Weighing Risks and Benefits of Laparoscopic Anti-Reflux Surgery in Patients With Idiopathic Pulmonary Fibrosis
Phase: NA
Conditions: Idiopathic Pulmonary Fibrosis, Gastroesophageal Reflux
Sponsor: University of California, San Francisco

Weighing Risks and Benefits of Laparoscopic Anti-Reflux Surgery in Patients With 
Idiopathic Pulmonary Fibrosis
NCT01982968 
Document Date: 08 Apr 2016

Page 1 of 35 
WEIGHING RISKS AND BENEFITS OF LAPAROSCOPIC
ANTI-REFLUX SURGERY IN PATIENTS WITH IDIOPATHIC
PULMONARY FIBROSIS (WRAP-IPF): A PHASE II
CLINICAL TRIAL 
Version 6.0 (amendment #4.1) 
Version date: 11 Dec 2015 

Page 2 of 35 
 
Protocol Summary 
TREATMENT 
Laparoscopic anti-reflux surgery 
CLINICALTRIALS.GOV IDENTIFIER NCT01982698 
PROTOCOL TITLE 
Weighing Risks and benefits of Laparoscopic Anti-
Reflux 
Surgery 
in 
Patients 
with 
Idiopathic 
Pulmonary Fibrosis (WRAP-IPF) 
DIAGNOSIS AND MAIN CRITERIA 
FOR INCLUSION 
Confirmed idiopathic pulmonary fibrosis (IPF) and  
evidence of abnormal acid gastro-esophageal 
reflux (GER) by 24-hour pH testing (DeMeester 
score of >14.7) 
STUDY OBJECTIVES 
To demonstrate slowed decline of forced vital 
capacity (FVC) through anti-reflux surgery 
compared with standard care. 
STUDY DESIGN 
Multi-center, randomized, un-blinded  
TREATMENT REGIMEN 
Laparoscopic anti-reflux surgery or standard care. 
DURATION OF STUDY 
PARTICIPATION 
52 weeks 
NUMBER OF SUBJECTS 
Approximately 58 (randomized in a 1:1 ratio) 
NUMBER OF SITES 
6 sites (U.S. only) 
PRIMARY ENDPOINTS 
Change in FVC from baseline to 48 weeks  
SECONDARY ENDPOINTS 
Mortality 
Non-elective hospitalization 
Acute exacerbation 
Disease Progression 
Change in UCSD SOBQ score 
Change in SGRQ score 
Time to death, acute exacerbation, or non-elective 
hospitalization (composite endpoint) 
Time to death, acute exacerbation, non-elective 
hospitalization, or disease progression (composite 
endpoint) 
Categorical change in FVC 
Change on cough visual analog scale (VAS) 

Page 3 of 35 
Change in ICECAP-O score 
Change in EuroQOL EQ-5D score 
Change in 6-minute walk distance (6MWD) 
Reduction in acid GER assessed by serial pH 
testing and GER questionnaire 
Quantitative change in HRCT fibrosis score 
 
 

Page 4 of 35 
Study Sponsor: 
 
National Heart Lung and Blood Institute, NIH  
 
 
 
 
 
 
Study Chairs:  
 
Harold R. Collard, MD – UCSF 
 
 
 
 
Ganesh Raghu, MD – University of Washington 
 
 
 
 
 
 
Steering Committee Members 
Kevin J. Anstrom - Duke University 
Harold R. Collard – University of California, San Francisco 
Rex Edwards – Pulmonary Fibrosis Foundation 
Jerry Eu – National Institute of Health 
Kevin Flaherty – University of Michigan 
Joyce Lee – University of Colorado Denver 
Keith Meyer – University of Wisconsin 
Ellen Morrow – University of Utah 
Imre Noth – University of Chicago 
Carlos Pellegrini - University of Washington 
Ganesh Raghu – University of Washington 
Mary Beth Scholand – University of Utah 
Lisa Webber – National Institute of Health 
Paul J. Wolters – University of California San Francisco 
 
 
 
Data Coordinating Center: Duke Clinical Research Institute, Durham, NC 
Laura Johnson - Duke University 
Sarah Ramey - Duke University 
Patricia Robles - Duke University 
Carmel Scharenbroich- Duke University 
Ramona Taylor - Duke University 
Eric Yow - Duke University 
 
 
 
 
 
 
 
 

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Table of Contents 
LIST OF TABLES ................................................................................................................................................ 7 
LIST OF FIGURES .............................................................................................................................................. 8 
LIST OF ABBREVIATIONS .............................................................................................................................. 9 
1. SUMMARY ..................................................................................................................................................... 10 
2. HYPOTHESIS AND SPECIFIC AIMS ........................................................................................................ 10 
2.1. STUDY HYPOTHESIS ................................................................................................................................ 10 
2.2. SPECIFIC AIM 1 ........................................................................................................................................ 10 
2.3. SPECIFIC AIM 2 ........................................................................................................................................ 10 
2.4. SPECIFIC AIM 3 ........................................................................................................................................ 10 
2.5. SPECIFIC AIM 4 ........................................................................................................................................ 11 
2.6. SPECIFIC AIM 5 ........................................................................................................................................ 11 
3. BACKGROUND AND SIGNIFICANCE ..................................................................................................... 11 
4. PRELIMINARY STUDIES ........................................................................................................................... 12 
4.1. ANIMAL MODELS ....................................................................................................................................... 12 
4.2. RETROSPECTIVE DATA IN PATIENTS WITH IPF ........................................................................................ 12 
5. METHODS ...................................................................................................................................................... 14 
5.1. INCLUSION CRITERIA ................................................................................................................................ 14 
5.2. DIAGNOSIS OF IDIOPATHIC PULMONARY FIBROSIS ................................................................................. 14 
5.3. EXCLUSION CRITERIA .............................................................................................................................. 15 
5.4 STUDY DESIGN AND STUDY VISITS........................................................................................................... 15 
5.5 TRAVEL REIMBURSEMENT ........................................................................................................................ 20 
5.6. RECRUITMENT PROCEDURES .................................................................................................................. 21 
6. STUDY ENDPOINTS .................................................................................................................................... 21 
6.1. PRIMARY ENDPOINT ................................................................................................................................. 21 
6.2. SECONDARY ENDPOINTS ......................................................................................................................... 21 
6.3. DEFINITION OF DISEASE PROGRESSION ................................................................................................. 22 
6.4 DEFINITION OF ACUTE EXACERBATIONS .................................................................................................. 22 
6.5 METHOD FOR IDENTIFICATION OF ACUTE EXACERBATION ....................................................................... 23 
7.1 DEFINITIONS .............................................................................................................................................. 23 
8. SURGICAL INTERVENTION ..................................................................................................................... 25 
9. DATA MANAGEMENT ................................................................................................................................ 26 
9.1. DESIGN AND DEVELOPMENT .................................................................................................................... 26 
9.2. DATA COLLECTION FORMS ...................................................................................................................... 27 
9.3. DATA ACQUISITION AND ENTRY ............................................................................................................... 27 
9.4. DATA CENTER RESPONSIBILITIES ........................................................................................................... 27 
9.5. DATA EDITING .......................................................................................................................................... 27 
9.6. TRAINING .................................................................................................................................................. 28 
10. DATA ANALYSIS ........................................................................................................................................ 28 
10.1. SAMPLE SIZE DETERMINATION AND RANDOMIZATION .......................................................................... 28 
10.2. SPECIFICATION OF THE PRIMARY ANALYSIS ......................................................................................... 29 
11. STUDY ADMINISTRATION ..................................................................................................................... 30 
11.1. STEERING COMMITTEE .......................................................................................................................... 30 
11.2. DATA AND SAFETY MONITORING BOARD .............................................................................................. 30 
12. INVESTIGATOR AND SPONSOR OBLIGATIONS .............................................................................. 31 

