Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by Department of Veterans Affairs
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT01265550
First received: December 21, 2010
Last updated: November 19, 2014
Last verified: November 2014

December 21, 2010
November 19, 2014
August 2012
June 2015   (final data collection date for primary outcome measure)
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.

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 ]
Complete list of historical versions of study NCT01265550 on ClinicalTrials.gov Archive Site
  • 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 ]
  • To determine the frequency with which non-GERD disorders underlie "PPI failure" in patients who have persistent heartburn while on PPIs. [ Designated as safety issue: No ]
  • To determine the frequency of functional gastrointestinal symptoms, anxiety and depression in patients who have persistent heartburn while on PPIs. [ Designated as safety issue: No ]
  • 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. [ Designated as safety issue: No ]
  • 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. [ Designated as safety issue: No ]
Not Provided
Not Provided
 
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: 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.

Not Provided
Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
GERD
  • Device: Nissen fundoplication
    laparoscopic antireflux surgery
  • Drug: baclofen

    Baclofen will be prescribed in a dose of 5 mg 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 HS for 1 week, then 50 mg HS for 1 week, then 100 mg HS until the next quarterly visit.
  • Arm 1
    Medical Treatment Group
    Interventions:
    • Drug: baclofen
    • Drug: Desipramine
  • Arm 2
    Surgical Treatment Group
    Intervention: Device: Nissen fundoplication
  • Arm 3
    Placebo Medical Treatment Group
    Interventions:
    • Drug: baclofen
    • Drug: Desipramine
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
393
January 2016
June 2015   (final data collection date for primary outcome measure)

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/MII monitoring in patients on omeprazole 20 mg BID:

    • Positive 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, pemozide, 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
    • INR >1.5 (off anticoagulants)
    • Serum creatinine >2.0 mg per deciliter
  • Endoscopic abnormalities including:

    • 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
Both
18 Years to 64 Years
Yes
Contact: Kerry Dunbar, MD (241) 857-1603 Kerry.dunbar@va.gov
United States
 
NCT01265550
573
Yes
Department of Veterans Affairs
Department of Veterans Affairs
Not Provided
Study Chair: Stuart J Spechler, MD VA North Texas Health Care System, Dallas
Department of Veterans Affairs
November 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP