RESULT (REflux Surgery in Lung Transplantation) Preliminary Study Protocol

Study Overview
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Brief Summary
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The purpose of the prospective study is to collect information surrounding lung transplant in order to develop a randomized study to determine if prevention of gastroesophageal reflux disease (GERD) related aspiration (stomach acid coming up from the stomach into the esophagus) by surgical fundoplication improves lung rejection. Lung transplantation has evolved into an effective treatment for patients with end-stage lung disease; however, a significant limitation to long-term survival is patients develop a condition of scarring known as chronic lung rejection, which can cause lung function to deteriorate, thereby reducing a patient's chances for survival. Preliminary research has shown a correlation between the presence of gastroesophageal reflux disease (GERD) and impaired early lung rejection as assessed by a breathing test, FEV1 (the amount of forced expired air volume in 1 second). The Investigator is interested in learning more about this condition and the potential for aspiration (inhaling fluid) injury. The primary goal of this preliminary study will be to identify aspiration markers that are correlated with adverse clinical outcomes (increased early rejection, decreased FEV1) that may be used as inclusion criteria for the future randomized trial. The purpose of the retrospective study is to collect information surrounding lung transplant in order to develop a randomized study to determine if prevention of gastroesophageal reflux disease (GERD) related aspiration (stomach acid coming up from the stomach into the esophagus) by surgical fundoplication improves lung rejection. The goal of this retrospective data collection is to review the following: subject outcome event rates for subjects with and without gastroesophageal reflux disease (GERD) for survival, Bronchiolitis Obliterans Syndrome (BOS), acute rejection and Forced Expiratory Volume in the first second (FEV-1), the estimated treatment effect of fundoplication on the above event rates, a threshold effect for Bronchiolitis Obliterans Syndrome (BOS) and/or death are more likely to occur at higher or more proximal acid or non-acid contact times. This data will be collected in order to better design and coordinate a multicenter prospective study.

Detailed Description
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Prospective Group: Approximately 125 Bronchoalveolar Lavage (BAL) samples will be collected from eligible subjects at the time of clinical bronchoscopies and will be within 2 weeks of their esophageal study. The Bronchoalveolar Lavage (BAL) samples will be assayed for bile acids; pepsin, pepsinogen I and II; trypsin; gastrin, and Lipopolysaccharide (LPS) content. Short-term clinical outcome measures including acute rejection episodes, and Forced Expiratory Volume in the first second (FEV-1) at one year will be collected. Correlation between markers of reflux and aspiration will be analyzed. Retrospective Group: Up to 800 charts within the past 5 years will be reviewed for 1) subject outcome event rates for subjects with and without Gastroesophageal Reflux Disease (GERD) for survival, Bronchiolitis Obliterans Syndrome (BOS), acute rejection and Forced Expiratory Volume in the first second (FEV-1), 2) what is the estimated treatment effect of fundoplication on the above event rates, 3) is there a threshold effect such that events such as BOS and death are more likely to occur only at higher or more proximal acid or non-acid contact times. This review will better address the role of Gastroesophageal Reflux Disease (GERD) in lung allograft failure, the clinical utility of surgical fundoplication in preventing lung allograft injury, and the role that acid and non-acid reflux as related to aspiration causes lung allograft injury as it relates to a wider population.

Official Title
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Prospective and Retrospective Study to Develop a Multi-center Randomized Study, to Determine if Prevention of GERD Related Aspiration by Surgical Fundoplication Improves Lung Allograft Function

Conditions
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Reflux, Gastroesophageal Reflux Disease (GERD)

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or non-pregnant female subject 16 years of age Recipient of a double-lung transplant Previously have a 24-hour esophageal pH and/or impedance probe study within 12 months prior to transplant and/or within 12 months following transplantation. If the subject expired prior to 12 months from transplant date, they must have had a 24-hour esophageal pH and/or impedance probe study to be eligible in the study. Exclusion Criteria: Recipient of a single-lung transplant Recipient of a re-do lung transplant Recipient of a double-lung/heart or double-lung/ other organ transplant Do not have a 24-hour esophageal pH and/or impedance probe study within 12 months pre-transplant or within 12 months following transplantation. The subject expired less than 12 months post transplant without having a 24-hour esophageal pH and/or impedance probe study No Spirometry data is available for the subject Subject who is participating in any other interventional clinical study Unable to provide written informed consent or participate in long-term follow-up

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Prospective Group<br>Those patients that will be consented and data collected prospectively | |
| Retrospective Group<br>Those charts that will be utilized to collect retrospective data, waiver of consent will be granted by the IRBs. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BAL aspiration markers | For the prospective study analysis, we will be assessing the relationship of gastroesophageal reflux and aspiration post lung transplantation with the occurrence of lung allograft dysfunction by reviewing BAL samples prospectively collected in approximately 125 subjects. These BAL samples will be assayed for bile acids; pepsin, pepsinogen I and II; trypsin; gastrin, and LPS content. The correlation of the aspiration biomarkers to acute rejection, BOS, death and FEV-1 at one year will be assessed. | 1 year | 
| Death | For the retrospective study, the first specific goal of data collection is outcome event rates for subjects with and without GERD for survival and the estimated treatment effect of fundoplication on the above event rates. A threshold effect for death is more likely to occur at higher or more proximal acid or non-acid contact times. Up to 5 years of follow-up data will be available for analysis with the primary comparison at one year. These data will be used to better design and coordinate a multicenter prospective study. | 1 year | 
| BOS | For the retrospective study, the second specific goal of data collection is event rates for subjects with and without GERD for BOS and the estimated treatment effect of fundoplication on the above event rates. A threshold effect for BOS is more likely to occur at higher or more proximal acid or non-acid contact times. Up to 5 years of follow-up data will be available for analysis with the primary comparison at one year. These data will be used to better design and coordinate a multicenter prospective study. | 1 year | 
| FEV-1 | For the retrospective study, the third goal of data collection is evaluation of FEV-1 changes for subjects with and without GERD and the estimated treatment effect of fundoplication. Up to 5 years of follow-up data will be available for analysis with the primary comparison at one year. Data will be used to design a multicenter prospective study, address the role of GERD in lung allograft failure, the clinical utility of surgical fundoplication in preventing lung allograft injury, and the role that acid and non-acid reflux as related to aspiration causes lung allograft injury. | 1 year | 
| Acute Rejection | For the retrospective study, the final goal of data collection is evaluation of acute rejection episodes for subjects with and without GERD and the estimated treatment effect of fundoplication. Up to 5 years of follow-up data will be available for analysis with the primary comparison at one year. Data will be used to design a multicenter prospective study and to address the role of GERD in lung allograft failure, the clinical utility of surgical fundoplication in preventing lung allograft injury, and the role that acid and non-acid reflux as related to aspiration causes lung allograft injury. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung Transplant, REflux Surgery, Gastroesophageal Reflux Disease (GERD), Fundoplication