A Randomized Trial of Medical and Surgical Treatments for Patients With GERD Symptoms That Are Refractory to Proton Pump Inhibitors

NCT01265550 | Completed Phase 3 Results DMC

• 1 other identifier: 573
• Study Type: interventional
• Target: 366
• Locations: 1 country
• Sites: 15

Brief Summary

Background: Gastroesophageal reflux disease (GERD), which affects at least 20% of adult Americans, may be especially common and severe in Veteran patients. Proton pump inhibitors (PPIs), which block gastric acid production, are the most effective medications for GERD, and the VA spends more than $177 million each year on outpatient PPI prescriptions. PPIs do not prevent the reflux of non-acidic material and do not completely eliminate esophageal acid exposure, however, and bothersome GERD symptoms persist in approximately 40% of patients treated with PPIs. Recent studies using the new technique of esophageal pH/ impedance monitoring, which detects the reflux of both acidic and non-acidic materials, have shown that PPI-resistant GERD symptoms correlate with episodes of reflux (acidic and/or non-acidic) in approximately one-half of patients. For those patients, an antireflux operation might relieve symptoms and obviate the expense of ineffective PPI therapy, but the efficacy of modern, laparoscopic fundoplication in this regard is not clear. For patients with PPI-resistant GERD symptoms, furthermore, the efficacy of medications that that can prevent gastroesophageal reflux (e.g. baclofen) or diminish pain of esophageal origin (e.g. neurotropic agents like desipramine) also is not clear. Study Hypothesis: Laparoscopic antireflux surgery (Nissen fundoplication) is superior to medical therapy (PPIs plus baclofen and desipramine) for GERD patients who, while on PPIs, have persistent episodes of heartburn that are associated with reflux episodes or with abnormal esophageal acid exposure by esophageal pH/impedance monitoring. Study Goals: The primary goal is to compare the efficacy of laparoscopic Nissen fundoplication and medical therapy (PPIs plus baclofen and desipramine) for GERD patients who, while on PPIs, have persistent episodes of heartburn that are associated with reflux episodes or with abnormal esophageal acid exposure by esophageal pH/impedance monitoring, and to compare the efficacy of each therapy with placebo. Secondary goals are: 1) To determine the frequency with which non-GERD disorders underlie "PPI failure," 2) To determine the frequency of functional gastrointestinal symptoms, anxiety and depression in patients who have persistent heartburn while on PPIs, 3) To determine whether functional gastrointestinal symptoms, anxiety and depression is associated with the outcomes of medical and surgical therapies, and 4) To determine whether the outcome of Nissen fundoplication is associated with adherence to technical aspects of the operation. Study Design: Up to 16 VA medical centers, there will be a 30-month recruitment period to enroll 108 patients with heartburn that is refractory to PPI therapy. Patients will have their baseline GERD symptoms scored using the GERD Health-Related Quality of Life (GERD-HRQL) index, and will have endoscopy, esophageal manometry and esophageal pH/impedance monitoring while on PPI therapy. Patients who have episodes of heartburn that are associated with reflux episodes or with abnormal esophageal acid exposure by esophageal pH/impedance monitoring will be randomized to one of three treatment groups: Surgical Treatment (laparoscopic Nissen fundoplication), Active Medical Treatment (omeprazole and baclofen initially; desipramine for baclofen failures) or Placebo Medical Treatment (omeprazole, placebo baclofen, placebo desipramine). All patients will have quarterly clinic visits for symptom scoring and laboratory testing. At one year, patients will have a final symptom scoring and repeat endoscopy, esophageal manometry and esophageal pH/impedance monitoring. Treatment success will be defined as 50% improvement in the GERD-HRQL score at 12 months. Patients also will complete the Hospital Anxiety and Depression Scale (HADS), Rome III Functional GI Disorders Questionnaire and the Short-Form Health Survey (SF-36) at baseline and one year. The results will be correlated with treatment outcomes.

Conditions

GERD

Outcome Measures

Primary Outcomes (1)

• Number of Participants Achieving at Least a 50% Improvement in the Gastroesophageal Reflux Disease Health-related Quality of Life Index (GERD-HRQL) From Baseline to 12 Months

  Success; ≥50% improvement in the baseline GERD-HRQL score at 12 months. Failure; \<50% improvement in the baseline GERD-HRQL score at 12 months or: 1. For patients randomized to Surgical Treatment: a.\<50% improvement in the baseline GERD-HRQL score and/or persistent heartburn of sufficient severity to warrant treatment with any antisecretory medication, antireflux medication or neurotropic medication at any quarterly clinic visit. 2. For patients randomized to Active Medical or Placebo Medical Treatment: a.inability to tolerate both study medications or b.For patients treated with desipramine, i.\<50% improvement in baseline GERD-HRQL score symptom after at least 10 weeks of treatment with the second drug at any quarterly clinic visit. c.For patients in whom desipramine is contraindicated,i.\<50% improvement in baseline GERD-HRQL score symptom after at least 10 weeks of treatment with baclofen or its corresponding placebo at any quarterly clinic visit.

  12 months

Secondary Outcomes (53)

• Number of Enrolled Participants With Esophageal Ulceration.

  Screening

• Number of Enrolled Participants With Reflux Esophagus.

  Screening

• Number of Enrolled Participants With Eosinophilic Esophagitis

  Screening

• Number of Enrolled Participants With Active Ulceration of the Stomach and/or Duodenum.

