Stress Ulcer Prophylaxis
Conditions
Keywords
SUP, Upper GI bleeding, Seriously ill patients
Brief summary
The efficacy of esomeprazole will be compared versus cimetidine (a drug that previously demonstrated prevention of bleeding events) during treatment period in proportion of patients for the prevention of upper GI bleeding.
Detailed description
Stress related upper Gastrointestinal (GI) bleedings are important events associated with morbidity and mortality among seriously ill patients. Data from the literature suggest that stress ulcer prevention with effective acid suppressive treatment can reduce bleeding events and is thus an important therapy in high-risk patients. Esomeprazole has the potential to reduce gastric acidity for prolonged periods of time adequate for both preventing mucosal damage and facilitating coagulation. This study is to reveal whether intravenous (iv) esomeprazole is effective in preventing upper gastrointestinal bleeding and if it is tolerated by Chinese seriously ill patients.
Interventions
DRUGEsomeprazole
iv esomeprazole 30 min intermittent infusions given for maximum 14 days
DRUGCimetidine
iv cimetidine 30 min bolus infusion followed by iv cimetidine continuous infusion given for maximum 14 days
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Critically ill patients 2. Requirement for mechanical ventilation 3. At least one major risk factor for stress ulcer related bleeding
Exclusion criteria
1. History of gastric or oesophageal surgery 2. Evidence of active GI bleeding 3. Advanced renal disease 4. Treatment with any Proton Pump Inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percent of Patients With Clinically Significant Upper-GI Bleeding During the Treatment Evaluation Phase | 1-14 days | Criteria for a clinically significant upper GI bleeding as: 1. Bright red blood per NG or OG tube that did not clear after NG or OG tube adjustment and 5 to 10 minutes of at least 100 ml lavage with room temperature normal saline-or, 2. Persistent gastroccult- positive coffee ground material During IMP treatment Day 1-2: Persistent gastroccult- positive coffee ground material for at least eight consecutive hours that did not clear with at least 100 ml of lavage with room temperature normal saline. During IMP treatment Day 3-14: Persistent gastroccult- positive coffee ground material in at least three consecutive gastric aspirates within 2 to 4 hours (at least 60 ±20 minutes apart), that did not clear with at least 100 ml of lavage with room temperature normal saline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Any Overt Upper-GI Bleeding (Significant and Non-significant) During the Treatment Evaluation Phase | 1-14 days | Criteria for a significant upper GI bleeding as described in primary outcome measure or, Criteria for a non-significant upper GI bleeding as: 1. Bright red blood per NG or OG tube that clear after NG or OG tube adjustment and 5 to 10 minutes of lavage with room temperature normal saline or, 2. Persistent gastroccult- positive coffee ground material During IMP treatment Day 1-2: Persistent gastroccult - positive coffee ground material for at less than eight consecutive hours or that clear with at least 100 ml of lavage with room temperature normal saline. During IMP treatment Day 3-14: Persistent gastroccult - positive coffee ground material in less than three consecutive gastric aspirates within 2 to 4 hours (at least 60±20 minutes apart), or that clear with at least 100 ml of lavage with room temperature normal saline or, 3. Any clinical signs of hematemesis or melena or haematochezia judged (by the Investigator) to be from an upper GI source. |
Countries
China
Participant flow
Recruitment details
Overall, 343 patients were enrolled from 27 centres in China. The first patient entered the study on 15 July 2014 and the last patient completed the study on 18 February 2016. Of the 343 patients enrolled into the study, 311 (90.7%) patients were randomised to treatment.
Pre-assignment details
32 patients were not randomised to treatment due to eligibility criteria not being fulfilled.
