AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA)

• ClinicalTrials.gov Identifier: NCT03192215
• Recruitment Status: Active, not recruiting
• First Posted: June 20, 2017
• Last Update Posted: December 16, 2022
• Sponsor: Columbia University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); University of Cincinnati; Medical University of South Carolina; Bristol-Myers Squibb; Pfizer; Roche Pharma AG; Weill Medical College of Cornell University; University of Washington
• Information provided by (Responsible Party): Randolph S. Marshall, MD, Columbia University

Tracking Information

• First Submitted Date: June 16, 2017
• First Posted Date: June 20, 2017
• Last Update Posted Date: December 16, 2022
• Actual Study Start Date: January 19, 2018
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 20, 2020)

Incidence of recurrent stroke [ Time Frame: 7 years ]

Recurrent stroke of any type (ischemic, hemorrhagic, or of unclear type)

Original Primary Outcome Measures (submitted: June 16, 2017)

Incidence of recurrent stroke [ Time Frame: 4 years ]

Recurrent stroke of any type (ischemic, hemorrhagic, or of unclear type)

Current Secondary Outcome Measures (submitted: May 20, 2020)

• Incidence of recurrent ischemic stroke or systemic embolism [ Time Frame: Up to 7 years ]
  Secondary efficacy outcome A
• Incidence of recurrent stroke of any type plus death from any cause [ Time Frame: Up to 7 years ]
  Secondary efficacy outcome B
• Incidence of symptomatic intracranial hemorrhage (including symptomatic hemorrhagic transformation of an ischemic stroke). [ Time Frame: Up to 7 years ]
  Primary safety outcome A
• Incidence of major hemorrhage other than intracranial hemorrhage [ Time Frame: Up to 7 years ]
  Primary safety outcome B
• Incidence of death from any cause [ Time Frame: Up to 7 years ]
  Secondary safety outcome

Original Secondary Outcome Measures (submitted: June 16, 2017)

• Incidence of recurrent ischemic stroke or systemic embolism [ Time Frame: Up to 4 years ]
  Secondary efficacy outcome A
• Incidence of recurrent stroke of any type plus death from any cause [ Time Frame: Up to 4 years ]
  Secondary efficacy outcome B
• Incidence of symptomatic intracranial hemorrhage (including symptomatic hemorrhagic transformation of an ischemic stroke). [ Time Frame: Up to 4 years ]
  Primary safety outcome A
• Incidence of major hemorrhage other than intracranial hemorrhage [ Time Frame: Up to 4 years ]
  Primary safety outcome B
• Incidence of death from any cause [ Time Frame: Up to 4 years ]
  Secondary safety outcome

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke
• Official Title: AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke

Brief Summary

Objectives

• Primary: To test the hypothesis that apixaban is superior to aspirin for the prevention of recurrent stroke in patients with cryptogenic ischemic stroke and atrial cardiopathy.
• Secondary: To test the hypothesis that the relative efficacy of apixaban over aspirin increases with the severity of atrial cardiopathy.

• Detailed Description: ARCADIA is a multicenter, biomarker-driven, randomized, double-blind, active-control, phase 3 clinical trial of apixaban versus aspirin in patients who have evidence of atrial cardiopathy and a recent stroke of unknown cause. Eleven hundred subjects will be recruited over 2.5 years at up to 200 sites in and out of the NINDS StrokeNet consortium. Subjects will be followed for a minimum of 1.5 years and a maximum of 7 years for the primary efficacy outcome of recurrent stroke and the primary safety outcomes of symptomatic intracranial hemorrhage and major hemorrhage other than intracranial hemorrhage.
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Active treatment will be either apixaban 5 mg or aspirin 81 mg. An adjusted dose of apixaban 2.5 mg will be used for subjects with at least two of the following: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or known serum creatinine greater than or equal to 1.5 mg/dL. There will be six possible study tablets: apixaban 5 mg (regular dose), apixaban 2.5 mg (adjusted dose), apixaban 5 mg placebo, apixaban 2.5 mg placebo, aspirin 81 mg, and aspirin placebo.

All subjects will be randomized to receive active treatment with either active apixaban or active aspirin. Study treatments will be supplied in a double-dummy fashion as apixaban 5 mg (2.5 mg for the adjusted dose) or matching placebo, and aspirin 81 mg or matching placebo.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Eligible patients will be allocated in a 1:1 ratio to apixaban or aspirin using the minimal sufficient balance randomization method to prevent serious treatment imbalances by study site.

Primary Purpose: Prevention

• Condition: Stroke

Intervention

• Drug: Apixaban
  5 mg by mouth twice daily (2.5 mg for subjects meeting standard criteria for an adjusted dose).
  Other Name: Eliquis
• Drug: Aspirin
  Aspirin 81 mg by mouth once daily.
  Other Name: Aspirin Tablet

Study Arms

• Experimental: Active agent: Apixaban
  Patients with a recent embolic stroke of undetermined source (ESUS) and evidence of atrial cardiopathy will receive Apixaban
  Intervention: Drug: Apixaban
• Active Comparator: Active control: Aspirin
  Patients with a recent embolic stroke of undetermined source (ESUS) and evidence of atrial cardiopathy will receive Aspirin
  Intervention: Drug: Aspirin

Publications *

• Kamel H, Okin PM, Elkind MS, Iadecola C. Atrial Fibrillation and Mechanisms of Stroke: Time for a New Model. Stroke. 2016 Mar;47(3):895-900. doi: 10.1161/STROKEAHA.115.012004. Epub 2016 Jan 19. No abstract available.
• Yaghi S, Kamel H, Elkind MS. Potential new uses of non-vitamin K antagonist oral anticoagulants to treat and prevent stroke. Neurology. 2015 Sep 22;85(12):1078-84. doi: 10.1212/WNL.0000000000001817. Epub 2015 Jul 17.
• Kamel H, Okin PM, Longstreth WT Jr, Elkind MS, Soliman EZ. Atrial cardiopathy: a broadened concept of left atrial thromboembolism beyond atrial fibrillation. Future Cardiol. 2015 May;11(3):323-31. doi: 10.2217/fca.15.22.
• Yaghi S, Moon YP, Mora-McLaughlin C, Willey JZ, Cheung K, Di Tullio MR, Homma S, Kamel H, Sacco RL, Elkind MS. Left atrial enlargement and stroke recurrence: the Northern Manhattan Stroke Study. Stroke. 2015 Jun;46(6):1488-93. doi: 10.1161/STROKEAHA.115.008711. Epub 2015 Apr 23.
• Longstreth WT Jr, Kronmal RA, Thompson JL, Christenson RH, Levine SR, Gross R, Brey RL, Buchsbaum R, Elkind MS, Tirschwell DL, Seliger SL, Mohr JP, deFilippi CR. Amino terminal pro-B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. Stroke. 2013 Mar;44(3):714-9. doi: 10.1161/STROKEAHA.112.675942. Epub 2013 Jan 22.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 15, 2022): 1015
• Original Estimated Enrollment (submitted: June 16, 2017): 1100
• Estimated Study Completion Date: June 2024
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age ≥ 45 years.
• Clinical diagnosis of ischemic stroke + brain imaging to rule out hemorrhagic stroke.
• Modified Rankin Scale (MRS) score ≤ 4.
• Ability to be randomized within 3 to 180 days after stroke onset.

• ESUS, defined as all of the following:

  • Stroke detected by CT or MRI that is not lacunar. Lacunar is defined as a subcortical (this includes pons and midbrain) infarct in the distribution of the small, penetrating cerebral arteries whose largest dimension is ≤1.5 cm on CT or ≤2.0 cm on MRI diffusion images/<1.5 cm on T2 weighted MR images. The following are not considered lacunes: multiple simultaneous small deep infarcts, lateral medullary infarcts, and cerebellar infarcts. Patients with a clinical lacunar stroke syndrome and no infarct on imaging are excluded.
  • Absence of extracranial or intracranial atherosclerosis causing ≥50 percent luminal stenosis of the artery supplying the area of ischemia. Patients must undergo vascular imaging of the extracranial and intracranial vessels using either catheter angiography, CT angiogram (CTA), MR angiogram (MRA), or ultrasound, as considered appropriate by the treating physician and local principal investigator.
  • No major-risk cardioembolic source of embolism, including intracardiac thrombus, mechanical prosthetic cardiac valve, atrial myxoma or other cardiac tumors, moderate or severe mitral stenosis, myocardial infarction within the last 4 weeks, left ventricular ejection fraction <30 percent, valvular vegetations, or infective endocarditis). Patent foramen ovale is not an exclusion. All patients must undergo electrocardiogram, transthoracic or transesophageal echocardiography (TTE or TEE) and at least 24 hours of cardiac rhythm monitoring (Holter monitor or telemetry or equivalent). Additional cardiac imaging, such as cardiac MRI, or cardiac CT will be performed at the discretion of the local treating physician and principal investigator. Additional cardiac rhythm monitoring, such as monitored cardiac outpatient telemetry (MCOT) or an implanted cardiac monitor, will be at the discretion of the treating physician and local principal investigator.
  • No other specific cause of stroke identified, such as arteritis, dissection, migraine, vasospasm, drug abuse, or hypercoagulability. Special testing, such as toxicological screens, serological testing for syphilis, and tests for hypercoagulability, will be performed at the discretion of the treating physician and local principal investigator.

Exclusion Criteria:

• History of atrial fibrillation (AF), AF on 12-lead ECG, or any AF of any duration during heart-rhythm monitoring prior to randomization.
• Clear indication for treatment-dose anticoagulant therapy, such as venous thromboembolism or a mechanical heart valve.
• Need for antiplatelet agent, such as aspirin or clopidogrel
• History of spontaneous intracranial hemorrhage.
• Chronic kidney disease with serum creatinine ≥2.5 mg/dL.For Canadian sites only, estimated creatinine clearance (eCrCl) <15 mL/min is also an exclusion criterion.
• Active hepatitis or hepatic insufficiency with Child-Pugh score B or C.
• Clinically significant bleeding diathesis.
• Unresolved anemia (hemoglobin <9 g/dL) or thrombocytopenia (<100 x 10E9/L).
• Clinically significant gastrointestinal bleeding within the past year (e.g., not due to external hemorrhoids).
• At risk for pregnancy: premenopausal or postmenopausal woman within 12 months of last menses without a negative pregnancy test or not committing to adequate birth control, which includes an oral contraceptive, two methods of barrier birth control such as condom with or without spermicidal lubricant + diaphragm, or abstinence.
• Known allergy or intolerance to aspirin or apixaban.
• Concomitant participation in another clinical trial involving a drug or acute stroke intervention.
• Considered by the investigator to have a condition that precludes follow-up or safe participation in the trial.
• Inability of either participant or surrogate to provide written, informed consent for trial participation.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 45 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT03192215
• Other Study ID Numbers: AAAR4607; 1U01NS095869-01A1 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: To share individual participant data (IPD) of baseline characteristics, follow up, outcomes, etc. based on NIH/NINDS requirements.
• Supporting Materials: Study Protocol
• Time Frame: As per NIH/NINDS requirements.
• Access Criteria: All items required by NIH/NINDS will be publicly shared.

• Current Responsible Party: Randolph S. Marshall, MD, Columbia University
• Original Responsible Party: Mitchell S Elkind, Columbia University, Professor of Neurology and Epidemiology in the Gertrude H. Serg, Department of Neurology Stroke
• Current Study Sponsor: Columbia University
• Original Study Sponsor: Same as current

Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS)
• University of Cincinnati
• Medical University of South Carolina
• Bristol-Myers Squibb
• Pfizer
• Roche Pharma AG
• Weill Medical College of Cornell University
• University of Washington

Investigators

• Principal Investigator: Randolph S Marshall, MD; Columbia University

• PRS Account: Columbia University
• Verification Date: December 2022