Cardiovascular Disease
Conditions
Keywords
Cardiovascular Outcomes, Heart Attack, Stroke, Drug Therapy, Physiology, Hyperuricemia, Uric Acid
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.
Interventions
DRUGFebuxostat
Febuxostat tablets
DRUGAllopurinol
Allopurinol tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis) | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Non-fatal Myocardial Infarction (MI) | 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 Antiplatelet Trialists' Collaborative (APTC) Event | 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 Unstable Angina With Urgent Coronary Revascularization | 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. |
| Percentage of Participants With Non-fatal Stroke | 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 Cardiovascular (CV) Death | Up to last dose of study drug (approximately 83 months) | Events were adjudicated by an independent cardiovascular endpoints committee as CV death. |
Countries
Mexico, United States
Participant flow
Recruitment details
Participants took part in the study at 320 investigative sites in Canada, Mexico and United States from 23 April 2010 to 18 July 2017.
Pre-assignment details
Participants with a diagnosis of gout and significant cardiovascular comorbidities were enrolled in a 1:1 ratio to receive either febuxostat or allopurinol.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 3,098 |
| 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). | 3,092 |
| Total | 6,190 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 191 | 172 |
| Overall Study | Lost to Follow-up | 226 | 223 |
| Overall Study | Major Protocol Deviation | 52 | 46 |
| Overall Study | Reason not Specified | 333 | 363 |
| Overall Study | Voluntary Withdrawal | 595 | 587 |
Baseline characteristics
| Characteristic | Total | Allopurinol | Febuxostat |
|---|---|---|---|
| Age, Continuous | 64.8 years STANDARD_DEVIATION 8.53 | 65.0 years STANDARD_DEVIATION 8.49 | 64.6 years STANDARD_DEVIATION 8.58 |
| Age, Customized 65 to <75 years | 2229 Participants | 1135 Participants | 1094 Participants |
| Age, Customized <65 years | 3090 Participants | 1506 Participants | 1584 Participants |
| Age, Customized ≥75 years | 871 Participants | 451 Participants | 420 Participants |
| Alcohol History Current drinker | 2997 Participants | 1496 Participants | 1501 Participants |
| Alcohol History Ex-drinker | 1617 Participants | 812 Participants | 805 Participants |
| Alcohol History Never drank | 1576 Participants | 784 Participants | 792 Participants |
| BMI Categorical <25 | 402 Participants | 201 Participants | 201 Participants |
| BMI Categorical 25-30 | 1706 Participants | 862 Participants | 844 Participants |
| BMI Categorical ≥30 | 4077 Participants | 2024 Participants | 2053 Participants |
| Body Mass Index (BMI) | 32.3 kg/m^2 | 32.1 kg/m^2 | 32.5 kg/m^2 |
| Height | 173.0 cm STANDARD_DEVIATION 9.65 | 173.0 cm STANDARD_DEVIATION 9.77 | 172.9 cm STANDARD_DEVIATION 9.54 |
| History of Kidney Stone No | 4936 Participants | 2465 Participants | 2471 Participants |
| History of Kidney Stone Yes | 1254 Participants | 627 Participants | 627 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 496 Participants | 234 Participants | 262 Participants |
| Race/Ethnicity, Customized Asian | 188 Participants | 96 Participants | 92 Participants |
| Race/Ethnicity, Customized Black or African American | 1145 Participants | 593 Participants | 552 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1060 Participants | 521 Participants | 539 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 27 Participants | 14 Participants | 13 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 5130 Participants | 2571 Participants | 2559 Participants |
| Race/Ethnicity, Customized Other | 34 Participants | 15 Participants | 19 Participants |
| Race/Ethnicity, Customized White | 4300 Participants | 2140 Participants | 2160 Participants |
| Region of Enrollment Canada | 140 Participants | 72 Participants | 68 Participants |
| Region of Enrollment Mexico | 734 Participants | 355 Participants | 379 Participants |
| Region of Enrollment United States | 5316 Participants | 2665 Participants | 2651 Participants |
| Renal Function Mildly Impaired | 2448 Participants | 1231 Participants | 1217 Participants |
| Renal Function Moderately Impaired | 3267 Participants | 1631 Participants | 1636 Participants |
| Renal Function Normal | 467 Participants | 228 Participants | 239 Participants |
| Sex: Female, Male Female | 994 Participants | 500 Participants | 494 Participants |
| Sex: Female, Male Male | 5196 Participants | 2592 Participants | 2604 Participants |
| Smoking History Current smoker | 805 Participants | 415 Participants | 390 Participants |
| Smoking History Ex-smoker | 3086 Participants | 1553 Participants | 1533 Participants |
| Smoking History Never smoked | 2299 Participants | 1124 Participants | 1175 Participants |
| Use of any Dose of Aspirin No | 2363 Participants | 1159 Participants | 1204 Participants |
| Use of any Dose of Aspirin Yes | 3827 Participants | 1933 Participants | 1894 Participants |
| Use of Clopidogrel and Other Antiplatelet Drugs No | 4964 Participants | 2465 Participants | 2499 Participants |
| Use of Clopidogrel and Other Antiplatelet Drugs Yes | 1226 Participants | 627 Participants | 599 Participants |
| Use of Low Dose Aspirin No | 3213 Participants | 1611 Participants | 1602 Participants |
| Use of Low Dose Aspirin Yes | 2977 Participants | 1481 Participants | 1496 Participants |
| Use of Nonsteroidal Anti-Inflammatory Drug (NSAIDs) No | 4426 Participants | 2184 Participants | 2242 Participants |
| Use of Nonsteroidal Anti-Inflammatory Drug (NSAIDs) Yes | 1764 Participants | 908 Participants | 856 Participants |
| Weight | 100.4 kg STANDARD_DEVIATION 22.68 | 100.3 kg STANDARD_DEVIATION 22.89 | 100.5 kg STANDARD_DEVIATION 22.47 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 243 / 3,098 | 199 / 3,092 |
| other Total, other adverse events | 1,450 / 3,098 | 1,467 / 3,092 |
| serious Total, serious adverse events | 1,046 / 3,098 | 995 / 3,092 |
Outcome results
Primary
Percentage of Participants With Primary MACE Composite (Final Analysis)
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.
Time frame: Up to last dose of study drug (approximately 83 months)
Population: FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat | Percentage of Participants With Primary MACE Composite (Final Analysis) | 10.8 percentage of participants |
| Allopurinol | Percentage of Participants With Primary MACE Composite (Final Analysis) | 10.4 percentage of participants |
Comparison: Statistical analysis for the primary endpoint was based on 1-sided repeated confidence intervals (CIs), using critical values from a 1-sided stopping boundary for a group sequential design (GSD), to preserve an overall false-rejection rate of 2.5%, to assess non-inferiority at each interim analysis and the final analysis.97% CI: [0.87, 1.23]
Primary
Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis)
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.
Time frame: Up to last dose of study drug (approximately 83 months)
Population: Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat | Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis) | 8.0 percentage of participants |
| Allopurinol | Percentage of Participants With Primary Major Adverse Cardiovascular Events (MACE) Composite (75% Interim Analysis) | 8.0 percentage of participants |
Comparison: Statistical analysis for the primary endpoint was based on 1-sided repeated confidence intervals (CIs), using critical values from a 1-sided stopping boundary for a group sequential design (GSD), to preserve an overall false-rejection rate of 2.5%, to assess non-inferiority at each interim analysis and the final analysis.
Secondary
Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event
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.
Time frame: Up to last dose of study drug (approximately 83 months)
Population: FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat | Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event | 9.6 percentage of participants |
| Allopurinol | Percentage of Participants With Antiplatelet Trialists' Collaborative (APTC) Event | 8.8 percentage of participants |
95% CI: [0.92, 1.28]
Secondary
Percentage of Participants With Cardiovascular (CV) Death
Events were adjudicated by an independent cardiovascular endpoints committee as CV death.
Time frame: Up to last dose of study drug (approximately 83 months)
Population: FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat | Percentage of Participants With Cardiovascular (CV) Death | 4.3 percentage of participants |
| Allopurinol | Percentage of Participants With Cardiovascular (CV) Death | 3.2 percentage of participants |
95% CI: [1.03, 1.73]
Secondary
Percentage of Participants With Non-fatal Myocardial Infarction (MI)
Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal MI.
Time frame: Up to last dose of study drug (approximately 83 months)
Population: FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat | Percentage of Participants With Non-fatal Myocardial Infarction (MI) | 3.6 percentage of participants |
| Allopurinol | Percentage of Participants With Non-fatal Myocardial Infarction (MI) | 3.8 percentage of participants |
95% CI: [0.72, 1.21]
Secondary
Percentage of Participants With Non-fatal Stroke
Events were adjudicated by an independent cardiovascular endpoints committee as non-fatal stroke.
Time frame: Up to last dose of study drug (approximately 83 months)
Population: FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat | Percentage of Participants With Non-fatal Stroke | 2.3 percentage of participants |
| Allopurinol | Percentage of Participants With Non-fatal Stroke | 2.3 percentage of participants |
95% CI: [0.73, 1.41]
Secondary
Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization
Events were adjudicated by an independent cardiovascular endpoints committee as unstable angina with urgent coronary revascularization.
Time frame: Up to last dose of study drug (approximately 83 months)
Population: FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat | Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization | 1.6 percentage of participants |
| Allopurinol | Percentage of Participants With Unstable Angina With Urgent Coronary Revascularization | 1.8 percentage of participants |
95% CI: [0.59, 1.26]