n: the number of patients with at least one TEAE within a specific category. Percentages are calculated as (100 x n/N). 
E: total number of TEAEs reported with appropriate severity. 
For “Overall” and for each SOC and SOC/PT, each patient is counted once in the category of the maximum severity. 
For "Overall", the number of all reported TEAEs are presented; for each SOC and SOC/PT, the number of TEAEs of maximum severity is given. 
NCI CTCAE version 4.0 was used for assessing AE severity. AEs are coded using MedDRA version XX.X. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
< System organ classes (SOC) and preferred terms (PT) within each SOC should be sorted in descending order of n (%). > 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 91 out of 151 
 
Similar to table 3.7.1, the following tables will be constructed (with the corresponding corrections of underlined fragments in the note): 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.7.2 Treatment-emergent adverse events during rollover study by maximum severity  
Treated set (TS, patients continuing in the rollover study) 
Page Х of Х 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.7.3 Treatment-emergent adverse events during whole study period by maximum severity  
Treated set (TS) 
Page Х of Х 
 
 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.8.1 Treatment-emergent adverse events related to the study drug during treatment period by maximum severity 
Treated set (TS) 
Page Х of Х 
  
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.8.2 Treatment-emergent adverse events related to the study drug during rollover study by maximum severity 
Treated set (TS, patients continuing in the rollover study) 
Page Х of Х 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.8.3 Treatment-emergent adverse events related to the study drug during whole study period by maximum severity 
Treated set (TS) 
Page Х of Х 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 92 out of 151 
 
Similar to table 3.3.1, the following tables will be constructed (with the corresponding corrections of underlined fragments in the note): 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.9.1 Treatment-emergent adverse events of special interest during treatment period  
Treated set (TS) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.9.2 Treatment-emergent adverse events of special interest during rollover study 
Treated set (TS, patients continuing in the rollover study) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.9.3 Treatment-emergent adverse events of special interest during whole study period 
Treated set (TS) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.10.1 Treatment-emergent adverse events leading to death during treatment period 
Treated set (TS) 
Page Х of Х 
  
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.10.2 Treatment-emergent adverse events leading to death during rollover study 
Treated set (TS, patients continuing in the rollover study) 
Page Х of Х 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.10.3 Treatment-emergent adverse events leading to death during whole study period 
Treated set (TS) 
Page Х of Х 
 
F. Hoffmann-La Roche Ltd 
ML39355 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 93 out of 151 
 
Table 3.11.1 Treatment-emergent adverse events leading to discontinuation of study drug during treatment period 
Treated set (TS) 
Page Х of Х 
  
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.11.2 Treatment-emergent adverse events leading to discontinuation of study drug during rollover study 
Treated set (TS, patients continuing in the rollover study) 
Page Х of Х 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.11.3 Treatment-emergent adverse events leading to discontinuation of study drug during whole study period 
Treated set (TS) 
Page Х of Х 
 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.12.1 Treatment-emergent adverse events related to the study drug and leading to death during treatment period 
Treated set (TS) 
Page Х of Х 
  
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.12.2 Treatment-emergent adverse events related to the study drug and leading to death during rollover study 
Treated set (TS, patients continuing in the rollover study) 
Page Х of Х 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.12.3 Treatment-emergent adverse events related to the study drug and leading to death during whole study period 
Treated set (TS) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.13.1 Non-serious treatment-emergent adverse events occurred at a frequency of >=5% during treatment period 
Treated set (TS) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 94 out of 151 
 
ML39355 
Table 3.13.2 Non-serious treatment-emergent adverse events occurred at a frequency of >=5% during rollover study 
Treated set (TS, patients continuing in the rollover study) 
Page Х of Х 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.13.3 Non-serious treatment-emergent adverse events occurred at a frequency of >=5% during whole study period 
Treated set (TS) 
Page Х of Х 
 
 
 
  
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 95 out of 151 
 
 
Table 3.14 Deaths 
Treated set (TS) 
Page Х of Х 
 
 
 
Total 
(N = XX) 
n (%) 
Total number of deaths 
 
XX (XX.X) 
 
 
 
Deaths during treatment period 
 
XX (XX.X) 
 
 
 
Deaths during rollover study 
 
XX (XX.X) 
 
 
 
 
N: the number of patients in the Treated set (TS). n: the number of patients who died. Percentages are calculated as (100 x n/N). 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 96 out of 151 
 
Pregnancies 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.15 Urine pregnancy test 
Treated set (TS) 
Page Х of Х 
 
 
Total 
(N = XX) 
n (%) 
 
 
Screening 
 
n’ 
XX 
Done [1] 
XX (XX.X) 
  Negative [2] 
XX (XX.X) 
  Positive [2] 
XX (XX.X) 
Not Done [1] 
XX (XX.X) 
  Male subject [1] 
XX (XX.X) 
  Female subject with no childbearing potential [1] 
XX (XX.X) 
  Other [1] 
XX (XX.X) 
 
 
Day 1 
 
n’ 
XX 
Done [1] 
XX (XX.X) 
  Negative [2] 
XX (XX.X) 
  Positive [2] 
XX (XX.X) 
Not Done [1] 
XX (XX.X) 
  Male subject [1] 
XX (XX.X) 
  Female subject with no childbearing potential [1] 
XX (XX.X) 
  Other [1] 
XX (XX.X) 
 
 
... 
 
  ... 
... 
 
N: the number of women of childbearing potential in the TS. n’ – the number of valid observations.  
n: the number of patients within a specific category.  
[1] Percentages are based on the corresponding number of valid observations.  
[2] Percentages are based on the number of patients for whom the pregnancy test was performed.  
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
<The following Urine pregnancy test assessments will be presented: Screening, Day 1, Week 4, Week 8, Week 12, Week 20, Week 26 Day 2>  


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 97 out of 151 
 
 
Laboratory tests 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.16 Hematology. Descriptive statistics 
Treated set (TS) 
Page Х of Х 
 
       Parameter: XXXXXXXXXXXXXXXXX, <units> 
 
Total 
(N = XX) 
Change from the baseline  
 
 
 
  Screening 
 
 
    n 
XX 
 
    Mean 
XX.X 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Day 1 
 
 
    n 
XX 
 
    Mean 
XX.X 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Baseline 
 
 
    n 
XX 
 
    Mean 
XX.X 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Week 2 
 
 
    n 
XX 
XX 
    Mean 
XX.X 
XX.X 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 98 out of 151 
 
 
 
 
  ... 
 
 
    ... 
... 
... 
     
 
 
 
N: the number of patients in the Treated set (TS). 
n: the number of valid measurements. 
 
