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

GERD Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01265550
• Other study ID #: 573
• Status: Completed
• Phase: Phase 3
• Start date: August 13, 2012
• Est. completion date: December 30, 2016

Study information

• Verified date: January 2020
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 366
• Est. completion date: December 30, 2016
• Est. primary completion date: December 30, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

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

Related Conditions & MeSH terms

• Gastroesophageal Reflux
• GERD

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	VA Ann Arbor Healthcare System, Ann Arbor, MI	Ann Arbor	Michigan
United States	Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD	Baltimore	Maryland
United States	Birmingham VA Medical Center, Birmingham, AL	Birmingham	Alabama
United States	VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA	Boston	Massachusetts
United States	VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX	Dallas	Texas
United States	Durham VA Medical Center, Durham, NC	Durham	North Carolina
United States	Michael E. DeBakey VA Medical Center, Houston, TX	Houston	Texas
United States	Kansas City VA Medical Center, Kansas City, MO	Kansas City	Missouri
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	Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC	Salisbury	North Carolina
United States	VA Puget Sound Health Care System Seattle Division, Seattle, WA	Seattle	Washington
United States	Syracuse VA Medical Center, Syracuse, NY	Syracuse	New York
United States	Southern Arizona VA Health Care System, Tucson, AZ	Tucson	Arizona
United States	VA Connecticut Healthcare System West Haven Campus, West Haven, CT	West Haven	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	12 months
Secondary	Number of Enrolled Participants With Esophageal Ulceration.		Screening
Secondary	Number of Enrolled Participants With Reflux Esophagus.		Screening
Secondary	Number of Enrolled Participants With Eosinophilic Esophagitis		Screening
Secondary	Number of Enrolled Participants With Active Ulceration of the Stomach and/or Duodenum.		Screening
Secondary	Number of Enrolled Participants With Neoplasm of the Esophagus, Stomach or Duodenum		Screening
Secondary	Number of Enrolled Participants With Candida Esophagitis.		Screening
Secondary	Number of Enrolled Participants With Gastric Outlet Obstruction		Screening
Secondary	Number of Enrolled Participants With Achalasia		Screening
Secondary	Number of Enrolled Participants With Aperistalsis		Screening
Secondary	Number of Enrolled Participants With Distal Esophageal Spasm		Screening
Secondary	Number of Enrolled Participants With Nutcracker Esophagus		Screening
Secondary	Number of Enrolled Participants With Ineffective Esophageal Motility		Screening
Secondary	Number of Enrolled Participants With Rapid Contraction		Screening
Secondary	Number of Enrolled Participants With Hypertensive Peristalsis		Screening
Secondary	Number of Enrolled Participants With Jackhammer Esophagus		Screening
Secondary	Number of Enrolled Participants With Weak Peristalsis I		Screening
Secondary	Number of Enrolled Participants With Weak Peristalsis II		Screening
Secondary	Number of Enrolled Participants With Anxiety and/or Depression		Screening
Secondary	Number of Enrolled Participants With Functional Heartburn		Screening
Secondary	Number of Enrolled Participants With Functional Chest Pain of Presumed Esophageal Origin		Screening
Secondary	Number of Enrolled Participants With Functional Dysphagia		Screening
Secondary	Number of Enrolled Participants With Globus		Screening
Secondary	Number of Enrolled Participants With Belching Disorders		Screening
Secondary	Number of Enrolled Participants With Chronic Idiopathic Nausea		Screening
Secondary	Number of Enrolled Participants With Functional Vomiting		Screening
Secondary	Number of Enrolled Participants With Cyclic Vomiting Syndrome		Screening
Secondary	Number of Enrolled Participants With Irritable Bowel Syndrome		Screening
Secondary	Number of Enrolled Participants With Functional Bloating		Screening
Secondary	Number of Enrolled Participants With Functional Diarrhea		Screening
Secondary	Number of Enrolled Participants With Unspecified Functional Bowel Disorder		Screening
Secondary	Number of Enrolled Participants With Functional Gallbladder Disorder		Screening
Secondary	Number of Successful Participants With Anxiety and/or Depression.	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.	12 months
Secondary	Number of Successful Participants With Functional Heartburn	Presence of functional heartburn as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Functional Chest Pain of Presumed Esophageal Origin	Presence of functional chest pain of presumed esophageal origin as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Functional Dysphagia	Presence of functional dysphagia as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Globus	Presence of globus as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Belching Disorders	Presence of belching disorders as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Chronic Idiopathic Nausea	Presence of chronic idiopathic nausea as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Functional Vomiting	Presence of functional vomiting as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Cyclic Vomiting Syndrome	Presence of cyclic vomiting syndrome as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Irritable Bowel Syndrome	Presence of irritable bowel syndrome as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Functional Bloating	Presence of functional bloating as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Functional Diarrhea	Presence of functional diarrhea as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Unspecified Functional Bowel Disorder	Presence of unspecified functional bowel disorder as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Participants With Functional Gallbladder Disorder	Presence of functional gallbladder disorder as assessed by the ROME III functional GI disorders questionnaire.	12 months
Secondary	Number of Successful Surgery Participants With Dissection of Distal Esophagus to Obtain at Least 2.5cm of Tension-free, Intra-abdominal Esophagus Performed.		12 months
Secondary	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.		12 months
Secondary	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.		12 months
Secondary	Number of Successful Surgery Participants With Passage of an Esophageal Dilator of at Least 56 French Diameter Performed.		12 months
Secondary	Number of Successful Surgery Participants With Fundoplication Between 1.5 and 2.5cm in Length Performed.		12 months
Secondary	Number of Successful Surgery Participants With Fundoplication Placed Above the Epiphrenic Fat Pad, Using 3 Sutures Performed.		12 months
Secondary	Number of Successful Surgery Participants With Fundoplication Secured to Esophagus With at Least Two Sutures Performed.		12 months
Secondary	Number of Successful Surgery Participants With Fundoplication Floppiness Demonstrated by Passing a Grasper Between Fundoplication and Dilator-filled Esophagus Performed.		12 months