Conditions: Disorder Related to Lung Transplantation Chronic Lung Allograft Dysfunction
Keywords: CLAD Chronic Rejection Lung Transplant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
Greater than 50% of lung transplant recipients show signs of chronic lung allograft dysfunction (CLAD) by 5 years post-transplantation.Therapies to prevent or slow CLAD are lacking. Anti-fibrotic therapies may offer an avenue to prevent progression of CLAD and prolong allograft survival. This study investigates if Pirfenidone therapy will stabilize lung function decline and slow progression of Functional small airways disease (fSAD) in lung transplant recipients with CLAD.

Detailed description:
The study aimed to enroll lung transplant recipients with an established diagnosis of CLAD. The patients were randomized to receive an anti-fibrotic drug Pirfenidone or Placebo pills for 6 month period. High-resolution CT scan of the chest was utilized to measure the primary endpoint of change in functional small airway disease (fSAD). Pulmonary function testing and spirometry were utilized to measure the secondary endpoint of change in FEV1 and FVC.

Arms:
arm 1: Method of Administration: Oral (capsule)

Dosing:

* Days 1 through 7, 267 mg three times daily;
* Days 8 through 14, 534 mg three times daily;
* Days 15 through end of treatment (24 weeks), 801 mg three times daily arm 2: Method of Administration: Oral (capsule)

Dosing:

* Days 1 through 7, 267 mg three times daily;
* Days 8 through 14, 534 mg three times daily;
* Days 15 through end of treatment (24 weeks), 801 mg three times daily

Interventions: intervention 1: Pirfenidone Capsule intervention 2: Placebo Capsule
Intervention descriptions: intervention 1: Dosing:

Days 1 through 7, 267 mg three times daily; Days 8 through 14, 534 mg three times daily; Days 15 through end of treatment (24 weeks), 801 mg three times daily duration: 24 weeks intervention 2: Dosing:

* Days 1 through 7, 267 mg three times daily;
* Days 8 through 14, 534 mg three times daily;
* Days 15 through end of treatment (24 weeks), 801 mg three times daily duration: 24 weeks

Protocol document:
Prot_SAP_000.pdf: 
1 
 
 
Title:  A phase two randomized, double-blinded, placebo-controlled study combining 
physiological, radiographic, and biological biomarkers to study the anti-fibrotic effect of 
pirfenidone in CLAD post lung-transplantation 
 
PI:  Vibha N. Lama, M.D., M.S. 
 
ID:  HUM00131610 
 
NCT:  NCT03473340    
 
IRB Approval Date:  5/11/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
CLINICAL TRIAL PROTOCOL 
 
 
Title: 
A phase two randomized, double-blinded, placebo-controlled 
study combining physiological, radiographic, and biological 
biomarkers to study the anti-fibrotic effect of pirfenidone in 
CLAD post lung-transplantation 
Brief Title: 
Role of pirfenidone in treatment of lung transplant rejection 
Clinical Phase: 
II 
Coordinating Investigator 
Vibha N. Lama, M.D., M.S. 
Division of Pulmonary and Critical Care Medicine, Department 
of Internal Medicine 
University of Michigan Health System 
1150 W. Medical Center Drive 
6301 MSRB III 
Ann Arbor, MI, 48109-0644 
Status: 
Final 
Version and Date: 
Version: 2.0 
Date: January 31, 2019 
 


3 
 
CLINICAL TRIAL PROTOCOL SYNOPSIS 
Name of company 
Genentech 
Name of finished product: pirfenidone 
Name of active ingredient pirfenidone 
Protocol date: 
January 31, 2019 
Title of Trial: 
A phase two randomized, double-blinded, placebo-controlled 
study combining physiological, radiographic, and biological 
biomarkers to study the anti-fibrotic effect of pirfenidone in 
CLAD post lung-transplantation 
Coordinating investigator: Vibha N. Lama, M.D., M.S. 
Trial site: 
University of Michigan  
Clinical phase: 
Phase II 
Objective: 
To evaluate the efficacy and safety of pirfenidone 801 mg TID  
over 24 weeks in lung transplant recipients with chronic lung 
allograft dysfunction 
Methodology: 
Single centre, placebo-controlled, randomized, double-blinded, 
clinical trial comparing safety and efficacy of Pirfenidone 801 
mg TID to placebo over 24 weeks in patients with chronic lung 
allograft dysfunction (CLAD) 
Number of patients 
60 (30 per group) 
Treatments: 
pirfenidone: 2403 mg daily 
placebo: 2403 mg daily 
Diagnosis: 
Spirometric and clinical diagnosis of CLAD 
Main inclusion criteria: 
- 
Patients > 6 months after lung transplantation with 
documented baseline values of FEV1 and FVC (mean of 
two highest value measured 3 weeks apart) 
- 
Baseline FEV1 and FVC > 50% predicted (to assure viable 
graft) 
- 
Diagnosis of CLAD (two consecutive spirometric values with 
FEV1 alone or both FEV1 and FVC < 80% of baseline)  
Endpoints/Outcomes: 
Primary: 
- 
Change in functional small airways disease (fSAD) as 
measured by parametric response mapping (PRM) at 24 
weeks by treatment arm 
Secondary: 
- 
Change in FEV1 over 24 weeks by treatment arm 
- 
Change in FVC over 24 weeks by treatment arm 
- 
Number of subjects with treatment intolerance 
- 
Number of subjects with adverse events related to 
treatment with Pirfenidone 
Exploratory: 
- 
Change in bronchoalveolar lavage (BAL) mesenchymal 
colony forming units (CFUs) by treatment arm 
- 
Change in fibrotic phenotype of BAL mesenchymal cells 
(expression of collagen, alpha smooth muscle actin, beta-
catenin, fibronectin) by treatment arm 
Safety criteria: 
- 
Vital signs, physical examination 
- 
Clinical laboratory tests (hepatic function tests, creatinine) 
- 
Reporting of adverse events 


4 
 
 
 
Statistical Methods: 
We will describe the distribution of fSAD change within and 
between treatment groups (n=30 per group) over a 6-month 
period. Preliminary data suggests that without treatment, fSAD 
increases 9% on average over a 6-month time period with SD 
of 9%.  If pirfenidone halves this increase over 6 months, we 
would have a confidence interval for the treatment effect of 
4.5+/-4.64%.  Power to detect 6-month treatment differences is 
sensitive to assumptions of the standard deviation above and 
the ability of pirfenidone to reduce 6-month fSAD progression; a 
power analysis table is given below for various effect sizes and 
standard deviations that might be seen in the trial based on a 
sample size of 60 (30 per group). 
 
