Bleeding Peptic Ulcer
Conditions
Keywords
peptic ulcer bleeding, prevention of rebleeding, successful endoscopic haemostatic therapy
Brief summary
To describe the rate of clinically significant rebleeding during 72 hours continuous i.v. infusion of high dose esomeprazole Na in patients in China with primary successful endoscopic haemostatic therapy of a bleeding peptic ulcer, with cimetidine i.v. in
Detailed description
A multi-center, randomised, double-blind, parallel-group phase III study to assess high dose esomeprazole Na i.v. treatment (bolus infusion of 80 mg followed by a continuous infusion of 8 mg per hour administered for 72 hours) for prevention of rebleeding
Interventions
DRUGEsomeprazole Na
Given as 80mg bolus infusion during 30 min and then 8mg/h constant infusion during 71.5 hous
DRUGCimetidine
Given as 200mg bolus infusion during 30 min and then 60mg/h constant infusion during 71.5 hours
DRUGEsomeprazole Mg
40 mg tablet once daily for 27 days
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Provision of informed consent prior to any study specific procedures. * Female or male aged =18 years and =70 years. * Acute upper gastrointestinal bleeding (haematemesis, melaena or haematochezia) or such signs within the last 24 hours as judged by the investigator. * One endoscopically confirmed bleeding gastric or duodenal peptic ulcer, at least 5 mm in diameter, classified as Forrest Ia, Ib, IIa, or IIb. Photo documentation of the source of bleeding should be provided. * Successful haemostasis (which is considered to have been established if bleeding has stopped and, if applicable, formerly bleeding vessels are flattened or cavitated) achieved by endoscopic treatment and confirmed by site staff.
Exclusion criteria
* Endoscopic suspicion of gastric malignancy or juxta pyloric stenosis as judged by the investigator. * Sign of multi PUB or concomitant other gastro bleeding from esophageal varices, reflux esophagitis, gastritis, Mallory Weiss rifts, ulcus simplex, Dieulafoy's lesion, colon, small bowel, or ulcer distal to the stom in Billroth-resected patients. * Need for treatment during the first 7 days of the study with NSAIDs, Cyclooxygenase-2 (COX-2) inhibitors, acetyl salicylic acid (ASA) (including low dose) or clopidogrel. * Planned treatment with: warfarin (including other vitamin K antagonists), cisapride, phenytoin, atazanavir, nelfinavir, digoxin, methotrexate, clopidogrel, tacrolimus, theophylline, lidocaine, nifedipine. * Chemotherapy or radiation therapies within 2 weeks prior to randomisation or planned during the course of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Clinically Significant Rebleeding Within 72 Hours | 72 hours | Diagnostic criteria for clinically significant rebleeding based on either A, B or C: A) Endoscopy - initiated by clinical signs of bleeding defined as one of B1 or B2 or B3 and endoscopic verification, ie one of A1 or A2. A1: Blood in stomach (this criteria cannot be used during the first 6 hours after primary endoscopic haemostasis). A2: A verified active bleeding from a peptic ulcer (Forrest Ia, Ib). B) A true clinically based definition, at least two of B1 and/or B2 and/or B3. B1: Vomiting of fresh blood or fresh blood in a gastric tube or haematochezia or melaena after a normal stool. B2: Decrease in Hb \>20g/L (or Hct \>6%) during 24 hours or an increase in Hb \<10g/L (or Hct \<3%) despite ≥2 units of blood has been transfused during 24hours. B3: Unstable circulation systolic blood pressure ≤ 90 mmHg or pulse ≥110/min (after have had a stable circulation). C) Haematemesis. Vomiting significant amounts (\>200 ml) of fresh blood as estimated by the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Clinically Significant Rebleeding During 30 Days | 30 days | Diagnostic criteria for clinically significant rebleeding based on either A, B or C: A) Endoscopy - initiated by clinical signs of bleeding defined as one of B1 or B2 or B3 and endoscopic verification, ie one of A1 or A2. A1: Blood in stomach (this criteria cannot be used during the first 6 hours after primary endoscopic haemostasis). A2: A verified active bleeding from a peptic ulcer (Forrest Ia, Ib). B) A true clinically based definition, at least two of B1 and/or B2 and/or B3. B1: Vomiting of fresh blood or fresh blood in a gastric tube or haematochezia or melaena after a normal stool. B2: Decrease in Hb \>20g/L (or Hct \>6%) during 24 hours or an increase in Hb \<10g/L (or Hct \<3%) despite ≥2 units of blood has been transfused during 24hours. B3: Unstable circulation systolic blood pressure ≤ 90 mmHg or pulse ≥110/min (after have had a stable circulation). C) Haematemesis. Vomiting significant amounts (\>200 ml) of fresh blood as estimated by the investigator. |
