Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE I) (ACTIVE I)

• ClinicalTrials.gov Identifier: NCT00249795
• Recruitment Status: Completed
• First Posted: November 7, 2005
• Results First Posted: October 15, 2010
• Last Update Posted: October 15, 2010
• Sponsor: Sanofi
• Collaborator: Bristol-Myers Squibb
• Information provided by: Sanofi

Tracking Information

• First Submitted Date: November 4, 2005
• First Posted Date: November 7, 2005
• Results First Submitted Date: August 24, 2010
• Results First Posted Date: October 15, 2010
• Last Update Posted Date: October 15, 2010
• Study Start Date: June 2003
• Actual Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 29, 2010)

• First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication [ Time Frame: Median follow-up of 4.5 years ]
  The first co-primary event is the first occurence of any component of the following cluster over the duration of follow-up: myocardial infarction (nonfatal or fatal), stroke (nonfatal or fatal) or vascular death - after validation by the Event Adjudication Committee (EAC).
• First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication [ Time Frame: Median follow-up of 4.5 years ]
  The second co-primary event is the first occurence of any component of the following cluster over the duration of follow-up: myocardial infarction (nonfatal or fatal), stroke (nonfatal or fatal), vascular death or hospitalization for heart failure - after validation by the EAC.

Original Primary Outcome Measures (submitted: November 4, 2005)

• The primary outcome of the study is: irbesartan, compared to placebo will reduce the risk of the first composite outcome of stroke, myocardial infarction or vascular death.
• The second primary outcome of the study is irbesartan, compared to placebo will reduce the risk of the second composite outcome of stroke, myocardial infarction, vascular death or hospitalization for heart failure.

Current Secondary Outcome Measures (submitted: September 29, 2010)

• First Occurrence of Stroke [ Time Frame: Median follow-up of 4.5 years ]
  The considered event is the first occurrence of stroke (nonfatal or fatal, ischemic, hemorrhagic or of uncertain type) over the duration of follow-up, after validation by the EAC.
• Death From Any Cause [ Time Frame: Median follow-up of 4.5 years ]
  The considered event is the death over the duration of the follow-up whatever the cause, cardiovascular or non-cardiovascular.
• First Occurrence of Any Heart Failure (HF) Episode [ Time Frame: Median follow-up of 4.5 years ]
  The considered event is the first occurence of any HF episode defined as evidence of signs and symptoms of HF with or without hospitalization over the duration of follow-up, as reported by the investigator (i.e. not validated by the Event Adjudication Committee).
• First Hospitalisation for Heart Failure (HF) [ Time Frame: Median follow-up of 4.5 years ]
  The considered event is the first overnight hospital stay for HF over the duration of the follow-up, after validation by the EAC.
• First Hospitalisation for Other Cardiovascular (CV) Cause [ Time Frame: Median follow-up of 4.5 years ]
  The considered event is the overnight hospital stay for any CV cause other than Heart Failure over the duration of follow-up, as reported by the investigator (i.e. not validated by the Event Adjudication Committee).

• Original Secondary Outcome Measures (submitted: November 4, 2005): The secondary outcomes are total mortality, stroke, hospitalization for heart failure and other heart failure episodes defined as evidence of symptoms or signs of heart failure (with or without hospitalization).
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE I)
• Official Title: A Parallel Randomized Controlled Evaluation of Clopidogrel Plus Aspirin, With Factorial Evaluation of Irbesartan, for the Prevention of Vascular Events, in Patients With Atrial Fibrillation
• Brief Summary: The purpose of this study was to determine if Irbesartan compared to Placebo would reduce the risk of vascular events such as heart attack, stroke, non-cerebral thromboembolic event and death in patients with Atrial Fibrillation (AF) and with at least one major risk of vascular events.

Detailed Description

ACTIVE I was one of the 3 separate but related trials of the ACTIVE program conducted in AF patients at risk of vascular events.

Patients were enrolled first into one of the 2 parallel trials of the ACTIVE program evaluating Clopidogrel:

• ACTIVE A comparing clopidogrel + acetylsalicylic acid (ASA) and ASA alone
• ACTIVE W comparing clopidogrel + ASA and oral anticoagulant (OAC).

Then those satisfying additional criteria related to blood pressure and angiotensin receptor blocking agents were re-randomized in the two ACTIVE I arms according to a separate randomization list.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Prevention

Condition

• Atrial Fibrillation
• Cardiovascular Disease

Intervention

• Drug: Irbesartan
  oral administration (tablets) once daily
  Other Name: Aprovel®
• Drug: placebo
  oral administration (tablets) once daily

Study Arms

• Experimental: Irbesartan
  150 mg for 2 weeks, then up-titrated to 300 mg up to final follow-up visit
  Intervention: Drug: Irbesartan
• Placebo Comparator: Placebo
  Matching placebo up to final follow-up visit
  Intervention: Drug: placebo

• Publications *: ACTIVE I Investigators, Yusuf S, Healey JS, Pogue J, Chrolavicius S, Flather M, Hart RG, Hohnloser SH, Joyner CD, Pfeffer MA, Connolly SJ. Irbesartan in patients with atrial fibrillation. N Engl J Med. 2011 Mar 10;364(10):928-38. doi: 10.1056/NEJMoa1008816.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 29, 2010): 9016
• Original Enrollment (submitted: November 4, 2005): 9000
• Actual Study Completion Date: August 2009
• Actual Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Should fulfill the eligibility criteria for ACTIVE A or ACTIVE W trial and:

• have a systolic blood pressure of at least 110 mmHg
• not already receiving an angiotensin receptor blocking agent, unless they are willing and able to be changed to another antihypertensive agent
• no previous intolerance to angiotensin receptor blocking agents
• no proven indication for angiotensin receptor blocking agents, unless an Angiotensin Converting Enzyme (ACE) inhibitor can be substituted

Exclusion Criteria:

Patients will be excluded from ACTIVE study if any of the following are present:

• requirement for clopidogrel (such as recent coronary stent procedure)
• requirement for oral anticoagulant (such as prosthetic mechanical heart valve)
• prior intolerance to acetylsalicyclic acid (ASA) or clopidogrel
• documented peptic ulcer disease within the previous 6 months
• prior intracerebral hemorrhage
• significant thrombocytopenia (platelet count <50 x 10(9)/L)
• psychosocial reason making study participation impractical
• geographic reason making study participation impractical
• ongoing alcohol abuse
• mitral stenosis
• pregnant or nursing woman or woman of child bearing potential and not on effective birth control for at least one month prior to start of study or not willing to continue on birth control for duration of study
• severe comorbid condition such that the patient is not expected to survive 6 months
• patient currently receiving an investigational pharmacologic agent
• requirement for chronic (> 3 months) non-cyclooxygenase-2 (non-COX-2) inhibitor nonsteroidal anti-inflammatory drug (NSAID) therapy unless willing enrolled in ACTIVE A

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 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: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Czech Republic, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, Italy, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Singapore, South Africa, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
• Removed Location Countries: Israel, Russian Federation, Turkey

Administrative Information

• NCT Number: NCT00249795
• Other Study ID Numbers: EFC4912 I; Clopidogrel (SR25990)
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: ICD Study Director, Sanofi-aventis
• Study Sponsor: Sanofi
• Collaborators: Bristol-Myers Squibb

Investigators

• Study Chair: Salim YUSUF, Prof.; Hamilton Health Sciences Corporation

• PRS Account: Sanofi
• Verification Date: September 2010