Clinical trial NCT03359863
Conditions: Restrictive Chronic Lung Allograft Dysfunction Lung Transplant Rejection
Sponsor: University of California, San Francisco
Start date: 2018-03-07; Completion date: 2021-10-28
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Despite advances in lung transplantation, the median survival remains only 55% at 5 years. The main limitation to long term survival is the development of chronic lung allograft dysfunction. In approximately 30% of cases, chronic lung allograft dysfunction has a restrictive phenotype (RCLAD) characterized by fibrosis with rapid progression to respiratory failure. Approximately 60% of patients with RCLAD die within one year, as currently there are no therapies available.

RCLAD, like Idiopathic Pulmonary Fibrosis (IPF), is characterized by fibroblast proliferation, extracellular matrix deposition, and architectural distortion leading to progressive lung scarring and death. Given their similarities, there is keen interest in the international transplant community to investigate whether the anti-fibrotic drug pirfenidone can slow the progression of RCLAD as it does of IPF. Pirfenidone has been proved to be safe and effective in patients with IPF, and is approved by the Food and Drug Administration.

This protocol will evaluate the safety and tolerability of pirfenidone in lung transplant recipients with RCLAD. Transplant recipients take carefully adjusted immunosuppressive medications for life to prevent rejection of the allograft. Current literature suggests the dose of tacrolimus, the main anti-rejection drug, may need to be adjusted when taken in combination with pirfenidone. The investigators will assess the side effects of pirfenidone in combination with the immunosuppressive regimen and determine the magnitude of the adjustment in tacrolimus dose. The results of this pilot study will provide the foundation for a multicenter randomized control trial to evaluate the efficacy of pirfenidone in slowing the progression of RCLAD.

Detailed description:
Despite advances in lung transplantation, median survival remains only 55% at 5 years. The primary cause of death is chronic lung allograft dysfunction (CLAD), occurring in 43% of recipients at 5 years. Recently, it has been recognized that CLAD can have an obstructive (BOS) or a restrictive (RCLAD) phenotype, also known as restrictive allograft syndrome (RAS), and that both may coexist. These phenotypes differ not only in their spirometric, radiographic and histologic features but also in their rates of progression and survival. Thus, there is a critical need to find therapies other than re-transplantation, which remains the only effective therapeutic option and explore the pathobiology driving RCLAD.

RCLAD shares features with Idiopathic Pulmonary Fibrosis (IPF), including its progressive and lethal course, extracellular matrix deposition, architectural distortion, fibroblast proliferation, and short telomeres in lung epithelial cells. These common features suggest RCLAD and IPF may share molecular pathogenesis. As a result, some have explored using FDA approved anti-fibrotic medications for IPF in RCLAD in case reports.

This proposal aims to gather the preliminary data needed to design a multicenter randomized controlled trial (RCT) of pirfenidone for RCLAD. To do so, the investigators first need evidence of tolerability, to understand drug interactions with the immunosuppressive regimen used to maintain allograft function and early evidence that pirfenidone may slow FVC decline and radiographic progression in RCLAD.

Evidence that pirfenidone is well tolerated in transplant recipients and that it slows the progression of RCLAD would be paradigm shifting. Further, identifying subjects at risk for RCLAD before the onset of spirometric changes would allow to start therapeutic interventions sooner, maximizing their benefit. Finding biomarkers that predict response to pirfenidone would identify patients most likely to benefit.

Arms: arm 1: Subjects will receive Pirfenidone as part of treatment for their restrictive chronic lung allograft dysfunction (RCLAD).
Interventions: intervention 1: Pirfenidone
Intervention descriptions: intervention 1: Subjects will receive pirfenidone for 52 weeks, titrated to 2403 mg/day (3 capsules, 3× daily) after a 4-week titration period (1 capsule, 3x daily for 2 weeks, 2 capsules, 3x daily for 2 weeks) for a total of 56 weeks of pirfenidone. Eligible participants will continue pirfenidone beyond 56 weeks.

Protocol documents:
Prot_SAP_002.pdf: 
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AIDA VENADO, PI
Clinical Research Protocol
PIRFENIDONE FOR RESTRICTIVE CHRONIC LUNG ALLOGRAFT 
DYSFUNCTION (PIRCLAD)
Protocol Number:
IRB study number 16-20710
Version Date:
May 8, 2020
Investigational Product:
None
IND Number:
N/A
Development Phase:
N/A
Aida Venado (PI)
500 Parnassus Avenue
MUW 420 Box 0115
Sponsor:
San Francisco, CA 94143-2203
Funding Organization:
Nina Ireland program for Lung Health discretionary funds 
from Dr. Jeffrey Golden
Principal Investigator:
Name: Aida Venado 
Telephone: 404-983-5704 
Fax:
E-mail: aida.venado@ucsf.edu
Medical Monitor:
Name: Leah Witt, MD 
Telephone:
Fax:
E-mail: leah.witt@ucsf.edu
Coordinating Center:
Approval:
PI or Sponsor Signature (Name and Title)
Date
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time. The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure. Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.