| Number of Patients With Endoscopic Re-treatment Within 72 Hours | 72 hours | — |
| Number of Patients With Endoscopic Re-treatment Within 30 Days | 30 days | — |
| Rate of Clinically Significant Rebleeding During 7 Days | 7 days | Diagnostic criteria for clinically significant rebleeding based on either A, B or C: A) Endoscopy - initiated by clinical signs of bleeding defined as one of B1 or B2 or B3 and endoscopic verification, ie one of A1 or A2. A1: Blood in stomach (this criteria cannot be used during the first 6 hours after primary endoscopic haemostasis). A2: A verified active bleeding from a peptic ulcer (Forrest Ia, Ib). B) A true clinically based definition, at least two of B1 and/or B2 and/or B3. B1: Vomiting of fresh blood or fresh blood in a gastric tube or haematochezia or melaena after a normal stool. B2: Decrease in Hb \>20g/L (or Hct \>6%) during 24 hours or an increase in Hb \<10g/L (or Hct \<3%) despite ≥2 units of blood has been transfused during 24hours. B3: Unstable circulation systolic blood pressure ≤ 90 mmHg or pulse ≥110/min (after have had a stable circulation). C) Haematemesis. Vomiting significant amounts (\>200 ml) of fresh blood as estimated by the investigator. |
| Number of Patients With Surgery Due to Rebleeding Within 30 Days | within 30 days | — |
| Number of Blood Units Transfused Within 72 Hours | within 72 hours | — |
| Number of Blood Units Transfused Within 30 Days | within 30 days | — |
| Number of Patients With Surgery Due to Rebleeding Within 72 Hours | within 72 hours | — |
Countries
China
Participant flow
Recruitment details
Overall, 239 patients were enrolled from 19 centres in China. The first patient entered the study on 26 February 2013 and the last patient completed the study on 30 December 2014. Of the 239 patients enrolled into the study, 222 (92.9%) patients were randomised to treatment.
Pre-assignment details
17 patients were not assigned to treatment, 15 patients did not fulfil the eligibility criteria, 1 was due to patient decision, and 1 patient due to other (not enough experimental drug).
Participants by arm
| Arm | Count |
|---|---|
| Esomeprazole Esomeprazole iv 80 mg bolus infusion for 30 min followed by Esomeprazole iv 8 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days | 108 |
| Cimetidine Cimetidine iv 200 mg bolus infusion for 30 min followed by Cimetidine iv 60 mg/hour for 71.5 hours and esomeprazole oral 40 mg once daily for 27 days | 107 |
| Total | 215 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Not treated | 3 | 4 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Esomeprazole | Cimetidine | Total |
|---|---|---|---|
| Age, Continuous Age | 42.4 years STANDARD_DEVIATION 12.79 | 41.8 years STANDARD_DEVIATION 12.96 | 42.1 years STANDARD_DEVIATION 12.85 |
| Age, Customized <=65 years | 104 participants | 103 participants | 207 participants |
| Age, Customized >65 years | 4 participants | 4 participants | 8 participants |
| Bleeding ulcer size | 8.2 mm STANDARD_DEVIATION 4.8 | 8.1 mm STANDARD_DEVIATION 3.6 | 8.1 mm STANDARD_DEVIATION 4.3 |
| Forrest class Ia | 5 participants | 4 participants | 9 participants |
| Forrest class Ib | 58 participants | 64 participants | 122 participants |
| Forrest class IIa | 33 participants | 24 participants | 57 participants |
| Forrest class IIb | 12 participants | 15 participants | 27 participants |
| Number of patients with one bleeding ulcer | 108 participants | 107 participants | 215 participants |
| Number of patients with single and multiple ulcers Multiple | 19 participants | 18 participants | 37 participants |
| Number of patients with single and multiple ulcers Single | 89 participants | 89 participants | 178 participants |
| Number of patients with ulcers of different sizes <=2 cm | 105 participants | 106 participants | 211 participants |
