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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
366
laparoscopic antireflux surgery
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.
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.
Birmingham VA Medical Center, Birmingham, AL
Birmingham, Alabama, United States
Southern Arizona VA Health Care System, Tucson, AZ
Tucson, Arizona, United States
VA Loma Linda Healthcare System, Loma Linda, CA
Loma Linda, California, United States
VA Long Beach Healthcare System, Long Beach, CA
Long Beach, California, United States
VA Connecticut Healthcare System West Haven Campus, West Haven, CT
West Haven, Connecticut, United States
Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD
Baltimore, Maryland, United States
VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
Boston, Massachusetts, United States
VA Ann Arbor Healthcare System, Ann Arbor, MI
Ann Arbor, Michigan, United States
Kansas City VA Medical Center, Kansas City, MO
Kansas City, Missouri, United States
Syracuse VA Medical Center, Syracuse, NY
Syracuse, New York, United States
...and 5 more locations
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.
Time frame: 12 months
Number of Enrolled Participants With Esophageal Ulceration.
Time frame: Screening
Number of Enrolled Participants With Reflux Esophagus.
Time frame: Screening
Number of Enrolled Participants With Eosinophilic Esophagitis
Time frame: Screening
Number of Enrolled Participants With Active Ulceration of the Stomach and/or Duodenum.
Time frame: Screening
Number of Enrolled Participants With Neoplasm of the Esophagus, Stomach or Duodenum
Time frame: Screening
Number of Enrolled Participants With Candida Esophagitis.
Time frame: Screening
Number of Enrolled Participants With Gastric Outlet Obstruction
Time frame: Screening
Number of Enrolled Participants With Achalasia
Time frame: Screening
Number of Enrolled Participants With Aperistalsis
Time frame: Screening
Number of Enrolled Participants With Distal Esophageal Spasm
Time frame: Screening
Number of Enrolled Participants With Nutcracker Esophagus
Time frame: Screening
Number of Enrolled Participants With Ineffective Esophageal Motility
Time frame: Screening
Number of Enrolled Participants With Rapid Contraction
Time frame: Screening
Number of Enrolled Participants With Hypertensive Peristalsis
Time frame: Screening
Number of Enrolled Participants With Jackhammer Esophagus
Time frame: Screening
Number of Enrolled Participants With Weak Peristalsis I
Time frame: Screening
Number of Enrolled Participants With Weak Peristalsis II
Time frame: Screening
Number of Enrolled Participants With Anxiety and/or Depression
Time frame: Screening
Number of Enrolled Participants With Functional Heartburn
Time frame: Screening
Number of Enrolled Participants With Functional Chest Pain of Presumed Esophageal Origin
Time frame: Screening
Number of Enrolled Participants With Functional Dysphagia
Time frame: Screening
Number of Enrolled Participants With Globus
Time frame: Screening
Number of Enrolled Participants With Belching Disorders
Time frame: Screening
Number of Enrolled Participants With Chronic Idiopathic Nausea
Time frame: Screening
Number of Enrolled Participants With Functional Vomiting
Time frame: Screening
Number of Enrolled Participants With Cyclic Vomiting Syndrome
Time frame: Screening
Number of Enrolled Participants With Irritable Bowel Syndrome
Time frame: Screening
Number of Enrolled Participants With Functional Bloating
Time frame: Screening
Number of Enrolled Participants With Functional Diarrhea
Time frame: Screening
Number of Enrolled Participants With Unspecified Functional Bowel Disorder
Time frame: Screening
Number of Enrolled Participants With Functional Gallbladder Disorder
Time frame: 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.
Time frame: 12 months
Number of Successful Participants With Functional Heartburn
Presence of functional heartburn as assessed by the ROME III functional GI disorders questionnaire.
Time frame: 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.
Time frame: 12 months
Number of Successful Participants With Functional Dysphagia
Presence of functional dysphagia as assessed by the ROME III functional GI disorders questionnaire.
Time frame: 12 months
Number of Successful Participants With Globus
Presence of globus as assessed by the ROME III functional GI disorders questionnaire.
Time frame: 12 months
Number of Successful Participants With Belching Disorders
Presence of belching disorders as assessed by the ROME III functional GI disorders questionnaire.
Time frame: 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.
Time frame: 12 months
Number of Successful Participants With Functional Vomiting
Presence of functional vomiting as assessed by the ROME III functional GI disorders questionnaire.
Time frame: 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.
Time frame: 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.
Time frame: 12 months
Number of Successful Participants With Functional Bloating
Presence of functional bloating as assessed by the ROME III functional GI disorders questionnaire.
Time frame: 12 months
Number of Successful Participants With Functional Diarrhea
Presence of functional diarrhea as assessed by the ROME III functional GI disorders questionnaire.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 12 months
Number of Successful Surgery Participants With Passage of an Esophageal Dilator of at Least 56 French Diameter Performed.
Time frame: 12 months
Number of Successful Surgery Participants With Fundoplication Between 1.5 and 2.5cm in Length Performed.
Time frame: 12 months
Number of Successful Surgery Participants With Fundoplication Placed Above the Epiphrenic Fat Pad, Using 3 Sutures Performed.
Time frame: 12 months
Number of Successful Surgery Participants With Fundoplication Secured to Esophagus With at Least Two Sutures Performed.
Time frame: 12 months
Number of Successful Surgery Participants With Fundoplication Floppiness Demonstrated by Passing a Grasper Between Fundoplication and Dilator-filled Esophagus Performed.
Time frame: 12 months
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