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PROTOCOL AGREEMENT
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing the sponsor with complete and timely information, as outlined in the protocol. It 
is understood that all information pertaining to the study will be held strictly confidential 
and that this confidentiality requirement applies to all study staff at this site. Furthermore, 
on behalf of the study staff and myself, I agree to maintain the procedures required to carry 
out the study in accordance with accepted GCP principles and to abide by the terms of this 
protocol.
Protocol Number:
Protocol Title: PIRFENIDONE FOR RESTRICTIVE ALLOGRAFT DYSFUNCTION 
(PIRCLAD)
Protocol Date: May 8, 2020
Investigator Signature
Date
Print Name and Title 
Site #
Site Name
UCSF
Address
500 Parnassus Avenue 
MUW 420, Box 0115
San Francisco, CA 94143
Phone Number
404-983-5704


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PROTOCOL SYNOPSIS
TITLE
PIRFENIDONE FOR RESTRICTIVE ALLOGRAFT 
DYSFUNCTION (PIRCLAD)
SPONSOR
Nina Ireland Program for Lung Health discretionary funds from Dr. 
Jeffrey Golden
FUNDING 
ORGANIZATION
UCSF
NUMBER OF SITES
1
RATIONALE
Long-term survival after lung transplant is limited by the development 
of chronic lung allograft dysfunction. In approximately 30% of cases, 
chronic lung  allograft dysfunction  has a  restrictive  phenotype 
(RCLAD) characterized by fibrosis with rapid progression. 
Approximately 60% of patients with RCLAD die within one year 
from respiratory failure. Currently, there are no therapies available 
for RCLAD. Due to the similarities between RCLAD and Idiopathic 
Pulmonary Fibrosis (IPF), there is keen interest in the transplant 
community to investigate the effect of the anti-fibrotic drug 
pirfenidone in RCLAD. Pirfenidone has been proved to slow the 
progression of IPF and is approved by the Food and Drug 
Administration (FDA) for that indication.
This protocol will evaluate the safety and tolerability of pirfenidone in 
lung transplant recipients with RCLAD. The results of this pilot study 
will provide the foundation for a multicenter randomized control trial 
to evaluate the efficacy of pirfenidone in slowing the progression of 
RCLAD.
STUDY DESIGN
Interventional, open-label, pilot study
PRIMARY 
OBJECTIVE
Asses the safety and tolerability of Pirfenidone in lung transplant 
recipients with RCLAD.
NUMBER OF 
SUBJECTS
10
SUBJECT 
SELECTION
CRITERIA
Inclusion Criteria:
Subjects aged 18 to 80 years old, who underwent bilateral lung 
transplantation at UCSF and have a diagnosis of RCLAD based on the 
International Heart and Lung Transplant (ISHLT) classification.
The diagnosis of RCLAD is based on spirometry (FEV1 ≤ 80% and 
FVC ≤ 80% of best post-transplant baseline) and CT scan (e.g. 
pleuroparenchymal fibroelastosis) findings.
Subjects with steady-state blood concentration of tacrolimus, as


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assessed by 10-12 hour trough level. 
Exclusion Criteria:
Patients with RCLAD will be excluded if they are, in the judgment of 
the investigator, unlikely to tolerate pirfenidone. Other exclusion 
criteria will include:
●
FVC decline related to non-RCLAD causes (e.g. pulmonary 
edema, pleural effusion, etc).
●
Patients with any severe comorbidity complicating RCLAD 
which might determine their prognosis and functional level 
(e.g. active malignant disease) within the last 12 months.
●
Patients who have resumed smoking after transplantation.
●
Renal insufficiency (creatinine clearance < 30 ml/min 
calculated by the CKD-Epi formula).
●
Total bilirubin above the upper limit of the normal range 
(ULN), except in patients with predominantly unconjugated 
hyperbilirubinemia (e. g. Gilbert’s disease).
●
Aspartate or alanine aminotransferase (AST or ALT) > 3 times 
the ULN.
●
Known allergy of hypersensitivity to Pirfenidone
●
Ongoing use or expected use of any of the following therapies:
- Strong inhibitors of CYP1A2 (e.g. fluvoxamine or enoxacin).
- Moderate inhibitors of CAYP1A2 (e. g. mexiletine, thiabendazole, 
or phenylpropanolamine). Ciprofloxacin will be allowed only at doses 
equal or less than 500 mg BID.
●
Inability to provide informed consent.
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION
Pirfenidone 2403 mg/day for 56 weeks. Pirfenidone dose will be 
titrated up as follows: 801 mg/day (1 capsule, 3 times daily) for 2
weeks, then 1602 mg/day (2 capsules, 3 times daily) for 2 weeks, then
2403 mg/day (3 capsules, 3 times daily) for 52 weeks.
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION
N/A