The baseline value for a variable is defined as the last non-missing value collected before the first study drug administration.  
<The following assessments will be presented: Screening, Day 1, Baseline, Week 2, Week 4, Week 8, Week 16, Week 20, Week 26 Day 2, Follow-up visit, 
Week 39, Week 52> 
<The following parameters will be presented: Leukocytes (10^9/L), Erythrocytes (10^12/L), Hemoglobin (g/L), Hematocrit (L/L), Platelets (10^9/L), 
Neutrophils/Leukocytes (%), Eosinophils/Leukocytes (%), Basophils/Leukocytes (%), Monocytes/Leukocytes (%), Lymphocytes/Leukocytes (%).> 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 99 out of 151 
 
Similar to table 3.16, the following tables will be constructed: 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.17 Blood chemistry. Descriptive statistics 
Treated set (TS) 
Page Х of Х 
 
 
<The following parameters will be presented: Albumin (g/L), Alkaline Phosphatase (U/L), Alanine Aminotransferase (U/L), Aspartate Aminotransferase 
(U/L), Direct bilirubin (umol/L), Bilirubin (umol/l), Protein (g/L), Cholesterol (mmol/L), Creatine Kinase (U/L), Creatinine (umol/L), Triglycerides 
(mmol/L), Gamma Glutamyl Transferase (U/L), Glucose (mmol/L), Lactate Dehydrogenase (U/L), Calcium (mmol/L), Phosphate (mmol/L), Magnesium (mmol/L), 
Potassium (mmol/L), Sodium (mmol/L), Urea nitrogen (mmol/L), Urate (umol/L), Creatinine Clearance (mL/min).> 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 100 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.18 Hematology. Shift table 
Treated set (TS) 
Page Х of Х 
 
     Parameter: XXXXXXXXXXXXXXXXX, <units> 
 
_____________________________________________Baseline_____________________________________________ 
Low 
Normal 
High 
Total 
 
 
 
 
 
  Baseline 
 
 
 
 
    Low 
 
 
 
XX (XX.X) 
    Normal 
 
 
 
XX (XX.X) 
    High 
 
 
 
XX (XX.X) 
    Total 
 
 
 
XX (100) 
 
 
 
 
 
  Week 2 
 
 
 
 
    Low 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Normal 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    High 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Total 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (100) 
 
 
 
 
 
  Week 4 
 
 
 
 
    Low 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Normal 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    High 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
    Total 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
XX (100) 
 
 
 
 
 
  ... 
 
 
 
 
    ... 
... 
... 
... 
... 
 
 
 
 
 
 
The baseline value for a variable is defined as the last non-missing value collected before the first study drug administration.  
Percentages are based on the number of patients with a non-missing assessment at the corresponding time point and at baseline. 
 
<The following assessments will be presented: Baseline, Week 2, Week 4, Week 8, Week 16, Week 20, Week 26 Day 2, Follow-up visit, Week 39, Week 52> 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 101 out of 151 
 
Similar to table 3.18, the following tables will be constructed: 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.19 Blood chemistry. Shift table 
Treated set (TS) 
Page Х of Х 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 102 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.20 Hematology. Out of range. Frequency table  
Treated set (TS) 
Page Х of Х 
       Parameter: XXXXXXXXXXXXXX, <units> 
 
Total 
(N = XX) 
n (%) 
 
 
  Screening 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Out of Range NCS 
XX (XX.X) 
    Out of Range CS 
XX (XX.X) 
 
 
  Day 1 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Out of Range NCS 
XX (XX.X) 
    Out of Range CS 
XX (XX.X) 
 
 
  Baseline 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Out of Range NCS 
XX (XX.X) 
    Out of Range CS 
XX (XX.X) 
 
 
  Week 2 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Out of Range NCS 
XX (XX.X) 
    Out of Range CS 
XX (XX.X) 
 
 
  ... 
 
    ... 
... 
 
N: the number of patients in the Treated set (TS). n’ – the number of valid observations.  
n: the number of patients within a specific category. Percentages are based on the corresponding number of valid observations. 
 
<The following assessments will be presented: Screening, Day 1, Baseline, Week 2, Week 4, Week 8, Week 16, Week 20, Week 26 Day 2, Follow-up visit, 
Week 39, Week 52> 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 103 out of 151 
 
Similar to table 3.20, the following tables will be constructed: 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.21 Blood chemistry. Out of range. Frequency table 
Treated set (TS) 
Page Х of Х 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 104 out of 151 
 
 
Vital signs 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.22 Vital signs. Descriptive statistics 
Treated set (TS) 
Page Х of Х 
       Parameter: XXXXXXXXXXXXXX, <units> 
 
Total 
(N = XX) 
Change from the baseline  
 
 
 
  Screening 
 
 
    n 
XX 
 
    Mean 
XX.X 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Day 1 
 
 
    n 
XX 
 
    Mean 
XX.X 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Baseline 
 
 
    n 
XX 
 
    Mean 
XX.X 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Week 2 
 
 
    n 
XX 
XX 
    Mean 
XX.X 
XX.X 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 105 out of 151 
 
 
 
 
  ... 
 
 
    ... 
... 
... 
 
 
 
 
N: the number of patients in the Treated set (TS). 
n: the number of valid measurements. 
 
The baseline value for a variable is defined as the last non-missing value collected before the first study drug administration.  
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
<Report all parameters: Systolic blood pressure, mm Hg/ Diastolic blood pressure, mm Hg/ Pulse rate, beats/minute/ Respiratory rate, breaths/minute/ 
Axillary temperature, C>  
<The following assessments will be presented: Screening, Day 1, Baseline, Week 2, Week 4, Week 8, Week 16, Week 20, Week 26 Day 1, Week 26 Day 2, 
Follow-up visit, Week 39, Week 52> 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 106 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.23 Vital signs. Out of range. Frequency table 
Treated set (TS) 
Page Х of Х 
       Parameter: XXXXXXXXXXXXXX, <units> 
 
Total 
(N = XX) 
n (%) 
 
 
  Screening 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Out of Range NCS 
XX (XX.X) 
    Out of Range CS 
XX (XX.X) 
 
 
  Day 1 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Out of Range NCS 
XX (XX.X) 
    Out of Range CS 
XX (XX.X) 
 
 
  Baseline 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Out of Range NCS 
XX (XX.X) 
    Out of Range CS 
XX (XX.X) 
 
 
  Week 2 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Out of Range NCS 
XX (XX.X) 
    Out of Range CS 
XX (XX.X) 
 
 
  ... 
 
    ... 
... 
 
 
 
N: the number of patients in the Treated set (TS). n’ – the number of valid observations.  
n: the number of patients within a specific category. Percentages are based on the corresponding number of valid observations. 
 
