Apixaban Versus Dual-antiplatelet Therapy (Clopidogrel and Aspirin) in Acute Non-disabling Cerebrovascular Events (ADANCE)

Apixaban Versus Dual-antiplatelet Therapy (Clopidogrel and Aspirin) in High-risk Patients With Acute Non-disabling Cerebrovascular Events (ADANCE): Rationale, Objectives, and Design

Nondisabling cerebrovascular events represent the largest group of cerebrovascular disease with a high risk of recurrent stroke. A recent trial indicated that clopidogrel and aspirin treatment reduced the risk of recurrent stroke and was not associated with increased hemorrhage events, compared with aspirin monotherapy. Apixaban, a new oral anticoagulant, is proved to be as effective as traditional anticoagulants with less risk of bleeding events.

To estimate whether apixaban is beneficial for acute TIA or minor stroke, a randomized, double-blind, multicenter, controlled clinical trial has been designed. The investigators will assess the hypothesis that a 21-days apixaban regimen is superior to clopidogrel and aspirin dual-therapy for the treatment of high-risk patients with acute nondisabling cerebrovascular event.

Study Overview

• Status: Unknown
• Conditions: Ischemic Stroke; TIA
• Intervention / Treatment: Drug: placebo; Drug: Clopidogrel; Drug: Aspirin; Drug: Apixaban

Detailed Description

The ADANCE study is a randomized, double-blind clinical trial with a target enrollment of 3,000 Chinese patients. Two subtypes of patients will be enrolled: I, acute disabling ischemic stroke (<24 hours of symptoms onset); II, acute TIA (<24 hours of symptoms onset).

Patients will be randomized into 3 groups:

Ⅰ Receiving a 75 mg dose of clopidogrel and 75mg dose of aspirin from day 1 to day 21, with placebo apixaban twice daily.

Ⅱ Receiving a 2.5-mg twice daily of apixaban, with placebo clopidogrel and placebo aspirin from day 1 to day 21.

Ⅲ Receiving a 5-mg twice daily of apixaban, with placebo clopidogrel and placebo aspirin from day 1 to day 21.

From day 22 to 3 months, all patients will receive 75-mg dose of clopidogrel long-term antiplatelet therapy.

The primary efficacy end point is percentage of patients with new stroke (ischemic or hemorrhage) at 90 days.

• Study Type: Interventional
• Enrollment (Anticipated): 10000
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 710032
      • Xijing Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult subjects (male or female ≥18 years old)
• Acute nondisabling ischemic stroke (NIHSS ≤3 at the time of randomization) that can be treated with study drug within 24 hours of symptoms onset. Symptom onset is defined by the "last see normal" principle
• TIA (neurologic deficit attributed to focal brain ischemia, with resolution of the deficit within 24 hours of symptom onset), that can be treated with investigational medication within 24 hours of symptoms onset. Symptom onset is defined by the "last see normal" principle
• Informed consent signed

Exclusion Criteria:

• Diagnosis of hemorrhage or other pathology, such as vascular malformation, tumor, abscess or other major nonischemic brain disease, on baseline head CT or MRI scan
• mRS score >2 at randomization (premorbid historical assessment) NIHSS ≥4 at randomization
• Clear indication for anticoagulation (atrial fibrillation, mechanical cardiac valves, deep venous thrombosis, pulmonary embolism or known hypercoagulable state)
• Contraindication to investigational medications
• Thrombolysis for ischemic stroke within preceding 7 days
• History of intracranial hemorrhage
• Current treatment (last dose given within 10 days before randomization) with heparin therapy or oral anticoagulation
• Gastrointestinal bleed or major surgery within 3 months
• Planned or likely revascularization (any angioplasty or vascular surgery) within the next 3 months
• TIA or minor stroke induced by angiography or surgery
• Severe noncardiovascular comorbidity with life expectancy <3 months
• Women of childbearing age not practicing reliable contraception who do not have a documented negative pregnancy test result
• Severe renal failure, defined as Glomerular Filtration Rate (GFR) <30 ml/min Severe hepatic insufficiency (Child-Pugh score B to C)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dual-antiplatelet Therapy; Receiving a 75 mg dose of clopidogrel and 75mg dose of aspirin from day 1 to day 21, with placebo apixaban twice daily	Drug: placebo; Drug: Clopidogrel; an irreversible inhibitor of the P2Y12 adenosine diphosphate receptor; Other Names: Plavix; Clopivid; Drug: Aspirin; a non-steroidal anti-inflammatory drug; Other Names: Acetylsalicylic acid
Experimental: Apixaban 2.5mg; Receiving a 2.5-mg twice daily of apixaban, with placebo clopidogrel and placebo aspirin from day 1 to day 21	Drug: placebo; Drug: Apixaban; orally active direct factor Xa inhibitor; Other Names: Eliquis; BMS-562247; BMS-562247-01
Experimental: Apixaban 5mg; Receiving a 5-mg twice daily of apixaban, with placebo clopidogrel and placebo aspirin from day 1 to day 21	Drug: placebo; Drug: Apixaban; orally active direct factor Xa inhibitor; Other Names: Eliquis; BMS-562247; BMS-562247-01

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
percentage of patients with new stroke (ischemic or hemorrhage)	90 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Total mortality	90 days
Percentage of patients with new clinical vascular events (ischemic stroke/hemorrhagic stroke/TIA/myocardial infarction/vascular death)	30 days
Changes in NIHSS scores	90 days
moderate to severe bleeding events	90 days
Adverse events/severe adverse events reported by the investigators	90 days
Percentage of patients with new clinical vascular events (ischemic stroke/hemorrhagic stroke/TIA/myocardial infarction/vascular death)	30 days and 90 days

Collaborators and Investigators

• Sponsor: Xijing Hospital
• Investigators: Principal Investigator: Gang Zhao, M.D., Neurology Department,Xijing Hospital

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Anticipated): December 1, 2015
• Study Completion (Anticipated): July 1, 2016

Study Registration Dates

• First Submitted: August 13, 2013
• First Submitted That Met QC Criteria: August 13, 2013
• First Posted (Estimate): August 16, 2013

Study Record Updates

• Last Update Posted (Estimate): August 16, 2013
• Last Update Submitted That Met QC Criteria: August 13, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: clopidogrel; aspirin; TIA; apixaban; new oral anticoagulant; acute minor ischemic stroke
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Clopidogrel; Apixaban
• Other Study ID Numbers: Xijing-ADANCE