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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development
ClinicalTrials.gov Identifier:
NCT01265550
First received: December 21, 2010
Last updated: August 18, 2016
Last verified: August 2016
  Purpose

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: At 15 VA medical centers, there will be a 30-month recruitment period to enroll 393 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.


Condition Intervention Phase
GERD
Device: Nissen fundoplication
Drug: baclofen
Drug: Desipramine
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: CSP #573 - A Randomized Trial of Medical and Surgical Treatments for Patients With GERD Symptoms That Are Refractory to Proton Pump Inhibitors

Resource links provided by NLM:


Further study details as provided by VA Office of Research and Development:

Primary Outcome Measures:
  • The primary outcome measure will be the gastroesophageal reflux disease health-related quality of life (GERD-HRQL) index, a validated instrument that has been used to assess the response of GERD to treatments with medications, endoscopic procedures and s [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    Patients randomized to Surgical Treatment: <50% improvement in the baseline GERD-HRQL score and 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: inability to tolerate both study medications or <50% improvement in baseline GERD-HRQL score symptom after at least 10 weeks of treatment with the second drug (desipramine or its corresponding placebo) at any quarterly clinic visit.



Secondary Outcome Measures:
  • 1.To determine the frequency with which non-GERD disorders underlie "PPI failure" in patients who have persistent heartburn while on PPIs. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    1. For patients with persistent heartburn while on PPIs, upper gastrointestinal endoscopy will be performed to determine the frequency of reflux esophagitis; active ulceration of the esophagus not due to reflux esophagitis; eosinophilic esophagitis; candida esophagitis; active ulceration of the stomach and/or duodenum; neoplasm of the esophagus, stomach or duodenum; and gastric outlet obstruction.
    2. For patients with persistent heartburn while on PPIs, the frequency of achalasia, complete aperistalsis and other esophageal motility disorders will be determined by esophageal manometry.

  • 2.To determine the frequency of functional gastrointestinal symptoms, anxiety and depression in patients who have persistent heartburn while on PPIs. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • 3.To determine whether functional gastrointestinal symptoms, anxiety and depression is associated with the outcomes of medical and surgical therapies for patients who have persistent heartburn while on PPIs. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • 4.To determine whether the outcome of Nissen fundoplication for patients who have persistent heartburn while on PPIs is associated with adherence to technical aspects of the operation. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 393
Study Start Date: August 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Arm 1
Medical Treatment Group
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.
Arm 2
Surgical Treatment Group
Device: Nissen fundoplication
laparoscopic antireflux surgery
Arm 3
Placebo Medical Treatment Group
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.

  Eligibility

Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 18-64 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 6 and at least one of the six heartburn questions must be scored 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 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 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 >64 years
  • History of surgery on the stomach or esophagus
  • History of seizure disorder
  • History of heart block
  • History of glaucoma
  • 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 bipolar disorder, schizophrenia or suicidal thoughts or suicide
  • Current use of thioridazine (Mellaril), monoamine oxidase inhibitors, pimozide, tricyclic antidepressants (TCAs), linezolid, metoclopramide
  • Current use of clopidogrel
  • Patients who have a contraindication to a study medication or who require therapy with a medication that has a clinically important drug interaction with study medication (omeprazole, baclofen, desipramine)
  • 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 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 (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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01265550

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

Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT01265550     History of Changes
Other Study ID Numbers: 573 
Study First Received: December 21, 2010
Last Updated: August 18, 2016
Health Authority: United States: Federal Government
United States: Food and Drug Administration
Individual Participant Data  
Plan to Share IPD: No

Additional relevant MeSH terms:
Proton Pump Inhibitors
Desipramine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antidepressive Agents, Tricyclic
Antidepressive Agents
Psychotropic Drugs
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Adrenergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 29, 2016