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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01265550
Recruitment Status : Completed
First Posted : December 23, 2010
Results First Posted : February 26, 2018
Last Update Posted : January 22, 2020
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Tracking Information
First Submitted Date  ICMJE December 21, 2010
First Posted Date  ICMJE December 23, 2010
Results First Submitted Date  ICMJE December 21, 2017
Results First Posted Date  ICMJE February 26, 2018
Last Update Posted Date January 22, 2020
Actual Study Start Date  ICMJE August 13, 2012
Actual Primary Completion Date December 30, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 22, 2018)
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 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 22, 2010)
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 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 17, 2020)
  • 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. [ Time Frame: 12 months ]
    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.
  • Number of Successful Participants With Functional Heartburn [ Time Frame: 12 months ]
    Presence of functional heartburn as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Functional Chest Pain of Presumed Esophageal Origin [ Time Frame: 12 months ]
    Presence of functional chest pain of presumed esophageal origin as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Functional Dysphagia [ Time Frame: 12 months ]
    Presence of functional dysphagia as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Globus [ Time Frame: 12 months ]
    Presence of globus as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Belching Disorders [ Time Frame: 12 months ]
    Presence of belching disorders as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Chronic Idiopathic Nausea [ Time Frame: 12 months ]
    Presence of chronic idiopathic nausea as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Functional Vomiting [ Time Frame: 12 months ]
    Presence of functional vomiting as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Cyclic Vomiting Syndrome [ Time Frame: 12 months ]
    Presence of cyclic vomiting syndrome as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Irritable Bowel Syndrome [ Time Frame: 12 months ]
    Presence of irritable bowel syndrome as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Functional Bloating [ Time Frame: 12 months ]
    Presence of functional bloating as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Functional Diarrhea [ Time Frame: 12 months ]
    Presence of functional diarrhea as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Unspecified Functional Bowel Disorder [ Time Frame: 12 months ]
    Presence of unspecified functional bowel disorder as assessed by the ROME III functional GI disorders questionnaire.
  • Number of Successful Participants With Functional Gallbladder Disorder [ Time Frame: 12 months ]
    Presence of functional gallbladder disorder as assessed by the ROME III functional GI disorders questionnaire.
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2010)
  • To determine the frequency with which non-GERD disorders underlie "PPI failure" in patients who have persistent heartburn while on PPIs.
  • To determine the frequency of functional gastrointestinal symptoms, anxiety and depression in patients who have persistent heartburn while on PPIs.
  • 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.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Randomized Trial of Medical and Surgical Treatments for Patients With GERD Symptoms That Are Refractory to Proton Pump Inhibitors
Official Title  ICMJE CSP #573 - A Randomized Trial of Medical and Surgical Treatments for Patients With GERD Symptoms That Are Refractory to Proton Pump Inhibitors
Brief 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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:
Partial Double Blind (Medical Treatment Groups)
Primary Purpose: Treatment
Condition  ICMJE GERD
Intervention  ICMJE
  • Device: Nissen fundoplication
    laparoscopic antireflux surgery
  • 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.
Study Arms  ICMJE
  • Medical Treatment Group
    Omeprazole or Omeprazole + baclofen or Omeprazole + desipramine
    Interventions:
    • Drug: baclofen
    • Drug: Desipramine
  • Surgical Treatment Group
    Laparoscopic nissen fundoplications
    Intervention: Device: Nissen fundoplication
  • Placebo Medical Treatment Group
    Omeprazole + placebo
    Interventions:
    • Drug: baclofen
    • Drug: Desipramine
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 17, 2020)
366
Original Estimated Enrollment  ICMJE
 (submitted: December 22, 2010)
393
Actual Study Completion Date  ICMJE December 30, 2016
Actual Primary Completion Date December 30, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 64 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01265550
Other Study ID Numbers  ICMJE 573
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party VA Office of Research and Development
Study Sponsor  ICMJE VA Office of Research and Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Stuart J Spechler, MD VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
PRS Account VA Office of Research and Development
Verification Date January 2020

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