% Increase in FSAD for Pirfenidone 
Group (vs 9% FSAD increase in 
Placebo Group) 
Std Dev 
0% 
2% 
4.5% 
5 
>99% 
>99% 
93% 
7 
>99% 
97% 
69% 
9 
97% 
84% 
48% 
We will similarly summarize changes in spirometric parameters 
and MSC CFU and phenotype over time between and within 
groups.   
We do not anticipate any significant drop out because of the 
short duration of the study and this specific patient population 
who receive their clinical care at a specialized lung transplant 
center with no loss to follow up.  
 
 


5 
 
 
TABLE OF CONTENTS 
 
 
Title Page 
1 
Clinical Trial Protocol Synopsis 
2 
Table Of Contents 
4 
Abbreviations 
5 
1. Specific Aims 
6 
2. Background/Rationale/Preliminary Studies 
7 
3. Investigator’s Experience In Subject Area 
9 
4. Experimental Design 
10 
4.1 Endpoints 
10 
4.2 Study Design 
10 
4.3   Inclusion Criteria 
10 
4.4   Exclusion Criteria 
10 
5. Study Visits 
11 
5.1 Screening 
11 
5.2   Baseline 
12  
5.3   Visits 2, 3, 5, 6 
12 
5.4   Visit 4 
12 
5.5   Visit 7 
 
12 
5.6   Visit 8 
13 
5.7   Early Discontinuation 
13 
5.8  Randomization 
13 
Table 1. Schedule Of Assessments 
14 
6. Recruitment 
15 
7. Study Timeline 
16 
8. Drug Dosage & Administration 
17 
9. Drug Storage & Handling 
19 
10. Data Analysis 
19 
10.1 Overview 
19 
10.2 Sample Size Justification 
19 
10.3 Primary Endpoint Analysis 
20 
11. Safety 
21 
11.1  Assessment Of Safety 
21 
11.2  Methods And Timing For Assessing And Recording Saftey Variables 
 
22 
11.3 Procedures For Eliciting, Recording And Reporting Adverse Events 
 
23 
11.4 Data Safety Officer 
29 
12. Study Closeout 
29 
13. References 
30 
 
 
 


6 
 
 
DEFINITIONS AND ABBREVIATIONS 
 
AE 
 
Adverse event 
ALT  
Alanine aminotransferase  
AP 
 
Alkaline phosphatase 
AR 
 
Acute rejection 
ATG  
Antithymocyte Globulin 
AST  
Aspartate aminotransferase 
BAL  
Bronchoalveolar lavage 
BOS  
Bronchiolitis obliterans syndrome 
CFU  
Colony forming units 
CLAD 
Chronic lung allograft dysfunction 
COPD 
Chronic obstructive pulmonary disease 
DSMB 
Data Safety Monitoring Board 
ECP  
Extracorporeal photopheresis 
EKG  
Electrocardiogram 
EOS  
End of study 
EOT  
End of treatment 
FEV1  
Forced expiratory volume in 1 second 
fSAD   
Functional small airways disease 
FVC  
Forced vital capacity 
HRCT 
High resolution computed tomography 
IMP  
Investigational Medicinal Product 
IPF  
Idiopathic pulmonary fibrosis 
IRB  
Institutional review board 
LFT  
Liver function test 
MSC  
Mesenchymal stromal cells 
OTIS  
Organ Transplant Information System 
NIH  
National Institutes of Health 
PFT  
Pulmonary Function Tests 
PI 
 
Principal investigator 
PRM  
Parametric response mapping 
RAS  
Restrictive allograft syndrome 
ULN  
Upper limit of normal 
UM  
University of Michigan 
 
 


7 
 
1. SPECIFIC AIMS 
 
Aim 1. 
To determine if pirfenidone compared to placebo will stabilize progression of 
functional small airways disease (fSAD) as measured by parametric response 
mapping (PRM), a novel CT-based biomarker. 
 
Aim 2. 
To determine if pirfenidone therapy will stabilize pulmonary function as measured by 
FEV1 and FVC in lung transplant recipients with chronic lung allograft dysfunction 
(CLAD). 
 
Aim 3.  
To investigate if pirfenidone therapy affects the fibrotic phenotype of mesenchymal 
cells collected from bronchoalveolar lavage (BAL). 
  
 
 
 
 
 
 
 
Decline in 
FEV1
Physiological 
Marker
Change in 
PRM fSAD
Radiographic
Marker
Mesenchymal
stromal cell 
phenotype
Biological
Marker
Targeting fibroproliferation in lung allograft


8 
 
2. BACKGROUND/RATIONALE/PRELIMINARY STUDIES 
 
Our principle hypothesis is that pirfenidone therapy will stabilize lung function decline and slow 
progression of fSAD in lung transplant recipients with CLAD. 
 
Greater than 50% of lung transplant recipients show signs of CLAD by 5 years post-
transplantation (1). This process arises from development of graft fibrosis in a peri-bronchial 
(bronchiolitis obliterans or BO), peri-vascular, or fulminant interstitial and airway luminal fibrosis 
distribution (2, 3). Therapies to prevent or slow CLAD are lacking.  Anti-fibrotic therapies may 
offer an avenue to prevent progression of CLAD and prolong allograft survival.  
 
Pirfenidone, an oral anti-fibrotic agent, was approved for treatment of idiopathic pulmonary fibrosis 
(IPF) in 2014.  In large multi-center, international clinical trials, pirfenidone has been shown to 
reduce the rate of FVC decline in patients with IPF with a favorable safety and tolerability profile 
(4, 5).  
 
Small airways, the predominant histologic target of fibrotic remodeling in a chronically rejecting 
lung allograft, have been termed the “silent zone” of the lung secondary to difficulty in evaluating 
this disease process by pathology or imaging (6). While high resolution CT (HRCT) scans are 
routinely obtained at CLAD onset, HRCT findings in CLAD lack specific diagnostic features, and 
small airways cannot be visualized or evaluated by standard methods.  
 
A novel imaging technology to evaluate functional small airways disease (fSAD) has been 
developed and validated at the University of Michigan.  This technology, termed parametric 
response mapping (PRM), utilizes voxel by voxel comparison of inspiratory and expiratory HRCT 
images through co-registration to provide quantitative measures of fSAD.  This tool has been 
utilized in patients with a variety of lung diseases including patients with chronic obstructive 
pulmonary disease (COPD) and lung transplant recipients (7-9).  Higher levels of fSAD in lung 
transplant recipients with CLAD has been associated with decreased survival, and fSAD values 
have been shown to increase over time compared to transplant patients without chronic rejection 
(8, 9).  We propose to utilize this novel imaging biomarker to track the change in fSAD, as it relates 
to change in traditional measures of FEV1 or FVC, in patients with CLAD enrolled in this clinical 
trial.  We have significant experience in longitudinal monitoring of lung function and have been 
pioneers in describing the natural history of spirometric decline after CLAD onset (10). Imbio 
Platform systems, a commercial company with quantitative image biomarker algorithms, will be 
utilized in this study. 
 
Furthermore, this study will employ a novel biological biomarker of fibroproliferation, 
mesenchymal stromal cells (MSCs), in assessing the effect of pirfenidone on CLAD.  Use of this 
biomarker is based on 10 years of work in our lab demonstrating that MSCs can be isolated from 
BAL of lung transplant recipients and are biomarkers of BOS (11, 12).  The number of MSCs can 
be quantitated by a colony forming assay and now as a nested PCR based mRNA measure of 
unique lung-MSC transcription factors Foxf1 (11).  The third aim of this study will investigate the 
effect of pirfenidone on MSC number and phenotype. This will be the first study analyzing novel 
imaging and MSC biologic markers of fibroproliferation following administration of a therapeutic 
agent for CLAD.  
 
 


9 
 
Schematic of Study Design 
 
 
Obtain informed consent. Screen potential subjects by inclusion and 
exclusion criteria; obtain medical history; HCRT, BAL (optional), vital signs, 
EKG, spirometry, pregnancy test (if applicable), concomitant medications, 
Adverse events from time of signing consent. 
Randomize 
Arm 1 
Pirfenidone (N=30) 
Arm 2 
Placebo (N=30) 
Prior to Enrollment 
-6 
 
0 
 
4 
 
8 
 
12 
 
16 
 
20 
 
24 
26 
Weeks: 
Screening 
(within 6 
weeks prior 
to dosing) 
Follow up 
phone call 
Baseline/Treatment start:  Study drug dosing: 2 week titration to full dose, then 
2403 mg daily through week 24 
Spirometry 
HCRT 
Safety 
Blood draw 
BAL 
(optional) 
STUDY ASSESSMENTS 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
8 
Visits: 


10 
 
3. INVESTIGATORS’ EXPERIENCE IN SUBJECT AREA 
 
This study has two Co-Principal Investigators: 
Dr. Vibha N. Lama, M.D., M.S. (Co-Principal Investigator) is the Henry Sewell is the Henry 
Sewall Research Professor of Pulmonary and Critical Care Medicine and Professor of Internal 
Medicine at University of Michigan. She serves as the Associate Chief of Basic and Translational 
Research in the Division of Pulmonary & Critical Care Medicine.  Dr. Lama is an internationally 
renowned physician researcher in the field of lung transplantation and has contributed immensely 
to the field of chronic lung allograft dysfunction or specifically bronchiolitis obliterans syndrome. 
She is a trained clinical translational physician scientist with a Master’s degree in biostatistics and 
clinical study design at the University of Michigan School of Public Health. Dr. Lama is an R0-1 
funded independent researcher and is the associate director of lung transplant research at 
University of Michigan. 
 
Dr. Kevin Flaherty M.D., M.S. (Co-Principal Investigator) is currently a Professor of Internal 
Medicine at the University of Michigan.  Over the past 15 years he has developed a scholarly 
niche in the study and care of patients with interstitial lung diseases.  He has served in leadership 
roles for industry and National Institutes of Health (NIH) sponsored trials of novel treatments for 
IPF.  He also directs the University of Michigan Destination program for Interstitial Lung Diseases 
and serves as Steering Committee Chair of the Pulmonary Fibrosis Foundation Clinical Care 
Network/Patient Registry.  Dr. Flaherty also serves as vice-chair for the University of Michigan 
Human Subjects Institutional Review Board. The University of Michigan has been a leading 
recruiter of subjects with IPF and thus has extensive experience in the design and conduct of 
clinical trials.  Dr. Flaherty is an active member of the University of Michigan lung transplant team 
caring for lung transplant patients for over 15 years.  Dr. Flaherty will aid in the development of 
the final clinical trial protocol and actively recruit and enroll subjects from the University of 
Michigan into this clinical trial evaluating the potential therapeutic role of pirfenidone for the 
slowing of progression of CLAD. 
 
The study team will also include University of Michigan Medicine pulmonologists experienced in 
lung transplant and clinical trials, who will serve as sub-investigators. These physicians have used 
pirfenidone for other pulmonary diseases. They will aid in recruitment of patients and perform 
study assessments. 
 
 


11 
 
4. EXPERIMENTAL DESIGN 
 
4.1 
ENDPOINTS 
Primary: 
- 
Change in functional small airways disease (fSAD) as measured by parametric response 
mapping (PRM) at 24 weeks by treatment arm 
Secondary: 
- 
Change in FEV1 over 24 weeks by treatment arm 
- 
Change in FVC over 24 weeks by treatment arm 
- 
Number of subjects with treatment intolerance over 24 weeks 
- 
Number of subjects with adverse events related to treatment with Pirfenidone 
 
Exploratory: 
- 
Change in bronchoalveolar lavage (BAL) mesenchymal colony forming units (CFUs) by 
treatment arm 
- 
Change in fibrotic phenotype of BAL mesenchymal cells (expression of collagen, alpha 
smooth muscle actin, beta-catenin, fibronectin) by treatment arm 
 
4.2 
STUDY DESIGN 
 
Single center, randomized, double-blind placebo controlled clinical trial of pirfenidone for the 
attenuation of progression of fSAD in lung transplant recipients with CLAD.  A total of 60 
patients will be enrolled in the trial. 
 
Eligible patients will be randomized 1:1 to receive either pirfenidone 801 mg TID or placebo.  
 
4.3 
INCLUSION CRITERIA 
- 
Lung transplant recipients 18 years of age or older. 
- 
Greater than 6 months after single or bilateral lung transplantation 
- 
Baseline FEV1 and FVC values (mean of two highest value measured 3 weeks apart) > 50% 
predicted (to assure viable graft) 
- 
Diagnosis of CLAD (two consecutive spirometric values of FEV1 alone or both FEV1 and FVC 
< 80% of baseline) 
 
4.4 
EXCLUSION CRITERIA 
- 
Acute Rejection (AR) diagnosis by biopsy in the 28 days prior to enrollment 
- 
Treatment with pulse steroids, Anti-thymocyte Globulin (ATG), extracorporeal photopheresis 
(ECP), plasmapheresis, or Immunoglobulin therapy aimed at CLAD within the 28 days prior 
to enrollment 
- 
If the subject is receiving chronic Azithromycin therapy, the dose must be stable for the 28 
days prior to enrollment 
- 
Presence of active pulmonary infection at the time of enrollment as determined by an 
investigator in consultation with the treating pulmonologist   
- 
Diagnosis of bronchial stenosis either a) requiring stenting, or b) thought to be responsible 
for the spirometric decline by principal investigator 
- 
Abnormal liver function tests (AST or ALT > 2 x upper limit of normal (ULN), Alkaline 
phosphatase > 2.5 x ULN, total bilirubin > ULN) or known cirrhosis (>2 times upper limit of 
normal of AST/ALT/AP) 
- 
Total WBC < 3.0 K/uL 
- 
Moderate to Severe Renal insufficiency (CrCl <15 mL/min calculated by the Cockcroft-Gault 
equation)  