  
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 107 out of 151 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<Report all parameters: Systolic blood pressure, mm Hg/ Diastolic blood pressure, mm Hg/ Pulse rate, beats/minute/ Respiratory rate, breaths/minute/ 
Axillary temperature, C>  
<The following assessments will be presented: Screening, Day 1, Baseline, Week 2, Week 4, Week 8, Week 16, Week 20, Week 26 Day 1, Week 26 Day 2, 
Follow-up visit, Week 39, Week 52> 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 108 out of 151 
 
Weight 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.24 Weight. Descriptive statistics 
Treated set (TS) 
Page Х of Х 
       Parameter: Weight, kg 
 
Total 
(N = XX) 
Change from the baseline  
 
 
 
  Screening 
 
 
    n 
XX 
 
    Mean 
XX.XX 
 
    SD 
XX.XXX 
 
    Median 
XX.XX 
 
    Min 
XX.X 
 
    Max 
XX.X 
 
 
 
 
  Day 1 
 
 
    n 
XX 
 
    Mean 
XX.XX 
 
    SD 
XX.XXX 
 
    Median 
XX.XX 
 
    Min 
XX.X 
 
    Max 
XX.X 
 
   
 
 
  Baseline 
 
 
    n 
XX 
 
    Mean 
XX.XX 
 
    SD 
XX.XXX 
 
    Median 
XX.XX 
 
    Min 
XX.X 
 
    Max 
XX.X 
 
 
 
 
  Week 2 
 
 
    n 
XX 
XX 
    Mean 
XX.XX 
XX.XX 
    SD 
XX.XXX 
XX.XXX 
    Median 
XX.XX 
XX.XX 
    Min 
XX.X 
XX.X 
    Max 
XX.X 
XX.X 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 109 out of 151 
 
  ... 
 
 
    ... 
... 
... 
 
N: the number of patients in the Treated set (TS). 
n: the number of valid measurements. 
 
The baseline value for a variable is defined as the last non-missing value collected before the first study drug administration.  
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<The following assessments will be presented: Screening, Day 1, Baseline, Week 2, Week 4, Week 8, Week 16, Week 20, Week 26 Day 2, Follow-up visit> 
 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 110 out of 151 
 
ECG 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.25 ECG. Descriptive statistics 
Treated set (TS) 
Page Х of Х 
       Parameter: XXXXXXXXXXXXXXX, <units> 
 
Total 
(N = XX) 
Change from the baseline  
 
 
 
  Screening 
 
 
    n 
XX 
 
    Mean 
XX.X 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Day 1 
 
 
    n 
XX 
 
    Mean 
XX.X 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Baseline 
 
 
    n 
XX 
 
    Mean 
XX.X 
 
    SD 
XX.XX 
 
    Median 
XX.X 
 
    Min 
XX 
 
    Max 
XX 
 
 
 
 
  Week 4 
 
 
    n 
XX 
XX 
    Mean 
XX.X 
XX.X 
    SD 
XX.XX 
XX.XX 
    Median 
XX.X 
XX.X 
    Min 
XX 
XX 
    Max 
XX 
XX 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 111 out of 151 
 
  ... 
 
 
    ... 
... 
... 
   
... 
... 
 
N: the number of patients in the Treated set (TS). 
n: the number of valid measurements. 
 
The baseline value for a variable is defined as the last non-missing value collected before the first study drug administration.  
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<Report all parameters: Heart rate, beats/min/ QT interval, ms/ QTC-F interval, ms>  
<The following assessments will be presented: Screening, Day 1, Baseline, Week 4, Week 8, Week 26 Day 2, Week 52> 
 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 112 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.26 ECG. Out of range and General assessment. Frequency table 
Treated set (TS) 
Page Х of Х 
       Parameter: XXXXXXXXXXXXXXXX 
 
Total 
(N = XX) 
n (%) 
 
 
  Screening 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Abnormal NCS 
XX (XX.X) 
    Abnormal CS 
XX (XX.X) 
 
 
  Day 1 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Abnormal NCS 
XX (XX.X) 
    Abnormal CS 
XX (XX.X) 
 
 
  Baseline 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Abnormal NCS 
XX (XX.X) 
    Abnormal CS 
XX (XX.X) 
 
 
  Week4 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Abnormal NCS 
XX (XX.X) 
    Abnormal CS 
XX (XX.X) 
 
 
  … 
 
    … 
… 
 
 
 
N: the number of patients in the Treated set (TS). n’ – the number of valid observations.  
n: the number of patients within a specific category. Percentages are based on the corresponding number of valid observations. 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 113 out of 151 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<Report all parameters: General assessment/ Heart rate, beats/min/ QT interval, ms/ QTC-F interval, ms>  
<The following assessments will be presented: Screening, Day 1, Baseline, Week 4, Week 8, Week 26 Day 2, Week 52> 
 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 114 out of 151 
 
Physical examinations 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Table 3.27 Physical examinations. Frequency table 
Treated set (TS) 
Page Х of Х 
       Body system: XXXXXXXXXXXX 
 
Total 
(N = XX) 
n (%) 
 
 
  Screening 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Abnormal NCS 
XX (XX.X) 
    Abnormal CS 
XX (XX.X) 
 
 
  Day 1 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Abnormal NCS 
XX (XX.X) 
    Abnormal CS 
XX (XX.X) 
 
 
  Baseline 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Abnormal NCS 
XX (XX.X) 
    Abnormal CS 
XX (XX.X) 
 
 
  Week 2 
 
    n’ 
XX 
    Normal 
XX (XX.X) 
    Abnormal NCS 
XX (XX.X) 
    Abnormal CS 
XX (XX.X) 
 
 
  ... 
 
    ... 
... 
 
N: the number of patients in the Treated set (TS). n’ – the number of valid observations.  
n: the number of patients within a specific category. Percentages are based on the corresponding number of valid observations. 
 
 
 


9
 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 115 out of 151 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<The following assessments will be presented: Screening, Day 1, Baseline, Week 2, Week 4, Week 8, Week 16, Week 20, Week 26 Day 1, Week 26 Day 2, 
Follow-up visit, Week 39, Week 52> 
 
 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_16 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 116 out of 151 
 
