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NCT Number: NCT01265550

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: 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.

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Key information

Conditions

GERD Deglutition Disorders Digestive System Diseases Esophageal Diseases Esophageal Motility Disorders Gastroesophageal Reflux Gastrointestinal Diseases

Age range

18 year–64 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Birmingham VA Medical Center, Birmingham, AL, Birmingham, Alabama, United States

Loading trial locations.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Nissen fundoplication

Device

laparoscopic antireflux surgery

Baclofen

Drug

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.

Desipramine

Drug

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.

Primary outcomes

  1. 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:

    • 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.
    • 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.

Secondary outcomes

  1. Number of Enrolled Participants With Esophageal Ulceration.

    Time frame: Screening

  2. Number of Enrolled Participants With Reflux Esophagus.

    Time frame: Screening

  3. Number of Enrolled Participants With Eosinophilic Esophagitis

    Time frame: Screening

  4. Number of Enrolled Participants With Active Ulceration of the Stomach and/or Duodenum.

    Time frame: Screening

  5. Number of Enrolled Participants With Neoplasm of the Esophagus, Stomach or Duodenum

    Time frame: Screening

  6. Number of Enrolled Participants With Candida Esophagitis.

    Time frame: Screening

  7. Number of Enrolled Participants With Gastric Outlet Obstruction

    Time frame: Screening

  8. Number of Enrolled Participants With Achalasia

    Time frame: Screening

  9. Number of Enrolled Participants With Aperistalsis

    Time frame: Screening

  10. Number of Enrolled Participants With Distal Esophageal Spasm

    Time frame: Screening

  11. Number of Enrolled Participants With Nutcracker Esophagus

    Time frame: Screening

  12. Number of Enrolled Participants With Ineffective Esophageal Motility

    Time frame: Screening

  13. Number of Enrolled Participants With Rapid Contraction

    Time frame: Screening

  14. Number of Enrolled Participants With Hypertensive Peristalsis

    Time frame: Screening

  15. Number of Enrolled Participants With Jackhammer Esophagus

    Time frame: Screening

  16. Number of Enrolled Participants With Weak Peristalsis I

    Time frame: Screening

  17. Number of Enrolled Participants With Weak Peristalsis II

    Time frame: Screening

  18. Number of Enrolled Participants With Anxiety and/or Depression

    Time frame: Screening

  19. Number of Enrolled Participants With Functional Heartburn

    Time frame: Screening

  20. Number of Enrolled Participants With Functional Chest Pain of Presumed Esophageal Origin

    Time frame: Screening

  21. Number of Enrolled Participants With Functional Dysphagia

    Time frame: Screening

  22. Number of Enrolled Participants With Globus

    Time frame: Screening

  23. Number of Enrolled Participants With Belching Disorders

    Time frame: Screening

  24. Number of Enrolled Participants With Chronic Idiopathic Nausea

    Time frame: Screening

  25. Number of Enrolled Participants With Functional Vomiting

    Time frame: Screening

  26. Number of Enrolled Participants With Cyclic Vomiting Syndrome

    Time frame: Screening

  27. Number of Enrolled Participants With Irritable Bowel Syndrome

    Time frame: Screening

  28. Number of Enrolled Participants With Functional Bloating

    Time frame: Screening

  29. Number of Enrolled Participants With Functional Diarrhea

    Time frame: Screening

  30. Number of Enrolled Participants With Unspecified Functional Bowel Disorder

    Time frame: Screening

  31. Number of Enrolled Participants With Functional Gallbladder Disorder

    Time frame: Screening

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. Number of Successful Participants With Globus

    Time frame: 12 months

    Presence of globus as assessed by the ROME III functional GI disorders questionnaire.

  37. 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.

  38. 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.

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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.

  44. 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.

  45. 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.

  46. 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

  47. 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

  48. 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

  49. Number of Successful Surgery Participants With Passage of an Esophageal Dilator of at Least 56 French Diameter Performed.

    Time frame: 12 months

  50. Number of Successful Surgery Participants With Fundoplication Between 1.5 and 2.5cm in Length Performed.

    Time frame: 12 months

  51. Number of Successful Surgery Participants With Fundoplication Placed Above the Epiphrenic Fat Pad, Using 3 Sutures Performed.

    Time frame: 12 months

  52. Number of Successful Surgery Participants With Fundoplication Secured to Esophagus With at Least Two Sutures Performed.

    Time frame: 12 months

  53. Number of Successful Surgery Participants With Fundoplication Floppiness Demonstrated by Passing a Grasper Between Fundoplication and Dilator-filled Esophagus Performed.

    Time frame: 12 months

Sponsors and collaborators

Lead sponsor

VA Office of Research and Development

Fed

Registry information

Official study title

CSP #573 - A Randomized Trial of Medical and Surgical Treatments for Patients With GERD Symptoms That Are Refractory to Proton Pump Inhibitors

Important dates

Study start
2012
Primary completion
2016
Study completion
2016
First posted
Dec 23, 2010
Registry last updated
Jan 22, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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