CSP594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat

Sponsor
VA Office of Research and Development (U.S. Fed)
Overall Status
Completed
CT.gov ID
NCT02579096
Collaborator
(none)
950
23
2
49.3
41.3
0.8

Study Details

Study Description

Brief Summary

This trial will compare two effective therapies, allopurinol and febuxostat, to lower serum uric acid and therefore prevent further gout attacks. These therapies have never been compared at appropriate doses. Further, they will be studied in patients with kidney disease for the first time.

Condition or Disease Intervention/Treatment Phase
  • Drug: allopurinol capsule, 100-800 mg by mouth once daily
  • Drug: febuxostat tablet 40-120 mg by mouth once daily
  • Drug: Placebo, vehicle control (febuxostat-shaped)
  • Drug: Placebo, vehicle control (allopurinol-shaped)
Phase 4

Detailed Description

Gout is the most common form of inflammatory arthritis affecting adults (1), with a disease frequency that continues to increase dramatically (2). Gout is associated with substantial morbidity and mortality which are concentrated in older men and magnified in patients with chronic kidney disease (CKD) (3-6), demographics common to the Veterans Affairs (VA) Health System. Effective gout therapies are readily available and are centered primarily on the use of approved urate lowering therapy (ULT). Despite having excellent ULT options available to patients (7), gout is extremely poorly managed especially in patients with CKD (8-10).

The two most widely used ULTs in clinical practice, allopurinol and febuxostat, have recently been endorsed as the two acceptable first-line treatment strategies in chronic gout (7). Although both agents appear to be efficacious and generally well-tolerated, allopurinol and febuxostat have significantly different costs and have never been compared to each other at appropriate doses. Randomized controlled trials completed to date comparing allopurinol with febuxostat in gout have used 'fixed' and, in many cases, insufficient doses of allopurinol (11-13), an approach that is contrary to current guideline recommendations (7). Furthermore, these studies have included only very small proportions of gout patients with CKD even though CKD is present in approximately 1 of every 2 gout sufferers (14).

To test the hypothesis that allopurinol is non-inferior to febuxostat in the treatment of gout, the investigators propose a randomized open-label non-inferiority trial, which for the first time compares allopurinol with febuxostat using appropriately titrated doses and a "treat-to-target" approach. Further, the investigators will assess the comparative effectiveness of these agents in a significant number of gout patients with co-morbid CKD.

The investigators plan to enroll 950 participants with a diagnosis of gout, including participants with stage 3 CKD, who are hyperuricemic defined as a serum uric acid concentration (sUA) above 6.8 mg/dl. Participants will be recruited from 18 Veteran Affairs and 5 Rheumatology and Arthritis Investigational Network (RAIN) sites. The total duration of the trial will be 4 years. Recruitment will occur over 24 months. Participants will be followed for 72 weeks. This will include a 24 week Dose Titration Phase (Phase 1) followed by a 24 week Maintenance and Optimization Phase (Phase 2) and then a 24 week Steady State Flare Observation Phase (Phase 3). The investigators will use a "treat-to-target" approach with specified titration of ULT dosing to obtain goal sUA. Maximal daily drug doses will be 800 mg/day for allopurinol or 120 mg/day for febuxostat.

The primary outcome will be the proportion of participants who have at least one gout flare in the allopurinol group compared to the febuxostat group during Phase 3. This primary outcome was endorsed by the patient and VA provider groups that were surveyed (see below). All participants will be followed during Phase 3 regardless of the achievement of sUA goal. The primary hypothesis will test the non-inferiority of allopurinol with regards to proportions of flares. The investigators anticipate that approximately 15 to 20% of patients will flare during Phase 3.

Study Design

Study Type:
Interventional
Actual Enrollment :
950 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
CSP #594 - Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat
Actual Study Start Date :
Mar 6, 2017
Actual Primary Completion Date :
Feb 1, 2021
Actual Study Completion Date :
Apr 15, 2021

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Allopurinol / Sham Comparator (Febuxostat)

Patients will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling Febuxostat will be given with allopurinol

Drug: allopurinol capsule, 100-800 mg by mouth once daily
Patients will be up-titrated up to the dose required to reach target uric acid levels.
Other Names:
  • Zyloprim; CAS: 315-30-0
  • Drug: Placebo, vehicle control (febuxostat-shaped)
    Placebo tablets resembling febuxostat will be given with allopurinol.