16.2. Figures 
No figures are planned in the study. 
16.3. Listings 
Listing 1 Disposition: analysis populations 
Listing 2 Disposition: patient visits 
Listing 3 Disposition: violation of inclusion/exclusion criteria 
Listing 4 Disposition: study completion 
Listing 5 Protocol deviations 
Listing 6 Demographic and anthropometric characteristics 
Listing 7 Baseline variables: Surgical lung biopsy (SLB) 
Listing 8 Baseline variables: HRCT scan for patient eligibility confirmation 
Listing 9 Baseline variables: Carbon monoxide diffusing capacity (DLCO) 
Listing 10 Baseline variables: Pre- and post-bronchodilator spirometry parameters 
Listing 11 Baseline variables: Serologic tests 
Listing 12 Baseline variables: GAP assessment 
Listing 13 Review transbronchial lung biopsy/Bronchoalveolar lavage (BAL) 
Listing 14 General medical history 
Listing 15 History of idiopathic pulmonary fibrosis (IPF) 
Listing 16 Prior/concomitant medications 
Listing 17 Prior/concomitant non-drug therapy and procedures 
Listing 18 Spirometry 
Listing 19 6-Minute Walk Test 
Listing 20 Borg scale 
Listing 21 EQ-5D questionnaire 
Listing 22 HRCT scan 
Listing 23 Adverse events 
Listing 24 Exacerbations 
Listing 25 Serious adverse events/Adverse events of special interest 
Listing 26 Study drug administration 
Listing 27 Exposure 
Listing 28 Cases of incorrect administration of study drug / overdose 
Listing 29 Urine pregnancy test 
Listing 30 Hematology 
Listing 31 Blood chemistry 
Listing 32 Vital signs 
Listing 33 ECG 
Listing 34 Physical examinations 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 117 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 1 Disposition: analysis populations 
All Enrolled patients 
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ 
Race 
Date, Time of 
informed 
consent 
signature 
The 
Allocated 
to 
treatment 
set 
Participation 
in the 
rollover 
study  
The 
Treated 
set (TS) 
The Full 
analysis 
set (FAS) 
Complete case  
set (CCS) 
Reason for 
missing 26 week 
FVC data 
Treatment 
until Week 26 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD  
HH:MM 
Yes 
Yes 
Yes 
Yes 
Yes 
 
Yes 
XXXXXXXX/ X/ 
XX/ 
YYYY-MM-DD  
HH:MM 
Yes 
No 
Yes 
No 
No 
Death 
No 
XXXXXXXX/ X/ 
XX/ 
YYYY-MM-DD  
HH:MM 
No 
No 
No 
No 
No 
Discontinuation 
Lung 
transplantation 
No 
No 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 118 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 2 Disposition: patient visits 
All Enrolled patients 
Page Х of Х 
 
Patient ID/ Sex/ 
Age (years)/ 
Race 
Visit 
Visit within visit 
window 
Date / Study day 
Main reason for unscheduled visit 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXXX 
Yes 
YYYY-MM-DD/ XX 
 
 
XXXXXX 
No 
YYYY-MM-DD/ XX 
 
 
XXXXXX 
 
YYYY-MM-DD/ XX 
XXXXXXXXXXX XXXXXXXXXXX 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 119 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 3 Disposition: violation of inclusion/exclusion criteria 
All Enrolled patients 
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ Race 
Category 
Criterion number/Criterion 
Result 
XXXXXXXX/ X/ 
XX/ XXXXX 
Inclusion criteria 
XX/XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
No 
 
Exclusion criteria 
XX/XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
Yes 
 
Exclusion criteria 
XX/XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
Yes 
 
Eligibility 
confirmation 
 
No 
... 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 120 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 4 Disposition: study completion 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ Sex/ Age 
(years)/ Race 
Date of study completion 
or discontinuation/ Study 
day 
End of study status 
Main reason for premature study termination 
XXXXXXXX/ X/ XX/ XXXXX 
YYYY-MM-DD/ XX 
Discontinued 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXX/ X/ XX/ XXXXX 
YYYY-MM-DD/ XX 
Discontinued 
Other: XXXXXXXXXXXXXXXXXXXXX 
XXXXXXXX/ X/ XX/ XXXXX 
YYYY-MM-DD/ XX 
Completed 
 
XXXXXXXX/ X/ XX/ XXXXX 
YYYY-MM-DD/ XX 
Screening failure 
Presence or development of Inclusion/Exclusion criterion 
(-a): XXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 121 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 5 Protocol deviations 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ Sex/ 
Age (years)/ Race 
Date of deviation 
revealed / Study day 
Visit name 
Form name 
Description of deviation 
XXXXXXXX/ X/ XX/ 
XXXXX 
YYYY-MM-DD / XX 
XXXXX 
XXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXX/ X/ XX/ 
XXXXX 
YYYY-MM-DD / XX 
XXXXX 
XXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXX/ X/ XX/ 
XXXXX 
YYYY-MM-DD / XX 
XXXXX 
XXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 122 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 6 Demographics and anthropometric characteristics 
All Patients 
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ Race 
Date of birth 
Age, years 
Sex 
Race 
Ethnicity 
Weight, kg 
Height, cm 
BMI, kg/m2 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
XX 
XXX 
XX.X 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
XX 
XXX 
XX.X 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
XX 
XXX 
XX.X 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 123 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 7 Baseline variables: Surgical lung biopsy (SLB) 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ Sex/ 
Age (years)/ Race 
Date of sample 
collection/ Study 
day 
Assessment of regional specialist: UIP Pattern 
Assessment of central specialist: UIP Pattern 
XXXXXXXX/ X/ XX/ 
XXXXX 
YYYY-MM-DD/ XX 
XXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXX/ X/ XX/ 
XXXXX 
YYYY-MM-DD/ XX 
XXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXX/ X/ XX/ 
XXXXX 
YYYY-MM-DD/ XX 
XXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 124 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 8 Baseline variables: HRCT scan for patient eligibility confirmation 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ Race 
Date of HRCT scan/ 
Study day 
Assessment of regional 
specialist: UIP Pattern 
Assessment of central 
specialist (1): UIP 
Pattern 
Assessment of central 
specialist (2): UIP 
Pattern or Not performed 
Reasons if Not Done 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD/ XX 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD/ XX 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX 
 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD/ XX 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 125 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 9 Baseline variables: Carbon monoxide diffusing capacity (DLCO) 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ Sex/ 
Age (years)/ Race 
Date, Time of 
assessment/ 
Study day 
Date, Time of 
Hb assessment/ 
Study day 
Hb value 
Hb units 
Parameter 
DLCO result, % 
XXXXXXXX/ X/ XX/ 
XXXXX 
YYYY-MM-DD HH:MM/ XX 
 
 
 
Predicted DLCO 
XXXXX 
 
 
YYYY-MM-DD 
HH:MM/ XX  
XX 
XXXXX 
Hb-corrected DLCO 
XXXXX 
XXXXXXXX/ X/ XX/ 
XXXXX 
YYYY-MM-DD HH:MM/ XX 
 
 
 
Predicted DLCO 
XXXXX 
 
 
YYYY-MM-DD 
HH:MM/ XX  
XX 
XXXXX 
Hb-corrected DLCO 
XXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 126 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 10 Baseline variables: Pre- and post-bronchodilator spirometry parameters 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ Race 
Date of 
assessment/ 
Study day 
Time of 
assessment 
Period of 
assessment 
Parameter 
Result 
Units 
Reason if Not Done 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD/ 
XX 
HH:MM 
Before 
bronchodilator 
administration 
FVC (absolute) 
XXX 
mL 
 
 
 
 
 
FVC (relative) 
predicted 
XXX 
% 
 
 
 
 
 
FEV1/FVC 
XX.X 
 
 
 
 
 
 
... 
... 
 