| Number of patients with ulcers of different sizes >2 cm | 3 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized Asian/Chinese | 108 participants | 107 participants | 215 participants |
| Sex: Female, Male Female | 25 Participants | 24 Participants | 49 Participants |
| Sex: Female, Male Male | 83 Participants | 83 Participants | 166 Participants |
| Ulcer location Duodenum | 84 participants | 89 participants | 173 participants |
| Ulcer location Stomach | 17 participants | 8 participants | 25 participants |
| Ulcer location Stomach and Duodenum | 7 participants | 10 participants | 17 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 110 | 20 / 105 |
| serious Total, serious adverse events | 5 / 110 | 5 / 105 |
Outcome results
Primary
Rate of Clinically Significant Rebleeding Within 72 Hours
Diagnostic criteria for clinically significant rebleeding based on either A, B or C: A) Endoscopy - initiated by clinical signs of bleeding defined as one of B1 or B2 or B3 and endoscopic verification, ie one of A1 or A2. A1: Blood in stomach (this criteria cannot be used during the first 6 hours after primary endoscopic haemostasis). A2: A verified active bleeding from a peptic ulcer (Forrest Ia, Ib). B) A true clinically based definition, at least two of B1 and/or B2 and/or B3. B1: Vomiting of fresh blood or fresh blood in a gastric tube or haematochezia or melaena after a normal stool. B2: Decrease in Hb \>20g/L (or Hct \>6%) during 24 hours or an increase in Hb \<10g/L (or Hct \<3%) despite ≥2 units of blood has been transfused during 24hours. B3: Unstable circulation systolic blood pressure ≤ 90 mmHg or pulse ≥110/min (after have had a stable circulation). C) Haematemesis. Vomiting significant amounts (\>200 ml) of fresh blood as estimated by the investigator.
Time frame: 72 hours
Population: Full analysis set (FAS). All randomised patients, who started the randomised iv treatment (bolus dose), were included in the FAS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esomeprazole | Rate of Clinically Significant Rebleeding Within 72 Hours | No rebleeding | 107 participants |
| Esomeprazole | Rate of Clinically Significant Rebleeding Within 72 Hours | Rebleeding | 1 participants |
| Cimetidine | Rate of Clinically Significant Rebleeding Within 72 Hours | No rebleeding | 101 participants |
| Cimetidine | Rate of Clinically Significant Rebleeding Within 72 Hours | Rebleeding | 6 participants |
Secondary
Number of Blood Units Transfused Within 30 Days
Time frame: within 30 days
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole | Number of Blood Units Transfused Within 30 Days | 18 blood units |
| Cimetidine | Number of Blood Units Transfused Within 30 Days | 21 blood units |
Secondary
Number of Blood Units Transfused Within 72 Hours
Time frame: within 72 hours
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole | Number of Blood Units Transfused Within 72 Hours | 14 blood units |
| Cimetidine | Number of Blood Units Transfused Within 72 Hours | 21 blood units |
Secondary
Number of Patients With Endoscopic Re-treatment Within 30 Days
Time frame: 30 days
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esomeprazole | Number of Patients With Endoscopic Re-treatment Within 30 Days | No re-treatment | 106 participants |
| Esomeprazole | Number of Patients With Endoscopic Re-treatment Within 30 Days | Re-treatment | 2 participants |
| Cimetidine | Number of Patients With Endoscopic Re-treatment Within 30 Days | No re-treatment | 106 participants |
| Cimetidine | Number of Patients With Endoscopic Re-treatment Within 30 Days | Re-treatment | 1 participants |
Secondary
Number of Patients With Endoscopic Re-treatment Within 72 Hours
Time frame: 72 hours
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esomeprazole | Number of Patients With Endoscopic Re-treatment Within 72 Hours | No re-treatment | 108 participants |
| Esomeprazole | Number of Patients With Endoscopic Re-treatment Within 72 Hours | Re-treatment | 0 participants |
| Cimetidine | Number of Patients With Endoscopic Re-treatment Within 72 Hours | No re-treatment | 106 participants |
| Cimetidine | Number of Patients With Endoscopic Re-treatment Within 72 Hours | Re-treatment | 1 participants |
Secondary
