Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Cardiovascular Safety of Febuxostat and Allopurinol in Participants With Gout and Cardiovascular Comorbidities (CARES) (CARES)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01101035
Recruitment Status : Completed
First Posted : April 9, 2010
Results First Posted : June 14, 2018
Last Update Posted : June 14, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda

Tracking Information
First Submitted Date  ICMJE April 7, 2010
First Posted Date  ICMJE April 9, 2010
Results First Submitted Date  ICMJE May 11, 2018
Results First Posted Date  ICMJE June 14, 2018
Last Update Posted Date June 14, 2018
Actual Study Start Date  ICMJE April 23, 2010
Actual Primary Completion Date May 15, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 12, 2018)
  • Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis) [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    Major adverse cardiovascular events (MACE) were defined as a composite of cardiovascular (CV) death, non-fatal myocardial infarction (MI), nonfatal stroke and unstable angina with urgent coronary revascularization; these events were adjudicated by an independent cardiovascular endpoints committee.
  • Percentage of Participants With Primary MACE Composite (Final Analysis) [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    Major adverse cardiovascular events (MACE) were defined as a composite of cardiovascular (CV) death, non-fatal myocardial infarction (MI), nonfatal stroke and unstable angina with urgent coronary revascularization; these events were adjudicated by an independent cardiovascular endpoints committee.
Original Primary Outcome Measures  ICMJE
 (submitted: April 7, 2010)
First occurrence of any event in the predefined Major Adverse Cardiovascular Events Composite. [ Time Frame: At first occurrence (up to 60 Months) ]
The time from randomization to the first occurrence of any event in the predefined Major Adverse Cardiovascular Events (MACE) Composite, which includes: Cardiovascular death, Non-fatal Myocardial Infarction, Nonfatal Stroke and Unstable Angina with Urgent Coronary Revascularization.
Change History Complete list of historical versions of study NCT01101035 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 12, 2018)
  • Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    APTC events were defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke; these events were adjudicated by an independent cardiovascular endpoints committee.
  • Percentage of Participants With Cardiovascular (CV) Death [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    Events were adjudicated by an independent cardiovascular endpoints committee as CV death.
  • Percentage of Participants With Non-fatal Myocardial Infarction (MI) [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal MI.
  • Percentage of Participants With Non-fatal Stroke [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal stroke.
  • Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization [ Time Frame: Up to last dose of study drug (approximately 83 months) ]
    Events were adjudicated by an independent cardiovascular endpoints committee as unstable angina with urgent coronary revascularization.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 7, 2010)
  • First occurrence of any Antiplatelet Trialists' Collaborative Event. [ Time Frame: At first occurrence (up to 60 Months) ]
    The time from randomization to the first occurrence of any Antiplatelet Trialists' Collaborative Event, which includes Cardiovascular Death, Non-fatal Myocardial Infarction or Non-fatal Stroke.
  • First occurrence of Cardiovascular Death death. [ Time Frame: At first occurrence (up to 60 Months) ]
    The time from randomization to the first occurrence of Cardiovascular Death.
  • First occurrence of Non-fatal Myocardial Infarction. [ Time Frame: At first occurrence (up to 60 Months) ]
    The time from randomization to the first occurrence of nonfatal Myocardial Infarction.
  • First occurrence of Non-fatal stroke. [ Time Frame: At first occurrence (up to 60 Months) ]
    The time from randomization to the first occurrence of Non-fatal Stroke.
  • First occurrence of Unstable Angina with Urgent Coronary Revascularization. [ Time Frame: At first occurrence (up to 60 Months) ]
    The time from randomization to the first occurrence of Unstable Angina with Urgent Coronary Revascularization.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cardiovascular Safety of Febuxostat and Allopurinol in Participants With Gout and Cardiovascular Comorbidities (CARES)
Official Title  ICMJE A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the Cardiovascular Safety of Febuxostat and Allopurinol in Subjects With Gout and Cardiovascular Comorbidities
Brief Summary The purpose of this study is to see whether subjects with gout who receive febuxostat or allopurinol for up to 9 years have a higher rate of serious heart and blood vessel complications (major cardiovascular events).
Detailed Description

The drug tested in this study was called Febuxostat (TMX-67). Febuxostat compared with allopurinol was evaluated for the cardiovascular (CV) safety in people with gout and significant CV comorbidities.

The study enrolled 6198 patients. Participants with a diagnosis of gout were enrolled in a 1:1 ratio to receive either:

  • Febuxostat
  • Allopurinol

Participants received febuxostat 40 mg or 80 mg for the study depending on their serum uric acid levels were either <6.0 mg/dL or ≥6.0 mg/dL during specified visits. Allopurinol 200 mg to 400 mg (for moderate renal impairment),or 300 mg to 600 mg (for normal and mild renal impairment), increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL was received.

