PROGRESSive Withdrawal Esomeprazole and Acid-related Symptoms

Study Overview
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Brief Summary
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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.

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

Conditions
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Stomach Diseases

Intervention / Treatment
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* Drug: Esomeprazole: Nexium® 20mg, Astra Zeneca
* Other: CYP2C19 phenotypical analysis
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Sudden discontinuation<br>placebo for 7 days | Other: CYP2C19 phenotypical analysis<br>* 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.<br>* Other names: omeprazole 40mg;Drug: Placebo<br>* Comparison of the prevalence of clinical symptoms of acid rebound, between patients with progressive (esomeprazole ) or sudden (placebo) discontinuation of Proton pump inhibitors.<br>|
| Active Comparator: Progressive discontinuation<br>Esomeprazole: Nexium® 20mg, Astra Zeneca , for 7 days | Drug: Esomeprazole: Nexium® 20mg, Astra Zeneca<br>* Comparison of the prevalence of clinical symptoms of acid rebound, between patients with progressive (esomeprazole ) or sudden (placebo) discontinuation of Proton pump inhibitors.<br>* Other names: Nexium®;Other: CYP2C19 phenotypical analysis<br>* 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.<br>* Other names: omeprazole 40mg;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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esomeprazole randomized study, proton pump inhibitor, gastric acid rebound, randomized study, esomeprazole