Effect of IV and Oral Esomeprazole in Prevention of Recurrent Bleeding From Peptic Ulcers After Endoscopic Therapy

Study Overview
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Brief Summary
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The investigators previously showed that the use of a high-dose intravenous PPI regimen after endoscopic control of bleeding from peptic ulcers reduced rate of recurrent bleeding, decreased the need for endoscopic and surgical interventions and in general improved patients' outcomes. A trend towards reduced mortality associated with the use of high-dose intravenous PPI was also observed. Recent clinical trials from Asia have provided evidence that high-dose oral PPIs are associated with a reduction in rebleeding. Current meta-analysis suggests that both high dose (intravenous) and low dose (oral) PPIs effectively reduce rebleeding vs placebo. However, there has been no clinical study to compare IV infusion to oral PPI in this patient population. The purpose of this clinical study is to compare the efficacy and safety of intravenous and oral Esomeprazole in patients with peptic ulcer hemorrhage who are at risk for recurrent bleeding. The investigators hypothesize that using IV infusion is superior to oral PPI.

Detailed Description
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The investigators previously showed that the use of a high-dose intravenous PPI regimen after endoscopic control of bleeding from peptic ulcers reduced rate of recurrent bleeding, decreased the need for endoscopic and surgical interventions and in general improved patients' outcomes. A trend towards reduced mortality associated with the use of high-dose intravenous PPI was also observed. Recent clinical trials from Asia have provided evidence that high-dose oral PPIs are associated with a reduction in rebleeding. Current meta-analysis suggests that both high dose (intravenous) and low dose (oral) PPIs effectively reduce rebleeding vs placebo. However, there has been no clinical study to compare IV infusion to oral PPI in this patient population. Endoscopic stigmata in bleeding peptic ulcers are prognostic and allow risk stratification. Patients with a clean ulcer base have a < 5% risk of rebleeding; this increases progressively with a flat spot, adherent clot, non-bleeding visible vessel and active bleeding (55%). Early endoscopy in patients with bleeding peptic ulcers selects the high risk ulcers for therapy and evaluation of adjuvant PPI use.

Official Title
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Phase 3 Study of Effect of Intravenous and Oral Esomeprazole in Prevention of Recurrent Bleeding From Peptic Ulcers After Endoscopic Therapy (IOE Study)

Conditions
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Peptic Ulcer, Bleeding

Intervention / Treatment
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* Drug: Oral esomeprazole
* Drug: Intravenous Esomeprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 Confirmed ulcer bleeding with Forrest Ia, Ib, IIa, IIb Endoscopic hemostasis achieved Informed consent obtained Exclusion Criteria: No consent Forrest II c, III (clear ulcer base/flat spot and no active bleeding, i.e., minimal risk for rebleeding) Unsuccessful endoscopic treatment (i.e., injection and/or thermal coagulation for the initial bleeding) or severe bleeding that immediate surgery is indicated Moribund patients in whom active treatment of any form is not considered. Polytrauma, severe injury, unconsciousness, burns, or need for continuous artificial ventilation Upper GI malignancy or disseminated malignant disease Esophageal varices A Mallory-Weiss lesion Phenytoin or theophylline treatment Uses of PPI or H2RAs within 3 days of admission, including uses at Emergency Department N.B. Usage of aspirin or NSAID is not an exclusion criteria.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: oral esomeprazole<br>Esomeprazole placebo IV loading bolus Esomeprazole placebo intravenous infusion for 72 hours Oral Esomeprazole: 80 mg/Day on Day 1, 2 and Day 3, and the drug will be given as 40 mg q12h. | Drug: Oral esomeprazole<br>* • Oral Esomeprazole 40mg on Day 1, 2 and Day 3 q12h<br>* Other names: nexium;|
| Active Comparator: Intravenous Esomeprazole<br>Esomeprazole IV loading bolus 80mg • Esomeprazole intravenous infusion 8mg/hr for 72 hours | Drug: Intravenous Esomeprazole<br>* Esomeprazole IV 80mg loading bolus Esomeprazole intravenous infusion 8mg/hr for 72 hours<br>* Other names: nexium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of clinical rebleeding within 30 day of endoscopic therapy | Definition of clinical rebleeding Recurrent hematemesis fresh melena after normal stool Hypotension SBP<90 or tachycardia >110 AND fresh melena Decrease in Hb >2g/dL (or Hct > 10%) during any 24 h or an increas in Hb <1 g/dL (or Hct <3%) despite ≥4 units of blood has been transfused during any 48h | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Un-scheduled further endoscopic therapy | Un-scheduled further endoscopic therapy Need for surgery (i.e., operation rate) Duration of hospitalization Blood transfusion | 30 days | 
| Need for surgery |  | 30 days | 
| Duration of hospitalization |  | 30 days | 
| Blood transfusion |  | 30 days | 
| mortality |  | 30 days | 
| need of surgery |  | 30 days | 
| un-scheduled further endoscopic therapy |  | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ulcer bleeding, endoscopic therapy