    Active Comparator: Febuxostat / Sham Comparator (Allopurinol)

    Febuxostat will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling Allopurinol will be given with Febuxostat

    Drug: febuxostat tablet 40-120 mg by mouth once daily
    Patients will be up-titrated to the dose required to reach target uric acid levels.
    Other Names:
  • Uloric; CAS: 144060-53-7; NDCs: 64764-677-11, 64764-677-13, 64764-677-19, 64764-677-30, 64764-918-11, 64764-918-18, 64764-918-30, 64764-918-90
  • Drug: Placebo, vehicle control (allopurinol-shaped)
    Placebo capsules resembling allopurinol will be given with febuxostat.

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants Experiencing ≥ 1 Gout Flare During Phase 3 [Phase III of the study (weeks 49-72 of study duration)]

      Participants were defined as flaring in Phase 3 if they: -1) met 3 of 4 following participant-reported criteria: a) warm joint(s) b) swollen joint(s) c) pain (>3) at rest on a scale of 0-10 (10 being the worst pain) d) self-identified gout flare OR -2) reported use of medications to treat flare

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Age 18 years

    • History of gout - crystal proven or historical as defined by ACR criteria listed above

    • Serum urate level > 6.8 mg/dl

    Exclusion Criteria:
    • Stage 4 or 5 Chronic Kidney Disease (CKD) - defined as eGFR < 30 ml/min/1.73 m2

    • Women less than 50 years of age

    • Patients with a history of prior solid organ / hematopoietic transplantation

    • Previous allergy or intolerance to allopurinol or febuxostat

    • Patients who are not candidates for any of the recommended prophylactic medications (colchicine, naprosyn or glucocorticoids)

    • Patients who in the opinion of the investigator have a high genetic risk for allopurinol hypersensitivity syndrome (AHS*) unless they have been found to be negative for HLA B5801.

    • Previous history of failure to reach target uric acid levels despite therapy with allopurinol at dose > 300 mg/day

    • Prior febuxostat use

    • Patients with malignancies that are currently active with exception of non-melanoma skin cancer

    • Patients with serum uric acid levels >15 mg/dl

    • Patients with myelodysplasia and hemoglobin of < 8.5 mg/dL

    • Patients with chronic liver disease with more than one of the following:

    • INR > 1.7, not on Warfarin therapy

    • Bilirubin 2 mg/dL

    • Serum albumin < 3.5 mg/dL

    • Ascites

    • Encephalopathy

    • Current use of azathioprine, mercaptopurine, didanosine, cyclophosphamide, probenecid, lesinurad or pegloticase

    • Enrollment in another randomized interventional clinical trial

    • Any severe medical condition that, in the enrolleer's opinion, is likely to compromise the participant's ability to complete the trial

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 VA Loma Linda Healthcare System, Loma Linda, CA Loma Linda California United States 92357
    2 VA San Diego Healthcare System, San Diego, CA San Diego California United States 92161
    3 San Francisco VA Medical Center, San Francisco, CA San Francisco California United States 94121
    4 Miami VA Healthcare System, Miami, FL Miami Florida United States 33125
    5 Edward Hines Jr. VA Hospital, Hines, IL Hines Illinois United States 60141-5000
    6 VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA Boston Massachusetts United States 02130
    7 Minneapolis VA Health Care System, Minneapolis, MN Minneapolis Minnesota United States 55417
    8 Mayo Clinic Rochester MN ? RAIN 1 Rochester Minnesota United States 55905
    9 Kansas City VA Medical Center, Kansas City, MO Kansas City Missouri United States 64128
    10 Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE Omaha Nebraska United States 68105-1873
    11 University of Nebraska Medical Center ? RAIN 5 Omaha Nebraska United States 68198-3025
    12 Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY New York New York United States 10010
    13 Asheville VA Medical Center, Asheville, NC Asheville North Carolina United States 28805
    14 Sanford Bismarck Medical Center ? RAIN 2 Bismarck North Dakota United States 58506
    15 Cincinnati VA Medical Center, Cincinnati, OH Cincinnati Ohio United States 45220
    16 VA Portland Health Care System, Portland, OR Portland Oregon United States 97239
    17 Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA Philadelphia Pennsylvania United States 19104
    18 VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA Pittsburgh Pennsylvania United States 15240
    19 Yankton Medical Clinic ? RAIN 3 Yankton South Dakota United States 57078
    20 VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX Dallas Texas United States 75216
    21 VA Salt Lake City Health Care System, Salt Lake City, UT Salt Lake City Utah United States 84148
    22 White River Junction VA Medical Center, White River Junction, VT White River Junction Vermont United States 05009-0001
    23 Salem VA Medical Center, Salem, VA Salem Virginia United States 24153