12 
 
- 
Use of any medication known to cause significant interactions with pirfenidone (strong 
CYP1A2 inhibitors such as Fluvoxamine or Enoxacin or inducers) 
- 
Pregnancy or lactation.  Women of child-bearing potential will have a pregnancy test at 
enrollment and must agree to maintain highly effective contraception with two methods of 
birth control from the date of consent through the end of the study. 
- 
Tobacco use within 6 months 
- 
History of alcohol abuse in the past 1 year as determined by the treating pulmonologist 
- 
Any condition other than CLAD that will likely result in death in the next 1 year 
- 
Any condition in the judgement of the principal investigator that would preclude participation 
in this study 
- 
EKG with QTc interval > 500 msec at screening 
- 
Listed for repeat lung transplantation 
 
 
Excluded therapies: 
The following therapies are not permitted during the study: 
Investigational therapy, enrollment in another therapeutic clinical trial within 30 days or 5 
half-lives of study medication (whichever is longer) 
• 
Fluvoxamine 
 
5.0 STUDY VISITS 
 
5.1 
Screening  
Lung transplant recipients at the University of Michigan will be screened by the study team for 
participation in this trial.  If deemed eligible, subjects will be approached regarding study, and 
the consent form as well as inclusion and exclusion criteria will be reviewed. 
 
Screening Visit (Performed up to 6 weeks prior to baseline visit and initial study drug dosing) 
The following procedures will be completed at screening: 
• 
Obtain and document informed consent 
• 
Obtain sex, race, ethnicity, date of birth  
• 
Vital signs (height, weight, temperature, blood pressure, heart rate, respiratory rate, 
pulse oximetry) 
• 
Review medical history, including transplant history 
• 
Review current medications 
• 
Date of spirometric decline (defined as date of first spirometric measurement used to 
document spirometric decline) and CLAD phenotype 
• 
Review of bronchoscopy results (if performed in the 6 weeks prior to screening visit) 
• 
Blood draw for screening labs 
o AST, ALT, AP, total bilirubin, creatinine 
 
 
Screening Bronchoscopy   
Bronchoscopy is often employed in routine clinical care to evaluate decline in lung function in 
lung transplant patients.  The University of Michigan (UM) has a standing Institutional Review 
Board (IRB) approved protocol that that allows for use of BAL fluid for research purposes.  If 
clinical bronchoscopy has been performed within 6 weeks of screening, and no clinical 
indications of new infection are present (as determined by the principal investigator in consult 
with the treating pulmonologist), we will utilize the MSC results for this study.  If bronchoscopy 
has not been performed, it may be done following screening and before enrollment, as an 


13 
 
optional part of this study.  The informed consent document includes opt in/opt out language for 
bronchoscopy. 
 
5.2 
Baseline Assessment (Visit 1, Week 0)  
At the time of baseline, the coordinator will document the following: 
• 
Vital signs (weight, temperature, blood pressure, heart rate, respiratory rate, pulse 
oximetry) 
• 
Physical exam including general appearance, HEENT, cardiovascular, pulmonary, 
abdominal, neurologic, dermatologic, and musculoskeletal exams 
• 
Current medications 
• 
Safety blood work for renal and liver evaluation 
o AST, ALT, AP, total bilirubin, creatinine 
• 
Review bronchoscopy results (if performed) 
• 
ECG 
• 
Perform spirometry 
• 
Undergo an HRCT scan with inspiratory and expiratory image acquisition (if HRCT was 
not done in preceding 6 weeks) 
• 
Serum pregnancy test (if applicable) 
• 
Review adverse events 
 
5.3  Visits 2, 3, 5, 6 (Weeks 4, 8, 16, 20): may be performed at study center or by local lab 
draw in conjunction with phone visit 
• 
Safety labs to monitor renal and liver function -  AP, ALT, AST, total bilirubin, 
creatinine 
• 
Review hospitalizations 
• 
Review medication compliance 
• 
Review concomitant medications 
• 
Review adverse events 
 
5.4 
Visit 4 (Week 12): 
• 
Vital Signs (weight, temperature, blood pressure, heart rate, respiratory rate, 
pulse oximetry) 
• 
Physical exam including general appearance, HEENT, cardiovascular, 
pulmonary, abdominal, neurologic, dermatologic, and musculoskeletal exams 
• 
Safety blood work for renal and liver evaluation 
o AP, ALT, AST, total bilirubin, creatinine 
• 
Spirometry 
• 
ECG 
• 
Review hospitalizations 
• 
Review medication adherence 
• 
Review concomitant medications 
• 
Review adverse events 
 
5.5 
Visit 7 (Week 24): 
• 
Vital Signs (weight, temperature, blood pressure, heart rate, respiratory rate, 
pulse oximetry) 
• 
Physical exam including general appearance, HEENT, cardiovascular, 
pulmonary, abdominal, neurologic, dermatologic, and musculoskeletal exams 
Safety blood work for renal and liver evaluation 


14 
 
o AP, ALT, AST, total bilirubin, creatinine 
• 
Spirometry 
• 
ECG 
• 
HRCT scan  
• 
Review hospitalizations 
• 
Review medication adherence 
• 
Review concomitant medications 
• 
Review adverse events 
• 
Collect unused study medication and return to investigational pharmacy  
• 
Bronchoscopy with consent of patient and primary physician if no 
contraindication identified  
 
5.6 
Visit 8 (Week 28) (Phone visit): 
At the 28 week phone visit, the coordinator will: 
• 
Review hospitalizations 
• 
Review adverse events 
• 
Collect vital status 
 
5.7 
Early discontinuation  
All subjects will be followed until study completion unless consent to do so is specifically 
withdrawn by the subject. If study treatment is discontinued, participants will be asked to 
continue with study assessments as planned including the HRCT at week 24 as per protocol.  
 
5.8  Randomization 
This is a randomized, double-blind, placebo-controlled multi-center study. Assignment to study 
treatment will be blinded to the study subjects, investigational site personnel, study vendors, 
and the Sponsor study team, except for the delegated personnel who will review and check the 
randomization and drug allocation for accuracy.  
 
