Comparing Omeprazole With Fluoxetine for Treatment of Non Erosive Reflux Disease and Its Subgroups: a Double-blind Placebo-controlled Clinical Trial

Gastro-esophageal reflux disease (GERD) is highly prevalent, affecting up to 20% of the adult population in North America. Up to 70% of GERD patients have non-erosive reflux disease (NERD), a term used to describe symptoms suggestive of GERD in patients with no endoscopic evidence of erosive esophagitis. NERD represents a heterogeneous group of patients whom are sub classified according to 24 hours-PH monitoring results and also symptom-acid association analysis(Symptom Index,SI).

Treatment of NERD can be a challenge for clinicians. According to the many studies , the pooled rate for symptomatic response after a period of proton pomp inhibitor(PPIs)therapy as the most frequently used drug, in NERD patients is lower than for erosive esophagitis patients. It is also shown that acid exposure is much lower in NERD patients than those with erosive esophagitis and NERD patients are less likely to exhibit a strong association between heartburn symptoms and acid reflux events than patients with erosive oesophagitis.

Furthermore, beside the high economic burden, there are concerns about the adverse effects of long time administration of PPIs.

Several hypothesis has been proposed to describe low response rate of NERD patients to PPIs. One of the most acceptable theories is that patients with anxiety or depression and psychological problems are at an increased risk of developing reflux symptoms. On the other hand, pain modulators such as sertraline, a selective serotonin reuptake inhibitor(SSRI), and other antidepressants have been shown to improve symptoms in patients with functional gastrointestinal disorders like non cardiac chest pain.

According to the above-mentioned tips, the investigators hypothesize that antidepressants like fluoxetine, as an SSRI, may have beneficial effects in improving symptoms of NERD patients.

The purpose of this study is to compare the effect of omeprazole with fluoxetine and placebo for treatment of NERD patients and its subgroups who all experience reflux symptoms and have normal endoscopic findings.

Study Overview

• Status: Completed
• Conditions: Non-erosive Reflux Disease
• Intervention / Treatment: Drug: Omeprazole; Drug: placebo; Drug: Fluoxetine

• Study Type: Interventional
• Enrollment (Actual): 144
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Iran, Islamic Republic of
  • Tehran, Iran, Islamic Republic of
    • Gasterointestinal endoscopy ward, Amir Alam hospital, Tehran university of medical sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age above 18 and below 60 years old
• experiencing heartburn during last 6 months before inclusion
• experiencing heartburn during at least 4 of 7 days before inclusion
• presence of normal mucosa in upper gastrointestinal(GI) endoscopy which has been documented during 7 days before inclusion provided that the patient has not administered any PPI during last 30 days before inclusion

Exclusion Criteria:

• inability to undergone upper GI endoscopy or PH monitoring
• presence of barret's esophagus or erosive esophagitis in upper GI endoscopy
• presence of active peptic ulcer disease or any disease which affects the absorption of drugs such as inflammatory bowel disease
• past history of esophageal or gastric surgery
• esophageal stricture which needs dilation
• administration of proton pomp inhibitors during 30 days before inclusion to the study
• administration of H2 blockers, anticholinergics, sucralfate and pro-kinetics during the assessments for eligibility and also during the study
• long time administration of non-steroidal anti-inflammatory drugs (NSAIDs)
• administration of neuroleptic or antidepressant drugs during 30 days before inclusion to the study
• known allergy to PPIs or SSRIs
• presence of significant systemic disease such as scleroderma , diabet mellitus , peripheral and autonomic neuropathies and ...
• pregnancy for females
• presence of known psychiatric disorder such as depression , panic disorder or drug addiction according to the DSM-IV criteria

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: pH positive-omeprazole	Drug: Omeprazole; 20 mg , oral , daily 30 mins before breakfast, for 6 weeks
Placebo Comparator: pH positive-placebo	Drug: placebo; oral , daily 30 mins before breakfast, for 6 weeks
Active Comparator: pH positive-fluoxetine	Drug: Fluoxetine; 20 mg , oral , daily 30 mins before breakfast, for 6 weeks
Active Comparator: pH negative-omeprazole	Drug: Omeprazole; 20 mg , oral , daily 30 mins before breakfast, for 6 weeks
Active Comparator: pH negative-fluoxetine	Drug: Fluoxetine; 20 mg , oral , daily 30 mins before breakfast, for 6 weeks
Placebo Comparator: pH negative-placebo	Drug: placebo; oral , daily 30 mins before breakfast, for 6 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
investigator-reported symptom severity	symptom severity at beginning and 6 weeks after the study ,assessed by the standard questionnaire	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
patient-reported symptom severity	symptom severity reported by the patient in daily diary	6 weeks
heartburn-free days	percentage of 24-h heartburn-free days (days with neither daytime nor nighttime heartburn) during treatment assessed by daily diary	6 weeks