Page 6 of 35 
12.1. SITE AND REMOTE MONITORING ........................................................................................................... 31 
12.2. CONFIDENTIALITY AND HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT (HIPAA) 
CONSIDERATIONS .................................................................................................................................. 31 
13. INVESTIGATOR AGREEMENT .............................................................................................................. 33 
14. REFERENCES ............................................................................................................................................ 34 
 

Page 7 of 35 
  
List of Tables 
 
Table 1. Table of Study Visits. 
 
Table 2. Final Diagnosis in the Evaluation of Suspected Acute Exacerbations. 
 
Table 3. Enrollment requirements for varying effect size and power.  
 

Page 8 of 35 
List of Figures 
 
 
Figure 1. Laparoscopic surgery was associated with increased survival compared to no 
therapy. 
 
Figure 2. Change in FVC before (pre) and after (post) laparoscopic anti-reflux surgery. 
 
 
 
 
 
 
 

Page 9 of 35 
List of Abbreviations 
 
6MWD 
6-minute walk distance  
6MWT 
6-minute walk test 
ABG 
arterial blood gas  
AE 
adverse event 
AEx 
acute exacerbation 
BAL 
bronchoalveolar lavage 
CRF 
case report form 
DCC 
Data Coordinating Center 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DSMB 
Data and Safety Monitoring Board  
eCRF 
Electronic case report form 
FVC 
forced vital capacity 
GER 
Gastroesophageal reflux 
HIPAA 
Health Insurance Portability and Accountability Act 
HRCT 
high-resolution computed tomography  
ICECAP-O 
ICEpop CAPability measure for Older People 
ILD 
interstitial lung disease 
IPF 
idiopathic pulmonary fibrosis 
IRB 
institutional review board 
MOP 
Manual of Operating Procedures 
NHLBI 
National Heart Lung and Blood Institute 
NIH 
National Institutes of Health (U.S.) 
PFT 
pulmonary function test 
PI 
principal investigator 
QOL 
quality of life 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SGRQ 
St. George’s Respiratory Questionnaire 
UCSD SOBQ 
University of California at San Diego Shortness of Breath Questionnaire 
VAS 
Visual Analog Scale 
 
 

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WEIGHING RISKS AND BENEFITS OF LAPAROSCOPIC ANTI-REFLUX SURGERY IN PATIENTS 
WITH IDIOPATHIC PULMONARY FIBROSIS (WRAP-IPF): A PHASE II CLINICAL TRIAL 
 
1. Summary 
 
This protocol proposes to test the following hypothesis: Treatment with laparoscopic anti-
reflux surgery in subjects with idiopathic pulmonary fibrosis (IPF) and abnormal 
gastroesophageal (GER) reflux will slow the decline of forced vital capacity (FVC) over 48 
weeks. 
 
This study will randomize approximately 58 subjects with IPF and abnormal acid reflux on 
24-hour pH monitoring to laparoscopic anti-reflux surgery or standard care (randomization 
ratio 1:1). Subjects will be followed for 52 weeks or until the time of lung transplantation or 
death. 
 
2. Hypothesis and Specific Aims 
 
2.1. Study Hypothesis 
Our primary hypothesis is that the reduction of abnormal GER with laparoscopic anti-reflux 
surgery will slow the progression of IPF as measured by FVC. We further hypothesize that 
laparoscopic anti-reflux surgery will reduce the frequency of acid reflux, will be safe and well 
tolerated, will improve symptoms and quality of life, and will reduce the incidence of acute 
exacerbation, hospitalization, disease progression and death. Specifically, we will address 
the following aims: 
2.2. Specific Aim 1 
We aim to determine the impact of laparoscopic anti-reflux surgery on change in FVC over 
48 weeks in patients with IPF and abnormal GER.  
2.3. Specific Aim 2  
We aim to correlate the reduction in acid reflux events with the change in FVC over 48 
weeks in patients with IPF and abnormal GER. 
2.4. Specific Aim 3  
We aim to determine the safety of laparoscopic anti-reflux surgery in patients with IPF and 
abnormal GER. 

Page 11 of 35 
2.5. Specific Aim 4  
We aim to explore the impact of laparoscopic anti-reflux surgery on key secondary 
endpoints over 48 weeks in patients with IPF and abnormal GER. 
2.6. Specific Aim 5 
To identify molecular markers of IPF disease activity and gastroesophageal reflux in 
biological samples from patients with IPF and abnormal GER. 
 