All patients will be randomized at the Baseline visit, using stratified block randomization with 
undisclosed block sizes. The stratification factor is FEV1 first vs concurrent FEV1 and FVC 
decline at time of CLAD onset.  Our statistician, Dr. Murray, will assist with randomization. She 
will provide the Research Pharmacy (via email) with randomization codes for two separate 
strata as mentioned above. Within each stratum the statistician will indicate treatment 
assignment“Active Pirfenidone” or “Placebo” and treatment label ID number. The Research 
Pharmacist (RP) will be told upon patient entry the stratum to which the patient belongs, 
identifying the appropriate randomization list for each patient. The RP will then dispense Active 
or Placebo based on the randomization code on the randomization list. The RP will refer to the 
randomization code at each dispensing. 
 
 
In the event of a medical emergency in which breaking the blind is required to provide medical 
care to the subject, the investigator may obtain treatment assignment directly from the study 
statistician for that subject. 
 
 
 
 


15 
 
Table 1.  Schedule of Assessments 
 
Visit 
ScreeningA 
1 
Baseline 
2B 
+/- 
7days 
3B 
+/- 
7days 
4 
+/- 
14day
s 
5B 
+/- 
7days 
6B 
+/- 
7days 
7 
EOT 
+/- 
14day
s 
8 
EOS 
+/- 
7days 
Week 
 -6 - 0 
0 
4 
8 
12 
16 
20 
24 
28C 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
Vital Signs 
x 
x 
 
 
x 
 
 
x 
 
Physical exam  
x 
x 
 
 
x 
 
 
x 
 
Medical history 
x 
x 
 
 
 
 
 
 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Non-elective 
hospitalizations 
 
x 
x 
x 
x 
x 
x 
x 
x 
Medication Compliance 
 
 
x 
x 
x 
x 
x 
x 
 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
 
Pregnancy testD 
 
x 
 
 
 
 
 
 
 
Standard of care labs 
including 
immunosuppressive  
drug levels 
x 
x 
x 
x 
x 
x 
x 
x 
 
Safety labs (LFTs)F 
x 
x 
x 
x 
x 
x 
x 
x 
 
Spirometry 
x 
 
 
 
x 
 
 
 
 
Full PFTs 
 
x 
 
 
 
 
 
x 
 
HRCTG 
 
x 
 
 
 
 
 
x 
 
EKG 
 
x 
 
 
x 
 
 
x 
 
Bronchoscopy with 
BALH 
x 
x 
 
 
 
 
 
x 
 
Vital status assessment 
 
 
 
 
 
 
 
 
x 
A The time period between the screening and enrollment visit may be up to 6 weeks   
B Weeks 4, 8, 16, 20: Laboratory testing may be performed locally 
C Week 28 visit may be performed as a telephone visit 
D In women of child-bearing potential 
E Immunosuppression drug levels will be collected and managed per standard of care 
F LFTs will be monitored monthly  
G HRCT may be done between screening visit and enrollment (visit 1) 
H Results of BAL, if performed per standard of care, will be utilized as baseline if performed within the 6 
weeks prior to baseline visit.   Other bronchoscopies are optional. 
 
 


16 
 
6. RECRUITMENT 
University of Michigan has in place a unique prospectively collected dataset of lung transplant 
patients (Organ Transplantation Information System (OTIS) database). We have, as a part of this 
database, devised a system in which every patient’s baseline lung function post-transplant is 
analyzed to generate their baseline FEV1 as well as their CLAD status. The trial’s study team will 
screen lung transplant patients using this program to identify potential subjects.   
 
We have run this profile once to determine if recruitment of 60 CLAD patients is viable in the 
planned two years. At present among all alive patients with lung transplant at our center, 92 
patients meet spirometric criterion for CLAD. Phenotype and grade distribution are shown below:  
 
* CLAD grade is based on ISHLT definition. 
The study plans to include all patients with 
diagnosis of CLAD irrespective of the stage. 
Fibroproliferative remodeling in a transplanted 
lung is an ongoing event as evidenced by 
continued progressive decline in lung function, 
worsening of small airway obstruction, and 
evidence of change in the phenotype of 
mesenchymal cells isolated from BAL of these 
patients. It is important that an anti-fibrotic 
agent be effective at all stages of CLAD 
because patients can present in any stage of 
CLAD at the very disease onset. Furthermore, 
CLAD becomes a chronic disease and patients 
can survive for prolonged periods of time after 
onset of CLAD. Hence, the ability of an anti-
fibrotic agent to halt fibroproliferation at various 
time points after onset of CLAD is of key    
significance. 
 
^ CLAD is identified by decline in FEV1 below 
80% of post-transplant baseline as per ISHLT 
definition. Our published work has shown that 
patients can present either as an isolated 
decline in FEV1 (BOS) or as a concurrent 
decline in both FEV1 and FVC, also termed 
restrictive allograft syndrome (RAS).10 As both 
of these presentations arise from fibrosis, we 
will not limit our study to one specific 
phenotype.  
 
  
 
 
 
 
 
 
 
 
 
Grade 1
33
Grade 2
29
Grade 3
30
Stage of CLAD* 
Grade 1
Grade 2
Grade 3
BOS
73%
RAS
27%
BOS vs. RAS distribution ^
BOS
RAS


17 
 
7. TIMELINE 
Based on the present design and assessment of our center’s patient population with CLAD, we 
estimate the study duration will be 2 years. Patient enrollment can start as soon as regulatory 
agency approval is obtained (IRB). We have experienced clinical coordinators in our transplant 
center. Mary Maliarik Ph.D., the clinical coordinator for the trial, has conducted lung transplant 
studies with Dr. Lama for nearly a decade. Dr. Flaherty and Dr. Belloli are both transplant 
pulmonologists and are committed to this trial. Dr. Susan Murray Sc.D. is an experienced 
biostatistician whose area of expertise is clinical trials and she has worked extensively with lung 
transplant cohorts. In summary, all infrastructure is already in place allowing for rapid start of the 
proposed clinical trial.   
 
 
 


18 
 
8. DRUG DOSAGE & ADMINISTRATION 
 
Dosage and Administration 
 
 
Pirfenidone 
Placebo 
Substance 
Pirfenidone 
- 
Pharmaceutical formulation 
Capsule 
Capsule 
Source 
Genentech 
Genentech 
Unit strength 
267 mg 
267 mg 
Route 
Oral 
Oral 
Dosage 
 
 
   Days 1 through 7 
267 mg three times daily 
267 mg three times daily 
   Days 8 through14 
534 mg three times daily 
534 mg three times daily 
   Days 15 onward 
801 mg three times daily 
801 mg three times daily 
 
- 
Take with food. 
- 
Upon initiation of treatment, titrate to the full dosage of 2403 mg/day over a 14-day period as 
above. 
 