 
 
 
HH:MM 
After 
bronchodilator 
administration 
FVC (absolute) 
XXX 
mL 
 
 
 
 
 
... 
... 
 
 
 
 
 
 
 
 
 
 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD/ 
XX 
HH:MM 
Before 
bronchodilator 
administration 
FVC (absolute) 
Not Done 
 
XXXX XX XXXXXXXX 
 
 
 
 
... 
... 
 
 
 
 
HH:MM 
After 
bronchodilator 
administration 
FVC (absolute) 
XXX 
mL 
 
 
 
 
 
... 
... 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 127 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 11 Baseline variables: Serologic tests 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ Sex/ 
Age (years)/ Race 
Date, Time of 
assessment/ Study 
day 
Lab Test 
Fasting Status 
Result 
Reason if Not Done 
XXXXXXXX/ X/ XX/ 
XXXXX 
YYYY-MM-DD HH:MM/ 
XX 
Rheumatoid factor 
Yes 
XXXXX 
 
 
 
Anticyclic citrullinated 
peptide 
Yes 
XXXXX 
 
 
 
Antinuclear antibody titer 
 
Not Done 
XXXXXXX XXXXXXXXXXXX 
XXXXXXXX/ X/ XX/ 
XXXXX 
YYYY-MM-DD HH:MM/ 
XX 
Rheumatoid factor 
No 
XXXXX 
 
 
 
Anticyclic citrullinated 
peptide 
No 
XXXXX 
 
 
 
Antinuclear antibody titer 
No 
XXXXX 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 128 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 12 Baseline variables: GAP assessment 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ 
Race 
Date of 
assessment/ 
Study day 
FVC, %, 
predicted 
Dlco, %, 
predicted 
Stage/ 
GAP Index 
Mortality 
(1-y) 
Mortality 
(2-y) 
Mortality 
(3-y) 
Reason if Not 
Done 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD/ XX 
XXXXX 
XXXXX 
X/XXXXX 
XXXXX 
XXXXX 
XXXXX 
XXXXXXXXXX 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD/ XX 
XXXXX 
XXXXX 
X/XXXXX 
XXXXX 
XXXXX 
XXXXX 
XXXXXXXXXX 
XXXXXXXX/ X/ 
XX/ XXXXX 
YYYY-MM-DD/ XX 
XXXXX 
XXXXX 
X/XXXXX 
XXXXX 
XXXXX 
XXXXX 
XXXXXXXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 129 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 13 Review transbronchial lung biopsy/ Bronchoalveolar lavage (BAL) 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ Sex/ 
Age (years)/ 
Race 
Visit 
Medical procedure 
Date of sample 
collection/ Study 
day 
Are there 
features 
supporting an 
alternative 
diagnosis? 
Comments if Yes 
Result 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXXXX 
Transbronchial biopsy 
YYYY-MM-DD/ XX 
XXXXX 
XXXXXXXXXXXXXXXXXXX
XXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
Bronchoalveolar 
lavage (BAL) 
YYYY-MM-DD/ XX 
XXXXX 
XXXXXXXXXXXXXXXXXXX
XXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXXXX 
Transbronchial biopsy 
YYYY-MM-DD/ XX 
XXXXX 
XXXXXXXXXXXXXXXXXXX
XXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
Bronchoalveolar 
lavage (BAL) 
YYYY-MM-DD/ XX 
XXXXX 
XXXXXXXXXXXXXXXXXXX
XXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXXXX 
Transbronchial biopsy 
YYYY-MM-DD/ XX 
XXXXX 
XXXXXXXXXXXXXXXXXXX
XXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
Bronchoalveolar 
lavage (BAL) 
YYYY-MM-DD/ XX 
XXXXX 
XXXXXXXXXXXXXXXXXXX
XXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 130 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 14 General medical history 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ 
Race 
System Organ Class/ 
Preferred Term/ 
Lowest Level Term/ 
Investigator Description 
Start Date / 
Study day 
End date /  
Study day 
Ongoing or 
Resolved 
Comments 
XXXXXXXX/ 
X/ XX/ 
XXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
YYYY-MM-DD/ XX 
YYYY-MM-DD/ XX 
Resolved 
XXXXXXXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Terms are coded by MedDRA version XX.X. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
< Sort by start date, end date, SOC, PT, LLT> 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 131 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 15 History of idiopathic pulmonary fibrosis (IPF) 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ Race 
Diagnosis 
Duration of clinical 
symptoms consistent 
with IPF (in months) 
Clinically significant 
environmental exposure 
known to cause 
pulmonary fibrosis 
Known explanation for 
interstitial lung 
disease 
Cigarette smoking 
within 28 days before 
the treatment start 
XXXXXXXX/ X/ 
XX/ XXXXX 
Idiophatic Pulmonary Fibrosis 
XX 
Yes 
No 
Yes 
XXXXXXXX/ X/ 
XX/ XXXXX 
Idiophatic Pulmonary Fibrosis 
XX 
Yes 
No 
No 
XXXXXXXX/ X/ 
XX/ XXXXX 
Idiophatic Pulmonary Fibrosis 
XX 
No 
Yes 
Yes 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 132 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 16 Prior/concomitant medications 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ 
Race 
1st Lvl, Anatomical main group/ 
2nd Lvl, Therapeutic subgroup/ 
3rd Lvl, Pharmacological subgroup/ 
4th Lvl, Chemical subgroup/ 
5th Lvl, Chemical substance/ 
Medication 
Prior/ 
Concomitant 
Start date, Time/  
Study day/ 
Stop date, Time/ 
Study day 
Dose (Units)/ 
Frequency/ 
Route 
Indication for use 
Comments 
XXXXXXXX/ X/ 
XX/ XXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
P 
YYYY-MM-DD HH:MM/ XX/  
YYYY-MM-DD HH:MM/ XX 
XXXXX (XXXXX)/ 
XXXXX/ 
XXXXX 
XXXXXXXXXXX 
XXXXXXXXXX 
 
 
 
 
 
 
 