Number of Patients With Surgery Due to Rebleeding Within 30 Days
Time frame: within 30 days
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esomeprazole | Number of Patients With Surgery Due to Rebleeding Within 30 Days | No surgery | 108 participants |
| Esomeprazole | Number of Patients With Surgery Due to Rebleeding Within 30 Days | Surgery | 0 participants |
| Cimetidine | Number of Patients With Surgery Due to Rebleeding Within 30 Days | No surgery | 106 participants |
| Cimetidine | Number of Patients With Surgery Due to Rebleeding Within 30 Days | Surgery | 1 participants |
Secondary
Number of Patients With Surgery Due to Rebleeding Within 72 Hours
Time frame: within 72 hours
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esomeprazole | Number of Patients With Surgery Due to Rebleeding Within 72 Hours | No surgery | 108 participants |
| Esomeprazole | Number of Patients With Surgery Due to Rebleeding Within 72 Hours | Surgery | 0 participants |
| Cimetidine | Number of Patients With Surgery Due to Rebleeding Within 72 Hours | No surgery | 107 participants |
| Cimetidine | Number of Patients With Surgery Due to Rebleeding Within 72 Hours | Surgery | 0 participants |
Secondary
Rate of Clinically Significant Rebleeding During 30 Days
Diagnostic criteria for clinically significant rebleeding based on either A, B or C: A) Endoscopy - initiated by clinical signs of bleeding defined as one of B1 or B2 or B3 and endoscopic verification, ie one of A1 or A2. A1: Blood in stomach (this criteria cannot be used during the first 6 hours after primary endoscopic haemostasis). A2: A verified active bleeding from a peptic ulcer (Forrest Ia, Ib). B) A true clinically based definition, at least two of B1 and/or B2 and/or B3. B1: Vomiting of fresh blood or fresh blood in a gastric tube or haematochezia or melaena after a normal stool. B2: Decrease in Hb \>20g/L (or Hct \>6%) during 24 hours or an increase in Hb \<10g/L (or Hct \<3%) despite ≥2 units of blood has been transfused during 24hours. B3: Unstable circulation systolic blood pressure ≤ 90 mmHg or pulse ≥110/min (after have had a stable circulation). C) Haematemesis. Vomiting significant amounts (\>200 ml) of fresh blood as estimated by the investigator.
Time frame: 30 days
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esomeprazole | Rate of Clinically Significant Rebleeding During 30 Days | No rebleeding | 105 participants |
| Esomeprazole | Rate of Clinically Significant Rebleeding During 30 Days | Rebleeding | 3 participants |
| Cimetidine | Rate of Clinically Significant Rebleeding During 30 Days | No rebleeding | 101 participants |
| Cimetidine | Rate of Clinically Significant Rebleeding During 30 Days | Rebleeding | 6 participants |
Secondary
Rate of Clinically Significant Rebleeding During 7 Days
Diagnostic criteria for clinically significant rebleeding based on either A, B or C: A) Endoscopy - initiated by clinical signs of bleeding defined as one of B1 or B2 or B3 and endoscopic verification, ie one of A1 or A2. A1: Blood in stomach (this criteria cannot be used during the first 6 hours after primary endoscopic haemostasis). A2: A verified active bleeding from a peptic ulcer (Forrest Ia, Ib). B) A true clinically based definition, at least two of B1 and/or B2 and/or B3. B1: Vomiting of fresh blood or fresh blood in a gastric tube or haematochezia or melaena after a normal stool. B2: Decrease in Hb \>20g/L (or Hct \>6%) during 24 hours or an increase in Hb \<10g/L (or Hct \<3%) despite ≥2 units of blood has been transfused during 24hours. B3: Unstable circulation systolic blood pressure ≤ 90 mmHg or pulse ≥110/min (after have had a stable circulation). C) Haematemesis. Vomiting significant amounts (\>200 ml) of fresh blood as estimated by the investigator.
Time frame: 7 days
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Esomeprazole | Rate of Clinically Significant Rebleeding During 7 Days | No rebleeding | 105 participants |
| Esomeprazole | Rate of Clinically Significant Rebleeding During 7 Days | Rebleeding | 3 participants |
| Cimetidine | Rate of Clinically Significant Rebleeding During 7 Days | No rebleeding | 101 participants |
| Cimetidine | Rate of Clinically Significant Rebleeding During 7 Days | Rebleeding | 6 participants |