 
3. Background and Significance 
 
 
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause 
and increasing prevalence in the United States.1,2 An estimated 100,000 Americans will die 
from IPF this year, and aside from lung transplantation, which only 1% will receive, there is 
no FDA-approved therapy. 
Over the last decade, a potential role for gastroesophageal reflux (GER) in the progression 
of IPF has been suggested.3 This is based on several observations: First, it is clear that the 
overwhelming majority of patients with IPF have abnormal GER.4-6 Second, small case 
series of patients with IPF treated for GER demonstrated stabilization of pulmonary 
physiology and oxygenation.7,8 Third, the treatment of GER has been associated with 
improved survival in two large, independent retrospective cohorts of patients with IPF.9  
Importantly, there are no prospective, randomized data addressing the treatment of GER in 
IPF and there is a real chance that the data collected to date are misleading. A prospective, 
controlled trial is essential to answer this question. 
The mechanistic hypothesis for GER causing progression of IPF is as follows. Abnormal 
GER is a known risk factor for microaspiration of gastric contents.10,11 In patients with IPF, 
microaspiration may be an important contributor to disease progression through increasing 
the alveolar epithelial stress and abnormal repair characteristic of the disease.12,13 In support 
of this are data from patients with IPF experiencing acute exacerbation of their disease that 
demonstrate increased levels of pepsin in the bronchoalveolar lavagate compared to stable 
IPF patients.14  
Both acid and non-acid GER may be important to disease progression in IPF based on data 
from animal models that show aspiration of both acid and non-acid refluxate causes 
pulmonary fibrosis,15-17 and data from IPF patients suggest an increased benefit of 

Page 12 of 35 
laparoscopic anti-reflux surgery over medical antacid therapy alone.9 Surgical treatment for 
GER with laparoscopic anti-reflux surgery reduces the incidence of all GER, both acid and 
non-acid; medical treatment for GER does not reduce the incidence of GER substantially – 
instead it simply reduces the acidity of the refluxate. Laparoscopic anti-reflux surgery has 
been safely performed in patients with IPF and other forms of advanced lung disease 
awaiting lung transplantation.8,18,19 
Together, these data provide an argument for a possible benefit to the treatment of 
abnormal GER in patients with IPF and associated GER, a fact recently recognized by the 
ATS/ERS/JRS/ALAT evidence-based guidelines committee authors and others.1,20 The data 
further suggest that therapy with laparoscopic anti-reflux surgery, that reduces the incidence 
of both acid and non-acid reflux, is the most appropriate intervention to test.  
 
 
4. Preliminary Studies 
 
4.1. Animal models 
Animal models show that both the acid and non-acid components of gastroesophageal 
refluxate are relevant. In one animal model of acute gastric acid aspiration, widespread 
collagen deposition developed in the lungs within two weeks.15 In other animal models 
investigating chronic aspiration of various components of the gastric refluxate showed that 
development of lung fibrosis was independent of the acidity of the aspirate, and suggesting 
perhaps gastric contents (e.g. bile, pepsin, or food particulates) were responsible.16,17 These 
data support the concept that there are multiple components of the gastroesophageal 
refluxate (both acid and non-acid) that could contribute to ongoing alveolar epithelial stress 
in patients with IPF through chronic aspiration into the lungs. 
4.2. Retrospective data in patients with IPF 
Abnormal GER is highly prevalent in patients with IPF, with a reported 67-88% of patients 
demonstrating abnormal 24-hour pH monitoring.4-6 The most recent and largest study 
studied 65 consecutive patients with IPF regardless of symptoms or a pre-existing diagnosis 
of abnormal GER.5 All patients underwent 24 hour pH monitoring and esophageal 
manometry testing. The prevalence of abnormal GER was 87%, with 63% demonstrating 
abnormal reflux into the proximal esophagus. Only 47% of patients had classic GER 
symptoms of heartburn and dyspepsia. Manometry was largely within normal limits. These 
and other data have led investigators to hypothesize that abnormal GER might contribute to 
the progression of IPF through predisposing patients to aspiration of gastroesophageal 

Page 13 of 35 
refluxate that in turn causes chronic stress to the alveolar epithelium.3 A small case series of 
four patients demonstrated relative stabilization of forced vital capacity (FVC) and diffusion 
capacity for carbon monoxide (DLCO) with medical therapy for GER.7 A second case series 
of fourteen patients with advanced IPF on the waiting list for lung transplantation 
demonstrated stabilization of oxygen requirements after laparoscopic anti-reflux surgery 
compared to 31 patients with IPF on the waiting list for lung transplantation that did not 
undergo laparoscopic anti-reflux surgery.8  
Retrospective data from a cohort of IPF patients followed as part of a clinical trials 
consortium demonstrated a reduction in the rate of decline in FVC over 30 weeks for 
subjects taking anti-acid therapy.21 Additional retrospective data from the University of 
California San Francisco and the Mayo Clinic, Rochester demonstrated that a history of 
laparoscopic anti-reflux surgery was associated with prolonged survival time in patients with 
IPF (Figure 1).9 Medical therapy (mostly with proton pump inhibitor (PPI)) appeared less 
effective. These data are limited by their retrospective nature, but support the hypothesis 
that treatment of abnormal GER in IPF slows progression of disease, and that laparoscopic 
anti-reflux surgery is more effective that medical therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A total of 14 patients with progressive IPF (mean age 63 years, mean FVC 66 percent 
predicted (range 40-99%)) and abnormal GER who underwent laparoscopic anti-reflux 
surgery at University of Washington had pre- and post-surgical FVC measurements 
obtained (Figure 2). FVC was assessed prior to the surgery (mean of 105 days prior to anti-
reflux surgery) and post-surgery (mean of 115 days following the anti-reflux surgery). Over 

Page 14 of 35 
the average of 7 months between the pre- and post-anti-reflux surgery assessments, the 
mean FVC increased by 0.08L (3.5 percent predicted) and the majority of participants 
(10/14) experienced an increase in FVC. All patients were discharged after the standard one 
night of post-operative observation without any medical or surgical complications. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. Methods 
 
5.1. Inclusion Criteria 
Only subjects with confirmed IPF, abnormal GER on 24-hour pH monitoring (as defined by a 
DeMeester score of > 14.7) and esophageal manometry that is acceptable for full 
laparoscopic anti-reflux surgery will be eligible for this study. Subjects must be able to 
provide informed consent and be willing to undergo laparoscopic anti-reflux surgery. 
 