Collaborators and Investigators

• Sponsor: Tehran University of Medical Sciences
• Investigators: Study Chair: Seyed Amir Mirbagheri, MD, Department of Internal Medicine, Faculty of medicine, Tehran university of medical sciences; Principal Investigator: Mohammad Reza Ostovaneh, MD,MPH, Tehran University of Medical Sciences; Principal Investigator: Arash Etemadi, MD, PhD, Tehran University of Medical Sciences; Principal Investigator: Yasin Farrokhi Khajeh Pasha, MD, MPH, Tehran University of Medical Sciences; Principal Investigator: Behtash Saeidi, MD, Tehran University of Medical Sciences; Principal Investigator: Kaveh Hajifathalian, MD, Tehran University of Medical Sciences; Principal Investigator: Akbar Fotouhi, MD, PhD, Tehran University of Medical Sciences; Principal Investigator: Seyed Mahmoud Eshagh hosseini, MD, Tehran University of Medical Sciences

Publications and helpful links

General Publications

• Fass R, Chey WD, Zakko SF, Andhivarothai N, Palmer RN, Perez MC, Atkinson SN. Clinical trial: the effects of the proton pump inhibitor dexlansoprazole MR on daytime and nighttime heartburn in patients with non-erosive reflux disease. Aliment Pharmacol Ther. 2009 Jun 15;29(12):1261-72. doi: 10.1111/j.1365-2036.2009.04013.x. Epub 2009 Apr 8.
• Heidelbaugh JJ, Goldberg KL, Inadomi JM. Overutilization of proton pump inhibitors: a review of cost-effectiveness and risk [corrected]. Am J Gastroenterol. 2009 Mar;104 Suppl 2:S27-32. doi: 10.1038/ajg.2009.49. Erratum In: Am J Gastroenterol. 2009 Apr;104(4):1072. Am J Gastroenterol. 2009 Mar;104(2 Suppl):S39.
• Martinez SD, Malagon IB, Garewal HS, Cui H, Fass R. Non-erosive reflux disease (NERD)--acid reflux and symptom patterns. Aliment Pharmacol Ther. 2003 Feb 15;17(4):537-45. doi: 10.1046/j.1365-2036.2003.01423.x.
• Raghunath AS, O'Morain C, McLoughlin RC. Review article: the long-term use of proton-pump inhibitors. Aliment Pharmacol Ther. 2005 Aug;22 Suppl 1:55-63. doi: 10.1111/j.1365-2036.2005.02611.x.
• Dean BB, Gano AD Jr, Knight K, Ofman JJ, Fass R. Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol. 2004 Aug;2(8):656-64. doi: 10.1016/s1542-3565(04)00288-5.
• Bradley LA, Richter JE, Pulliam TJ, Haile JM, Scarinci IC, Schan CA, Dalton CB, Salley AN. The relationship between stress and symptoms of gastroesophageal reflux: the influence of psychological factors. Am J Gastroenterol. 1993 Jan;88(1):11-9.
• DeVault KR. Review article: the role of acid suppression in patients with non-erosive reflux disease or functional heartburn. Aliment Pharmacol Ther. 2006 Mar;23 Suppl 1:33-9. doi: 10.1111/j.1365-2036.2006.02798.x.
• Venes DJ. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med. 1994 Sep 29;331(13):882; author reply 882-3. No abstract available.
• Handa M, Mine K, Yamamoto H, Hayashi H, Tsuchida O, Kanazawa F, Kubo C. Antidepressant treatment of patients with diffuse esophageal spasm: a psychosomatic approach. J Clin Gastroenterol. 1999 Apr;28(3):228-32. doi: 10.1097/00004836-199904000-00008.
• Varia I, Logue E, O'connor C, Newby K, Wagner HR, Davenport C, Rathey K, Krishnan KR. Randomized trial of sertraline in patients with unexplained chest pain of noncardiac origin. Am Heart J. 2000 Sep;140(3):367-72. doi: 10.1067/mhj.2000.108514.
• Broekaert D, Fischler B, Sifrim D, Janssens J, Tack J. Influence of citalopram, a selective serotonin reuptake inhibitor, on oesophageal hypersensitivity: a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2006 Feb 1;23(3):365-70. doi: 10.1111/j.1365-2036.2006.02772.x.
• Rentz AM, Kahrilas P, Stanghellini V, Tack J, Talley NJ, de la Loge C, Trudeau E, Dubois D, Revicki DA. Development and psychometric evaluation of the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) in patients with upper gastrointestinal disorders. Qual Life Res. 2004 Dec;13(10):1737-49. doi: 10.1007/s11136-004-9567-x.
• Ostovaneh MR, Saeidi B, Hajifathalian K, Farrokhi-Khajeh-Pasha Y, Fotouhi A, Mirbagheri SS, Emami H, Barzin G, Mirbagheri SA. Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: double-blind placebo-controlled trial. Neurogastroenterol Motil. 2014 May;26(5):670-8. doi: 10.1111/nmo.12313. Epub 2014 Feb 7.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: December 21, 2010
• First Submitted That Met QC Criteria: January 2, 2011
• First Posted (Estimate): January 4, 2011

Study Record Updates

• Last Update Posted (Estimate): March 6, 2012
• Last Update Submitted That Met QC Criteria: March 5, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: functional; heartburn; Antidepressive Agents, Second-Generation; Proton Pump Inhibitors; non-erosive reflux disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Gastroesophageal Reflux; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Anti-Ulcer Agents; Proton Pump Inhibitors; Fluoxetine; Omeprazole
• Other Study ID Numbers: 89-02-30-10638