PROGRESSive Withdrawal Esomeprazole and Acid-related Symptoms (PROGRESS)

Study of the Effect of PROGRESSive Withdrawal Esomeprazole of on Acid-related Symptoms, PROGRESS Study A Randomized, Placebo-controlled, Double Blinded Study

Rebound acid hypersecretion (RAHS), defined as an increase in gastric acid secretion above pre-treatment levels after PPIs therapy is observed within two weeks after withdrawal of treatment and could theoretically lead to acid-related symptoms such as heartburn, acid regurgitation, or dyspepsia that might result in resumption of therapy. A plausible physiologic theory for the rebound phenomenon suggests that long-term, elevated gastric pH caused by blockage of the proton-pumps stimulates compensatory gastrin release. Interestingly, Reimer et al. demonstrated the occurrence of RAHS in healthy volunteers who had received eight weeks of esomperazole. The clinical symptoms occured in a different prevalence compared with placebo treated patients at ten weeks after withdrawal and until the end of the study (twelve weeks). Twenty to twenty-two percent of patients displayed symptoms ten or twelve weeks after having discontinued PPIs while they occured in 1.7-7% of placebo-treated patients. Efforts should be pursued to restrict PPI therapy use to patients likely to benefit from it.

In this context, we propose to investigate the benefit of a progressive decrease in doses of esomeprazole compared to a sudden discontinuation. This is a randomized, double-blind, placebo-controlled trial with 156 patients treated by esomeprazole 40mg since four weeks least, randomized to one week of placebo or one week of esomeprazole 20mg. We want to compare the prevalence of clinical gastrointestinal symptoms between patients with progressive discontinuation (one week of esomeprazole, 20mg, then discontinuation) or those with sudden discontinuation of esomeprazole 40mg.

Study Overview

• Status: Active, not recruiting
• Conditions: Stomach Diseases
• Intervention / Treatment: Other: CYP2C19 phenotypical analysis; Drug: Placebo; Drug: Esomeprazole: Nexium® 20mg, Astra Zeneca

• Study Type: Interventional
• Enrollment (Estimated): 58
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jules Desmeules, Pr; Phone Number: 41(0)22 23 05 53 87; Email: jules.desmeules@hcuge.ch

Study Locations

• Switzerland
  • Genève, Switzerland
    • Service de de médecine interne et de rehabilitation, Beau-séjour, HUG
  • Sion, Switzerland
    • Service de réadaptation de l'appareil locomoteur Clinique romande de réadaptation, Sion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Treatment by esomeprazole 40mg since 4 weeks or more
• Esomeprazole withdrawal decided by the clinician
• Male and female aged 18-90 years
• Volunteers to participate to the study
• Must understand and read French language
• Must be able to give a written informed consent

Exclusion Criteria:

• Impairment of cognitive status
• Current indication to continue PPI treatment
• History of erosive and ulcerative esophagitis, Barrett esophagus, Zollinger-Ellison syndrome
• Short-term treatment of documented ulcer disease, as part of a combination regimen for Helicobacter pylori (HP) eradication
• Prevention of ulcers due to non-steroidal anti-inflammatory drugs.
• Hepatic impairment (TP<60%)
• Hypersensitivity to omeprazole (CYP2C19 activity) or esomeprazole
• Current pregnancy or current breastfeeding