5.2. Diagnosis of Idiopathic Pulmonary Fibrosis 
Subjects will be evaluated for IPF at the enrolling center. Study investigators will follow the 
most current ATS/ERS/JRS/ALAT evidence-based guidelines in making this determination. 
 
A subject with suspected interstitial lung disease (ILD) should be evaluated for secondary 
causes including, but not limited to, environmental exposures, drugs, and systemic 
diseases. Presence of any of these findings felt to be significant enough to cause an ILD 
should disqualify the subject from entry into the trial. 
 

Page 15 of 35 
5.3. Exclusion Criteria 
1. FVC < 50% predicted 
2. FEV1/FVC ratio < 0.65 
3. Resting room air PaO2 < 60mm Hg 
4. Unable to walk 50 meters on 6 minute walk test 
5. Recent acute respiratory illness in last 12 weeks 
6. Participated in an interventional clinical trial for an IPF therapy in the last 28 days 
(subjects may be screened, but cannot be enrolled until 28 days after trial participation)  
[Note: open-label extensions or expanded access programs (EAPs) for 
pirfenidone or nintedanib are not considered interventional clinical trials and 
are not exclusionary.] 
7. Listed for lung transplantation at screening 
8. Unable to safely undergo full (complete) laparoscopic gastric anti-reflux surgery (i.e. 
not a partial fundoplication), in the judgment of the investigators 
9. History of esophageal / bariatric / gastric surgery 
10. History of cancer (other than non-melanoma skin cancer) in the last 3 years 
11. Pregnant at the time of screening or enrollment 
12. Unlikely to obtain pre-authorized approval from a third party payer for laparoscopic 
anti-reflux surgery and related costs in the opinion of the investigators. 
13. Life expectancy < 48 weeks due to another illness 
14. BMI > 35 
15. Known severe pulmonary hypertension (mean pressure > 35 mm Hg on RHC; RVSP 
> 50 mm Hg on ECHO) 
 
5.4 Study Design and Study Visits 
 
Subjects who appear to meet entry criteria will review the informed consent (a written 
description of the purpose, procedures, and risks of the study) with the principal investigator 
(PI), co-investigator, or study coordinator, and all questions will be answered. The informed 
consent form will be signed by the subject at the beginning of the screening visit. No 
protocol-specific procedures will be performed until the subject has signed and dated an 
informed consent form. This includes the screening procedures.  
 

Page 16 of 35 
The enrollment visit should occur within 90 days of the screening visit.  However, it is 
preferred that the enrollment visit occur within 28 days of the screening visit to avoid 
repeating procedures. 
 
All follow-up study visits will occur within 10 business days of their designation (e.g. week 12 
will occur +/- 10 business days from the week 12 timepoint). 
 
 

Page 17 of 35 
 
Table 1. Table of Study Visits 
Study Procedure 
Procedure details 
Visit 
 
Screen 
V1 
Enroll 
V2 
Surgery 
V2A 
Wk 
12 
V3 
Wk 
24 
V4 
Wk 
36 
V5 
Wk 
48 
V6 
Wk 
52 
Medical history 
 Complete medical 
history 
● 
 
 
 
 
 
 
 
 
 
 
 
P 
H 
O 
N 
E 
 
V 
I 
S 
I 
T 
Physical 
examination 
 
 Physical exam 
● 
 
 
● 
● 
● 
● 
Documentation of 
GER 
 Symptom 
questionnaire 
● 
 
 
 
● 
 
● 
Assessment of 
esophageal 
motility and pH 
 pH and manometry 
●+ 
 
 
 
●& 
 
 
Laparoscopic anti-
reflux surgery * 
 
 
 
● 
 
 
 
 
Bronchoscopy * 
 
 
 
● 
 
 
 
●^ 
Spirometry 
(Hand-held) 
 
 
 
 
 
 
 
 
Spirometry 
(Office based) 
 
● 
●# 
 
●! 
●! 
●! 
●! 
DLCO 
 
 
● 
 
●! 
●! 
 
●! 
Arterial blood gas 
 
● 
 
 
● 
● 
 
● 
6 minute walk test 
 
● 
●# 
 
● 
● 
 
● 
HRCT 
 
 
●@ 
 
 
 
 
● 
Patient reported 
outcomes 
 UCSD SOBQ 
 Cough VAS 
 SGRQ 
 ICECAP 
 EQ-5D 
 
● 
 
● 
● 
● 
● 
Blood collection 
 
 
● 
 
● 
● 
● 
● 
 
* These procedures will be performed only in those subjects randomized to surgery.  
+Does not need to be completed if done within 6 months of V2 at the study site in 
accordance with the study protocol. 
@ Does not need to be completed if done within 3 months of V2 at the study site in 
accordance with the study protocol. 
# Only performed if V2 performed > 28 days after V1.  
^ This is an optional procedure and will only be performed if the subject has consented for it. 
! If a subject has undergone fundoplication surgery (regardless of treatment assignment) 
within 8 weeks of this visit date, the subject should not undergo this procedure. 
& The pH and manometry should be done a minimum of 12 weeks after surgery, and only in 
those subjects randomized to surgery.   
 
 
  
 
 

Page 18 of 35 
At screening, all potential subjects will undergo a complete medical history, physical 
examination and testing (spirometry (performed pre-bronchodilator), arterial blood gas, GER 
symptom questionnaire, and 6 minute walk testing) with assessment of eligibility according 
to the inclusion and exclusion criteria. All potential subjects who meet entry criteria based on 
these assessments will undergo 24-hour pH testing and esophageal manometry, unless 
these procedures have been performed within 6 months of the enrollment visit (Visit 2) at 
the study site in accordance with the study protocol.  
 