XXXXXXXX/ X/ 
XX/ XXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
C 
YYYY-MM-DD HH:MM/ XX/  
Ongoing 
XXXXX (XXXXX)/ 
XXXXX/ 
XXXXX 
XXXXXXXXXXX 
XXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P=Prior, C=Concomitant. 
Medications are coded using WHODD version XX.X. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 133 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 17 Prior/concomitant non-drug therapy and procedures 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ Sex/ 
Age (years)/ 
Race 
System Organ Class/ 
Preferred Term/ 
Lowest Level Term/ 
Treatment 
Prior/ 
Concomitant 
Start date, Time/  
Study day/ 
Stop date, Time/ 
Study day 
Indication 
Comments 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
P 
YYYY-MM-DD HH:MM/ XX/  
YYYY-MM-DD HH:MM/ XX 
XXXXXXXXXXXXXXXX 
XXXXXXXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non-drug therapy and procedures are coded using MedDRA version XX.X. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 134 out of 151 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 18 Spirometry 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ Race 
Visit 
Date, Time of 
assessment/ Study 
day 
Parameter 
Result 
Units 
Change from 
baseline/Base
line 
Reason if 
Not Done 
XXXXXXXX/ X/ 
XX/ XXXXX 
Screening/Retrospe
ctive values 
YYYY-MM-DD/ XX  
FVC 
(absolute) 
XXXXX 
mL 
 
 
 
 
 
FVC 
(relative) 
predicted 
XXXXX 
% 
 
 
 
 
YYYY-MM-DD/ XX 
FVC 
(absolute) 
XXXXX 
mL 
 
 
 
 
 
FVC 
(relative) 
predicted 
XXXXX 
% 
 
 
 
 
... 
... 
 
 
 
 
 
Screening 
YYYY-MM-DD/ XX 
FVC 
(absolute) 
XXXXX 
mL 
 
 
 
 
 
FVC 
(relative) 
predicted 
XXXXX 
% 
 
 
 
Day 1 
YYYY-MM-DD HH:MM/ 
XX 
FVC 
(absolute) 
XXXXX 
mL 
 
 
 
 
 
FVC 
(relative) 
predicted 
XXXXX 
% 
 
 
 
Week 12 
 
FVC 
(absolute) 
Not 
Done 
 
 
XXXXXXXXX 
 
 
YYYY-MM-DD HH:MM/ 
XX 
FVC 
(relative) 
predicted 
XXXXX 
% 
XXXXX/XXXXX 
 
 
Week 26 
YYYY-MM-DD/ XX 
FVC 
(absolute) 
XXXXX 
mL 
XXXXX/XXXXX 
 
 
 
 
FVC 
(relative) 
predicted 
XXXXX 
% 
XXXXX/XXXXX 
 
 
... 
... 
... 
... 
... 
... 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 135 out of 151 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
<For screening list values before bronchodilator administration only.> 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 136 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 19 6-Minute Walk Test 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ Race 
Visit 
Date of assessment / 
Study day 
Result, m 
Change from 
Baseline/Baseline 
Reason if Not Done 
XXXXXXXX/ X/ 
XX/ XXXXX 
XXXXX 
YYYY-MM-DD / XX 
XXXXX 
XXXXX/XXXXX 
 
 
XXXXX 
YYYY-MM-DD / XX 
XXXXX 
XXXXX/XXXXX 
 
 
XXXXX 
YYYY-MM-DD / XX 
XXXXX 
XXXXX/XXXXX 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 137 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 20 Borg scale 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ Race 
Visit 
Date of 
assessment/ 
Study day 
Timepoint 
Time of 
assessment 
Result 
Change from Pre-
test Baseline/  
Pre-test 
Baseline 
Change from 
Baseline/ 
Baseline 
Reason if Not 
Done 
XXXXXXXX/ X/ 
XX/ XXXXX 
XXXXX
XXX 
YYYY-MM-DD/ 
XX 
Before the 6-
minute exercise 
HH:MM 
XXXXX 
 
 
 
 
 
 
After the 6-
minute exercise 
HH:MM 
XXXXX 
XXXXX/XXXXX 
 
 
 
XXXXX
XX 
YYYY-MM-DD/ 
XX 
Before the 6-
minute exercise 
HH:MM 
XXXXX 
 
XXXXX/XXXXX 
 
 
 
 
After the 6-
minute exercise 
HH:MM 
XXXXX 
XXXXX/XXXXX 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 138 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 21 EQ-5D-5L questionnaire 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ Sex/ 
Age (years)/ Race 
Visit 
Date, Time of 
assessment/  
Study day 
Mobility/ 
Self-care/ 
Usual activities/ 
Pain/Discomfort/ 
Anxiety/Depression 
Your own health 
state today 
(VAS)/ 
Change from 
Baseline/ 
Baseline 
 
Index score/  
Change from 
Baseline/ 
Baseline 
Reason if Not 
Done 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXX 
YYYY-MM-DD 
HH:MM/ XX 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXX/XXXX/XXXX XXXXX/XXXXX/XXXX XXXXXXXXXXXXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 139 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 22 HRCT scan 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ Sex/ 
Age (years)/ Race 
Visit 
Date of HRCT scan / 
Study day 
Parameter 
Result 
Change from 
Baseline/Baseline 
Reason if Not Done 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXX 
YYYY-MM-DD / XX 
HRCT fibrosis 
score 
XXXXX 
XXXXX/XXXXX 
 
 
 
 
Ground-glass 
opacity 
XXXXX 
XXXXX/XXXXX 
 
 
XXXXX 
YYYY-MM-DD / XX 
HRCT fibrosis 
score 
XXXXX 
XXXXX/XXXXX 
 
 
 
 
Ground-glass 
opacity 
Not Done 
 
XXXXXXXXXXXXXXXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 140 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 23 Adverse events 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ 
Race 
AE No/ 
TEAE 
[1]/ 
SAE 
[2] 
 
System Organ Class/ 
Preferred Term/ 
Lowest Level Term/ 
Reported Term 
Start Date, Time/  
Study Day/  
End Date, Time/  
Study Day/ 
Study period 
 
Intermittent or 
persistent/ 
Severity/ 
Relationship to IMP/ 
Outcome 
Action taken with IMP/ 
Concomitant medications?/ AESI?/ 
Exacerbation of IPF?/ 
Causality to concomitant medications 
taken  
XXXXXXXX/ 
X/ XX/ 
XXXXX 
XX/ 
XXX/ 
XXX 
(X,X) 
 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
YYYY-MM-DD HH:MM/ XXX/ 
YYYY-MM-DD HH:MM/ XXX/ 
XXXXXXXXXXXXXXXXX 
 
XXXXXXXXXX/ 
XXXXXXXXXX/ 
XXXXXXXXXX/ 
XXXXXXXXXX 
XXXXXXXXXX/ 
XXX/ XXX/ XXX/ 
XXXXXXXX, XXXXXXXXXXX, XXXXXXXXXX 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = Adverse Event, SAE = Serious Adverse Event, TEAE = Treatment-Emergent Adverse Event. 
[1] TEAE is any reported adverse event that starts after initiation of the study therapy. 
[2] Seriousness criteria: 1 = <<fatal>>, 2 = <<life-threatening>>, 3 = <<requires or prolongs in-patient hospitalization>>, 4 = <<results in persistent 
or significant incapacity/disability>>, 5 = <<congenital abnormality or birth defect>>, 6 = <<other significant medical event>>. 
AEs are coded using MedDRA version XX.X. 
 
