Monday, 17 March 2014
Enrollment completed for EUCLID study in patients with Peripheral Artery Disease
United States recruitment has begun for SOCRATES and THEMIS
AstraZeneca (NYSE: AZN) today announced it has completed patient enrollment approximately four months ahead of plan in the Phase III clinical trial EUCLID studying BRILINTA® (ticagrelor) tablets. Part of PARTHENON, AstraZeneca’s largest clinical trial program, EUCLID has randomized more than 13,500 patients globally with peripheral artery disease (PAD); approximately 20 percent are patients in the United States (US) from more than 300 active clinical trial sites across the country. EUCLID is designed to evaluate the effects of ticagrelor (monotherapy) compared to clopidogrel (monotherapy) on cardiovascular (CV) events and safety in PAD patients. Ticagrelor is currently not approved for the treatment of patients with PAD.
“We are very excited to have completed enrollment in the EUCLID study ahead of schedule. This study will provide important information regarding the use of oral antiplatelet agents in peripheral artery disease,” said EUCLID study chair William Hiatt, MD, Professor of Medicine, Division of Cardiology, University of Colorado School of Medicine and CPC Clinical Research. “PAD affects approximately 202 million people globally and 8.5 million people in the US. Patients living with the disease are at high risk for developing myocardial infarctions, strokes, and other health complications.”
AstraZeneca also announced today that US recruitment and enrollment is underway in two additional Phase III PARTHENON studies – SOCRATES and THEMIS. SOCRATES (AcuteStroke Or Transient IsChaemic Attack TReated with Aspirin or Ticagrelor and Patient OutcomES) will evaluate the efficacy of ticagrelor compared to aspirin in reducing major vascular events in patients with acute ischemic stroke or transient ischemic attack (TIA). BRILINTA is currently not approved for the treatment of patients with ischemic stroke or TIA. THEMIS (Effect of Ticagrelor on Health Outcomes in DiabEtes Mellitus Patients InterventionStudy) will evaluate the efficacy of ticagrelor vs placebo, on top of standard of care including aspirin, for the long-term prevention of major vascular events in patients with Type 2 diabetes and coronary atherosclerosis. BRILINTA is not currently approved for the prevention of CV events in patients with diabetes and coronary atherosclerosis.
“Even with aspirin, more than 10 percent of patients who have had an acute ischemic stroke or transient ischemic attack will have a subsequent major stroke within 90 days. We strongly encourage physicians to refer appropriate patients for enrollment in the SOCRATES clinical trial, which will be investigating whether the use of ticagrelor in this patient population can help address a substantial unmet need,” said SOCRATES study co-chair Clay Johnston, MD, PhD, Director, Clinical and Translational Science Institute, Associate Vice Chancellor of Research, University of California, San Francisco (UCSF).
“Of the approximately 26 million people in the US who suffer from diabetes, over 90 percent have Type 2 diabetes – and nearly two-thirds of them will die from cardiovascular disease,” said THEMIS study co-chair Deepak L. Bhatt, MD, MPH, Executive Director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart and Vascular Center, and Professor of Medicine at Harvard Medical School. “The THEMIS study will explore the use of ticagrelor in patients with diabetes, and hopes to provide new scientific evidence to guide appropriate treatment for these high-risk patients, with all of their associated comorbidities.”
“We really value our collaborations with these top academic institutions and clinician-scientists leading the studies that may add substantially to our scientific understanding of appropriate treatment across the spectrum of atherosclerotic disease – including PAD, stroke and diabetes,” said James Ferguson, MD, Vice President, Cardiovascular Therapeutic Area, US Medical Affairs, AstraZeneca. “AstraZeneca is fully committed to broader exploration of the potential for BRILINTA in these additional high-risk clinical circumstances.”
EUCLID, SOCRATES, and THEMIS each have an Independent Data Monitoring Committee, which will review the safety and efficacy of treatments in these trials. The trials will be conducted in accordance with Good Clinical Practice.
SOCRATES and THEMIS Now Enrolling
SOCRATES is designed to randomize 9,600 patients globally who have experienced an acute ischemic stroke or TIA, with approximately 200 US clinical trial sites planned. It is a randomized, parallel group study evaluating the efficacy of ticagrelor compared to aspirin in reducing major CV events, defined as the composite of all-cause mortality, myocardial infarction (MI), and stroke in this patient population. Men or women 40 years of age or older who have experienced either acute ischemic stroke or high-risk TIA may qualify for randomization in this trial within 24 hours after onset of symptoms. Additional information about SOCRATES trial sites and/or patient enrollment is available at www.clinicaltrials.gov by searching under the term SOCRATES or by contacting ClinicalTrialTransparency@astrazeneca.com.
THEMIS is designed to randomize 17,000 patients globally, with approximately 250 US clinical trial sites planned. It is an event-driven, randomized, parallel group study evaluating the efficacy of long-term treatment with ticagrelor compared with placebo for the prevention of major CV events, defined as the composite of CV death, MI, or stroke with Type 2 diabetes, without a history of previous MI or stroke but with documented coronary atherosclerosis. Men or women 50 years of age or older with Type 2 diabetes who have been on treatment with a glucose-lowering medication for at least six months, and have either documented coronary artery occlusive disease or previous revascularization of a coronary artery, may qualify for participation in this trial. Additional information about THEMIS trial sites and/or patient enrollment is available at www.clinicaltrials.gov by searching under the term THEMIS or by contacting THEMIS-RD@astrazeneca.com.
Interested physicians may also visit the AstraZeneca Cardiovascular Research booth (#3407) at the 2014 Annual American College of Cardiology Scientific Session in Washington, DC on March 29–31.
EUCLID (Examining Use of tiCagreLor In paD) recruited more than 13,500 patients globally, including patients from more than 300 active US clinical trial sites. It is a randomized, double-blind, parallel group, multi-center study evaluating the efficacy of ticagrelor (monotherapy) compared to clopidogrel (monotherapy) in reducing the primary endpoint – a composite of CV death, MI, or ischemic stroke – in patients with PAD. BRILINTA is currently not approved for the treatment of patients with PAD.
AstraZeneca is currently collaborating with over 4,000 clinical investigators in more than 30 countries as part of the PARTHENON program, and has established partnerships with a number of pre-eminent research institutions. In addition to EUCLID, SOCRATES and THEMIS, PEGASUS-TIMI 54 is another ongoing global study evaluating ticagrelor for the secondary prevention of CV events in patients with previous MI.
BRILINTA is currently not approved for the treatment of patients with ischemic stroke, TIA, PAD, for the prevention of CV events in patients with diabetes and coronary atherosclerosis, or for secondary prevention in patients with a history of previous MI.
Approved Use for BRILINTA (ticagrelor) tablets
BRILINTA is indicated to reduce the rate of thrombotic CV events in patients with ACS (unstable angina [UA], non–ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]). In PLATO, BRILINTA has been shown to reduce the rate of a combined end point of CV death, MI, or stroke compared to clopidogrel. In PLATO, the difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with an artery-opening procedure known as percutaneous coronary intervention (PCI), BRILINTA reduces the rate of stent thrombosis.
BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily.
IMPORTANT SAFETY INFORMATION ABOUT BRILINTA
WARNING: (A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS
A. BLEEDING RISK
- BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding
- Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage
- Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery
- Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA
- If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events
B. ASPIRIN DOSE AND BRILINTA EFFECTIVENESS
- Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75 mg - 100 mg per day
- BRILINTA is contraindicated in patients with a history of intracranial hemorrhage and active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure; it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins. BRILINTA is also contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product
WARNINGS AND PRECAUTIONS
- Moderate Hepatic Impairment: Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor
- Premature discontinuation increases the risk of MI, stent thrombosis, and death
- Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea resulting from BRILINTA is self-limiting. Rule out other causes
- BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers. Avoid simvastatin and lovastatin doses >40 mg
- Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy
- The most commonly observed adverse reactions associated with the use of BRILINTA vs clopidogrel were Total Major Bleeding (11.6% vs 11.2%) and dyspnea (14% vs 8%)
- In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardic events. Consider the risks and benefits of treatment
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/safety/medwatch or call 1-800-FDA-1088.
Patients can find out more information about BRILINTA at www.BRILINTAtouchpoints.com or by calling 1-888-412-7454.
AstraZeneca offers the AZ&Me™ Prescription Savings Program. To determine eligibility, patients can visit www.AZandMe.com or call 1-800-AZandMe (292-6363).
NOTES TO EDITORS
About BRILINTA® (ticagrelor) tablets
BRILINTA is an oral antiplatelet treatment for ACS. BRILINTA is a direct-acting P2Y12 receptor antagonist in a chemical class called cyclopentyltriazolopyrimidines (CPTPs). BRILINTA works by inhibiting platelet activation and has been shown to reduce the rate of thrombotic CV events, such as a heart attack or CV death, in patients with ACS.
BRILINTA is a registered trademark of the AstraZeneca group of companies.
PLATO (PLATelet Inhibition and Patient Outcomes) was a large (18,624 patients in 43 countries), head-to-head patient outcomes study of BRILINTA vs clopidogrel, both given in combination with aspirin and other standard therapy. The study was designed to establish whether BRILINTA could achieve a clinically meaningful reduction in cardiovascular (CV) events in acute coronary syndrome (ACS) patients, above and beyond that afforded by clopidogrel. Patients were treated for at least six months and up to 12 months.
PLATO demonstrated that treatment with BRILINTA led to a significantly greater reduction in the primary end point – a composite of CV death, MI (excluding silent MI), or stroke – compared to patients who received clopidogrel (9.8% vs 11.7% at 12 months; 1.9% absolute risk reduction [ARR]; 16% relative risk reduction [RRR]; 95% CI, 0.77 to 0.92; P<0.001). The difference in treatments was driven by CV death and MI with no difference in stroke. In PLATO, the absolute difference in treatment benefit vs clopidogrel was seen at 30 days and the Kaplan-Meier survival curves continued to diverge throughout the 12-month treatment period.
The PLATO study also demonstrated that treatment with BRILINTA for 12 months was associated with a 21% RRR in CV death (4% vs 5.1%; 1.1% ARR; P=0.001) and a 16% RRR in MI (excluding silent MI) compared to clopidogrel at 12 months (5.8% vs 6.9%; 1.1% ARR; P<0.005).
The primary safety end point in the PLATO study was Total Major Bleeding, which includes Fatal and Life-threatening bleeding, (11.6% for BRILINTA and 11.2% for clopidogrel) at 12 months. In PLATO, Non-CABG-related major + minor bleeding events were more common with BRILINTA vs clopidogrel (8.7% vs 7% respectively). The rate of non-CABG-related major bleeding was higher for BRILINTA (4.5%) vs clopidogrel (3.8%). The PLATO trial did not show an advantage for BRILINTA compared with clopidogrel for CABG-related Bleeding (Total Major 85.8% vs 86.9% and Fatal/Life-threatening 48.1% vs 47.9%, respectively).
Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients treated with clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment.
*PLATO used the following bleeding severity categorization: Major Bleed–Fatal/Life-threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells [PRBCs]) for bleeding. Major Bleed–Other. Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding. Minor Bleed. Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing). Minimal Bleed. All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.
About Acute Coronary Syndrome (ACS)
ACS is an umbrella term for conditions that result from insufficient blood supply to the heart muscle. These conditions include unstable angina (UA), non–ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). The conditions are defined by ECG changes and heart muscle enzyme leakage. Non–ST-elevation acute coronary syndrome (NSTE-ACS) includes unstable angina (UA) and non–ST-elevation myocardial infarction (NSTEMI); the term is usually used before heart muscle enzymes have been analyzed.
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development, and commercialization of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection, and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.
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