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

NCT ID: NCT01265550

Last Updated: 2020-01-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 366 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-08-13
• Study Completion Date: 2016-12-30

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.

Conditions

GERD

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Medical Treatment Group

Omeprazole or Omeprazole + baclofen or Omeprazole + desipramine

Group Type: OTHER

baclofen

Intervention Type: 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

Intervention Type: 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.

Surgical Treatment Group

Laparoscopic nissen fundoplications

Group Type: OTHER

Nissen fundoplication

Intervention Type: DEVICE

laparoscopic antireflux surgery

Placebo Medical Treatment Group

Omeprazole + placebo

Group Type: OTHER

baclofen

Intervention Type: 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

Intervention Type: 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.

Interventions

Nissen fundoplication

laparoscopic antireflux surgery

Intervention Type: DEVICE

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.

Intervention Type: 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.

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

VA Office of Research and Development

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stuart J Spechler, MD

Role: STUDY_CHAIR

VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Locations

Birmingham VA Medical Center, Birmingham, AL

Birmingham, Alabama, United States

Southern Arizona VA Health Care System, Tucson, AZ

Tucson, Arizona, United States

VA Loma Linda Healthcare System, Loma Linda, CA

Loma Linda, California, United States

VA Long Beach Healthcare System, Long Beach, CA

Long Beach, California, United States

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

West Haven, Connecticut, United States

Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD

Baltimore, Maryland, United States

VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Boston, Massachusetts, United States

VA Ann Arbor Healthcare System, Ann Arbor, MI

Ann Arbor, Michigan, United States

Kansas City VA Medical Center, Kansas City, MO

Kansas City, Missouri, United States

Syracuse VA Medical Center, Syracuse, NY

Syracuse, New York, United States

Durham VA Medical Center, Durham, NC

Durham, North Carolina, United States

Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC

Salisbury, North Carolina, United States

VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Dallas, Texas, United States

Michael E. DeBakey VA Medical Center, Houston, TX

Houston, Texas, United States

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 31618539 (View on PubMed)

Other Identifiers

573

Identifier Type: -

Identifier Source: org_study_id