8.1 
Adverse reactions 
The most common adverse reactions (≥10%) are liver problems, photosensitivity, rash, 
abdominal pain, nausea, vomiting, diarrhea, dyspepsia, fatigue, headache, dizziness, anorexia, 
sinusitis, insomnia, weight loss, and arthralgia. These possible adverse events are documented 
in the informed consent. 
 
Management of abnormal liver function tests 
Elevated ALT, AST, and bilirubin elevations have occurred with pirfenidone and will be 
monitored monthly as above.   The investigator will monitor patients for toxicities.   
 
The following protocol will be followed for management of elevation in AST, ALT, and total 
bilirubin: 
 
Magnitude of AST 
or ALT elevation 
Recommendation 
3 to 5 x ULN 
Confounding medications should be discontinued if clinically 
indicated, other causes excluded, and the patient monitored 
closely.  The dose of study treatment may be reduced or 
interrupted if clinically appropriate, with subsequent repeat 
titration to full dose, as tolerated 
≤5 x ULN 
accompanied by 
symptoms or 
hyperbilirubinemia 
(>2x ULN) 
Study treatment should be permanently discontinued 
>5 x ULN 
Study treatment should be permanently discontinued 
 
 
Management of photosensitivity and rash 
Photosensitivity and rash have been noted with pirfenidone. Patients will be instructed to avoid 
exposure to sunlight and sunlamps. Patients will be instructed to wear sunscreen (sun 


19 
 
protection factor 50 or higher) and protective clothing daily. Temporary dosage reductions or 
discontinuations may be required.   
 
If a patient experiences significant rash or photosensitivity, treatment of symptoms and/or 
temporary dose reductions, interruptions, or discontinuation of study treatment should be 
considered.   
 
Management of gastrointestinal disorders 
Nausea, vomiting, diarrhea, dyspepsia, gastroesophageal reflux disease, and abdominal pain 
have occurred with pirfenidone. Temporary dosage reductions or discontinuations may be 
required.  
 
 
Dosage Modification due to Drug Interactions 
Ciprofloxacin is a moderate CYP1A2 inhibitor.  With the use of ciprofloxacin at a dosage of 750 
mg twice daily, reduce pirfenidone to 534 mg three times a day (1602 mg/day). 
 
 
EKG abnormalities 
If the QTc interval is > 550 msec, this should be confirmed with a repeat EKG within 24 hours.  
The study drug should be interrupted until the repeat EKG reading. If QTc is still >550 msec 
than cardiology will be consulted and drug discontinued if abnormality persists. 
 
If the QTc interval is between 500 and 550 msc, confirmed by a repeat EKG within 24 hours, 
and verified by a local cardiologist, study treatment should be interrupted.  If an alternative 
explanation is identified (electrolyte abnormality or concomitant medication), the study treatment 
may be re-initiated at the investigator’s discretion in consultation with the medical monitor.   
 
 
 
 


20 
 
 
9. DRUG STORAGE & HANDLING 
Pirfenidone capsules and film-coated tablets are packaged in high-density polythylene bottles 
with a child-resistant closure system. 
 
Hard capsules should be stored under the recommended storage conditions “Do not store above 
30 degrees C”.  Film-coated tablets should be stored under the recommended storage condition 
“Do not store above 25 degrees C”. 
 
For batch specific instructions on storage and information on shelf-life, see the packaging. 
 
The Michigan Medicine Research Pharmacy is responsible for developing and implementing 
procedures for the proper control and handling of investigational drugs, including procurement, 
storage, medication labeling and dispensing, drug inventory management, and other distribution 
and control functions. Information on a drug accountability log includes but is not limited to: receipt 
date, dispensation date, patient identifier, quantity, lot number, expiration date, and dispenser's 
initials. Appropriate inventory levels will be maintained by RP to ensure availability of study 
drugs.  As indicated by the sponsor, outdated study medications will be returned by RP to the 
study sponsor or destroyed.  
 
Drug shipping information: 
University of Michigan Hospitals 
Department of Pharmacy Services-Research Pharmacy 
UHB2D400 
1500 East Medical Center Drive 
Ann Arbor, MI 48109-5008 
 
Phone: (734) 936-7469 
 
10. DATA ANALYSIS 
 
10.1 Overview 
Our Endpoints are: 
Primary: 
- 
Change in functional small airways disease (fSAD) as measured by parametric response 
mapping (PRM) at 24 weeks by treatment arm 
Secondary: 
- 
Change in FEV1 over 24 weeks by treatment arm 
- 
Change in FVC over 24 weeks by treatment arm 
- 
Number of subjects permanently discontinuing study medication before 24 weeks 
- 
Number of subjects with one or more serious adverse events  
Exploratory: 
- 
Change in bronchoalveolar lavage (BAL) mesenchymal colony forming units (CFUs) by 
treatment arm 
- 
Change in fibrotic phenotype of BAL mesenchymal cells (expression of collagen, alpha 
smooth muscle actin, beta-catenin, fibronectin) by treatment arm 
 
10.2 Sample Size Justification 


21 
 
We will describe the distribution of fSAD change within and between treatment groups (n=30 
per group) over a 6-month period. Preliminary data suggests that without treatment, fSAD 
increases 9% on average over a 6-month time period with SD of 9%. If pirfenidone halves this 
increase over 6 months, we would have a confidence interval for the treatment effect of 4.5+/-
4.64%.  Power to detect 6-month treatment differences is sensitive to assumptions of the 
standard deviation above and the ability of pirfenidone to reduce 6-month fSAD progression; a 
power analysis table is given below for various effect sizes and standard deviations that might 
be seen in the trial based on a sample size of 60 (30 per group). 
 
 
% Increase in FSAD for Pirfenidone 
Group (vs 9% FSAD increase in 
Placebo Group) 
Std Dev 
0% 
2% 
4.5% 
5 
>99% 
>99% 
93% 
7 
>99% 
97% 
69% 
9 
97% 
84% 
48% 
We will similarly summarize changes in spirometric parameters and MSC CFU and phenotype 
over time between and within groups.   
While the above power is shown with 60 patients (30 per group), we will plan to enroll 66 
patients (33 per group) to account for subject drop out. 
 
10.3 Primary Endpoint Analysis  
We believe the data obtained from our study will provide important radiographic and biological 
signals regarding the efficacy of pirfenidone. We expect a lower SD as the patient population 
selected will be much better phenotyped for CLAD presence. The high SD in the preliminary 
data came from patients who improved over time as this data is derived from patients who had 
CT scans available as routine care rather than in our study where they will be done 
prospectively. Furthermore, if fibrotic remodeling by pirfenidone is effective we can potentially 
even see a decrease in fSAD.    
 
We believe that this CT based novel methodology to evaluate small airway disease will provide 
us with much stronger signal over 6-month period than FEV1 which reaches a floor effect. So 
the disease progresses even though FEV1 changes are not very evident ultimately leading to 
graft failure and death. Furthermore, our ability to isolate mesenchymal cells from BAL offers a 
first unique scenario to directly study the anti-fibrotic effect of pirfenidone. 
 
This trial will also provide information regarding the tolerance of pirfenidone in a lung transplant 
population who already take multiple medications with serious possible side effects.  Tolerance 
of pirfenidone in addition to baseline transplant medications will be assessed. 
 
Secondary: 
- 
Change in FEV1 over 24 weeks by treatment arm (e.g, percent or time weighte) 
- 
Change in FVC over 24 weeks by treatment arm 
- 
Number of subjects with treatment intolerance over 24 weeks 
o Measured by elevated  AST, ALT, total bilirubin that results in dose reduction or 
discontinuing study treatment ( the 3 – 5 or greater ULN) 
- 
 Number of subjects with Adverse events related to treatment with Pirfenidone 
o Safety of pirfenidone will be measured by adverse events determined to be 
related to the study drug as determined by the principal investigator through 


22 
 
review of medical history, physical exam and laboratory findings or be measured 
by liver and renal function tests, physical exam  
o  
11.   SAFETY REPORTING OF ADVERSE EVENTS 
11.1 Assessment of safety 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) per protocol.  This includes all events of death, and any study specific 
issue of concern. 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution. 
 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with CLAD that were not 
present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
• 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period.  
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
• 
It results in death (i.e., the AE actually causes or leads to death). 
• 
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.). 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
• 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical intervention 
to prevent one of the outcomes listed above). 


23 
 
11.2 Methods And Timing For Assessing And Recording Safety Variables 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. 
in accordance with CFR 312.32  
11.2.1 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of any study procedures and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier. After 
this period, investigators should only report SAEs that are attributed to prior study treatment. 
11.2.2 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the {study 
drug} (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of the 
{study drug}, and the AE cannot be readily explained by the subject’s clinical state, intercurrent 
illness, or concomitant therapies; and/or the AE follows a known pattern of response to the 
{study drug}; and/or the AE abates or resolves upon discontinuation of the {study drug} or dose 
reduction and, if applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the {study drug} (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or 
the AE has no plausible temporal relationship to {study drug} administration (e.g., cancer 
diagnosed 2 days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert (P.I) or current Investigator Brochure (I.B).  
 
Unexpected adverse events are those not listed in the P.I or current I.B or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the description 
in the P.I. or I.B. For example, under this definition, hepatic necrosis would be unexpected if the 
P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
 


24 
 
11.3 Procedures For Eliciting, Recording, And Reporting Adverse Events 
11.3.1 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted. Examples of non-directive questions include:  
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last here?”  
11.3.2 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
a. Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to 
report the information that is currently available. If a diagnosis is subsequently established, it 
should be reported as follow-up information. 
b. Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section I), 
regardless of attribution, will be reported to the appropriate parties. When recording a death, the 
event or condition that caused or contributed to the fatal outcome should be reported as the 
single medical concept. If the cause of death is unknown and cannot be ascertained at the time 
of reporting, report “Unexplained Death”. 
c. Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be 
re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
d. Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease 
of the study. 


25 
 
e. Pregnancy 
If a female subject becomes pregnant while receiving the study drug or within 30 days after the 
last dose of study drug, a report should be completed and expeditiously submitted to 
Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, 
whether accidental, therapeutic, or spontaneous, should always be classified as serious, and 
expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born 
to a female subject exposed to the study drug should be reported as an SAE. 
 
 
Additional information on any pirfenidone exposed pregnancy and infant will be 
requested by GenentechDrug Safety at specific time points (i.e. after having received 
the initial report, at the end of the second trimester, 2 weeks after the expected date of 
delivery, and at 3, 6, and 12 months of the infant’s life). 
 
f. Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior {study drug} exposure. If the investigator 
should become aware of the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject who participated in the study, this should be reported as 
an SAE.  
 
g.   Reconciliation 
 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor will 
agree to the reconciliation periodicity and format, but agree at minimum to exchange quarterly 
line listings of cases received by the other party.  
 
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by-
case basis until satisfactory resolution.  The sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’. 
 
h.   AEs of Special Interest (AESIs) 
 
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product  
  
For this study, there are no AESIs. 
 
I. Adverse Event Reporting 
Investigators must report all SAEs to Genentech within the timelines described below. The 
completed MedWatch/case report should be faxed immediately upon completion to Genentech 
Drug Safety at: 
650-238-6067 
 
Serious adverse events (SAEs), pregnancy reports and AEs of special interest (AESIs), where 
the patient has been exposed to the Product, will be sent on a MedWatch or CIOMS I form to 
the Genentech contact specified in Addendum 2 of this SDEA. Transmission of these reports 


26 
 
(initial and follow-up) will be either electronically or by fax and within the timelines specified 
below:] 
• 
SADRs 
Serious AE reports that are related to the Product shall be transmitted to Genentech within 
fifteen (15) calendar days of the awareness date. 
 
• 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech 
within thirty (30) calendar days of the awareness date. 
 
• 
Pregnancy reports 
While such reports are not serious AEs or ADRs per se, as defined herein, any reports of 
pregnancy, where the fetus may have been exposed to the Product, shall be transmitted 
to Genentech within thirty (30) calendar days of the awareness date. Pregnancies will be 
followed up until the outcome of the pregnancy is known, whenever possible, based upon 
due diligence taken to obtain the follow-up information. 
 
 
Special situation reports 
In addition to all AEs, pregnancy reports and AESIs, the following Special Situations Reports 
should be collected and transmitted to Genentech even in the absence of an Adverse Event 
within thirty (30) calendar days: 
 
• 
Data related to the Product usage during pregnancy or breastfeeding 
• 
Data related to overdose, abuse, off-label use, misuse, inadvertent/erroneous 
administration, medication error or occupational exposure, with or without association with 
an AE/SAE unless otherwise specified in the protocol 
• 
Data related to a suspected transmission of an infectious agent via a medicinal product 
(STIAMP) 
• 
Lack of therapeutic efficacy 
 
In addition, reasonable attempts should made to obtain and submit the age or age group of the 
patient, in order to be able to identify potential safety signals specific to a particular population 
 
 
j.   Aggregate Reports 
 
Dr Lama will forward a copy of the Final Study Report to Genentech upon completion of the 
Study.  
 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form: 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 