Path to the program code, DDMMMYYYY, HH:MM  
 
 
 
 
 
 
 
 
Date of data extraction: DDMMMYYYY 
 
 
 
 
 
 
 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 141 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 24 Exacerbations 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years)/ Race 
AE No/ 
TEAE [1]/ 
SAE [2]/ 
Study 
period 
System Organ Class/ 
Preferred Term/ 
Lowest Level Term/ 
Reported Term 
Start Date, Time/  
Study Day/  
End Date, Time/  
Study Day/ 
 
Intermittent or persistent/ 
Severity/ 
Relationship to Study 
Treatment/Outcome 
Action taken with IMP/ 
Concomitant medications?/ 
AESI?/ 
Exacerbation of IPF?/ 
Causality to concomitant 
medications taken 
XXXXXXXX/ X/ 
XX/ XXXXX 
XX/ 
XXX/ 
XXX (X)/ 
XXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX/ 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
YYYY-MM-DD HH:MM/XXX/ 
YYYY-MM-DD HH:MM/XXX 
XXXXXXXXXX/XXXXXXXXXX/ 
XXXXXXXXXX/XXXXXXXXXX 
XXXXXXXXXX/ 
XXX/ XXX/ XXX/ 
XXXXXXXX, XXXXXXXXXXX, 
XXXXXXXXXX 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = Adverse Event, SAE = Serious Adverse Event, TEAE = Treatment-Emergent Adverse Event. 
[1] TEAE is any reported adverse event that starts after initiation of the study therapy. 
[2] Seriousness criteria: 1 = <<fatal>>, 2 = <<life-threatening>>, 3 = <<requires or prolongs in-patient hospitalization>>, 4 = <<results in persistent 
or significant incapacity/disability>>, 5 = <<congenital abnormality or birth defect>>, 6 = <<other significant medical event>>. 
Exacerbations are coded using MedDRA version XX.X. 
 
Path to the program code, DDMMMYYYY, HH:MM  
 
 
 
 
 
 
 
 
Date of data extraction: DDMMMYYYY 
 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 142 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 25 Serious adverse events/Adverse events of special interest 
All Enrolled patients  
Page Х of Х 
 
Patient 
ID/ Sex/ 
Age 
(years)/ 
Race 
SAE 
No 
 
Reported Term/ 
Date of Initial 
SAE/AESI Report 
Release/ Study Day 
Report 
type 
 
Date event became 
serious/ Study Day/  
End date of 
SAE/AESI/ Study Day/ 
Last dose prior to 
SAE/AESI/ Study Day/ 
 
 
Action taken due to 
SAE/AESI/ 
Suspected causes 
Description for Initial Report/ 
Description for Follow-up Report 
XXXXXXXX/ 
X/ XX/ 
XXXXX 
XX 
 
XXXXXXXXXXX 
XXXXXXXXXXXXX 
XXXXXXXXXX/ 
YYYY-MM-DD/XXX 
 
 
Initial 
 
YYYY-MM-DD/XXX/ 
YYYY-MM-DD/XXX/ 
YYYY-MM-DD/XXX  
XXXXXXXXXX, 
XXXXXXXXXX/ 
XXXXXXXXXX, 
XXXXXXXXXX 
XXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX 
XXXX/ 
XXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXX 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SAE = Serious Adverse Event, AESI = AE of Special Interest. 
Terms are coded using MedDRA version XX.X. 
 
Path to the program code, DDMMMYYYY, HH:MM  
 
 
 
 
 
 
 
 
Date of data extraction: DDMMMYYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 143 out of 151 
 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 26 Study drug administration 
Treated set (TS) 
Page Х of Х 
 
Patient ID/ Sex/ 
Age (years)/ Race 
Study period 
Trade name 
Single dose 
(capsules)/ 
Frequency 
Start Date/ 
Study day /  
End Date / Study 
day or Ongoing 
Reason for dose 
change or stop 
Comments 
XXXXXXXX/ X/ XX/ 
XXXXX 
Treatment 
period 
Pirfenidone 
XXXXX/ 
XXXXX 
YYYY-MM-DD/ XX / 
YYYY-MM-DD/ XX 
XXXXX 
XXXXXXXXXXXXXXX 
 
Treatment 
period 
Pirfenidone 
XXXXX/ 
XXXXX 
YYYY-MM-DD/ XX / 
YYYY-MM-DD/ XX 
XXXXX 
XXXXXXXXXXXXXXX 
 
Rollover study 
XXXXXXXXXX 
XXXXX/ 
XXXXX 
YYYY-MM-DD/ XX / 
YYYY-MM-DD/ XX 
XXXXX 
XXXXXXXXXXXXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 144 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 27 Exposure 
Treated set (TS) 
Page Х of Х 
 
Patient ID/ Sex/ Age 
(years)/ Race 
Study period 
Duration of exposure, weeks 
Number of capsules taken  
XXXXXXXX/ X/ XX/ 
XXXXX 
Treatment period 
XX.X 
XXX 
 
Rollover study 
XX.X 
XXX 
 
Total 
XX.X 
XXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 145 out of 151 
 
 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 28 Cases of incorrect administration of study drug / overdose 
Treated set (TS) 
Page Х of Х 
 
Patient ID/ Sex/ Age 
(years)/ Race 
Study period 
Date, Time/ Study day 
Dose (capsules) 
Category 
Comments/Description 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXX 
YYYY-MM-DD HH:MM/ XX 
XXXXX 
Incorrect 
administration of 
study drug 
XXXXXXXXXXXXXXX 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXX 
YYYY-MM-DD HH:MM/ XX 
XXXXX 
Incorrect 
administration of 
study drug 
XXXXXXXXXXXXXXX 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXX 
YYYY-MM-DD HH:MM/ XX 
XXXXX 
Overdose 
XXXXXXXXXXXXXXX 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 146 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 29 Urine pregnancy test 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ Sex/ 
Age (years)/ Race 
Visit 
Date, Time of test 
performed/ Study day 
Result 
Reasons if Not Done 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXX 
YYYY-MM-DD HH:MM/ XX 
XXXXX 
 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXX 
YYYY-MM-DD HH:MM/ XX 
Not Done 
XXXXXX XXXXXXXXX XXXX 
XXXXXXXX/ X/ XX/ 
XXXXX 
XXXXX 
YYYY-MM-DD HH:MM/ XX 
XXXXX 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 147 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 30 Hematology 
All Enrolled patients  
Page Х of Х 
 
