Eso_1y_R6PUB: Long-term Oral Esomeprazole for Prevention of Peptic Ulcer Rebleeding in High-risk Patients

Sponsor

Hsiu-Chi Cheng (Other)

Overall Status

Completed

CT.gov ID

NCT02456012

Collaborator

(none)

268

Enrollment

Location

Arms

Actual Duration (Months)

3.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether a long-term prophylactic use of esomeprazole 20 mg twice daily or once daily has prevention effectiveness in reducing the recurrence of peptic ulcer bleeding after ulcer healed with 16-week oral esomeprazole therapy in high-risk patients whose Rockall score ≥ 6.

Condition or Disease	Intervention/Treatment	Phase
Peptic Ulcer Hemorrhage	Drug: oral esomeprazole 20 mg twice daily Drug: oral esomeprazole 20 mg once daily	Phase 4

Detailed Description

This study is conducted at the inpatient wards of National Cheng Kung University Hospital, a tertiary health care center in Tainan, and Kaohsiung Medical University Hospital in Kaohsiung City, Taiwan. All participants give written informed consent before enrollment. Each enrolled patient receives an 80 mg loading dose of intravenous esomeprazole (Nexium®, AstraZeneca AB, Södertälje, Sweden) immediately after achieving haemostasis by gastroscopy. Patients then receive a 3-day continuous high-dose (8 mg/h) esomeprazole infusion and then receive 40 mg oral esomeprazole twice daily for 11 days and once daily for following 98 days. The total duration of intravenous and oral esomeprazole is 16 weeks. After gastroscopy to confirm enrollment eligibility and ulcer healed, all patients are assessed using the Rockall risk scoring system at the primary endoscopy. Patients with Rockall scores ≥ 6 are randomized into the double-dose (D) group or the single-dose (S) group following simple randomization procedures with a 1:1 allocation ratio according to the result by the investigator who draw an envelope from a large box of sealed envelopes each containing a written code designating the D group or the S group. Patients in the D group and S groups receive 20 mg oral esomeprazole twice daily or once daily for 36 weeks, respectively. The cohort control group includes patients from a previous study who had peptic ulcer bleeding and Rockall scores ≥ 6 but who did not receive esomeprazole or other proton pump inhibitors after 16-week proton pump inhibitor treatment.

One investigator generates the random allocation sequence and enrolls the participants and a different investigator assigns participants to interventions. The endoscopists and staff who check hemoglobin levels, hemodynamic status, melena, hematochezia or the aspirates through a nasogastric tube are blinded to the study group allocation. All enrolled patients are included in the intention-to-treat (ITT) analysis, but patients who are lost to follow-up, discontinued intervention because of adverse events, have a protocol violation or die are excluded from the per-protocol (PP) analysis of the primary endpoint.

The range of co-morbidities evaluated by the Rockall scores include disseminated malignant diseases, liver disease (liver cirrhosis, Child-Pugh A, B, or C), renal disease (end-stage renal disease, chronic kidney disease or acute kidney injury with estimated glomerular filtration rates <30 ml/min [a score of 3 for co-morbidity], or between 30 ml/min and 60 ml/min [a score of 2 for co-morbidity]), heart disease (congestive heart failure, New York Heart Association Function I to IV or coronary artery disease). Other serious co-morbidities include lung disease (chronic obstructive pulmonary disease, pulmonary tuberculosis, pneumonia or empyema), rheumatoid arthritis, sepsis, new onset cerebrovascular accident or recent history of any major surgery (on the thorax, abdomen, central nervous system, long bones or spinal bones) requiring general anesthesia within 14 days before bleeding.

The estimated rebleeding rate within 12 months in the cohort control group is about 15% based on the previous study. The investigators want to be able to detect a difference between the cohort control group and the D group, in which the rebleeding rate is proposed to be 2%, equal to patients with H. pylori ulcers after eradication. The ratio of the patient number in each experiment group (the D group and the S group) to the patient number in the control group is 2:5. With a two-side α value of 0.05 and power of 80% (β=0.20), the total number of patients required is 54 in each experiment group and 135 in the control to detect a difference between the two groups. Assuming the rate of loss follow-up is 10%, 60 patients in each experimental group are enrolled. The investigators use a nominal 0.05 rate of the p value. Data related to baseline characteristics and end points are evaluated using the Student t test, Pearson's χ2 test or Fisher's exact test and the Mann-Whitney U test. In the survival analysis, the log-rank test is used to compare the Kaplan-Meier curves among the three study groups. All tests are two-tailed and p values of less than 0.05 indicate significant differences.

