A Prospective, Observational Study of the PPI Non-responder

March 29, 2019 updated by: Dartmouth-Hitchcock Medical Center
Gastroesophageal reflux disease (GERD) is a common chronic condition, affecting approximately 20% of the American adult population. Proton pump inhibitors (PPIs) are now the mainstay of medical therapy for symptoms of GERD. Despite their efficacy, several studies have shown that a significant proportion of GERD patients are either partial or non-responders to PPI therapy, defined as symptoms of heartburn and/or regurgitation not relieved by either a standard or double dose of a PPI during a minimum trial of 8 weeks. If GERD symptoms persist, further testing is required. This study will mirror the real world setting to assess the value of published guidelines which recommend specific testing and treatment.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Gastroesophageal reflux disease (GERD) is a common chronic condition, affecting approximately 20% of the American adult population. Gastroesophageal reflux disease is characterized by a number of symptoms, the 2 most common being frequent heartburn and acid regurgitation. Untreated or undertreated gastroesophageal reflux (GER) can lead to complications including esophageal erosions, strictures, esophageal adenocarcinoma, and impaired quality of life.

Proton pump inhibitors (PPIs) are now the mainstay of medical therapy for symptoms of GERD. Despite their efficacy, several studies have shown that a significant proportion of GERD patients are either partial or non-responders to PPI therapy, defined as symptoms of heartburn and/or regurgitation not relieved by either a standard or double dose of a PPI during a minimum trial of 8 weeks. A review of 19 studies looking at GERD patients treated with PPIs found an overall prevalence of partial and non-responders of up to 45% in observational studies. Non-randomized studies revealed a prevalence of 17% when defined as "persisting troublesome heartburn" and 28% when defined as troublesome regurgitation, while randomized studies revealed prevalence rates of 32% and 28%, respectively.

Current guidelines recommend an 8-week trial of a daily PPI for the treatment of symptoms thought secondary to GERD. However, if GERD symptoms persist despite taking the PPI correctly, then testing is required. National guidelines recommend that patients with GERD symptoms who have failed empiric therapy with a PPI undergo upper endoscopy (EGD). This recommendation is based on data showing that the PPI non-responsive patient may have a disorder (e.g., peptic ulcer disease, dyspepsia, eosinophilic esophagitis, cancer) that can only be identified by EGD. During upper endoscopy a 48-hour wireless pH capsule can be placed to measure acid reflux into the distal esophagus. This recommended practice has been shown to be cost effective. If the 48 hour wireless pH capsule study documents pathologic acid reflux, then the diagnosis of acid reflux is confirmed and the patient should be restarted on a PPI with appropriate counseling regarding how to take a PPI properly. Switching the patient to an alternative PPI is a reasonable strategy, as some patients respond better to one PPI than another . In addition, during this index endoscopy, biopsies of the esophagus should be taken to rule out eosinophilic esophagitis.

Some patients in clinical practice have previously undergone testing due to their GERD symptoms. In patients with proven GERD (e.g., prior EGD with LA Grade B-D esophagitis, known Barrett's esophagus, prior positive pH tests either on or off PPI therapy) who continue to have GERD symptoms on a daily PPI, guidelines recommend that impedance pH-testing be performed on daily PPI therapy. Guidelines do not recommend testing on b.i.d. PPI therapy, since most patients with GERD do not require twice-daily PPI therapy. In this patient population (the PPI non-responder with proven GERD), impedance-pH testing is preferable to 48-hour wireless pH capsule testing as non-acid reflux can be detected as well. To be cost effective, and to reduce the number of unnecessary EGDs, if upper endoscopy was recently performed, then impedance-pH testing can be performed after accurate localization of the lower esophageal sphincter using high resolution esophageal manometry (HREM). If the impedance-pH test is negative (normal) on daily PPI therapy, demonstrating that acid reflux is controlled, then a second diagnosis should to be considered (e.g., functional dyspepsia, gastroparesis, an esophageal motility disorder). If impedance-pH monitoring demonstrates abnormal acid reflux on daily PPI therapy, then guidelines recommend that the PPI dose should be increased to twice daily and symptoms reassessed at 8 weeks.

The clinical treatment pathways outlined above are based on national guidelines and are promoted as standards of care. However, despite the fact that these guidelines recommend distinct diagnostic pathways for patients who are non-responsive to PPIs, there is little "real-world" data to support these guidelines and no information about the outcomes of these patients who are treated using these diagnostic pathways. The simple goal of this study is to identify the PPI non-responder patient with GERD symptoms and identify and quantify the type, number and outcomes of diagnostic tests recommended by national guidelines.

Study Type

Observational

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients with persistent GERD symptoms despite treatment with a minimum of 8 weeks daily PPI.

Description

Inclusion Criteria:

  • Willing and able to sign informed consent
  • Persistent GERD symptoms after minimum 8 week trial on daily PPI

Exclusion Criteria:

  • Unwilling to sign informed consent
  • Prior anti-reflux surgery

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Other
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Unproven GERD
Subjects with no prior testing, normal prior EGD or prior LA Grade A esophagitis
Diagnostic test: EGD with biopsy
Stop PPI and schedule for EGD with biopsy and Wireless pH capsule testing for 7-10 days later. Consider gastric emptying scan or high resolution esophageal manometry
Other Names:
  • Wireless pH Capsule
Proven GERD
LA Grade B-D esophagitis, long-segment Barrett's, prior positive pH study
Diagnostic test: EGD and impedance-pH study on PPI
Continue PPI and schedule EGD and Impedance-pH study on PPI. Consider gastric emptying scan or high resolution esophageal manometry

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objectively evaluate PPI non-responder
Time Frame: 8 Weeks after visit 2
Number of participants with unproven GERD who have reflux esophagitis and eosinophile esophagitis
8 Weeks after visit 2
Esophageal acid exposure
Time Frame: 8 Weeks after visit 2
Number and extent of abnormal acid exposure as measured by pH-metry (Bravo capsule) off PPI.
8 Weeks after visit 2
Response to different PPI
Time Frame: 8 Weeks after visit 2
Percentage of patients with GERD who fail standard PPI Therapy as documented by wireless pH capsule testing that then respond to an alternative PPI
8 Weeks after visit 2
Document the amount of esophageal acid and non-acid exposure in the PPI non-responder patient with proven GERD
Time Frame: 8 Weeks after visit 2
Amount of acid and non-acid exposure in PPI-nonresponder patients with proven GERD as measured by impedance-pH testing on daily PPI therapy.
8 Weeks after visit 2
Determine the type, frequency and extent of esophageal motility disorders
Time Frame: 8 Weeks after visit 2
Determine the type, frequency and extent of esophageal motility disorders using HREM (high resolution esophageal manometry) in patients with persistent GERD symptoms despite PPI therapy
8 Weeks after visit 2
Nepean Dyspepsia Index
Time Frame: 8 Weeks after visit 2
Using a validated questionnaire determine the prevalence and severity of functional dyspepsia in patients presenting with GERD symptoms using the Nepean Dyspepsia Index.
8 Weeks after visit 2
Correlate subjective symptoms of GERD with objective evidence of acid reflux
Time Frame: 8 Weeks after visit 2
Comparison of symptomatic GERD based on GERD-Q validated questionnaire and pH testing
8 Weeks after visit 2
Assess overlapping symptoms of dysphagia and GERD
Time Frame: 8 Weeks after visit 2
Assess overlapping symptoms of dysphagia in patients with GERD symptoms who do not respond to empiric PPI therapy using a validated dysphagia questionnaire.
8 Weeks after visit 2

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Dartmouth-Hitchcock Medical Center

Investigators

  • Principal Investigator: Brian E Lacy, MD, PhD, Dartmouth-Hitchcock Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 20, 2017

Primary Completion (Actual)

June 15, 2018

Study Completion (Actual)

June 15, 2018

Study Registration Dates

First Submitted

June 9, 2017

First Submitted That Met QC Criteria

September 12, 2017

First Posted (Actual)

September 13, 2017

Study Record Updates

Last Update Posted (Actual)

April 2, 2019

Last Update Submitted That Met QC Criteria

March 29, 2019

Last Verified

March 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • D17109

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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