Participants by arm
| Arm | Count |
|---|---|
| Esomeprazole iv Esomeprazole 40 mg bid 30 min intermittent infusion given for maximum 14 days | 147 |
| Cimetidine iv Cimetidine 300 mg 30 min bolus infusion, followed by iv Cimetidine continuous infusion (50 mg/h) given for maximum 14 days | 153 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 10 | 4 |
| Overall Study | Eligibility criteria not fulfilled | 0 | 1 |
| Overall Study | Investigator's misjudgement | 1 | 2 |
| Overall Study | Not treated | 8 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 8 |
Baseline characteristics
| Characteristic | Esomeprazole | Cimetidine | Total |
|---|---|---|---|
| Age, Continuous | 50.6 years STANDARD_DEVIATION 11.8 | 50.1 years STANDARD_DEVIATION 12.4 | 50.4 years STANDARD_DEVIATION 12.1 |
| Age, Customized <65 years | 131 participants | 132 participants | 263 participants |
| Age, Customized >=65 years | 16 participants | 21 participants | 37 participants |
| Race/Ethnicity, Customized Asian/Chinese | 147 participants | 153 participants | 300 participants |
| Sex: Female, Male Female | 43 Participants | 38 Participants | 81 Participants |
| Sex: Female, Male Male | 104 Participants | 115 Participants | 219 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 88 / 153 | 85 / 147 |
| serious Total, serious adverse events | 12 / 153 | 14 / 147 |
Outcome results
Primary
The Percent of Patients With Clinically Significant Upper-GI Bleeding During the Treatment Evaluation Phase
Criteria for a clinically significant upper GI bleeding as: 1. Bright red blood per NG or OG tube that did not clear after NG or OG tube adjustment and 5 to 10 minutes of at least 100 ml lavage with room temperature normal saline-or, 2. Persistent gastroccult- positive coffee ground material During IMP treatment Day 1-2: Persistent gastroccult- positive coffee ground material for at least eight consecutive hours that did not clear with at least 100 ml of lavage with room temperature normal saline. During IMP treatment Day 3-14: Persistent gastroccult- positive coffee ground material in at least three consecutive gastric aspirates within 2 to 4 hours (at least 60 ±20 minutes apart), that did not clear with at least 100 ml of lavage with room temperature normal saline.
Time frame: 1-14 days
Population: Full analysis set (FAS). All randomized patients in whom at least one dose of randomized treatment has been initiated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole | The Percent of Patients With Clinically Significant Upper-GI Bleeding During the Treatment Evaluation Phase | 2.7 % of participants |
| Cimetidine | The Percent of Patients With Clinically Significant Upper-GI Bleeding During the Treatment Evaluation Phase | 4.6 % of participants |
Comparison: Assuming a bleeding percent of 6.3% for the active comparator, a risk reduction of 3.7% for esomeprazole, and a 5% non-inferiority margin, 150 patients per treatment arm will provide 94% power to demonstrate non-inferiority. The null hypothesis is that the bleeding rate for iv esomeprazole 40 mg bid exceeds the rate for iv cimetidine by an amount at least as large as 5%.p-value: 0.39395% CI: [-2.8, 6.5]Pearson's Chi-square
Secondary
Proportion of Patients With Any Overt Upper-GI Bleeding (Significant and Non-significant) During the Treatment Evaluation Phase
Criteria for a significant upper GI bleeding as described in primary outcome measure or, Criteria for a non-significant upper GI bleeding as: 1. Bright red blood per NG or OG tube that clear after NG or OG tube adjustment and 5 to 10 minutes of lavage with room temperature normal saline or, 2. Persistent gastroccult- positive coffee ground material During IMP treatment Day 1-2: Persistent gastroccult - positive coffee ground material for at less than eight consecutive hours or that clear with at least 100 ml of lavage with room temperature normal saline. During IMP treatment Day 3-14: Persistent gastroccult - positive coffee ground material in less than three consecutive gastric aspirates within 2 to 4 hours (at least 60±20 minutes apart), or that clear with at least 100 ml of lavage with room temperature normal saline or, 3. Any clinical signs of hematemesis or melena or haematochezia judged (by the Investigator) to be from an upper GI source.
Time frame: 1-14 days
Population: Full analysis set (FAS). All randomized patients in whom at least one dose of randomized treatment has been initiated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Esomeprazole | Proportion of Patients With Any Overt Upper-GI Bleeding (Significant and Non-significant) During the Treatment Evaluation Phase | 0.109 proportion of participants |
| Cimetidine | Proportion of Patients With Any Overt Upper-GI Bleeding (Significant and Non-significant) During the Treatment Evaluation Phase | 0.105 proportion of participants |