Clinical trial NCT01265550: A Randomized Trial of Medical and Surgical Treatments for Patients With GERD Symptoms That Are Refractory to Proton Pump Inhibitors
Official title: CSP #573 - A Randomized Trial of Medical and Surgical Treatments for Patients With GERD Symptoms That Are Refractory to Proton Pump Inhibitors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: GERD
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2010-12-23
Enrollment: 366
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: 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
timeFrame: 12 months
Secondary outcomes:
measure: Number of Enrolled Participants With Esophageal Ulceration.
timeFrame: Screening
measure: Number of Enrolled Participants With Reflux Esophagus.
timeFrame: Screening
measure: Number of Enrolled Participants With Eosinophilic Esophagitis
timeFrame: Screening
measure: Number of Enrolled Participants With Active Ulceration of the Stomach and/or Duodenum.
timeFrame: Screening
measure: Number of Enrolled Participants With Neoplasm of the Esophagus, Stomach or Duodenum
timeFrame: Screening
measure: Number of Enrolled Participants With Candida Esophagitis.
timeFrame: Screening
measure: Number of Enrolled Participants With Gastric Outlet Obstruction
timeFrame: Screening
measure: Number of Enrolled Participants With Achalasia
timeFrame: Screening
measure: Number of Enrolled Participants With Aperistalsis
timeFrame: Screening
measure: Number of Enrolled Participants With Distal Esophageal Spasm
timeFrame: Screening
measure: Number of Enrolled Participants With Nutcracker Esophagus
timeFrame: Screening
measure: Number of Enrolled Participants With Ineffective Esophageal Motility
timeFrame: Screening
measure: Number of Enrolled Participants With Rapid Contraction
timeFrame: Screening
measure: Number of Enrolled Participants With Hypertensive Peristalsis
timeFrame: Screening
measure: Number of Enrolled Participants With Jackhammer Esophagus
timeFrame: Screening
measure: Number of Enrolled Participants With Weak Peristalsis I
timeFrame: Screening
measure: Number of Enrolled Participants With Weak Peristalsis II
timeFrame: Screening
measure: Number of Enrolled Participants With Anxiety and/or Depression
timeFrame: Screening
measure: Number of Enrolled Participants With Functional Heartburn
timeFrame: Screening
measure: Number of Enrolled Participants With Functional Chest Pain of Presumed Esophageal Origin
timeFrame: Screening
measure: Number of Enrolled Participants With Functional Dysphagia
timeFrame: Screening
measure: Number of Enrolled Participants With Globus
timeFrame: Screening
measure: Number of Enrolled Participants With Belching Disorders
timeFrame: Screening
measure: Number of Enrolled Participants With Chronic Idiopathic Nausea
timeFrame: Screening
measure: Number of Enrolled Participants With Functional Vomiting
timeFrame: Screening
measure: Number of Enrolled Participants With Cyclic Vomiting Syndrome
timeFrame: Screening
measure: Number of Enrolled Participants With Irritable Bowel Syndrome
timeFrame: Screening
measure: Number of Enrolled Participants With Functional Bloating
timeFrame: Screening
measure: Number of Enrolled Participants With Functional Diarrhea
timeFrame: Screening
measure: Number of Enrolled Participants With Unspecified Functional Bowel Disorder
timeFrame: Screening
measure: Number of Enrolled Participants With Functional Gallbladder Disorder
timeFrame: Screening
measure: Number of Successful Participants With Anxiety and/or Depression.
timeFrame: 12 months
measure: Number of Successful Participants With Functional Heartburn
timeFrame: 12 months
measure: Number of Successful Participants With Functional Chest Pain of Presumed Esophageal Origin
timeFrame: 12 months
measure: Number of Successful Participants With Functional Dysphagia
timeFrame: 12 months
measure: Number of Successful Participants With Globus
timeFrame: 12 months
measure: Number of Successful Participants With Belching Disorders
timeFrame: 12 months
measure: Number of Successful Participants With Chronic Idiopathic Nausea
timeFrame: 12 months
measure: Number of Successful Participants With Functional Vomiting
timeFrame: 12 months
measure: Number of Successful Participants With Cyclic Vomiting Syndrome
timeFrame: 12 months
measure: Number of Successful Participants With Irritable Bowel Syndrome
timeFrame: 12 months
measure: Number of Successful Participants With Functional Bloating
timeFrame: 12 months
measure: Number of Successful Participants With Functional Diarrhea
timeFrame: 12 months
measure: Number of Successful Participants With Unspecified Functional Bowel Disorder
timeFrame: 12 months
measure: Number of Successful Participants With Functional Gallbladder Disorder
timeFrame: 12 months
measure: Number of Successful Surgery Participants With Dissection of Distal Esophagus to Obtain at Least 2.5cm of Tension-free, Intra-abdominal Esophagus Performed.
timeFrame: 12 months
measure: 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.
timeFrame: 12 months
measure: 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.
timeFrame: 12 months
measure: Number of Successful Surgery Participants With Passage of an Esophageal Dilator of at Least 56 French Diameter Performed.
timeFrame: 12 months
measure: Number of Successful Surgery Participants With Fundoplication Between 1.5 and 2.5cm in Length Performed.
timeFrame: 12 months
measure: Number of Successful Surgery Participants With Fundoplication Placed Above the Epiphrenic Fat Pad, Using 3 Sutures Performed.
timeFrame: 12 months
measure: Number of Successful Surgery Participants With Fundoplication Secured to Esophagus With at Least Two Sutures Performed.
timeFrame: 12 months
measure: Number of Successful Surgery Participants With Fundoplication Floppiness Demonstrated by Passing a Grasper Between Fundoplication and Dilator-filled Esophagus Performed.
timeFrame: 12 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Birmingham VA Medical Center, Birmingham, AL
state: Alabama
city: Tucson
country: United States
facility: Southern Arizona VA Health Care System, Tucson, AZ
state: Arizona
city: Loma Linda
country: United States
facility: VA Loma Linda Healthcare System, Loma Linda, CA
state: California
city: Long Beach
country: United States
facility: VA Long Beach Healthcare System, Long Beach, CA
state: California
city: West Haven
country: United States
facility: VA Connecticut Healthcare System West Haven Campus, West Haven, CT
state: Connecticut
city: Baltimore
country: United States
facility: Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD
state: Maryland
city: Boston
country: United States
facility: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
state: Massachusetts
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System, Ann Arbor, MI
state: Michigan
city: Kansas City
country: United States
facility: Kansas City VA Medical Center, Kansas City, MO
state: Missouri
city: Syracuse
country: United States
facility: Syracuse VA Medical Center, Syracuse, NY
state: New York
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
city: Salisbury
country: United States
facility: Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC
state: North Carolina
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System Seattle Division, Seattle, WA
state: Washington
Study officials:
affiliation: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
name: Stuart J Spechler, MD
role: STUDY_CHAIR
References:
citation: 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.