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

CSP #573 - A Randomized Trial of Medical and Surgical Treatments for Patients With GERD Symptoms That Are Refractory to Proton Pump Inhibitors

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.

Study Overview

• Status: Completed
• Conditions: GERD
• Intervention / Treatment: Drug: baclofen; Drug: Desipramine; Device: Nissen fundoplication

• Study Type: Interventional
• Enrollment (Actual): 366
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Birmingham VA Medical Center, Birmingham, AL
  • Arizona
    • Tucson, Arizona, United States, 85723
      • Southern Arizona VA Health Care System, Tucson, AZ
  • California
    • Loma Linda, California, United States, 92357
      • VA Loma Linda Healthcare System, Loma Linda, CA
    • Long Beach, California, United States, 90822
      • VA Long Beach Healthcare System, Long Beach, CA
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • VA Connecticut Healthcare System West Haven Campus, West Haven, CT
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02130
      • VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • VA Ann Arbor Healthcare System, Ann Arbor, MI
  • Missouri
    • Kansas City, Missouri, United States, 64128
      • Kansas City VA Medical Center, Kansas City, MO
  • New York
    • Syracuse, New York, United States, 13210
      • Syracuse VA Medical Center, Syracuse, NY
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Durham VA Medical Center, Durham, NC
    • Salisbury, North Carolina, United States, 28144
      • Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC
  • Texas
    • Dallas, Texas, United States, 75216
      • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VA Medical Center, Houston, TX
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System Seattle Division, Seattle, WA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 62 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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)

Exclusion Criteria:

• 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
• Patients who have a contraindication to omeprazole or baclofen or who require therapy with a medication that has a clinically important drug interaction with omeprazole or baclofen.
• Patients who, in the judgment of the PI, are not suitable candidates for therapy with a study medication (omeprazole, baclofen, desipramine)
• Initial GERD-HRQL score: Total score <6 and/or all heartburn scores <2
• Inability to tolerate omeprazole during the 2-week treatment phase (before randomization)
• GERD-HRQL after two weeks of treatment with omeprazole: Total score less than or equal to 50% of initial GERD-HRQL score and/or all heartburn scores <2

• Laboratory abnormalities including:

  • Platelet count <100,000
  • international normalized ratio (INR) >1.5 (off anticoagulants)
  • Serum creatinine >2.0 mg per deciliter

• Endoscopic abnormalities including:

  • Los Angeles Classification of Oesophagitis (LA grade) C or D reflux esophagitis
  • Active ulceration of the esophagus that is not due to reflux esophagitis
  • Candida esophagitis
  • Esophageal varices
  • Active ulceration of the stomach and/or duodenum
  • Neoplasm of the esophagus, stomach or duodenum
  • Gastric outlet obstruction
  • Eosinophilic esophagitis at least (15 eosinophils per high power field in any esophageal biopsy specimen)

• Manometric abnormalities including:

  • Achalasia
  • Complete aperistalsis
• Negative SAP ( 95%) for acid reflux, non-acid reflux and all reflux on baseline combined esophageal pH/MII monitoring and normal acid reflux (esophageal pH<4 for <4.2% of the 24-hour monitoring period)
• Study surgeon identifies a contraindication to laparoscopic Nissen fundoplication
• Morbid obesity (BMI at least 40)
• Large paraesophageal hernia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Medical Treatment Group; Omeprazole or Omeprazole + baclofen or Omeprazole + desipramine	Drug: baclofen; 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.; Drug: Desipramine; 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.
Other: Surgical Treatment Group; Laparoscopic nissen fundoplications	Device: Nissen fundoplication; laparoscopic antireflux surgery
Other: Placebo Medical Treatment Group; Omeprazole + placebo	Drug: baclofen; 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.; Drug: Desipramine; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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: 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.; 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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Number of Enrolled Participants With Candida Esophagitis.		Screening
Number of Enrolled Participants With Gastric Outlet Obstruction		Screening
Number of Enrolled Participants With Achalasia		Screening
Number of Enrolled Participants With Aperistalsis		Screening
Number of Enrolled Participants With Distal Esophageal Spasm		Screening
Number of Enrolled Participants With Nutcracker Esophagus		Screening
Number of Enrolled Participants With Ineffective Esophageal Motility		Screening
Number of Enrolled Participants With Rapid Contraction		Screening
Number of Enrolled Participants With Hypertensive Peristalsis		Screening
Number of Enrolled Participants With Jackhammer Esophagus		Screening
Number of Enrolled Participants With Weak Peristalsis I		Screening
Number of Enrolled Participants With Weak Peristalsis II		Screening
Number of Enrolled Participants With Anxiety and/or Depression		Screening
Number of Enrolled Participants With Functional Heartburn		Screening
Number of Enrolled Participants With Functional Chest Pain of Presumed Esophageal Origin		Screening
Number of Enrolled Participants With Functional Dysphagia		Screening
Number of Enrolled Participants With Globus		Screening
Number of Enrolled Participants With Belching Disorders		Screening
Number of Enrolled Participants With Chronic Idiopathic Nausea		Screening
Number of Enrolled Participants With Functional Vomiting		Screening
Number of Enrolled Participants With Cyclic Vomiting Syndrome		Screening
Number of Enrolled Participants With Irritable Bowel Syndrome		Screening
Number of Enrolled Participants With Functional Bloating		Screening
Number of Enrolled Participants With Functional Diarrhea		Screening
Number of Enrolled Participants With Unspecified Functional Bowel Disorder		Screening
Number of Enrolled Participants With Functional Gallbladder Disorder		Screening
Number of Successful Participants With Anxiety and/or Depression.	Association between anxiety and/or depression (GAD-7 and PHQ-9) and the outcome of medical and surgical treatments (success or failure) will be evaluated.	12 months
Number of Successful Participants With Functional Heartburn	Presence of functional heartburn as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Functional Chest Pain of Presumed Esophageal Origin	Presence of functional chest pain of presumed esophageal origin as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Functional Dysphagia	Presence of functional dysphagia as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Globus	Presence of globus as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Belching Disorders	Presence of belching disorders as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Chronic Idiopathic Nausea	Presence of chronic idiopathic nausea as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Functional Vomiting	Presence of functional vomiting as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Cyclic Vomiting Syndrome	Presence of cyclic vomiting syndrome as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Irritable Bowel Syndrome	Presence of irritable bowel syndrome as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Functional Bloating	Presence of functional bloating as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Functional Diarrhea	Presence of functional diarrhea as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Unspecified Functional Bowel Disorder	Presence of unspecified functional bowel disorder as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Participants With Functional Gallbladder Disorder	Presence of functional gallbladder disorder as assessed by the ROME III functional GI disorders questionnaire.	12 months
Number of Successful Surgery Participants With Dissection of Distal Esophagus to Obtain at Least 2.5cm of Tension-free, Intra-abdominal Esophagus Performed.		12 months
Number of Successful Surgery Participants With Complete Mobilization of the Fundus, to Include All Short Gastric and Posterior Gastric Vessels to the Base of the Left Crus Performed.		12 months
Number of Successful Surgery Participants With Closure of the Crura With Non-absorbable Suture to be Snug With a Dilator of at Least 56 French Diameter Performed.		12 months
Number of Successful Surgery Participants With Passage of an Esophageal Dilator of at Least 56 French Diameter Performed.		12 months
Number of Successful Surgery Participants With Fundoplication Between 1.5 and 2.5cm in Length Performed.		12 months
Number of Successful Surgery Participants With Fundoplication Placed Above the Epiphrenic Fat Pad, Using 3 Sutures Performed.		12 months
Number of Successful Surgery Participants With Fundoplication Secured to Esophagus With at Least Two Sutures Performed.		12 months
Number of Successful Surgery Participants With Fundoplication Floppiness Demonstrated by Passing a Grasper Between Fundoplication and Dilator-filled Esophagus Performed.		12 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Study Chair: Stuart J Spechler, MD, VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2012
• Primary Completion (Actual): December 30, 2016
• Study Completion (Actual): December 30, 2016

Study Registration Dates

• First Submitted: December 21, 2010
• First Submitted That Met QC Criteria: December 22, 2010
• First Posted (Estimate): December 23, 2010

Study Record Updates

• Last Update Posted (Actual): January 22, 2020
• Last Update Submitted That Met QC Criteria: January 17, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Gastroesophageal Reflux; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; GABA Agents; Antidepressive Agents, Tricyclic; Neuromuscular Agents; Adrenergic Uptake Inhibitors; Muscle Relaxants, Central; GABA Agonists; GABA-B Receptor Agonists; Desipramine; Baclofen
• Other Study ID Numbers: 573

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No