Patient 
ID/ Sex/ 
Age 
(years) / 
Race 
Visit 
Date, 
Time of 
specimen 
collected
/ Study 
day 
Fasting 
Status 
Parameter, 
units 
Result 
Units 
Change from 
Baseline/ 
Baseline 
Reference 
Limits 
Lower/Upper 
Out of 
Range 
(L/N/H) 
CS (Yes/No) 
Reason 
if Not 
Done 
XXXXXXXX/ 
X/ XX/ 
XXXXX 
XXXXX 
YYYY-MM-
DD HH:MM/ 
XX 
Yes 
XXXXX 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX/XXXXX 
X 
XXXXX 
 
 
 
 
 
XXXXX 
Not Done 
 
 
 
 
 
XXXXXXXX
XXXXX 
 
 
 
 
XXXXX 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX/XXXXX 
X 
XXXXX 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
XXXXX 
YYYY-MM-
DD HH:MM/ 
XX 
Yes 
XXXXX 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX/XXXXX 
X 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
L = below lower reference limit. H = above upper reference limit. N = Normal range. CS = Clinically Significant. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 148 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 31 Blood chemistry 
All Enrolled patients  
Page Х of Х 
 
Patient 
ID/ Sex/ 
Age 
(years) / 
Race 
Visit 
Date, 
Time of 
specimen 
collected
/ Study 
day 
Fasting 
Status 
Parameter, 
units 
Result 
Units 
Change from 
Baseline/ 
Baseline 
Reference 
Limits 
Lower/Upper 
Out of 
Range 
(L/N/H) 
CS (Yes/No) 
Reason 
if Not 
Done 
XXXXXXXX/ 
X/ XX/ 
XXXXX 
XXXXX 
YYYY-MM-
DD HH:MM/ 
XX 
Yes 
XXXXX 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX/XXXXX 
X 
XXXXX 
 
 
 
 
 
XXXXX 
Not Done 
 
 
 
 
 
XXXXXXXX
XXXXX 
 
 
 
 
XXXXX 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX/XXXXX 
X 
XXXXX 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
XXXXX 
YYYY-MM-
DD HH:MM/ 
XX 
Yes 
XXXXX 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX/XXXXX 
X 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
L = below lower reference limit. H = above upper reference limit. N = Normal range. CS = Clinically Significant. 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 149 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 32 Vital signs 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years) / 
Race 
Visit 
Date, Time 
of 
assessment/ 
Study day 
Parameter 
Result 
Units 
Change from 
Baseline/ 
Baseline 
Out of 
Range 
(Yes/No) 
Clinically 
Significant 
(Yes/No) 
Reason if Not 
Done 
XXXXXXXXX/ 
X/ XX/ XXXXX 
XXXXX 
YYYY-MM-DD 
HH:MM/ XX 
Systolic Blood 
Pressure 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
 
Diastolic Blood 
Pressure 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
 
Pulse rate 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
 
Respiratory rate 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
 
Axillary 
temperature 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
 
Weight 
BMI 
XXXXX 
XXXXX 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX/XXXXX 
 
 
 
 
 
 
Height 
XXXXX 
XXXXX 
 
 
 
 
 
XXXXX 
YYYY-MM-DD 
HH:MM/ XX 
Systolic Blood 
Pressure 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
 
Diastolic Blood 
Pressure 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
 
Pulse rate 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
 
Respiratory rate 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
 
Axillary 
temperature 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
 
Weight 
BMI 
XXXXX 
XXXXX 
XXXXX/XXXXX 
 
 
 
 
 
 
Height 
XXXXX 
XXXXX 
 
 
 
XXXXXXXXXXXXXXX 
 
... 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 150 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 33 ECG 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years) / 
Race 
Visit 
Date, Time 
of 
assessment / 
Study day 
Parameter 
Result 
Units 
Change from 
Baseline/ 
Baseline 
Out of 
Range 
(Yes/No) 
Clinically 
Significant 
(Yes/No) 
Reason / 
Comments if 
Not Done / 
Abnormal 
XXXXXXXXX/ X/ 
XX/ XXXXX 
XXXXX 
YYYY-MM-DD 
HH:MM/ XX 
Heart rate 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
QT interval 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
QTC-F interval 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
General assessment 
XXXXX 
 
 
 
XXXXX 
 
 
XXXXX 
YYYY-MM-DD 
HH:MM/ XX 
Heart rate 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
QT interval 
Not Done 
 
 
 
 
XXXXXXX XXXX 
 
 
QTC-F interval 
XXXXX 
XXXXX 
XXXXX/XXXXX 
XXXXX 
XXXXX 
 
 
 
General assessment 
XXXXX 
 
 
 
XXXXX 
 
 
... 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY 
 
 
 


 
SF_STAT001_ver 2_Eng 
Approval Date 19 July 2017 
ML39355_STATISTICAL ANALYSIS PLAN_Final 2.0_17 June 2020 
 
 
CONFIDENTIAL AND PROPRIETARY 
Data MATRIX Ltd. 
Page 151 out of 151 
 
F. Hoffmann-La Roche Ltd 
ML39355 
Listing 34 Physical examinations 
All Enrolled patients  
Page Х of Х 
 
Patient ID/ 
Sex/ Age 
(years) / Race 
Visit 
Date, Time 
of 
assessment / 
Study day 
Body system/Site 
Result 
Clinically 
Significant 
(Yes/No) 
Reason/ Comments if Not Done/ 
Abnormal 
XXXXXXXXX/ X/ 
XX/ XXXXX 
XXXXX 
YYYY-MM-DD 
HH:MM/ XX 
Head 
XXXXX 
XXXXX 
 
 
 
Eyes 
XXXXX 
XXXXX 
 
 
 
Ears, nose and throat 
XXXXX 
XXXXX 
 
 
 
Cardiovascular system 
Not Done 
 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
Dermatological system 
XXXXX 
XXXXX 
 
 
 
Musculoskeletal system 
XXXXX 
XXXXX 
 
 
 
... 
XXXXX 
XXXXX 
 
XXXXXXXXX/ X/ 
XX/ XXXXX 
XXXXX 
YYYY-MM-DD 
HH:MM/ XX 
Head 
XXXXX 
XXXXX 
 
 
 
Eyes 
XXXXX 
XXXXX 
 
 
 
Ears, nose and throat 
XXXXX 
XXXXX 
 
 
 
Cardiovascular system 
XXXXX 
XXXXX 
 
 
 
Dermatological system 
XXXXX 
XXXXX 
 
 
 
Musculoskeletal system 
XXXXX 
XXXXX 
 
 
 
... 
XXXXX 
XXXXX 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Path to the program code, date and time of output 
 
 
 
 
 
 
 
 
 
 
Data extracted: DD.MM.YYYY