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DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY
Subjects will be in the study for 56 weeks. Subjects that wish to 
continue taking pirfenidone beyond 56 weeks may be eligible for 
PIRCLAD extension until September 30, 2021. The Principal 
Investigator will determine eligibility for PIRCLAD extension on a 
case by case basis. Subjects must continue to meet the inclusion and 
exclusion criteria, and continue monitoring with laboratory tests,  
study coordinator calls, clinic visits, pulmonary function tests, and CT 
scan imaging.
The total duration of the study is expected to be up to 48 months. 
Fifteen months will be for subject recruitment and an additional 14 
months for subject follow-up. Subjects eligible for PIRCLAD 
extension will have up to 19 months of follow up. The last study 
coordinator call will be 28 days after the last pirfenidone dose.
CONCOMMITANT 
MEDICATIONS
Patients will continue their current immunosuppression regimen 
consisting of prednisone, mofetil mycophenolate, tacrolimus and 
sirolimus.
Strong inhibitors of CYP1A2 (e.g. fluvoxamine or enoxacin) and 
moderate inhibitors of CYP1A2 (e. g. mexiletine, thiabendazole, or 
phenylpropanolamine) will not be allowed. Ciprofloxacin will be 
allowed only at doses equal or less than 500 mg twice daily.
SAFETY 
EVALUATIONS
(PRIMARY 
OUTCOMES)
Tolerability of pirfenidone: The primary outcome will be the number 
of subjects that discontinue pirfenidone due to a treatment emergent 
adverse event (TEAE). A secondary outcome will be the proportion 
of subjects experiencing a TEAE.
Tacrolimus dose change: The outcome will be the ratio of 
tacrolimus-on-pirfenidone to tacrolimus-off-pirfenidone corrected for 
the subject’s specific steady-state tacrolimus concentration. Subjects 
with steady-state blood concentration of tacrolimus, as assessed by 
10-12 hour trough level, will initiate pirfenidone. Tacrolimus trough 
level will be measured weekly for the first 6 weeks after starting 
pirfenidone. Another measurement will be done at week 8. Once a 
therapeutic 
blood 
concentration 
(8-12 
ng/ml) 
is 
achieved, 
measurements will be done monthly. First, we will calculate the 
concentration-to-dose ratio of tacrolimus on and off pirfenidone by 
dividing the tacrolimus blood concentration by the corresponding 
total daily dose of tacrolimus for each period. To obtain the 
conversion ratio, then we will divide the concentration-to-dose ratio 
for tacrolimus-on-pirfenidone by the concentration-to-dose ratio for 
tacrolimus-off-pirfenidone 
([blood 
 
concentration 
 
on 
pirfenidone/daily dose on pirfenidone]/[blood concentration off 
pirfenidone/daily dose off pirfenidone]).
EFFICACY 
EVALUATIONS
FVC decline: We will evaluate change in FVC every 3 months after 
initiation of pirfenidone.


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(SECONDARY 
OUTCOMES)
Radiographic progression: We will evaluate fibrosis scores on chest 
CT at RCLAD onset and in the follow up CT scans performed as part 
of routine clinical care.
PLANNED INTERIM 
ANALYSES
Quarterly
Rationale for Number 
of Subjects
This is a pilot study with the primary outcome of determining 
pirfenidone tolerability and its effect on tacrolimus dosing. Even with 
a small cohort, we hypothesize we will be powered to detect a 
significance difference in tacrolimus dosing. Based on the single  
report of tacrolimus dosing increase of 2.5 fold, and conservatively 
estimating a standardized effect size of 1 (doubling of tacrolimus dose 
and a standard deviation of the change of 50%), a sample of 8 subjects 
would be required to detect a significant difference, assuming a two- 
sided  of  0.05 and   of 0.20.


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1
BACKGROUND
Despite advances in lung transplantation, median 
survival remains only 55% at 5 years.1 The primary 
cause of death is chronic lung allograft dysfunction 
(CLAD), occurring in 43% of recipients at 5 years.1 
Recently, it has been recognized that CLAD can have 
an obstructive (BOS) or a restrictive (RCLAD) 
phenotype, also  known  as  restrictive  allograft 
syndrome (RAS), and that both may coexist.2,3 These 
phenotypes differ not only in their spirometric, 
radiographic4 and  histologic 5,6  features  but also  in 
their rates of progression7 and survival8-13 (Figure 1). 
Thus, there is a critical need to find therapies other 
than re-transplantation, which remains the only 
effective 
therapeutic 
option 
and 
explore 
the 
pathobiology driving RCLAD.14
RCLAD shares features with Idiopathic Pulmonary 
Fibrosis (IPF), including its progressive and lethal 
course, extracellular matrix deposition, architectural 
distortion, fibroblast proliferation15, and short 
telomeres in lung epithelial cells16 (Fig 2). These 
common features suggest RCLAD and IPF may share 
molecular pathogenesis. As a result, some have 
explored using FDA approved anti-fibrotic 
medications for IPF in RCLAD in case reports.17,18
BOS
RCLAD / RAS
2
STUDY RATIONALE
This proposal aims to gather the preliminary data needed to design a multicenter 
randomized controlled trial (RCT) of pirfenidone for RCLAD. To do so, we first need 
evidence of tolerability, to understand drug interactions with the immunosuppressive 
regimen used to maintain allograft function and early evidence that pirfenidone may slow 
FVC decline and radiographic progression in RCLAD.
Evidence that pirfenidone is well tolerated in transplant recipients and that it slows the 
progression of RCLAD would be paradigm shifting. Further, identifying subjects at risk for 
RCLAD before the onset of spirometric changes would allow to start therapeutic 
interventions sooner, maximizing their benefit. Finding biomarkers that predict response to 
pirfenidone would identify patients most likely to benefit.
3
STUDY OBJECTIVES
3.1
Primary Objectives
The  primary  objectives  of  this  proposal  are  to  assess  tolerability  of  pirfenidone  and 
determine its impact on tacrolimus blood concentration.
Fig 1. Restrictive Allograft syndrome (RAS). 3.


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We hypothesize that treatment-emergent adverse effects (TEAE) in lung transplant 
recipients will be similar to subjects with IPF, leading to drug discontinuation in the same 
proportion of subjects.19
Based on available literature, we hypothesize that initiation of pirfenidone will be 
associated with an increase in tacrolimus dose.17
3.2
Secondary Objectives
To determine if pirfenidone slows allograft dysfunction in RCLAD as evidenced by a 
slower FVC decline and/or a slower progression of radiographic findings.
4
STUDY DESIGN
4.1
Study Overview
1) We will screen for eligible subjects using the computer algorithm on spirometry data 
abstracted from Apex monthly and by suggestion of the transplant pulmonologists. 2) 
Then, we will review CT scans to adjudicate a diagnosis of RCLAD. 3) Finally, our 
pharmacist will determine if tacrolimus dose is stable. After these 3 steps are completed 
subjects will be eligible for the study.
Subjects will be recruited at their transplant clinic visit or by phone if they previously 
consented to be contacted with new research study opportunities. We will seek to enroll ten 
subjects, who will receive pirfenidone for 52 weeks, titrated to 2403 mg/day (3 capsules, 
3× daily) over a period of six weeks. 20 Genentech has agreed to provide study drug free of 
cost.
TEAE will be recorded and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) v3.021. Our study coordinator will contact subjects by phone 
every 2 weeks for the first 6 weeks to inquire about TEAE and then monthly. Subjects will 
be provided a phone number to report any additional TEAE. A Data Safety Monitoring 
Board will be convened.
As part of their routine post-transplant surveillance, subjects have monthly laboratory 
testing that includes tacrolimus blood concentration and liver function tests. Therefore, the 
manufacturer recommendations of monitoring liver function tests monthly for the first six 
months and then every 3 months while taking Pirfenidone, will be followed.
Subjects will continue their routine care with clinic visits, spirometry and CT as clinically 
indicated. In our clinical practice, subjects with RCLAD are expected to have a clinic visit 
and spirometry approximately every 3 months and a CT scan every 6 to 12 months.
If RCLAD subjects in the study undergo bronchoscopy for a clinical indication, 
bronchoalveolar lavage, biopsies, airway brushes and plasma specimens will be collected in 
the biorepository for future analysis of changes in pro-fibrotic mediators after initiation of 
pirfenidone. These specimens will be collected as part of the ongoing “Lung 
Transplantation: Improving outcomes through the development of a clinical database and 
biorepository” study number 13-10738. In the future, we plan to explore whether subjects 
with RCLAD have a greater rate of decline in telomere length in airway epithelial cells 
compared subjects without RCLAD.


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5
SUBJECT SELECTION
5.1
Study Population
Subjects with a diagnosis of RCLAD who meet the inclusion and exclusion criteria will be 
eligible for participation in this study.
5.2
Inclusion Criteria
1. Subjects aged 18 to 80 years old who underwent bilateral lung transplantation at UCSF.
2. Diagnosis of RCLAD based on the International Heart and Lung Transplant (ISHLT) 
classification. The diagnosis of RCLAD is based on spirometry (FEV1 ≤ 80% and FVC ≤ 
80% of best post-transplant baseline) and CT scan (e.g. pleuroparenchymal fibroelastosis) 
findings.
3. Subjects with steady-state blood concentration of tacrolimus, as assessed by 10-12 hour 
trough level.
5.3
Exclusion Criteria
Patients with RCLAD will be excluded if they are, in the judgment of the investigator, 
unlikely to tolerate pirfenidone. Other exclusion criteria will include:
1. FVC decline related to non-RCLAD causes (e.g. pulmonary edema, pleural 
effusion, etc).
2. Patients with any severe comorbidity complicating RCLAD which might determine 
their prognosis and functional level (e.g. active malignant disease) within the last 12 
months.
3. Patients who have resumed smoking after transplantation.
4. Renal insufficiency (creatinine clearance < 30 ml/min calculated by the CKD-Epi 
formula).
5. Total bilirubin above the upper limit of the normal range (ULN)
6. Aspartate or alanine aminotransferase (AST or ALT) > 3 times the ULN.
7. Known allergy of hypersensitivity to Pirfenidone
8. Ongoing use or expected use of any of the following therapies:
-
Strong inhibitors of CYP1A2 (e.g. fluvoxamine or enoxacin).
-
Moderate inhibitors of CAYP1A2 (e. g. mexiletine, thiabendazole, or 
phenylpropanolamine). Ciprofloxacin will be allowed only at doses equal or 
less than 500 mg BID.
9. Inability to provide informed consent.
6
STUDY PROCEDURES AND GUIDELINES
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed below.


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Week
1
2
3
4
5
6
8
12
16
20
24
28
32
36
40
44
48
52
56
57
60
Start 
Pirfenidone
x
Study 
coordinator 
call
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tacrolimus 
level
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Liver 
function 
tests
x
x
x
x
x
x
x
x
Clinic visit
x
x
x
x
FVC
measure
x
x
x
x
CT scan
x
Stop 
Pirfenidone
x
Prior to conducting any study-related activities, written informed consent must be signed 
and dated by the subject.
Any clinically significant findings will be communicated to the patients and, with their 
consent, to the patients’ clinical providers.
Study coordinator call: Our study coordinator will contact subjects by phone every 2 
weeks for the first 6 weeks to inquire about treatment-emergent adverse events (TEAE) and 
then monthly. TEAE will be recorded and graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) v3.021. The last phone call will be 28 days after the 
last pirfenidone dose. Subjects will be provided a phone number to report any additional 
TEAE. A Data Safety Monitoring Board will be convened.


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Tacrolimus concentration measurement: Patients will continue to use their chosen 
laboratory for tacrolimus measurement, as part of their clinical care. As it is our clinical 
practice, the results will be reviewed daily through Titus and the transplant nurse 
coordinators will contact the patients with instructions to adjust their tacrolimus dose.
Liver function test measurement: Patients will continue to use their chosen laboratory for 
monthly liver function test measurement according to the post-transplant surveillance 
protocol. We will track these values every month for the first 6 months of Pirfenidone 
therapy and every 3 months for the remaining 6 months, following manufacturer’s 
recommendations.
Office spirometry (FVC): As part of their clinical care, patients will have office FVC 
measurement (spirometry) approximately every 3 months or more often if clinically 
indicated according to ATS/ERS guidelines.
High-resolution chest CT (HRCT): Patients will have a HRCT every 6 to 12 months as 
part of their clinical care. We will review these images to evaluate fibrosis scores.
Reporting of clinical events: All patients will be asked to report clinical events (e.g. new 
or worsening symptoms, unscheduled medical visits, hospitalizations) to the study 
coordinator over the phone. The study coordinator will ask the transplant nurse 
coordinators and review the medical record to investigate if any other events occurred.
Protocol Amendment
Subjects that wish to continue taking pirfenidone beyond 56 weeks may be eligible for 
PIRCLAD extension for up to 76 weeks. The Principal Investigator will determine 
eligibility for PIRCLAD extension after reviewing the 52-week study coordinator call. 
Subjects must continue to meet the original inclusion and exclusion criteria. Subjects will 
continue to be monitored per study protocol (laboratory tests, study coordinator calls, clinic 
visits, pulmonary function tests, and CT scan imaging) as long as they remain on 
pirfenidone. The last pirfenidone dose will be on September 30, 2021. The last study 
coordinator call will occur 28 days after the last pirfenidone dose. Reporting of adverse 
events and protocol violations for these subjects will remain the same. The duration of 
PIRCLAD extension is diagrammed below.


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Week
56
60
64
68
72
76
80
84
88
92
96
100
104
108
112
116
120
124
128
129
132
Continue 
Pirfenidone
x
Study 
coordinator 
call
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tacrolimus 
level
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Liver 
function 
tests
x
x
x
x
x
x
x
Clinic visit
x
x
x
x
x
x
x
FVC
measure
x
x
x
x
x
x
x
CT scan
x
Stop 
Pirfenidone
x
7
PROTOCOL VIOLATIONS
A protocol violation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria. Failure to comply with Good Clinical Practice (GCP) guidelines will also 
result in a protocol violation. The investigator will determine if a protocol violation will 
result in withdrawal of a subject.
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by the 
Investigator. A copy of the form will be filed.
8
STATISTICAL METHODS AND CONSIDERATIONS
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed. The SAP will contain any 
modifications to the analysis plan described below.
Interim analysis plans: We will plan interim analyses of data quality and patient 
compliance on a quarterly basis to insure adequate study conduct. Modifications to the 
study conduct (e.g. changes to the outcome measures, or even cessation of the study if 
indicated by issues with performance or outcomes) will be considered at each of these 
analyses.
Power: This is a pilot study with the primary outcome of determining pirfenidone 
tolerability and its effect on tacrolimus dosing. Even with a small cohort, we hypothesize 
we will be powered to detect a significance difference in tacrolimus dosing. Based on the 
single report of tacrolimus dosing increase of 2.5 fold, and conservatively estimating a 
standardized effect size of 1 (doubling of tacrolimus dose and a standard deviation of the


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change of 50%), a sample of 8 subjects would be required to detect a significant difference, 
assuming a two-sided  of 0.05 and  of 0.20.
Data analysis plan: Since we will be comparing within subject changes, we will use paired 
t-test to compare the tacrolimus-on-pirfenidone to tacrolimus-off-pirfenidone ratio. For 
analyses involving repeated measures including change in FVC, fibrosis score, and telomere 
length, we will use mixed effects models22 including subject as a fixed effect.
Slopes before and after the initiation of pirfenidone will be compared.
9
DATA COLLECTION, RETENTION AND MONITORING
9.1
Data Collection and Management
Data will be collected on paper worksheets and entered into the Research Electronic Data 
Capture (REDCap) system by dedicated clinical research coordinators using study-specific 
clinical research forms. REDCap is an easy-to-use highly secure data management system 
provided by UCSF to investigators for research use at no charge. All REDCap data will be 
reviewed and cleaned by the study investigators after data entry. Paper worksheets will be 
kept in patient binders as backup and securely stored.
9.2
Availability and Retention of Investigational Records
The Investigator will make study data accessible to the IRB, and other interested parties 
upon request. A file for each subject must be maintained that includes the signed Informed 
Consent and copies of all source documentation related to that subject. The Investigator 
must ensure the reliability and availability of source documents from which the information 
on the CRF was derived. All study documents (patient files, signed informed consent  
forms, copies of CRFs, Study File Notebook, etc.) must be kept secured for a period of two 
years.
9.3
Subject Confidentiality
In order to maintain subject confidentiality, only a site number, subject number and subject 
initials will identify all study subjects on CRFs.
10 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of
Clinical Investigators (21 CFR 312).
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only. All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet. Clinical 
information will not be released without written permission of the subject, except as legally 
required. The Investigator must also comply with all applicable privacy regulations (e.g., 
Health Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 
95/46/EC).