27 
 
• 
Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• 
Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-
up information is being submitted (The patient identifiers are important so that the 
new information is added to the correct initial report) 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom an adverse event was reported. For questions regarding 
SAE reporting, you may contact the Genentech Drug Safety representative noted above or the 
MSL assigned to the study. Relevant follow-up information should be submitted to Genentech 
Drug Safety as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
https://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/ucm115894.htm 
 
 
 
7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that 
is unexpected and assessed by the Investigator to be possibly related to the use of pirfenidone. 
An unexpected adverse event is one that is not already described in the pirfenidone Investigator 
Brochure. Such reports are to be telephoned or faxed to the FDA and Genentech within 7 
calendar days of first learning of the event. 
FDA fax: 1-800-FDA-0178. 
Genentech Drug Safety Fax: 650-238-6067 
 
 
 
 
   Phone: 1-888-835-2555 
  


28 
 
15 Calendar Day Written Report 
RANDOMIZATION CODES FOR BLINDED CLINICAL TRIALS (IF APPLICABLE) 
 
The blind will be broken only in the case of emergent situations in which the identity of the trial 
drug must be known to the investigator in order to provide appropriate medical treatment or 
otherwise assure safety of trial participants.  The reason for unblinding will be documented in 
source documents. 
 
Drug Safety: 
 For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
 
 
 


29 
 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
 
Fax: 650-238-6067 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 
 


30 
 
11.4 Data Safety Officer 
The Safety Officer will be responsible for assessing subject safety, and monitoring overall conduct 
and integrity of the study.  In fulfilling these responsibilities, the safety officer may make 
recommendations concerning: recruitment, retention and management of participants; data 
quality; study compliance; and continuation or stopping of the study.   
 
The Safety Officer will specifically review adverse event data as well as summary reports of all 
serious adverse events (SAEs) and available lab data, and may review the medical records of 
individual cases if deemed appropriate or necessary to determine if a safety concern is 
emerging.  The Principal Investigators may also make recommendations to the Safety Officer 
for additional data review should a concern arise.  The Safety Officer may suggest appropriate 
courses of action to address general study safety issues which may arise.  If warranted, the 
Safety Officer may recommend at any time that the entire protocol be suspended temporarily or 
terminated permanently.  These recommendations, containing fully blinded information, will be 
directed to the investigator, the  IRBMED and Genentech which has the responsibility to accept, 
reject or modify the Safety Officer’s recommendations. The Safety Officer may also review 
medical record information, as needed. 
 
12.    STUDY CLOSEOUT 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech and IRBMED This includes all  the Clinical Study Report (final study report). 
Additionally, any literature articles that are a result of the study should be sent to Genentech. 
Copies of such reports should be mailed to the assigned Clinical Operations contact for the 
study: 
 
 


31 
 
13.  REFERENCES 
1. Meyer KC, Raghu G, Verleden GM, Corris PA, Aurora P, Wilson KC, Brozek J, Glanville AR, 
the IATSERSBOSTFC, the IATSERSBOSTFC. An international ISHLT/ATS/ERS clinical 
practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. The 
European respiratory journal 2014; 44: 1479-1503. 
2. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for 
chronic lung allograft dysfunction. The Journal of heart and lung transplantation : the 
official publication of the International Society for Heart Transplantation 2014; 33: 127-
133. 
3. Sato M, Waddell TK, Wagnetz U, Roberts HC, Hwang DM, Haroon A, Wagnetz D, Chaparro 
C, Singer LG, Hutcheon MA, Keshavjee S. Restrictive allograft syndrome (RAS): a novel 
form of chronic lung allograft dysfunction. The Journal of heart and lung transplantation : 
the official publication of the International Society for Heart Transplantation 2011; 30: 
735-742. 
4. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE, Jr., 
Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, du Bois RM, Group CS. Pirfenidone in 
patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 
2011; 377: 1760-1769. 
5. King TE, Jr., Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina 
E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn 
SA, Sussman R, Swigris JJ, Noble PW, Group AS. A phase 3 trial of pirfenidone in 
patients with idiopathic pulmonary fibrosis. The New England journal of medicine 2014; 
370: 2083-2092. 
6. Burgel PR, Bergeron A, de Blic J, Bonniaud P, Bourdin A, Chanez P, Chinet T, Dalphin JC, 
Devillier P, Deschildre A, Didier A, Kambouchner M, Knoop C, Laurent F, Nunes H, 
Perez T, Roche N, Tillie-Leblond I, Dusser D. Small airways diseases, excluding asthma 
and COPD: an overview. European respiratory review : an official journal of the 
European Respiratory Society 2013; 22: 131-147. 
7. Galban CJ, Han MK, Boes JL, Chughtai KA, Meyer CR, Johnson TD, Galban S, Rehemtulla 
A, Kazerooni EA, Martinez FJ, Ross BD. Computed tomography-based biomarker 
provides unique signature for diagnosis of COPD phenotypes and disease progression. 
Nature medicine 2012; 18: 1711-1715. 
8. Verleden SE, Vos R, Vandermeulen E, Ruttens D, Bellon H, Heigl T, Van Raemdonck DE, 
Verleden GM, Lama V, Ross BD, Galban CJ, Vanaudenaerde BM. Parametric 
Response Mapping of Bronchiolitis Obliterans Syndrome Progression After Lung 
Transplantation. American journal of transplantation : official journal of the American 
Society of Transplantation and the American Society of Transplant Surgeons 2016. 
9. Belloli EA, Degtiar I, Wang X, Yanik GA, Stuckey LJ, Verleden SE, Kazerooni EA, Ross BD, 
Murray S, Galban CJ, Lama VN. Parametric Response Mapping as an Imaging 
Biomarker in Lung Transplant Recipients. American journal of respiratory and critical 
care medicine 2016. 
10. Belloli EA, Wang X, Murray S, Forrester G, Weyhing A, Lin J, Ojo T, Lama VN. Longitudinal 
Forced Vital Capacity Monitoring as a Prognostic Adjunct after Lung Transplantation. 
American journal of respiratory and critical care medicine 2015. 
11. Lama VN, Smith L, Badri L, Flint A, Andrei AC, Murray S, Wang Z, Liao H, Toews GB, 
Krebsbach PH, Peters-Golden M, Pinsky DJ, Martinez FJ, Thannickal VJ. Evidence for 
tissue-resident mesenchymal stem cells in human adult lung from studies of 
transplanted allografts. The Journal of clinical investigation 2007; 117: 989-996. 
12. Badri L, Murray S, Liu LX, Walker NM, Flint A, Wadhwa A, Chan KM, Toews GB, Pinsky DJ, 
Martinez FJ, Lama VN. Mesenchymal stromal cells in bronchoalveolar lavage as 


32 
 
predictors of bronchiolitis obliterans syndrome. American journal of respiratory and 
critical care medicine 2011; 183: 1062-1070.