This multi-center trial was conducted in Canada, Mexico and United States. The overall time to participate in this study was approximately 7 years (84 months). Participants made multiple visits to the clinic and were also contacted through the telephone.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Cardiovascular Disease
Intervention  ICMJE
  • Drug: Febuxostat
    Febuxostat tablets
    Other Names:
    • Uloric
    • TMX-67
  • Drug: Allopurinol
    Allopurinol tablets
    Other Names:
    • Zyloprim
    • Allohexal
    • Allosig
    • Milurit
    • Alloril
    • Progout
    • Zyloric
    • Puricos
    • Zyrik 300
    • Aluron
Study Arms  ICMJE
  • Experimental: Febuxostat
    Febuxostat 40 mg (or 80 mg beginning on week 4 if serum uric acid level was ≥6.0 mg/dL), tablets, orally, once daily for up to approximately 82 months.
    Intervention: Drug: Febuxostat
  • Active Comparator: Allopurinol
    Allopurinol 300 mg to 600 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with mildly impaired renal function or normal renal function (estimated creatinine clearance [eCLcr] ≥60 mL/min) or allopurinol 200 mg to 400 mg (increased in 100 mg increments each month until serum uric acid was <6.0 mg/dL), tablets, orally, once daily for up to approximately 83 months to participants with moderately impaired renal function (eCLcr ≥30 but <60 mL/min).
    Intervention: Drug: Allopurinol
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 17, 2016)
6198
Original Estimated Enrollment  ICMJE
 (submitted: April 7, 2010)
7500
Actual Study Completion Date  ICMJE July 18, 2017
Actual Primary Completion Date May 15, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. The participant or the participant's legally acceptable representative signs and dates a written, informed consent form/Health Insurance Portability and Accountability Act (HIPAA) Authorization prior to the initiation of any study procedures.
  2. The participant is male ≥50 years of age or female ≥55 years of age and at least 2-years post-menopausal.
  3. The participant has a history of major CV or cerebrovascular disease including at least one of the following:

    • Myocardial infarction (MI).
    • Hospitalized unstable angina.
    • Cardiac or cerebrovascular revascularization procedure.
    • Stroke.
    • Hospitalized transient ischemic attack (TIA).
    • Peripheral vascular disease (ankle brachial index ≤0.6, revascularization and/or well-documented history of claudication).
    • History of diabetes mellitus with evidence of micro- or macrovascular disease (retinopathy, neuropathy, nephropathy, small vessel vascular diseases).
  4. The participant has a history or presence of gout defined as having one or more of the American Rheumatism Association criteria for the diagnosis of gout:

    • A tophus proven to contain urate crystals by chemical or polarized light microscopic means, and/or
    • Characteristic urate crystals in the joint fluid, and/or
    • History of at least 6 of the following clinical, laboratory, and X-ray phenomena:

      • More than 1 attack of acute arthritis.
      • Maximum inflammation developed within 1 day.
      • Monoarticular arthritis.
      • Redness observed over joints.
      • First metatarsophalangeal joint painful or swollen.
      • Unilateral first metatarsophalangeal joint attack.
      • Unilateral tarsal joint attack.
      • Tophus (proven or suspected).
      • Hyperuricemia.
      • Asymmetric swelling within a joint on x-ray.
      • Subcortical cysts without erosions on x-ray.
      • Joint fluid culture negative for organisms during attack.
  5. The participants must have either:

    • a serum urate or serum uric acid (sUA) level ≥7.0 mg/dL (≥416 μmol/L) at the Day -7 Visit OR
    • a sUA level ≥6.0 mg/dL (≥354 μmol/L) at the Day -7 Visit AND inadequately controlled gout (≥1 flare in the 12 months prior to screening and/or the presence of tophi).
  6. The participant is capable of understanding and complying with protocol requirements

Exclusion Criteria:

Participants who meet any of the following criteria will not qualify for entry into this study:

  1. The participant has secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ transplant).
  2. The participant has a history of xanthinuria.
  3. The participant has received urate-lowering therapy (i.e., febuxostat, allopurinol, probenecid, etc.) or excluded medication during the screening period (beginning with Day -7).
  4. The participant has a known hypersensitivity to febuxostat or allopurinol or any components of their formulation.
  5. The participant has active peptic ulcer disease.
  6. The participant has a history of cancer (other than basal cell carcinoma of the skin) within 5 years prior to the first dose of study medication.
  7. The participant had MI or stroke within 60 days prior to the Screening Visit.
  8. The participant has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values greater than 2 times the upper limit of normal (×ULN) during the Screening period.
  9. The participant has a significant medical condition and/or conditions that would interfere with the treatment, safety, or compliance with the protocol.
  10. The participant has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 5 years prior to the Screening Visit or the participant consumes >14 alcoholic beverages per week.
  11. The participant has received any investigational medicinal product within the 30 days prior to the Screening Visit and throughout the study.
  12. The participant's estimated creatinine clearance (CLcr) is <30 mL/min, where CLcr is calculated using the Cockcroft and Gault formula based on ideal body weight (IBW),
  13. The participant is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
  14. The participant is required to take excluded medications
  15. The participant has a known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Mexico,   United States
Removed Location Countries Canada
 
Administrative Information
NCT Number  ICMJE NCT01101035
Other Study ID Numbers  ICMJE TMX-67_301
U1111-1114-4194 ( Registry Identifier: WHO )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Takeda
Study Sponsor  ICMJE Takeda
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Takeda
PRS Account Takeda
Verification Date June 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP