| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| MINS (myocardial injury after noncardiac surgery) |
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| E.1.1.1 | Medical condition in easily understood language |
| Heart injury after noncardiac surgery |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066592 |
| E.1.2 | Term | Post procedural myocardial infarction |
| E.1.2 | System Organ Class | 10022117 - Injury, poisoning and procedural complications |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary efficacy objective for dabigatran: To determine the effect of dabigatran versus placebo on the risk of a major vascular complication (i.e., a composite of vascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, nonfatal peripheral arterial thrombosis, and nonfatal symptomatic pulmonary embolism[PE]) in patients who have suffered myocardial injury after noncardiac surgery (MINS) and are followed on average for 1 year.
Primary efficacy objective for omeprazole: To determine the effect of omeprazole versus placebo on the risk of a major upper gastrointestinal complication (i.e., a composite of overt gastroduodenal bleeding, overt upper gastrointestinal bleeding of unknown origin, or upper gastrointestinal perforation) in patients who have suffered MINS and are followed on average for 1 year.
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| E.2.2 | Secondary objectives of the trial |
| To determine the effect of dabigatran on the individual outcome of all-cause death, vascular death, MI, stroke, cardiac revascularization, symptomatic venous thromboembolism (i.e., PE or DVT), amputation, peripheral arterial thrombosis (PAT), and rehospitalization for vascular reasons. To determine the effect of omeprazole on the composite of a: 1) upper gastrointestinal (UGI) complication (i.e. composite of overt gastroduodenal (GD) bleeding, overt UGI bleeding of unknown origin, symptomatic GD ulcer, GI pain with underlying multiple GD erosions, or UGI perforation); and 2) major vascular complication (i.e., a composite of vascular death, MI, stroke; PAT, and symptomatic PE). To determine the effect of omeprazole on the individual secondary outcomes of: overt GD bleeding, overt esophageal bleeding, overt UGI bleeding of unknown origin, symptomatic GD ulcer, GI pain with underlying multiple GD, UGI perforation, bleeding of assumed occult GI origin with a hemoglobin drop of ≥3.0 g/dL. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible if they:
1. have undergone noncardiac surgery;
2. are ≥45 years of age;
3. have suffered MINS based upon fulfilling one of the following
criteria:
A. Elevated troponin or CK-MB measurement with one or more of the following defining features
i. ischemic signs or symptoms (i.e., chest, arm, neck, or jaw discomfort; shortness of breath, pulmonary edema);
ii. development of pathologic Q waves present in any two contiguous leads that are ≥30 milliseconds;
iii. electrocardiogram (ECG) changes indicative of ischemia (i.e., ST segment elevation [≥2 mm in leads V1, V2, or V3 OR ≥1 mm in the other leads], ST segment depression [≥1 mm], OR symmetric inversion of T waves ≥1 mm) in at least two contiguous leads;
iv. new LBBB; or
v. new or presumed new cardiac wall motion abnormality on echocardiography or new or presumed new fixed defect on radionuclide imaging
B. Elevated troponin measurement after surgery with no alternative explanation (e.g., pulmonary embolism, sepsis) to myocardial injury; AND
4. provide written informed consent to participate within 35 days of suffering their MINS.
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| E.4 | Principal exclusion criteria |
We will exclude patients meeting any of the following criteria:
1. hypersensitivity or known allergy to dabigatran;
2. history of intracranial, intraocular, or spinal bleeding;
3. hemorrhagic disorder or bleeding diathesis;
4. known hepatic impairment or liver disease expected to have an impact on survival;
5. condition that requires therapeutic dose anticoagulation (e.g., prosthetic heart valve, venous thromboembolism, atrial fibrillation);
6. currently using or plan to initiate rifampicin, cyclosporine, itraconazole, tacrolimus, ketoconazole, or dronedarone;
7. women who are pregnant, breastfeeding, or of childbearing potential who refuse to use a medically acceptable form of contraception throughout the study;
8. investigator considers the patient unreliable regarding requirement for study follow-up or study drug compliance; OR
9. previously enrolled in the MANAGE Trial.
