WRAP-IPF: Treatment of IPF With Laparoscopic Anti-Reflux Surgery

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT01982968
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 58
• Locations: 5
• Arms: 2
• Duration (Months): 47
• Patients Per Site: 11.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study will test the hypothesis that treatment with laparoscopic anti-reflux surgery in subjects with idiopathic pulmonary fibrosis (IPF) and abnormal gastroesophageal reflux (GER) will slow the decline of forced vital capacity (FVC) over 48 weeks.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Pulmonary Fibrosis; Gastroesophageal Reflux	Procedure: Surgery	N/A

Detailed Description

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 impedance / pH monitoring to laparoscopic anti-reflux surgery or standard care (randomization ratio 1:1). Subjects will be followed for 48 weeks or until the time of lung transplantation or death.

We aim to achieve the following: determine the impact of laparoscopic anti-reflux surgery on change in FVC over 48 weeks in patients with IPF and abnormal GER; correlate the reduction in acid and non-acid reflux events with the change in FVC over 48 weeks in patients with IPF and abnormal GER; determine the safety of laparoscopic anti-reflux surgery in patients with IPF and abnormal GER; explore the impact of laparoscopic anti-reflux surgery on key secondary endpoints over 48 weeks in patients with IPF and abnormal GER; identify molecular markers of IPF disease activity and gastroesophageal reflux in biological samples from patients with IPF and abnormal GER.

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Weighing Risks and Benefits of Laparoscopic Anti-Reflux Surgery in Patients With Idiopathic Pulmonary Fibrosis
• Study Start Date: Dec 1, 2013
• Actual Primary Completion Date: Nov 1, 2017
• Actual Study Completion Date: Nov 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Control Subjects to receive standard anti-reflux treatment per clinical discretion
Active Comparator: Surgery Subjects will receive laparoscopic fundoplication surgery	Procedure: Surgery; Full fundoplication surgery for the treatment of abnormal GER; Other Names: Nissen fundoplication Laparoscopic fundoplication Laparoscopic anti-reflux surgery

Outcome Measures

Primary Outcome Measures

1. Forced Vital Capacity (FVC) [Baseline and 48 weeks]

   Change in FVC (in liters) between enrollment and 48 weeks.

Secondary Outcome Measures

1. Change in Score From Baseline for Acid and Non-acid Reflux Events at 48 Weeks [Baseline and 48 weeks]

   Change in acid and non-acid reflux events from baseline to week 48. All subjects answered questions related to their reflux using a Likert scale (0 = never, 1 =occasionally, 2 = sometimes, 3 = often, 4 = always).

2. Safety of Laparoscopic Anti-reflux Surgery [48 weeks]

   Overall safety of laparoscopic anti-reflux surgery in patients with IPF and abnormal GER as measured by number of participants who experienced death, serious adverse event, or other (not including serious) adverse event. See Adverse Events section for additional details.

3. All-cause Mortality [48 weeks]

   Impact of anti-reflux surgery on all-cause mortality from enrollment to 48 weeks

4. Non-elective Hospitalization [Baseline and 48 weeks]

   Impact on non-elective hospitalizations from baseline to 48 weeks.

5. Acute Exacerbations [Baseline and 48 weeks]

   Impact on acute exacerbations of IPF from baseline to week 48.

6. University of California San Diego (UCSD) Shortness of Breath Questionnaire (SOQB) Score [Baseline and 48 weeks]

   Change in UCSD SOQB score from baseline to week 48. The score range is 0-120. Higher scores indicate higher breathlessness.

7. St. George's Respiratory Questionnaire (SGRQ) Score [Baseline and 48 weeks]

   Change in SGRQ score from baseline to week 48. The score range is 0-100. Higher scores indicate more limitations.

8. 6-minute Walk Distance [Baseline and 48 weeks]

   Change in 6-minute walk distance from baseline to week 48

9. Cough Visual Analog Scale (VAS) [Baseline and 48 weeks]

   Change in VAS from baseline to week 48. The scale range is 1-100. Lower scores indicate no cough and 100 indicates the worst cough.

10. High-Resolution CT (HRCT) Fibrosis Score. [Baseline to 48 weeks]

    Change in HRCT fibrosis score from baseline to week 48. HRCT Fibrosis score is calculated as a percentage. Higher percentage indicates more fibrosis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of idiopathic pulmonary fibrosis

• Abnormal GER on 24-hour pH monitoring (DeMeester score > 14.7)

• Able to provide informed consent

• Willing to undergo laparoscopic anti-reflux surgery

Exclusion Criteria:

• FVC < 50% predicted

• FEV1/FVC ratio < 0.65

• Resting room air PaO2 < 60mm Hg

• Unable to walk 50 meters on 6 minute walk test

• Acute respiratory illness in last 12 weeks

• Experimental medication for IPF in last 28 days

• Listed for lung transplantation at screening

• Unable to safely undergo surgery

• History of esophageal / bariatric / gastric surgery

• History of cancer (other than non-melanoma skin cancer) in last 3 years

• Pregnant at time of screening or enrollment

• Unable to obtain pre-authorized approval from a third party payer for surgery and related costs

• Life expectancy < 48 weeks due to another illness

• BMI > 35

• Known severe pulmonary hypertension (mean pressure > 35 mm Jg on RHC; RVSP > 50 mm Hg on ECHO)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California	San Francisco	California	United States
2	University of Chicago	Chicago	Illinois	United States
3	University of Michigan	Ann Arbor	Michigan	United States
4	University of Washington	Seattle	Washington	United States
5	University of Wisconsin	Madison	Wisconsin	United States

Sponsors and Collaborators

• University of California, San Francisco
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Harold R Collard, MD, University of California, San Francisco
• Principal Investigator: Ganesh Raghu, MD, University of Washington
• Principal Investigator: Kevin J Anstrom, PhD, Duke University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 8, 2016
• Informed Consent Form - Jul 19, 2016

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01982968
• Other Study ID Numbers: Pro00049804; 1UM1HL119089
• First Posted: Nov 13, 2013
• Last Update Posted: Oct 25, 2021
• Last Verified: Sep 1, 2021

• Keywords provided by University of California, San Francisco: Idiopathic pulmonary fibrosis; IPF; Gastroesophageal reflux; GER; GERD
• Additional relevant MeSH terms: Gastroesophageal Reflux; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis

Study Results

Participant Flow

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal GER
Period Title: Overall Study
STARTED	29	29
COMPLETED	21	27
NOT COMPLETED	8	2

Baseline Characteristics

Arm/Group Title	Control	Surgery	Total
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal GER	Total of all reporting groups
Overall Participants	29	29	58
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.2 (7.35)	70.6 (5.97)	69.9 (6.67)
Sex: Female, Male (Count of Participants)
Female	10 34.5%	1 3.4%	11 19%
Male	19 65.5%	28 96.6%	47 81%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3.4%	2 6.9%	3 5.2%
Not Hispanic or Latino	28 96.6%	27 93.1%	55 94.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 3.4%	1 3.4%	2 3.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 3.4%	0 0%	1 1.7%
White	27 93.1%	27 93.1%	54 93.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 3.4%	1 1.7%
Region of Enrollment (participants) [Number]
United States	29 100%	29 100%	58 100%

Outcome Measures

1. Primary Outcome

Title	Forced Vital Capacity (FVC)
Description	Change in FVC (in liters) between enrollment and 48 weeks.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

Randomized patients

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal Gastroesophageal reflux (GER)
Measure Participants	29	29
Mean (95% Confidence Interval) [liters]	-0.13	-0.05

2. Secondary Outcome

Title	Change in Score From Baseline for Acid and Non-acid Reflux Events at 48 Weeks
Description	Change in acid and non-acid reflux events from baseline to week 48. All subjects answered questions related to their reflux using a Likert scale (0 = never, 1 =occasionally, 2 = sometimes, 3 = often, 4 = always).
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal Gastroesophageal reflux (GER)
Measure Participants	29	29
Do you get heartburn?	-0.65 (1.09)	-1.04 (0.95)
Does your stomach get bloated?	-0.40 (0.82)	-0.39 (0.99)
Do you get bitter liquid (acid) in throat?	-0.63 (1.01)	-1.13 (0.90)
Do you burp a lot?	-0.25 (0.72)	-0.74 (1.18)

3. Secondary Outcome

Title	Safety of Laparoscopic Anti-reflux Surgery
Description	Overall safety of laparoscopic anti-reflux surgery in patients with IPF and abnormal GER as measured by number of participants who experienced death, serious adverse event, or other (not including serious) adverse event. See Adverse Events section for additional details.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal Gastroesophageal reflux (GER)
Measure Participants	29	29
All Cause Mortality	4 13.8%	1 3.4%
Serious Adverse Events	8 27.6%	5 17.2%
Other (Not Including Serious) Adverse Events	0 0%	9 31%

4. Secondary Outcome

Title	All-cause Mortality
Description	Impact of anti-reflux surgery on all-cause mortality from enrollment to 48 weeks
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal Gastroesophageal reflux (GER)
Measure Participants	29	29
Count of Participants [Participants]	4 13.8%	1 3.4%

5. Secondary Outcome

Title	Non-elective Hospitalization
Description	Impact on non-elective hospitalizations from baseline to 48 weeks.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal Gastroesophageal reflux (GER)
Measure Participants	29	29
Count of Participants [Participants]	8 27.6%	5 17.2%

6. Secondary Outcome

Title	Acute Exacerbations
Description	Impact on acute exacerbations of IPF from baseline to week 48.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal Gastroesophageal reflux (GER)
Measure Participants	29	29
Count of Participants [Participants]	4 13.8%	1 3.4%

7. Secondary Outcome

Title	University of California San Diego (UCSD) Shortness of Breath Questionnaire (SOQB) Score
Description	Change in UCSD SOQB score from baseline to week 48. The score range is 0-120. Higher scores indicate higher breathlessness.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal Gastroesophageal reflux (GER)
Measure Participants	29	29
Mean (95% Confidence Interval) [score on a scale]	0.69	0.71

8. Secondary Outcome

Title	St. George's Respiratory Questionnaire (SGRQ) Score
Description	Change in SGRQ score from baseline to week 48. The score range is 0-100. Higher scores indicate more limitations.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal Gastroesophageal reflux (GER)
Measure Participants	29	29
Mean (95% Confidence Interval) [score on a scale]	-3.18	1.04

9. Secondary Outcome

Title	6-minute Walk Distance
Description	Change in 6-minute walk distance from baseline to week 48
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal Gastroesophageal reflux (GER)
Measure Participants	29	29
Mean (95% Confidence Interval) [meters]	9.13	16.54

10. Secondary Outcome

Title	Cough Visual Analog Scale (VAS)
Description	Change in VAS from baseline to week 48. The scale range is 1-100. Lower scores indicate no cough and 100 indicates the worst cough.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal Gastroesophageal reflux (GER)
Measure Participants	29	29
Mean (95% Confidence Interval) [score on a scale]	7.15	4.74

11. Secondary Outcome

Title	High-Resolution CT (HRCT) Fibrosis Score.
Description	Change in HRCT fibrosis score from baseline to week 48. HRCT Fibrosis score is calculated as a percentage. Higher percentage indicates more fibrosis.
Time Frame	Baseline to 48 weeks

Outcome Measure Data

Analysis Population Description

Data are not available to be reported due to inability to obtain imaging data on participants and generate a score.

Arm/Group Title	Control	Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion	Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal Gastroesophageal reflux (GER)
Measure Participants	0	0

Adverse Events

Time Frame	48 weeks
Arm/Group Title	Control		Surgery
Arm/Group Description	Subjects to receive standard anti-reflux treatment per clinical discretion		Subjects will receive laparoscopic fundoplication surgery Surgery: Full fundoplication surgery for the treatment of abnormal GER
All Cause Mortality
	Control		Surgery
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/29 (13.8%)		1/29 (3.4%)
Serious Adverse Events
	Control		Surgery
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/29 (27.6%)		5/29 (17.2%)
Blood and lymphatic system disorders
anaemia	1/29 (3.4%)	1	0/29 (0%)	0
Cardiac disorders
acute myocardial infarction	0/29 (0%)	0	2/29 (6.9%)	2
cardiac disorder	0/29 (0%)	0	1/29 (3.4%)	1
myocardial infarction	1/29 (3.4%)	1	0/29 (0%)	0
Gastrointestinal disorders
gastrointestinal haemorrhave	0/29 (0%)	0	1/29 (3.4%)	1
intestinal obstruction	0/29 (0%)	0	1/29 (3.4%)	1
cholecytitis	0/29 (0%)	0	1/29 (3.4%)	1
Hepatobiliary disorders
bile duct obstruction	1/29 (3.4%)	1	0/29 (0%)	0
Infections and infestations
pneumonia	2/29 (6.9%)	2	0/29 (0%)	0
sepsis	1/29 (3.4%)	1	0/29 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
lung cancer metastatic	1/29 (3.4%)	1	0/29 (0%)	0
Nervous system disorders
carotid artery stenosis	1/29 (3.4%)	1	0/29 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory Worsening	5/29 (17.2%)	5	2/29 (6.9%)	2
Hypoxia	1/29 (3.4%)	1	0/29 (0%)	0
Respiratory Failure	1/29 (3.4%)	1	0/29 (0%)	0
Vascular disorders
shock	0/29 (0%)	0	1/29 (3.4%)	1
Other (Not Including Serious) Adverse Events
	Control		Surgery
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		9/29 (31%)
Gastrointestinal disorders
dysphagia	0/29 (0%)	0	4/29 (13.8%)	4
abdominal distension	0/29 (0%)	0	1/29 (3.4%)	1
flatulence	0/29 (0%)	0	1/29 (3.4%)	1
gastrointestinal haemorrhage	0/29 (0%)	0	1/29 (3.4%)	1
gastrointestinal motility disorder	0/29 (0%)	0	1/29 (3.4%)	1
nausea	0/29 (0%)	0	1/29 (3.4%)	1
Injury, poisoning and procedural complications
incision site pain	0/29 (0%)	0	1/29 (3.4%)	1
Metabolism and nutrition disorders
dehydration	0/29 (0%)	0	1/29 (3.4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.