Subjects meeting eligibility criteria will return for an enrollment visit within 90 days (but 
preferably within 28 days), and will complete baseline evaluations as outlined in this 
protocol, including: 
 
Physical examination 
 
Diffusing capacity of the lung for carbon monoxide (DLCO) 
 
High-resolution computed tomography (HRCT) (unless performed in the past 3 
months according to study protocol and available for review and databasing) 
 
Patient reported outcome questionnaires 
o UCSD Shortness of Breath Questionnaire (UCSD SOBQ) 
o St. George’s Respiratory Questionnaire (SGRQ) 
o Cough visual analog scale (VAS) 
o ICECAP-O 
o EuroQOL EQ-5D 
 
Blood collection (5 tsp) for measurement of biomarkers 
 
If the enrollment visit occurs within 28 days of screening, the screening values for spirometry 
and the 6 minute walk test (6MWT) will be recorded as the baseline values.  If the subject is 
unable to return for enrollment until more than 28 days from screening, the spirometry and 
6MWT procedures will need to be repeated, and those measurements recorded as the 
baseline values. 
 
Enrolled subjects will be randomized to either receive anti-reflux surgery or standard medical 
care. 
 
Subjects randomized to anti-reflux surgery will undergo additional evaluations as directed by 
the surgical team (these may include but are not limited to esophagram, endoscopy, and 
echocardiography) and will have pre-surgical evaluation by anesthesiology. These subjects 

Page 19 of 35 
will undergo preapproval for billing the laparoscopic anti-reflux surgery and related activities 
and tests to the subject’s insurance (all other study procedures will be paid for by the study). 
In the unlikely event that a randomized subject is denied authorization, the subject will not 
have surgery but will be followed on an intention to treat basis. All subjects in the surgical 
arm will receive a bronchoscopy at the time of surgery. Bronchoscopy is a separate 
procedure from the surgical intervention. Bronchoscopy will be performed according to 
standardized protocol and samples (BAL and endobronchial brushings) will be collected. 
These patients will then undergo surgery according to study protocol (see section 8). They 
will have a post-operative visit with the surgeon at approximately 2 weeks to ensure 
appropriate recovery. 
 
Subjects randomized to no surgery will be followed clinically. If there is evidence of 
significant disease progression (defined by a relative decline in FVC of ≥ 10% over 24 
weeks or longer), these patients will be allowed to undergo laparoscopic anti-reflux surgery 
as part of the clinical trial. These patients will otherwise complete the study visits as 
scheduled. 
 
All subjects in the study will be provided with a home spirometer and instructed to perform 
spirometry daily throughout the course of the clinical trial. Subjects who are randomized to 
surgery will be instructed to halt daily spirometry from the date of their surgery until they 
return to the site for the week 12 visit. 
 
Subjects will be blinded to the results of the home spirometry measurements. Subjects will 
be instructed to bring home spirometers to each study visit so that data can be downloaded 
and sent to the DCC for databasing. Subjects will have the option after study completion to 
keep the home spirometer for personal use. 
 
Safety assessments: Subjects will be contacted by telephone for safety assessments in 
months where no study visit occurs (months 1, 2, 4, 5, 7, 8, 10, 11) and at week 52.  The 
calls should visits will occur within 10 business days of their designation (e.g. month 1 will 
occur +/- 10 business days from the month 1 timepoint). One month is defined as 28 days.  
These phone calls will involve confirming the subject’s vital status and asking questions 
about serious adverse events or adverse events related to the surgical procedure, for 
subjects randomized to surgery.   
 

Page 20 of 35 
At weeks 12, 24, and 36, and 48, subjects will return for evaluation. Each visit will include: 
 
Physical examination 
 
Spirometry 
 
DLCO (except week 36) 
 
Arterial blood gas (ABG) measurement (except week 36) 
 
6MWT (except week 36) 
 
Patient reported outcome questionnaires (USCD SOBQ, SGRQ, Cough VAS, 
ICECAP-O, EuroQOL EQ-5D) 
 
GER questionnaire (at weeks 24, and 48 only) 
 
Manometry and 24-hour pH testing (at week 24 only, and for subjects randomized to 
surgery only) 
 
Blood collection (5 tsp) for measurement of biomarkers 
 
HRCT (at week 48 only) 
 
Bronchoscopy with collection of samples (at week 48 only, and for subjects 
randomized to surgery who have consented to the procedure). This procedure will 
be performed in an outpatient setting.  
 
At week 52, or 4 weeks after the final study visit, subjects will be contacted by the site 
coordinator for updates on outstanding AEs and serious adverse events (SAEs). 
 
Study staff may make a long-term follow up at one or more times after subjects complete the 
study visits to request additional information or talk to subjects about clinical or research 
issues that are relevant to patients with IPF.  
 
If a subject withdraws early from the study, s/he will be asked to return to complete the 
battery of assessments scheduled at week 48. 
5.5 Travel Reimbursement 
Subjects participating in this study will be eligible to receive up to $250 per study visit for 
covered costs associated with travel to study visits.  Covered costs may include: 
 
Mileage (round-trip from the subject’s home address to the study clinic) 
 
Parking fees at the study clinic 
 
Airfare to and from the study clinic 
 
Hotel costs 
 
Taxi fare 

Page 21 of 35 
Sites will reimburse subjects as necessary, and submit documentation of payment to the 
Data Coordinating Center for reimbursement of these expenses. 
 
Subjects who are screened and enrolled on consecutive days and stay overnight for these 
visits can be reimbursed for two study visits (screening and enrollment) – up to $500. 
5.6. Recruitment Procedures 
 
Subjects recruited for this study will be physician-referred or self-referred to centers 
participating in this study.  
 
Clinical center subjects previously diagnosed with IPF will be notified of the trials by mail 
whenever possible. 
 
Recruitment of minorities and women will be monitored by the Data Coordinating Center 
(DCC) and Data and Safety Monitoring Board (DSMB). If necessary, additional recruitment 
efforts will be made at specific centers to ensure that the aggregate subject sample contains 
appropriate representation of women and minorities. 
 
 
6. Study Endpoints 
 
6.1. Primary Endpoint 
The primary endpoint of this study will be the change in FVC (in liters) from baseline to week 
48. 
6.2. Secondary Endpoints 
The secondary endpoints of this study will be: 
 
 
Disease progression  
 
Categorical change in FVC  
 
Acute exacerbation 
 
Non-elective hospitalization 
 
Mortality 
 
Time to disease progression 
 
Time to categorical change in FVC, acute exacerbation, or death (composite 
endpoint) 

Page 22 of 35 
 
Time to non-elective hospitalization or death (composite endpoint) 
 
Change in UCSD SOBQ score (continuous and categorical) 
 
Change in SGRQ score (continuous and categorical) 
 
Change on cough visual analog scale (VAS) 
 
Change in ICECAP-O score (continuous and categorical) 
 
Change in EuroQOL EQ-5D scores (continuous and categorical) 
 
Change in 6-minute walk distance (6MWD) (continuous and categorical) 
 
Reduction in acid GER by serial pH testing and GER questionnaire 
 
Quantitative change in HRCT fibrosis score and honeycombing 
 
6.3. Definition of Disease Progression 
Disease progression is defined as one or more of the following: relative decline in FVC of ≥ 
10%; increase in UCSD SOBQ of ≥ 5 points; suspected or definite acute exacerbation; 
death. Subjects and their treating physician will be notified of disease progression 
documented during the course of the study. 
 
6.4 Definition of Acute Exacerbations 
 
Both definite and suspected acute exacerbations of IPF will be identified. The following 4 
criteria will define definite AEx in subjects with acute exacerbation of IPF: 
 
1. Unexplained worsening or development of dyspnea within 30 days 
2. High-resolution computed tomography with new bilateral ground glass abnormality 
and/or consolidation superimposed on a background UIP pattern 
3. No evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar 
lavage. 
4. Exclusion of alternative causes including heart failure, pulmonary embolism, or an 
identifiable cause of acute lung injury. 
 
Idiopathic acute respiratory worsening thought to represent acute exacerbation but failing to 
meet one or more criteria will be classified as suspected acute exacerbations. 

Page 23 of 35 
6.5 Method for Identification of Acute Exacerbation 
All subjects will be educated regarding the importance of identifying AEx. At the time of 
enrollment, subjects will be educated to the possibility of developing acute symptomatic 
worsening that might represent an AEx of IPF and instructed to contact their study site 
coordinator within 48 to 72 hours of the apparent event. All subjects will be questioned about 
any change in dyspnea or cough at any interim clinic visits or hospitalizations.  
 
All respiratory worsenings will be identified and classified by site investigators utilizing the 
following template: 
 
-- Community/hospital acquired pneumonia 
-- Bronchitis 
-- Aspiration pneumonitis 
-- Pulmonary embolism 
-- Pneumothorax 
-- Unknown cause 
-- Non-pulmonary cause (e.g. anxiety) 
 
If “unknown cause” is selected by the site investigator, further categorization as follows will 
be required: 
 
-- Definite acute exacerbation (meets protocol criteria in section 6.4) 
-- Suspected acute exacerbation as defined in section 6.4. 
-- Unclassifiable 
 
 
An AEx will be treated at the discretion of the treating physician.  
 
 
7. Policies and procedures for identifying, reviewing, and reporting adverse events  
 
 
7.1 Definitions 
 

Page 24 of 35 
Adverse event (AE) means any unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research. 
 
Serious adverse event (SAE) means any event temporally associated with the subject’s 
participation in research that meets any of the following criteria: 
• 
results in death; 
• 
is life threatening (places the subject at immediate risk of death from the event as it 
occurred); 
• 
requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
results in a persistent or significant disability/incapacity 
 
In addition, important medical events that may be considered an SAE if they require medical 
or surgical intervention to prevent one of the outcomes listed above. 
 
An Unexpected SAE is an SAE that the nature or severity of which is not expected from the 
disease or interventions within the clinical trial. 
 
An AE Associated with Research means there is a reasonable possibility that the AE may 
have been caused by the interventions (including tests) in the clinical trial. 
 
7.2 Reporting 
 
SAE Reporting - All deaths and all SAEs require reporting from the start of randomization to 
week 52.  Any ongoing SAEs as of week 52 should be followed to resolution. The research 
staff at the site where the subject is seen is required to contact the coordinating center to 
inform them of the SAE within 1 business day of knowledge of the event. The site should 
also submit an SAE form via the eCRF system within 1 business day of knowledge of the 
event.  
 
The clinical center investigator will provide an assessment of causality of the event to the 
study intervention (i.e. is it an SAE associated with research) based upon the information 
available at the time of the report. It is understood that complete information about the event 
may not be known at the time the initial report is submitted, though investigators should 
make every effort to obtain information. All events submitted without a causality assessment 

Page 25 of 35 
will be considered “associated with research” until a clarification is made. The investigator 
must also sign each SAE form. 
 
The clinical center investigator must enter follow-up information (e.g., diagnosis, outcome, 
and results of specific investigations) as it becomes available. Follow-up should be 
submitted according to the same process used for reporting the initial event as described 
above (i.e. within 1 business day of knowledge). All SAEs will be followed until resolution, 
stabilization, or the event returns to baseline condition or value, whichever occurs first. 
Investigators are responsible for reporting SAEs to their local IRB in accordance with local 
guidelines. The coordinating center will be responsible for tracking all SAEs, performing a 
clinical review of the SAE data, querying the clinical centers for additional data, and 
following unresolved SAEs. 
 
AE Reporting 
This study intends to capture information on all serious adverse events, acute exacerbations 
as described in section 6.5, as well as non-serious adverse events related to the surgical 
intervention.  Non-serious, non-surgery related adverse events should not be reported. 
 
The DCC will submit a detailed report of pre-specified AEs of interest and all SAEs monthly 
to NHLBI and DSMB chair. In addition, each SAE will be reported to NHLBI and DSMB chair 
by DCC within one business day after receiving the report. The DSMB Chair will review the 
information presented and determine if any additional information is needed, and/or a DSMB 
teleconference should be held. Guidelines for the DSMB procedures will be detailed in the 
DSMB charter. 
 