We will also exclude patients in whom any of the following criteria persist beyond 35 days of their suffering MINS:
1. the attending surgeon believes it is not safe to initiate therapeutic dose anticoagulation therapy;
2. the attending physician believes ASA, intermittent pneumatic compression, or elastic stockings are not sufficient for venous thromboembolism (VTE) prophylaxis and that the patient requires a prophylactic-dose anticoagulant;
3. the patient has an indwelling epidural or spinal catheter that cannot be removed, or the first dose of dabigatran will occur within 4 hours of epidural catheter removal; OR
4. estimated glomerular filtration rate (eGFR) <35 ml/min as estimated by calculated creatinine clearance.
5. it is expected that the patient will undergo cardiac catheterization for MINS.
Exclusion Criteria Specific to Patients in the Omeprazole Factorial Component of the Trial
We will exclude patients meeting any of the following criteria:
1. hypersensitivity or known allergy to omeprazole;
2. requirement for a proton pump inhibitor, an H2-receptor antagonist, sucralfate, atazanavir, clopidogrel, or misoprostol;
3. esophageal or gastric variceal disease; OR
4. patient declines participation in the omeprazole arm of MANAGE.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome for dabigatran is a major vascular complication (i.e., a composite of vascular mortality, nonfatal myocardial infarction, nonfatal stroke, nonfatal peripheral arterial thrombosis, and nonfatal symptomatic pulmonary embolism).
The primary outcome for omeprazole is a major upper gastrointestinal complication (i.e., a composite of overt gastroduodenal bleeding, overt upper gastrointestinal bleeding of unknown origin, or upper gastrointestinal perforation).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Three interim efficacy analyses based on the primary outcome will occur when 25%, 50% and 75% of the patients have been followed on average for 1 year. The Data Monitoring Committee (DMC) will employ the modified Haybittle-Peto rule of 4 standard deviations (SDs) ( = 0.0001) for analyses in the first half of the trial (including the second planned interim analysis) and 3 SDs ( = 0.00047) for all analyses in the second half. For a finding of 1 or both active treatments to be considered significant, these predefined boundaries will have to be exceeded in at least 2 consecutive analyses, 3 or more months apart. The -level for the final analysis will remain the conventional = 0.05 |
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| E.5.2 | Secondary end point(s) |
Secondary outcomes for dabigatran include each of the following individual secondary outcomes: all-cause mortality, vascular mortality, myocardial infarction, stroke, cardiac revascularization procedure, symptomatic venous thromboembolism (i.e., symptomatic pulmonary embolism or deep symptomatic venous thrombosis), amputation, peripheral arterial thrombosis, and rehospitalization for vascular reasons.
Secondary outcomes for omeprazole include: 1. A upper gastrointestinal complication (i.e., composite of overt gastroduodenal bleeding, overt upper gastrointestinal bleeding of unknown origin, symptomatic gastroduodenal ulcer, gastrointestinal pain with underlying multiple gastroduodenal erosions, or upper gastrointestinal perforation), 2. A major vascular complication (i.e., a composite of vascular mortality, nonfatal myocardial infarction, nonfatal stroke, nonfatal peripheral arterial thrombosis and nonfatal symptomatic pulmonary embolism), and 3. Each of the following individual secondary outcomes: overt gastroduodenal bleeding, overt esophageal bleeding, overt upper gastrointestinal bleeding of unknown origin, symptomatic gastroduodenal ulcer, gastrointestinal pain with underlying multiple gastroduodenal erosions, upper gastrointestinal perforation, and bleeding of assumed occult gastrointestinal origin with a documented drop in hemoglobin of ≥3.0 g/dL.
Safety outcomes for dabigatran include: life-threatening bleeding, major bleeding, intracranial bleeding, minor bleeding, significant lower gastrointestinal bleeding, non-significant lower gastrointestinal bleeding, and dyspepsia.
Safety outcomes for omeprazole include: Clostridium difficile-associated diarrhea, diarrhea, community-acquired pneumonia, and fractures.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| These endpoints will be evaluated at the end of the trial when all of the data has been collected. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| A partial 2x2 factorial to randomize patients not already on a proton pump inhibitor to omeprazole |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| Colombia |
| Hong Kong |
| India |
| Israel |
| Kenya |
| Nigeria |
| Peru |
| Philippines |
| Russian Federation |
| South Africa |
| Switzerland |
| Uganda |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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