  Screening

• Number of Enrolled Participants With Neoplasm of the Esophagus, Stomach or Duodenum

  Screening

Study Arms (3)

Medical Treatment Group

OTHER

Omeprazole or Omeprazole + baclofen or Omeprazole + desipramine

Drug: baclofen; Drug: Desipramine

Surgical Treatment Group

OTHER

Laparoscopic nissen fundoplications

Device: Nissen fundoplication

Placebo Medical Treatment Group

OTHER

Omeprazole + placebo

Drug: baclofen; Drug: Desipramine

Interventions

Nissen fundoplication DEVICE

laparoscopic antireflux surgery

Surgical Treatment Group

baclofen DRUG

Baclofen will be prescribed in a dose of 5 mg three times a day (TID) with meals. The dose of baclofen will be increased by 5 mg TID every week until a total dose of 20 mg TID has been achieved.

Medical Treatment Group; Placebo Medical Treatment Group

Desipramine DRUG

Dose of 25 mg at bedtime (HS) for 1 week, then 50 mg HS for 1 week, then 100 mg HS until the next quarterly visit.

Medical Treatment Group; Placebo Medical Treatment Group

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-70 years
• History of heartburn (defined as a burning sensation in the retrosternal area of the chest) that is refractory to antisecretory medications
• Initial GERD-HRQL:
• Total score must be at least 6 and at least one of the six heartburn questions must be scored at least 2
• GERD-HRQL after two weeks of treatment with omeprazole:
• Total score must be \>50% of the initial GERD-HRQL score and at least one of the six heartburn questions must be scored at least 2
• Either or both of the following by baseline esophageal pH/multichannel intraluminal impedance (MII) monitoring in patients on omeprazole 20 mg two times a day (BID):
• Positive symptom association probability (SAP) (\>95%) for acid reflux, non-acid reflux or all reflux.
• Abnormal acid reflux (esophageal pH\<4 for at least 4.2% of the 24-hour monitoring period)

You may not qualify if:

• Patients who do not have heartburn, defined as a burning sensation in the chest
• Patients unwilling or unable to provide informed consent
• Pregnancy or women unwilling to use effective contraception
• Age \<18 or \>70 years
• History of surgery on the stomach or esophagus
• History of seizure disorder
• History of heart block
• Allergy to or previous inability to tolerate study medications (omeprazole, baclofen, desipramine)
• Esophageal varices
• Cirrhosis
• Co-morbidity of sufficient severity to preclude elective surgery (e.g. pulmonary, cardiac, renal, liver disease)
• History of disorders that can cause medically-refractory "GERD symptoms" (eosinophilic esophagitis, neoplasms of the upper gastrointestinal tract, gastroparesis, achalasia)
• Myocardial infarction within the past 6 months
• History of schizophrenia
• Current use of clopidogrel

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (15)

Birmingham VA Medical Center, Birmingham, AL

Birmingham, Alabama, 35233, United States

Location

Southern Arizona VA Health Care System, Tucson, AZ

Tucson, Arizona, 85723, United States

Location

VA Loma Linda Healthcare System, Loma Linda, CA

Loma Linda, California, 92357, United States

Location

VA Long Beach Healthcare System, Long Beach, CA

Long Beach, California, 90822, United States

Location

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

West Haven, Connecticut, 06516, United States

Location

Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD

Baltimore, Maryland, 21201, United States

Location

VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Boston, Massachusetts, 02130, United States

Location

VA Ann Arbor Healthcare System, Ann Arbor, MI

Ann Arbor, Michigan, 48105, United States

Location

Kansas City VA Medical Center, Kansas City, MO

Kansas City, Missouri, 64128, United States

Location

Syracuse VA Medical Center, Syracuse, NY

Syracuse, New York, 13210, United States

Location

Durham VA Medical Center, Durham, NC

Durham, North Carolina, 27705, United States

Location

Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC

Salisbury, North Carolina, 28144, United States

Location

VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Dallas, Texas, 75216, United States

Location

Michael E. DeBakey VA Medical Center, Houston, TX

Houston, Texas, 77030, United States

Location

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Seattle, Washington, 98108, United States

Location

Related Publications (1)

• Spechler SJ, Hunter JG, Jones KM, Lee R, Smith BR, Mashimo H, Sanchez VM, Dunbar KB, Pham TH, Murthy UK, Kim T, Jackson CS, Wallen JM, von Rosenvinge EC, Pearl JP, Laine L, Kim AW, Kaz AM, Tatum RP, Gellad ZF, Lagoo-Deenadayalan S, Rubenstein JH, Ghaferi AA, Lo WK, Fernando RS, Chan BS, Paski SC, Provenzale D, Castell DO, Lieberman D, Souza RF, Chey WD, Warren SR, Davis-Karim A, Melton SD, Genta RM, Serpi T, Biswas K, Huang GD. Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn. N Engl J Med. 2019 Oct 17;381(16):1513-1523. doi: 10.1056/NEJMoa1811424.

  PMID: 31618539 DERIVED

MeSH Terms

Conditions

Gastroesophageal Reflux

Interventions

Fundoplication; Baclofen; Desipramine

Condition Hierarchy (Ancestors)

Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Gastrointestinal Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Digestive System Surgical Procedures; Surgical Procedures, Operative; gamma-Aminobutyric Acid; Aminobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Dibenzazepines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Stuart Spechler
• Organization: Dallas VA Medical Center

sjspechler@aol.com

Study Officials

• Stuart J Spechler, MD

  VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Partial Double Blind (Medical Treatment Groups)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2010
• First Posted: December 23, 2010
• Study Start: August 13, 2012
• Primary Completion: December 30, 2016
• Study Completion: December 30, 2016
• Last Updated: January 22, 2020
• Results First Posted: February 26, 2018

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (15)