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Sudden discontinuation; placebo for 7 days	Other: CYP2C19 phenotypical analysis; All patients included will undergo an assessment of the CYP2C19 activity by the administration of omeprazole 40mg and following measurement of omeprazole metabolic ratio respectively, once during the study.; Other Names: omeprazole 40mg; Drug: Placebo; Comparison of the prevalence of clinical symptoms of acid rebound, between patients with progressive (esomeprazole ) or sudden (placebo) discontinuation of Proton pump inhibitors.
Active Comparator: Progressive discontinuation; Esomeprazole: Nexium® 20mg, Astra Zeneca , for 7 days	Other: CYP2C19 phenotypical analysis; All patients included will undergo an assessment of the CYP2C19 activity by the administration of omeprazole 40mg and following measurement of omeprazole metabolic ratio respectively, once during the study.; Other Names: omeprazole 40mg; Drug: Esomeprazole: Nexium® 20mg, Astra Zeneca; Comparison of the prevalence of clinical symptoms of acid rebound, between patients with progressive (esomeprazole ) or sudden (placebo) discontinuation of Proton pump inhibitors.; Other Names: Nexium®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportions of patients answering "yes" to the clinical gastrointestinal symptoms questions were comparable at visit 1.	The five-item PASS test is a valid tool for the evaluation of persistent acid-related symptoms in patients receiving PPI therapy. It demonstrates good content validity, test-retest reliability, responsiveness and construct validity in both English and French forms. The PASS test is a simple, clinically applicable tool for the identification of patients with persistent acid-related symptoms during therapy and the assessment of their responses to a change in therapy. The investigators will modifiy the first question for the study. While, it is usually asked: " Are you taking prescription medication for any of the following stomach problems/symptoms:… " ; in the study, the investigators will ask : " Do you have any of the following stomach problems/symptoms : … ". With any of the 7 symptoms, the patient will be considered as symptomatic.	day 8
The proportions of patients answering "yes" to the clinical gastrointestinal symptoms questions were comparable at visit 2.	The five-item PASS test is a valid tool for the evaluation of persistent acid-related symptoms in patients receiving PPI therapy. It demonstrates good content validity, test-retest reliability, responsiveness and construct validity in both English and French forms. The PASS test is a simple, clinically applicable tool for the identification of patients with persistent acid-related symptoms during therapy and the assessment of their responses to a change in therapy. The investigators will modifiy the first question for the study. While, it is usually asked: " Are you taking prescription medication for any of the following stomach problems/symptoms:… " ; in the study, the investigators will ask : " Do you have any of the following stomach problems/symptoms : … ". With any of the 7 symptoms, the patient will be considered as symptomatic.	day 15
The proportions of patients answering "yes" to the clinical gastrointestinal symptoms questions were comparable at visit 3.	The five-item PASS test is a valid tool for the evaluation of persistent acid-related symptoms in patients receiving PPI therapy. It demonstrates good content validity, test-retest reliability, responsiveness and construct validity in both English and French forms. The PASS test is a simple, clinically applicable tool for the identification of patients with persistent acid-related symptoms during therapy and the assessment of their responses to a change in therapy. The investigators will modifiy the first question for the study. While, it is usually asked: " Are you taking prescription medication for any of the following stomach problems/symptoms:… " ; in the study, the investigators will ask : " Do you have any of the following stomach problems/symptoms : … ". With any of the 7 symptoms, the patient will be considered as symptomatic.	day 22
The proportions of patients answering "yes" to the clinical gastrointestinal symptoms questions were comparable at visit 4.	The five-item PASS test is a valid tool for the evaluation of persistent acid-related symptoms in patients receiving PPI therapy. It demonstrates good content validity, test-retest reliability, responsiveness and construct validity in both English and French forms. The PASS test is a simple, clinically applicable tool for the identification of patients with persistent acid-related symptoms during therapy and the assessment of their responses to a change in therapy. The investigators will modifiy the first question for the study. While, it is usually asked: " Are you taking prescription medication for any of the following stomach problems/symptoms:… " ; in the study, the investigators will ask : " Do you have any of the following stomach problems/symptoms : … ". With any of the 7 symptoms, the patient will be considered as symptomatic.	day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The intensity of the acid rebound symptoms	The entire modified-PASS test will be evaluated with respect to patients' responses to the individual question; For each symptom, its severity will be measured and scored (minimum score 0: patient has no symptoms; maximum score 4: patient has symptoms requiring supplemental medications and affecting sleep, eating, drinking and daily activities). The overall score will represent the consequence of the rebound acid symptoms.	day 8
The intensity of the acid rebound symptoms	The entire modified-PASS test will be evaluated with respect to patients' responses to the individual question; For each symptom, its severity will be measured and scored (minimum score 0: patient has no symptoms; maximum score 4: patient has symptoms requiring supplemental medications and affecting sleep, eating, drinking and daily activities). The overall score will represent the consequence of the rebound acid symptoms.	day 15
The intensity of the acid rebound symptoms	The entire modified-PASS test will be evaluated with respect to patients' responses to the individual question; For each symptom, its severity will be measured and scored (minimum score 0: patient has no symptoms; maximum score 4: patient has symptoms requiring supplemental medications and affecting sleep, eating, drinking and daily activities). The overall score will represent the consequence of the rebound acid symptoms.	day 22
The intensity of the acid rebound symptoms	The entire modified-PASS test will be evaluated with respect to patients' responses to the individual question; For each symptom, its severity will be measured and scored (minimum score 0: patient has no symptoms; maximum score 4: patient has symptoms requiring supplemental medications and affecting sleep, eating, drinking and daily activities). The overall score will represent the consequence of the rebound acid symptoms.	day 29

Collaborators and Investigators

• Sponsor: Victoria Rollason

Publications and helpful links

General Publications

• Katz MH. Failing the acid test: benefits of proton pump inhibitors may not justify the risks for many users. Arch Intern Med. 2010 May 10;170(9):747-8. doi: 10.1001/archinternmed.2010.64. No abstract available.
• Waldum HL, Arnestad JS, Brenna E, Eide I, Syversen U, Sandvik AK. Marked increase in gastric acid secretory capacity after omeprazole treatment. Gut. 1996 Nov;39(5):649-53. doi: 10.1136/gut.39.5.649.
• Bjornsson E, Abrahamsson H, Simren M, Mattsson N, Jensen C, Agerforz P, Kilander A. Discontinuation of proton pump inhibitors in patients on long-term therapy: a double-blind, placebo-controlled trial. Aliment Pharmacol Ther. 2006 Sep 15;24(6):945-54. doi: 10.1111/j.1365-2036.2006.03084.x.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Estimated): December 1, 2023
• Study Completion (Estimated): December 1, 2023

Study Registration Dates

• First Submitted: June 15, 2015
• First Submitted That Met QC Criteria: June 18, 2015
• First Posted (Estimated): June 19, 2015

Study Record Updates

• Last Update Posted (Actual): May 26, 2023
• Last Update Submitted That Met QC Criteria: May 24, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: proton pump inhibitor; esomeprazole; randomized study; esomeprazole randomized study; gastric acid rebound
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Omeprazole; Esomeprazole
• Other Study ID Numbers: 15-003