A Randomized Trial of Medical and Surgical Treatments for Patients With GERD Symptoms That Are Refractory to Proton Pump Inhibitors
Condition: GERD
MeSH terms: Gastroesophageal Reflux
Intervention: Nissen fundoplication; baclofen; Desipramine
Intervention description: 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.
Intervention MeSH terms: Baclofen; Desipramine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Masking description: Partial Double Blind (Medical Treatment Groups)
Enrollment: 366.0
Sex: All
Minimum age: 18 Years
Maximum age: 64 Years
Healthy volunteers: Accepts Healthy Volunteers

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.
    

Eligibility criteria:

        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