Study Design

Study Type:

Interventional

Actual Enrollment :

268 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Participant)

Primary Purpose:

Prevention

Official Title:

Secondary Prevention With Long-term Oral Esomeprazole for Peptic Ulcer Recurrence and Rebleeding in High-risk Rockall Scores ≥ 6 Patients

Actual Study Start Date :

Apr 1, 2015

Actual Primary Completion Date :

Dec 31, 2020

Actual Study Completion Date :

Dec 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: The D group After 3-day intravenous 8 mg/h and 16-week oral 40 mg/day esomeprazole treatment, patients receive oral esomeprazole 20 mg twice daily for 36 weeks.	Drug: oral esomeprazole 20 mg twice daily for 36 weeks Other Names: Nexium®, 20 mg, AstraZeneca AB, Södertälje, Sweden
Experimental: The S group After 3-day intravenous 8 mg/h and 16-week oral 40 mg/day esomeprazole treatment, patients receive oral esomeprazole 20 mg once daily for 36 weeks.	Drug: oral esomeprazole 20 mg once daily for 36 weeks Other Names: Nexium®, 20 mg, AstraZeneca AB, Södertälje, Sweden
No Intervention: The C group The cohort control group includes patients from a previous study who had peptic ulcer bleeding and Rockall scores ≥ 6 but who did not receive esomeprazole or other proton pump inhibitors after 3-day intravenous 8 mg/h and 16-week oral 40 mg/day esomeprazole treatment.

Arm

Intervention/Treatment

Experimental: The D group

After 3-day intravenous 8 mg/h and 16-week oral 40 mg/day esomeprazole treatment, patients receive oral esomeprazole 20 mg twice daily for 36 weeks.

Drug: oral esomeprazole 20 mg twice daily

for 36 weeks

Other Names:

Nexium®, 20 mg, AstraZeneca AB, Södertälje, Sweden

Experimental: The S group

After 3-day intravenous 8 mg/h and 16-week oral 40 mg/day esomeprazole treatment, patients receive oral esomeprazole 20 mg once daily for 36 weeks.

Drug: oral esomeprazole 20 mg once daily

for 36 weeks

Other Names:

Nexium®, 20 mg, AstraZeneca AB, Södertälje, Sweden

No Intervention: The C group

The cohort control group includes patients from a previous study who had peptic ulcer bleeding and Rockall scores ≥ 6 but who did not receive esomeprazole or other proton pump inhibitors after 3-day intravenous 8 mg/h and 16-week oral 40 mg/day esomeprazole treatment.

Outcome Measures

Primary Outcome Measures

The recurrent peptic ulcer bleeding during the 1st year [52 weeks]
The recurrent bleeding is deﬁned as 1) recurrent melena, haematochezia, the presence of bloody aspirates through a nasogastric tube and 2) relapse of haemodynamic instability, including systolic blood pressure <90 mm Hg, heart rate >120 bpm or a drop in haemoglobin concentration of >2 g/dL, or sudden increase in transfusion requirements. For each patient with either suspected or active rebleeding, the hemoglobin level and gastroscopy are performed to confirm any blood or coffee-ground-like materials in the stomach, or the persistence of stigmata indicating recent haemorrhage. The gastroscopy also determines whether the source of rebleeding was a peptic ulcer or some other non-ulcer bleeding source, such as varices.

Secondary Outcome Measures

The recurrence of peptic ulcer confirmed by follow-up endoscopy [between the 17th and 52th weeks]
In each patient, the follow-up endoscopy will be performed during the period between the 17th and 52th weeks and the definition of recurrence of ulcer is the size of ulcer > 0.5 cm.
The recurrent peptic ulcer bleeding during the second year-and-thereafter [Since the 2nd year to the study end]
After the 52-week therapy, the patients in Group D and S used oral PPIs or not at the discretion of their physicians according to clinical needs. Thus, these patients are divided into the PPIs on-demand group and the PPIs discontinued group. The definition of recurrent bleeding is as the primary outcome.

Other Outcome Measures

Medical events, including diarrhea and pneumonia, and bone fracture [During the period of taking PPIs and until two weeks after discontinuing PPIs.]
The definition of diarrhea is that the presence of loose or watery stools ≥ three times a day lasted for one day at least. The definition of pneumonia is the presence of one of the symptoms and signs of fever, chills, purulent productive cough, and shortness of breath plus a typical infiltrative patch on chest X-ray. Additionally, any bone fracture, including a partial or complete break in the bone, is monitored until the last follow-up date at outpatient departments.

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 95 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Eligible participants included patients ≥20 years who had undergone gastroscopy for melena, haematochezia, or haematemesis due to bleeding peptic ulcers with major stigmata of recent hemorrhage. The major stigmata of recent haemorrhage were classified as Forrest class Ia, Ib, IIa, and IIb. All of the stigmata are given one or a combination of endoscopic therapies, including local injection of diluted epinephrine 1:10000, bipolar heated probe, argon plasma coagulation, band ligation, or hemoclip therapy. Patients will undergo a follow-up endoscopy about 12 to 16 weeks later to confirm that the ulcer has healed to be less than 0.5 cm; otherwise, patients are not enrolled.

Exclusion Criteria:

Patients are excluded if they had tumor bleeding or ulcer bleeding due to the presence of a Dieulafoy lesion or mechanical factors (e.g, gastrostomy tube induction), comorbid with reflux esophagitis grade C or D, Barrett's esophagus, or marginal ulcer bleeding, hypersensitivity to esomeprazole or any component of the formulation, or had previously participated in the study. Because of concern for patient safety with certain drug-drug interactions, patients who receive anti-platelet therapy, e.g., aspirin, clopidogrel, or others for prophylaxis of established cardiovascular or cerebrovascular diseases will be excluded.