| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients at risk of Peri operative associated cardiovascular events |
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| MedDRA Classification |
| 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 |
| What is the effect of low-dose clonidine versus placebo and low-dose ASA versus placebo on the 30-day risk of all-cause mortality or nonfatal MI in patients with, or at risk of, atherosclerotic disease who are undergoing noncardiac surgery? |
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| E.2.2 | Secondary objectives of the trial |
| 1. To determine the impact of perioperative administration of low-dose clonidine and separately low-dose ASA on each of the following individual secondary outcomes at 30 days after randomization: all-cause mortality, vascular mortality, MI, nonfatal cardiac arrest, cardiac revascularization procedure, pulmonary emboli, deep venous thrombosis, clinically important atrial fibrillation, rehospitalization for vascular reasons, length of hospital stay, length of intensive care unit / cardiac care unit (ICU/CCU) stay, and new acute renal failure requiring dialysis. 2. To determine the impact of perioperative administration of low-dose clonidine and separately low-dose ASA on the composite of all-cause mortality, nonfatal MI, and nonfatal stroke at 30 days after randomization. 3. To determine in each ASA stratum the impact on a composite outcome of all-cause mortality, nonfatal MI, cardiac revascularization procedure, nonfatal pulmonary emboli, and nonfatal deep venous thrombosis at 30 da |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.3 | Principal inclusion criteria |
| 1. are undergoing noncardiac surgery; 2. are ≥ 45 years of age; 3. are expected to require at least an overnight hospital admission after surgery; AND 4. fulfill > 1 of the following 5 criteria: A. history of coronary artery disease as defined by any one of the following 6 criteria i. history of angina ii. history of a myocardial infarction or acute coronary syndrome iii. history of a segmental cardiac wall motion abnormality on echocardiography or a segmental fixed defect on radionuclide imaging iv. history of a positive radionuclide exercise, echocardiographic exercise, or pharmacological cardiovascular stress test demonstrating cardiac ischemia v. history of a coronary angiographic or CT coronary angiographic evidence of atherosclerotic stenosis ≥ 50% of the diameter of any coronary artery vi. ECG with pathological Q waves in two contiguous leads POISE-2 Trial Version 4 March 1, 2010April 6, 2011 13 vii. previous coronary artery revascularization, i.e. percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) B. history of peripheral vascular disease as defined by a physician diagnosis of a current or prior history of any one of the following 4 criteria i. intermittent claudication ii. vascular surgery for atherosclerotic disease iii. an ankle/arm systolic blood pressure ratio < 0.90 in either leg at rest iv. angiographic or doppler study demonstrating > 70% stenosis in a noncardiac artery C. history of stroke as defined by any one of the following 2 criteria i. a physician diagnosis of stroke ii. CT or MRI evidence of a prior stroke D. undergoing major vascular surgery defined as all vascular surgery except arteriovenous shunt, vein stripping procedures, and carotid endarterectomies;, and endovascular abdominal aortic aneurysm repair (EVAR); OR E. any 3 of 9 risk criteria i. undergoing major surgery defined as intraperitoneal, intrathoracic, retroperitoneal or major orthopedic surgery (i.e., hip arthroplasty, internal fixation of hip or femur, pelvic arthroplasty, knee arthroplasty, above-knee amputation or amputation below the knee but above the foot) ii. history of congestive heart failure defined as a physician diagnosis of a current or prior episode of congestive heart failure OR prior radiographic evidence of vascular redistribution, interstitial pulmonary edema, or frank alveolar pulmonary edema iii. history of a transient ischemic attack; iv. diabetes and currently taking an oral hypoglycemic agent or insulin; v. age > 70 years; vi. hypertension; vii. serum creatinine > 175 μmol/L (> 2.0 mg/dl); viii. history of smoking within 2 years of surgery; ix. undergoing emergent/urgent surgery defined as surgery that a surgeon schedules to go to the operating room within 48 hours of an acute presentation to the hospital |
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| E.4 | Principal exclusion criteria |
| We will exclude patients meeting any of the following criteria: 1. consumption of ASA within 72 hours prior to surgery; 2. hypersensitivity or known allergy to ASA or clonidine; 3. systolic blood pressure < 105 mm Hg; 4. heart rate < 55 beats per minute in a patient who does not have a permanent pacemaker; 5. second or third degree heart block without a permanent pacemaker; 6. active peptic ulcer disease or gastrointestinal bleeding within previous 6 weeks; 7. intracranial hemorrhage (including subdural hematoma and parenchymal hematoma as a complication of primary ischemic stroke) documented by neuro-imaging, in the 6 months prior to randomization. This does not include petechial hemorrhagic transformation of a primary ischemic stroke; 8. subarachnoid hemorrhage or epidural hematoma unless the event occurred more than 6 months prior to randomization and the offending aneurysm or arterial lesion has been repaired; 9. drug-eluting coronary stent in the year prior to randomization;96 10. bare-metal coronary stent in the 6 weeks prior to randomization;96 11. thienopyridine (e.g., clopidogrel, ticlopidine, prasugrel) or ticagrelor within 72 hours prior to surgery; or intent to restart a thienopyridine or ticagrelor during the first 7 days post-op; or POISE-2 Trial Version 4 March 1, 2010April 6, 2011 14 currently taking an alpha-2 agonist, alpha methyldopa, monoamine oxidase inhibitors or reserpine, ticagrelor, or thienopyridine (e.g., clopidogrel, ticlopidine, prasugrel);; 12. planned use – during the first 3 days after surgery – therapeutic dose anticoagulation (e.g., warfarin with a target INR > 2.0, dabigatran > 250 mg/day, or rivaroxaban > 10 mg/day) or a therapeutic subcutaneous or intravenous antithrombotic agent (defined as full dose unfractionated heparin [i.e., > 15, 000 u/24hrs], low molecular weight heparin [i.e., > 6,000 u/24hrs or enoxaparin: > 60 mg/24hrs], or fondaparinux [i.e., > 2.5mg/24hrs]; 13. undergoing intracranial surgery, carotid endarterectomy, or retinal surgery; 14. not consenting to participate in POISE-2 prior to surgery; OR 15. previously enrolled in POISE-2 Trial |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The overall primary outcome of the POISE-2 Trial is a composite of all-cause mortality and nonfatal MI at 30 days after randomization. We will present the time-to-the first occurrence of one of the components of the primary outcome using the Kaplan-Meier estimator. We will use log-rank tests to compare the rate of occurrence of the primary outcome between the ASA versus ASA placebo group and separately the clonidine versus the clonidine placebo group. We will use Cox proportional hazards models to estimate the effect of clonidine, and of ASA, on the hazard ratio for the primary and secondary outcomes (with stratification according to whether treatment included the other agent). We will calculate the hazard ratios and their associated 95% confidence intervals. We will infer statistical significance if the computed 2-sided p-value is < 0.05. We anticipate that the treatment effect of clonidine and ASA, if present, will act independently, but we will, however, evaluate the possibility of synergism or antagonism by formally testing the interaction term in a Cox model. |
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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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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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| last visit of the last subject undergoing the trial where he/she would be follow-up for a year. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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