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10.1 Protocol Amendments
Protocol amendments will not be implemented without prior written IRB approval except 
as necessary to eliminate immediate safety hazards to patients. A protocol amendment 
intended to eliminate an apparent immediate hazard to patients may be implemented 
immediately, provided the IRBs are notified within five working days.
10.2 Institutional Review Boards
The protocol and consent form will be reviewed and approved by the IRB at UCSF prior to 
study initiation. Serious adverse experiences will be reported to the IRB/IEC in accordance 
with the standard operating procedures and policies of the IRB, and the Investigator will 
keep the IRB informed as to the progress of the study. The Investigator will obtain 
assurance of IRB compliance with regulations.
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, 
protocol amendments, consent forms, information concerning patient recruitment, payment 
or compensation procedures, or other pertinent information) will be submitted to the IRB. 
The IRBs written unconditional approval of the study protocol and the informed consent 
form will be in the possession of the Investigator before the study is initiated. This approval 
must refer to the study by exact protocol title and number and should identify the documents 
reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB approval except when necessary to eliminate immediate hazards to the 
patients or when the change(s) involves only logistical or administrative aspects of the 
study. Such modifications will be submitted to the IRB and written verification that the 
modification was submitted and subsequently approved should be obtained.
The IRB must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance 
with the standard operating procedures and policies of the IRB; new information that may 
affect adversely the safety of the patients of the conduct of the study; an annual update 
and/or request for re-approval; and when the study has been completed.
10.3 Informed Consent Form
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations.
The Investigator will prepare the informed consent form and HIPAA authorization prior to 
submission to the IRB/IEC. The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will 
also comply with local regulations. The Investigator will send an IRB-approved copy of the 
Informed Consent Form to the Sponsor (or designee) for the study file.
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial. Information should be given in both oral and written 
form and subjects must be given ample opportunity to inquire about details of the study. If


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appropriate and required by the local IRB, assent from the subject will also be obtained. A 
copy of the signed consent form will be given to the subject and the original will be 
maintained with the subject’s records.
10.4 Publications
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by the investigators. The publication or 
presentation of any study results shall comply with all applicable privacy laws, including, 
but not limited to, the Health Insurance Portability and Accountability Act of 1996.
A publication will be done at the end of the 52-week trial, and a separate publication will 
potentially be done at the end of the extension phase of trial.
10.5   Investigator Responsibilities
By signing the Agreement of Investigator form, the Investigator agrees to:
1.
Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects.
2.
Personally conduct or supervise the study (or investigation).
3.
Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.
4.
Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments.
5.
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection when required.
6.
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study.
7.
Promptly report to the IRB all changes in the research activity and all unanticipated 
problems involving risks to subjects or others.
8.
Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects.
9.
Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312.


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11 SAFETY REPORTING OF ADVERSE EVENTS
11.1 Assessment of Safety
11.1.1 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.
11.1.2 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 
RCLAD 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.
11.1.3 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).


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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 (IND Safety Reports).
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 study treatment and ends 28 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 Pirfenidone (see following guidance), and actions taken.
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline:
11.2.3 Yes
There is a plausible temporal relationship between the onset of the AE and administration 
of Pirfenidone, 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 Pirfenidone; and/or the AE abates or resolves upon discontinuation of 
Pirfenidone or dose reduction and, if applicable, reappears upon re-challenge.
11.2.4 No
Evidence exists that the AE has an etiology other than Pirfenidone (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to Pirfenidone 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.


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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.
11.3.2.1 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.
11.3.2.2 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”.
11.3.2.3 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”).
11.3.2.4 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:


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●
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.
11.3.2.5 Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE v5.0 will be used for assessing 
adverse event severity. Below Table should be used for assessing severity for adverse events that 
are not specifically listed in the NCI CTCAE.
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 (v5.0), 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
d.
Grade 4 and 5 events must be reported as serious adverse events
11.3.2.6 e.
Pregnancy
If a female subject becomes pregnant while receiving the study drug or within 28 days after 
the last dose of study drug, or if the female partner of a male study subject becomes pregnant 
while the study subject is receiving the study drug or within 28 days after the last dose of study  
drug, a report should be completed and expeditiously submitted to Genentech, Inc. Follow-


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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 Pirfenidone should be reported as an SAE.
11.3.2.7 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 Pirfenidone 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/CTV
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.
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the agreed 
time period. Confirmation of receipt should be received within the time period mutually agreed 
upon.
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’.
Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by Sponsor (UCSF) to Genentech within five (5) calendar days from 
request by Genentech.
At the end of the study, a final cumulative Case Transmission Verification report will 
be sent to Genentech
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.
Pirfenidone Events of Special Interest are:


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Hys and Stiamp:
1.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.
●
Treatment-emergent ALT or AST > 3 x ULN in combination with total bilirubin > 2  x ULN
●
Treatment-emergent ALT or AST > 3 x ULN in combination with clinical jaundice
●
There is a risk of pirfenidone causing elevation in liver function tests. ALT, AST, and bilirubin 
elevations have occurred with pirfenidone including cases of drug-induced liver injury. In the 
postmarketing setting, non-serious and serious cases of drug-induced liver injury, including 
severe liver injury with fatal outcomes, have been reported.
2.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.
11.3.2.8 I.Adverse Event Reporting
UCSF will be responsible for collecting all protocol-defined Adverse Events (AEs)/Serious Adverse 
Events (SAEs), AEs of Special Interest (AESIs), Special Situation Reports (including pregnancy 
reports) and Product Complaints (with or without an AE) originating from the Study for the Product.
Investigators must report all above mentioned single case reports to Genentech within the 
timelines described below. The completed MedWatch/case report should be faxed 
immediately upon completion to Genentech Drug Safety at:
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) and 
Product Complaints with an AE should be sent to
Fax:650-238-6067
Email: usds_aereporting-d@gene.com
All Product Complaints without an AE should be sent to:
Email: kaiseraugst.global_impcomplaint_management@roche.com
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 Roche contact specified in Addendum 2 of this SDEA. Transmission of these 
reports (initial and follow-up) will be either electronically or by fax and within the 
timelines specified below:]


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●
SADRs
Serious AE reports that are related to the Product shall be transmitted to Roche 
within fifteen (15) calendar days of the awareness date.
●
Other SAEs
Serious AE reports that are unrelated to the Product shall be transmitted to Roche 
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 Roche 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.
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 30 days after 
the last dose of study drug. A Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to Genentech within thirty (30) calendar days of the awareness 
date
●
AESIs
AESIs requiring expedited reporting shall be forwarded to Roche within fifteen (15) 
calendar days of the awareness date. Others shall be sent within thirty (30) calendar 
days.
●
Non-serious AEs
Non-serious AEs shall be transmitted to Roche on a periodic (e.g., monthly) line- 
listing containing the following elements (Protocol number, Patient ID, Patient birth 
date, Adverse Event/MedDRA term, Seriousness of event, Onset date of event, 
Death date, Product received, Date of first dose, Cause(s) of event, Adverse Event 
description).
●
Relevant follow-up information should be submitted to Genentech Drug Safety as 
soon as it becomes available.


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Special situation reports
In addition to all AEs, pregnancy reports and AESIs, the following Special Situations 
Reports should be collected and transmitted to Roche 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)
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
●
Product Complaints
All Product Complaints (with or without an AE) shall be forwarded to Genentech within 
fifteen (15) calendar days of the awareness date.
A Product Complaint is defined as any written or oral information received from a 
complainant that alleges deficiencies related to identity, quality, safety, strength, purity, 
reliability, durability, effectiveness, or performance of a product after it has been released 
and distributed to the commercial market or clinical trial.
REPORTING TO REGULATORY AUTHORITIES, ETHICS COMMITTEES AND 
INVESTIGATORS
Genentech as the Marketing Authorization Holder will be responsible for the reporting of individual 
case safety reports from the study to the regulatory authority in compliance with applicable 
regulations.
UCSF, as the Sponsor of the Study, will be responsible for the expedited reporting of safety 
reports originating from the study to the EMA through Eudravigilance Clinical Trial Module 
(EVCTM), where applicable.
UCSF will be responsible for the expedited reporting of safety reports originating from the Study to 
the Ethics Committees and Institutional Review Boards (IRB), where applicable.


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j.  Aggregate Reports
Development Safety Update Report
Sponsor as the Sponsor of the Study, will be responsible for the preparation of their own 
Development Safety Update Report (DSUR) for the Study and for the submission of the report to 
the regulatory authorities and Ethics Committees of the concerned Member States, where 
applicable. Sponsor agrees to share a copy of their own DSUR with Genentech as soon as 
reasonably possible after completion.
Genentech agrees to forward to Sponsor an executive summary of the Genentech DSUR upon 
request. Furthermore, Genentech agrees that Sponsor may cross-reference the executive summary 
of the Genentech/Roche DSUR, as applicable.
Other Reports:
UCSF will forward a copy of the Publication to Roche upon completion of the Study.
Note: Investigators should also report events to their IRB as required.
For questions related to safety reporting, please contact Genentech/Roche Drug Safety:
Tel: (888) 835-2555
Fax: (650) 225-4682 or (650) 225-4630
11.3.3 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
●
Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication
11.3.3.1 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


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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/media/69876/download
11.4 Study Close-Out
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and 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:
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com
QUERIES
Queries related to the Study will be answered by Genentech. However, 
responses to all safety queries from regulatory authorities or for 
publications will be discussed and coordinated between the Parties. The  
Parties agree that Genentech/Roche shall have the final say and control over 
safety queries relating to the Product. Genentech agrees that it shall not answer 
such queries from regulatory authorities and other sources relating to the 
Product independently but shall redirect such queries to Genentech/Roche.
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests for information or review of data are met. The Parties will clearly indicate on the 
request the reason for urgency and the date by which a response is required
SAFETY CRISIS MANAGEMENT
In case of a safety crisis, e.g., where safety issues have a potential impact on 
the indication(s), on the conduct of the Study, may lead to labeling changes or 
regulatory actions that limit or restrict the way in which the Product is used, or 
where there is media involvement, the Party where the crisis originates will 
contact the other Party as soon as possible.
The Parties agree that Genentech/Roche shall have the final say and control 
over safety crisis management issues relating to the Product. Genentech


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agrees that it shall not answer such queries from media and other sources 
relating to the Product but shall redirect such queries to Genentech/Roche.
Data and Safety Monitoring Plan (required by the UCSF IRB)
DATA REVIEW
Investigators (Dr. Venado and Dr. Dewey) will conduct continuous review of data from 
UCSF enrolled patient safety at monthly study group meetings where the results of each 
patient’s treatment are discussed. The discussion will include the number of patients, 
significant toxicities as described in the protocol, doses adjustments, and observed 
responses. The research team will adhere to the UCSF IRB reporting requirements.
INTERIM ANALYSIS
Interim analyses will be discussed quarterly with Dr. Leah Witt, who will serve as the 
Medical Monitor to assess safety. Enrollment will continue except if there were unexpected 
toxicities. These evaluations will not be assessed by any formal statistical test, only listings 
and summary estimates will be provided. The results of interim analyses will be 
documented and assessed internally by the study core team. Written letters will be 
submitted to the IRB and the investigators as necessary.
STOPPING RULES
On section 5.4.2.1 “Overview of Adverse Events” of the Investigator’s Brochure 
provided by Genentech it states that almost every patient in both the pirfenidone and 
placebo treatment groups experienced an adverse event (AE) (99% and 97.9%, 
respectively). A total of 42.7% of patients in the pirfenidone treatment group had an AE 
that led to a dose reduction or interruption of any duration compared to 16.2% of patients in 
the placebo groups; a much lower percentage discontinued treatment early (14.6%) due to 
any AE. Overall 71 patients died. Fewer patients died in the pirfenidone group than in the 
placebo group (27 patients, 4.3% vs 44 patients, 7.1%). The treatment group difference was 
driven in part by a reduction in deaths due to IPF in the pirfenidone-treated patients (10 
patients, 1.6% vs 21 patients, 3.4%). On section 5.4.2.5 “Adverse Events Leading to Early 
Discontinuation of Study Treatment” it states that 14.6% of subjects discontinued treatment 
due to an AE in the pirfenidone group, compared to 9.6% in the placebo group. Most 
patients discontinued the treatment in the first year.
Our null hypothesis is that tolerability of pirfenidone in the PIRCLAD study will be 
similar to that in the PIPF-004, PIPF-006 (CAPACITY), and PIPF-016 (ASCEND) studies.  
Therefore, we expect the proportion of subjects enrolled in the PIRCLAD study will be 
similar pirfenidone early due to an AE will be the same or lower. Given the small sample size 
of the PIRCLAD study, we calculated the maximum early discontinuation proportion that 
would be similar to 14.6% considering a p<0.05 for statistical significance. This proportion is 
25% of study participants (p=0.0451), which would be consistent with the findings of the 
PASSPORT study. The PASSPORT study, a multicenter, prospective, observational post-
authorization study that evaluated long-term safety of pirfenidone found that in real-world 
practice, AE lead to pirfenidone discontinuation in 28.7% (290/1009) of patients, after a 
median of 99.5 days23.  


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Thus, we expect that up to 3 of the 10 subjects in the study will discontinue pirfenidone early 
due to an AE. 
The PIRCLAD study will stop enrolling new participants if more than 3 subjects discontinue 
pirfenidone early due to an AE. 
Participants who are tolerating pirfenidone well and wish to continue taking it will be    
allowed to remain in the PIRCLAD study. 
Discontinuation:
Patients may temporarily suspend all study drugs for up to 28 consecutive days if they 
experience toxicity that is considered related to study treatment and that requires a study


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treatment hold. Patients who miss > 28 consecutive days of scheduled study treatment 
because of drug-related adverse events will be discontinued from the study. Exceptions 
may be made after discussions with the investigators, approval by the Medical Monitor, 
and consistency with the regulations of the Institutional Review Board/Ethics Committee 
(IRB/EC).
Patients who miss 14 or more days of Pirfenidone should reinitiate treatment by undergoing 
the initial 4 week titration regimen up to the full maintenance dosage. For treatment 
interruption of less than 14 days, the dosage prior to the interruption can be resumed.
DOSE MODIFICATIONS
Dose-reduction Procedure for Adverse Event Management:
If patients experience significant adverse reactions (i.e., gastrointestinal, photosensitivity 
reaction or rash), they will have the following temporary dose reduction: reduce dose to 
267 mg three times daily (801 mg/day) for 14 days, followed by 534 mg three times daily 
(1602 mg/day) for another 14 days, prior to returning to the protocol dose of 801 mg three 
times daily (2403 mg/day). If adverse reactions do not resolve with reducing dose to 267 
mg three times daily (801 mg/day) for 14 days, patients will discontinue pirfenidone for 14 
days. Any return to protocol dose level after dose reduction must follow documentation of 
resolution of the adverse event and after discussion with the medical monitor.
If a patient exhibits 2-3 times the upper limit of normal (ULN) ALT and/or AST elevation 
without symptoms or hyperbilirubinemia after starting Pirfenidone therapy, he/she will 
discontinue Pirfenidone for 14 days and reinitiate treatment by undergoing the initial 4- 
week titration regimen up to the full maintenance dosage if tolerated and repeat liver 
chemistry tests are within normal limits. We will exclude other causes, monitor the patient 
closely, and repeat liver chemistry tests as clinically indicated.
If a patient exhibits >3 times ULN ALT and/or AST elevation he/she will permanently 
discontinue Pirfenidone and will not be re-challenged with it.
Dosage Modification due to Drug Interactions
Strong CYP1A2 Inhibitors (e.g., fluvoxamine, enoxacin): Reduce Pirfenidone to 267 mg 
three times a day (801 mg/day).
Moderate CYP1A2 Inhibitors (e.g., ciprofloxacin) With use of ciprofloxacin at a dosage of 
750 mg twice daily, patients will reduce Pirfenidone to 534 mg three times a day (1602 
mg/day).
WITHDRAWAL
Discontinuation of Patients:
The investigator will discontinue patients from the study drug or the study or both in the 
following circumstances:
●
The patient, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication. In this 
case, discontinuation from the study occurs prior to introduction of the new agent.


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●
The investigator decides that the patient should be withdrawn from the study. If a 
serious adverse event or a clinically significant laboratory value is the basis for this 
decision, the investigator will discontinue the study therapy and take appropriate 
measures. The investigator must immediately notify the study sponsor or its 
designee.
●
The patient or attending physician requests withdrawal of the patient from the 
study.
●
The investigator or the study sponsor stops the study or stops the patient’s 
participation in the study for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and good clinical practice (GCP).
●
The study therapies have shown unacceptable toxicity.
●
The patient becomes pregnant or fails to use adequate birth control (for women with 
reproductive potential).
●
The patient is noncompliant with study procedures.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document.
Study agents assigned to the withdrawn subject may not be assigned to another subject. 
Subjects who withdraw will not be replaced.
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