8. Surgical Intervention 
 
 
Subjects randomized to laparoscopic anti-reflux surgery will undergo preoperative 
evaluation by the surgical team after randomization. This will include a standard pre-
operative surgical assessment, anesthesia clearance, and other testing as medically 
indicated. During surgery, standard American Society of Anesthesiologists protocols will be 
used to monitor patients under general anesthesia. All subjects will be mechanically 
ventilated using the minimal tidal volumes and supplemental oxygen required to maintain 
adequate gas exchange. All subjects who undergo laparoscopic anti-reflux surgery will have 

Page 26 of 35 
a post-operative visit to insure appropriate recovery. There will be no scheduled study 
procedures during this visit. 
Laparoscopic anti-reflux surgery generally involves the following steps. Individual patient 
issues may require modifications depending on the surgeon’s intraoperative assessment. All 
efforts will be made to adhere exactly to the same surgical procedure, but if needed, the 
surgical team can deviate from the standardized protocol to ensure the safety of the patient 
and to achieve maximum beneficial results. Completion or modification of each stage will be 
documented in the clinical research form. 
Step 1: Division of gastrohepatic ligament; identification of right crus of the diaphragm and 
posterior vagus nerve.  
Step 2: Division of peritoneum and phreno-esophageal membrane above esophagus; 
identification of the left crus of diaphragm and anterior vagus nerve. 
Step 3: Division of short gastric vessels.  
Step 4: Creation of a window between gastric fundus, esophagus, and diaphragmatic crura. 
Step 5: Placement of Penrose drain around the esophagus.  
Step 6: Closure of crura. 
Step 7: Insertion of the bougie into esophagus and through esophageal junction. 
Step 8: Wrapping of gastric fundus around lower esophagus. 
Step 9: Final inspection, removal of instruments and trocars from the abdomen, and closure 
of the port sites. 
 
9. Data Management 
 
9.1. Design and Development 
 
The DCC will be responsible for development of the electronic case report forms (eCRFs), 
development and validation of the clinical study database, ensuring data integrity, and 

Page 27 of 35 
training clinical center staff on applicable data management procedures. A web-based 
distributed data entry model will be implemented. This system will be developed to ensure 
that guidelines and regulations surrounding the use of computerized systems used in clinical 
trials are upheld.  
 
9.2. Data Collection Forms 
 
The data collection process consists of direct data entry at the study clinical centers into the 
EDC system(s) provided by the DCC. A data collection worksheet will be provided to clinical 
centers for recording data in the event the EDC system is unavailable.  Data entry of the 
eCRFs should be completed according to the instructions provided and project specific 
training.  The investigator is responsible for maintaining accurate, complete and up-to-date 
records, and for ensuring the completion of the eCRFs for each research participant.  
 
9.3. Data Acquisition and Entry 
 
Data entry into eCRFs shall be performed by authorized individuals. Selected eCRFs may 
also require the investigator’s written signature or electronic signature, as appropriate. 
Electronic CRFs will be monitored for completeness, accuracy, and attention to detail during 
the study.  
 
9.4. Data Center Responsibilities 
 
The DCC will 1) develop a data management plan and will conduct data management 
activities, 2) provide final eCRFs for the collection of all data required by the study, 3) 
develop data dictionaries for each eCRF that will comprehensively define each data 
element, 4) conduct ongoing data monitoring activities on study data, 5) monitor any 
preliminary analysis data clean-up activities, and 6) rigorously monitor final study data clean 
up. 
 
9.5. Data Editing 
 
Completed data will be entered into the DCC automated data acquisition and management 
system. If incomplete or inaccurate data are found, a data clarification request will be 

Page 28 of 35 
generated and distributed to clinical centers for a response. Clinical centers will resolve data 
inconsistencies and errors and enter all corrections and changes into the DCC automated 
data acquisition and management system. 
 
9.6. Training 
 
The training plan for clinical center staff includes provisions for training on assessments, 
eCRF completion guidelines, data management procedures, and the use of computerized 
systems. 
 
 
10. Data Analysis 
 
10.1. Sample Size Determination and Randomization 
 
We are planning to enroll approximately 58 subjects randomized in a 1:1 ratio to 
laparoscopic anti-reflux surgery or standard care. Patients will be allocated using a 
computer generated randomization scheme. Due to the unblinded nature of the study 
intervention, the randomization will not be stratified. If enough subjects randomized to 
surgery are unable to undergo surgery due to failure of insurance authorization or medical 
eligibility reasons, consideration will be given to rebalancing and/or adjusting randomization 
to insure sufficient subjects undergo surgery to meet the aims of the study. 
 
In powering the study, we have considered the potential impact of PPI use for symptomatic 
GER (part of standard medical care) on the rate of FVC change in the no surgery group. 
Under the assumption that the use of PPIs will be partly effective, our statistical power will 
be reduced. Based on historical knowledge of change in FVC over time in patients with IPF 
a difference of 1.0 standard deviation over a one-year period would be approximately 0.25 
liters. We believe that a treatment difference of that size would be both clinically meaningful 
and consistent with our preliminary data. We have conservatively estimated that 40% of 
individuals in the no surgery group will take PPIs on a regular basis for control of typical 
GER symptoms (i.e. heartburn and dyspepsia), and that PPIs are 50% as effective as 
surgery in reducing the rate of decline in FVC over time. With these adjustments, the 
expected effect size is reduced to 0.8 standard deviations. For that reason, this study is 
powered to detect an effect size of 0.8 standard deviations (or approximately 0.20 liters) in 

Page 29 of 35 
the change in FVC between the two groups with a two-sided alpha of 0.05 and 80% power. 
The estimated number of subjects required for varying effect size and power are shown in 
Table 3. These calculations are based on the two-sample t-test with an increase in the 
sample size to allow for up to 10% withdrawal of consent.  
Table 3: Enrollment requirements for varying effect size and power  
Total subjects 
Effect size 
Two-sided alpha 
Power 
38 
1.0 
0.05 
80% 
52 
1.0 
0.05 
90% 
58 
0.8 
0.05 
80% 
76 
0.8 
0.05 
90% 
100 
0.6 
0.05 
80% 
134 
0.6 
0.05 
90% 
*Calculations allow for 10% withdrawal of consent. 
10.2. Specification of the Primary Analysis 
 
The primary endpoint will be change in FVC (in liters) from baseline to 48 weeks. A mixed 
model repeated measures (MMRM) analysis, will be used to compare differences in the FVC 
measurements across treatment groups at 48 weeks.22 Response variables are values of 
the FVC measured at baseline and every 12 weeks until study completion at 48 weeks. 
Covariates in the model will include treatment time terms and the baseline FVC values. 
Contrast estimates of differences between treatments (along with confidence intervals) will 
be used to estimate the treatment effect. The validity of this model in terms of meeting 
modeling assumptions will be assessed via standard modeling diagnostics and goodness-
of-fit measures. The MMRM models will be implemented using PROC MIXED in SAS. For 
subjects randomized to no surgery who subsequently undergo surgery as part of the study 
(per protocol), post-surgical FVC measurements will be obtained but will not be included in 
the assessment of the primary endpoint. Instead, a 48 week FVC value will be imputed 
based on the pre-surgical FVC values obtained in each individual patient. 
 
10.3. Analysis of Secondary Endpoints 
 
The MMRM models will be applied to analyze the longitudinal data secondary endpoints. 
Regression modeling approaches using either the logistic regression model or Cox 
proportional hazards regression model will be employed for binary and time-to-event 
endpoints, respectively. All statistical analysis will be conducted using SAS version 9 or 
higher software. Statistical significance will be defined at the two-sided 0.05 level. 
 

Page 30 of 35 
11. Study Administration 
 
11.1. Steering Committee 
 
Members of the study Steering Committee will be responsible for overseeing the study 
conduct and will make all decisions regarding the trial.  
11.2. Data and Safety Monitoring Board 
 
An independent data safety and monitoring board (DSMB) comprised of experts in lung 
disease and clinical trials, GER, laparoscopic anti-reflux surgery, and biostatistics who are 
not involved in any other way with this study will be responsible for monitoring the clinical 
trial for the duration of this award. A chair of the DSMB will be identified who will be 
responsible as the point of contact for DSMB-related matters. Written documentation of no 
conflict of interest will be required. Prior to enrollment, the DSMB will review and approve 
the study protocol and other documents as appropriate. The DSMB will meet prior to the 
start of enrollment and at intervals as defined in the DSMB charter to review the safety and 
conduct of the study procedures, in particular laparoscopic anti-reflux surgery, as well as the 
following additional duties: 
1. Evaluate the progress of the trial, including assessment of recruitment and retention 
rates, data quality and timeliness, and participant risk versus benefit (including reviewing  
all significant adverse events). 
2. Consider factors external to the clinical trial that may have an impact on the safety of the 
participants or the ethics of the trial (e.g. an approved therapy for IPF becomes 
available). 
3. Assist in the resolution of concerns or problems expressed by the principal investigators 
or staff. 
4. Report on the safety and progress of the trial on a twice-yearly schedule. 
5. Make recommendations to the NHLBI, the principal investigators, and if required other 
organizations concerning the continuation, termination, or other modifications to the trial 
based on the observed beneficial or adverse effects of the treatment under study. 
Specific guidance regarding stopping criteria will be provided to the DSMB. 
6. Request the data-coordinating center to conduct interim analyses of the data to perform 
the above duties. 
7. Insure the confidentiality of the trial data and the results of monitoring. 

Page 31 of 35 
The data-coordinating center at the DCRI will provide logistical support to the DSMB by 
providing reports of adverse events, recruitment, and efficacy, analyses, and other items as 
required and requested by the DSMB.  
 
12. Investigator and Sponsor Obligations 
 
12.1. Site and Remote Monitoring 
 
All site and remote monitoring activities will be performed in accordance with the DCRI 
standard operating procedures. Information regarding the methods and frequency of 
monitoring will be outlined in the study clinical monitoring plan. 
12.2. Confidentiality and Health Insurance Portability and Accountability Act (HIPAA) 
Considerations 
 
Subject confidentiality will be protected throughout the study. All subject data will be kept 
strictly confidential, and no subject-identifying information will be released to anyone outside 
the project. Confidentiality will be assured through several mechanisms. First, each subject 
will be assigned a unique study ID number, which will then be used on all study forms. 
Second, any study forms, blood samples, and paper records that contain subject information 
(eg, address lists and phone lists) will be kept at the clinical sites in secured, locked areas, 
coded by study ID number. Once blood or bronchoscopy samples are collected, there will be 
no subject identifiers placed on the samples—only the study ID number and the date of 
sample collection will be identified. Third, access to all subject data and information, 
including laboratory specimens, will be restricted to authorized personnel. In the case of 
computerized data, this restricted access will be assured through user logon IDs and 
password protection. 
 
At the DCC only authorized personnel will have access to the study data files containing 
study data. Security will be assured through user logon IDs, passwords, and appropriate 
access privileges. Personal identifying information, such as name, address, and Social 
Security number, will not be entered into the DCC database. Subject-specific data reported 
to the Steering Committee will be identified by the study ID number only. 
 
Finally, subjects will not be identified by name in any reports or publications, nor will the data 
be presented in such a way that the identity of individual subjects can be inferred. Analysis 

Page 32 of 35 
files created for further study by the scientific community will have no subject identifiers. 
These data files will be created in accordance with the DCC SOPs. 

Page 33 of 35 
 
Investigator Agreement 
 
 WEIGHING RISKS AND BENEFITS OF LAPAROSCOPIC ANTI-REFLUX SURGERY IN 
PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS (WRAP-IPF): A PHASE II 
CLINICAL TRIAL 
 
I have read the foregoing protocol, and agree that it contains all necessary details for 
carrying out this study. I will conduct the study as outlined herein.  
 
I will provide copies of the protocol and all pertinent information to all individuals 
accountable to me who assist in the conduct of this study. I will discuss this material with 
them to ensure they are fully informed regarding the intervention and the conduct of the 
study. 
 
I will fulfill all responsibilities for submitting pertinent information to the local IRB, if 
applicable, that is responsible for this study. 
 
I further agree that NHLBI and/or DCRI will have access to any source documents from 
which case report form information may have been generated. 
 
__________________________________________         ________________ 
Signature of Principal Investigator                                      Date 
 
 
__________________________________________ 
Name of Principal Investigator (printed or typed) 
 
Protocol Version Date 11 Dec 2015 
 
 
 
 
 
 
 

Page 34 of 35 
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