    Sponsors and Collaborators

    • VA Office of Research and Development

    Investigators

    • Study Chair: James R O'Dell, Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    VA Office of Research and Development
    ClinicalTrials.gov Identifier:
    NCT02579096
    Other Study ID Numbers:
    • 594
    First Posted:
    Oct 19, 2015
    Last Update Posted:
    May 17, 2022
    Last Verified:
    Apr 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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
    Keywords provided by VA Office of Research and Development
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Total of 950 subjects were enrolled into the study. However, 10 subjects were excluded from study participation : 3 due to screening errors 7 dropped out before receiving study treatment
    Arm/Group Title Allopurinol / Sham Comparator (Febuxostat) Febuxostat / Sham Comparator (Allopurinol)
    Arm/Group Description Patients will be up-titrated up to the dose required to reach target uric acid levels. Allopurinol: allopurinol capsule, 100-800 mg by mouth once daily Placebo: tablets resembling febuxostat will be given with allopurinol. Patients will be up-titrated to the dose required to reach target uric acid levels. Febuxostat: tablet 40-120 mg by mouth once daily Placebo: capsules resembling allopurinol will be given with febuxostat.
    Period Title: Phase 1, Weeks 0 - 24
    STARTED 468 472
    COMPLETED 411 422
    NOT COMPLETED 57 50
    Period Title: Phase 1, Weeks 0 - 24
    STARTED 411 422
    COMPLETED 389 391
    NOT COMPLETED 22 31
    Period Title: Phase 1, Weeks 0 - 24
    STARTED 389 391
    COMPLETED 367 373
    NOT COMPLETED 22 18

    Baseline Characteristics

    Arm/Group Title Allopurinol / Sham Comparator (Febuxostat) Febuxostat / Sham Comparator (Allopurinol) Total
    Arm/Group Description Patients will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling febuxostat will be given with allopurinol allopurinol: Patients will be titrated up to the dose that will lower to target uric acid levels. Placebo, vehicle control (febuxostat-shaped): Placebo in the shape of febuxostat will be given with allopurinol febuxostat will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling Allopurinol will be given with febuxostat febuxostat: febuxostat will be titrated up to the dose that will lower to target uric acid levels. Placebo, vehicle control (allopurinol-shaped): Placebo in the shape of allopurinol will be given with febuxostat Total of all reporting groups
    Overall Participants 468 472 940
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    62.9
    (11.8)
    61.3
    (12.9)
    62.1
    (12.4)
    Sex: Female, Male (Count of Participants)
    Female
    7
    1.5%
    8
    1.7%
    15
    1.6%
    Male
    461
    98.5%
    464
    98.3%
    925
    98.4%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    20
    4.3%
    27
    5.7%
    47
    5%
    Not Hispanic or Latino
    444
    94.9%
    443
    93.9%
    887
    94.4%
    Unknown or Not Reported
    4
    0.9%
    2
    0.4%
    6
    0.6%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    3
    0.6%
    2
    0.4%
    5
    0.5%
    Asian
    14
    3%
    15
    3.2%
    29
    3.1%
    Native Hawaiian or Other Pacific Islander
    10
    2.1%
    9
    1.9%
    19
    2%
    Black or African American
    104
    22.2%
    102
    21.6%
    206
    21.9%
    White
    315
    67.3%
    322
    68.2%
    637
    67.8%
    More than one race
    10
    2.1%
    7
    1.5%
    17
    1.8%
    Unknown or Not Reported
    12
    2.6%
    15
    3.2%
    27
    2.9%
    CKD3 (Count of Participants)
    Count of Participants [Participants]
    181
    38.7%
    170
    36%
    351
    37.3%
    Tophus (Count of Participants)
    Count of Participants [Participants]
    81
    17.3%
    71
    15%
    152
    16.2%
    sUA >= 9 mg/dL (Count of Participants)
    Count of Participants [Participants]
    160
    34.2%
    148
    31.4%
    308
    32.8%
    Pre-study allopurinol users with dose <= 300 mg (Count of Participants)
    Count of Participants [Participants]
    178
    38%
    167
    35.4%
    345
    36.7%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants Experiencing ≥ 1 Gout Flare During Phase 3
    Description Participants were defined as flaring in Phase 3 if they: -1) met 3 of 4 following participant-reported criteria: a) warm joint(s) b) swollen joint(s) c) pain (>3) at rest on a scale of 0-10 (10 being the worst pain) d) self-identified gout flare OR -2) reported use of medications to treat flare
    Time Frame Phase III of the study (weeks 49-72 of study duration)

    Outcome Measure Data

    Analysis Population Description
    Primary analysis excluded patients who either never received the trial interventions, or were identified as ineligible after randomization, or dropouts; a complete case analysis was conducted on total of 749 subjects: 740 who completed phase 3 of the study plus 9 subjects who terminated in phase 3 after having an outcome.
    Arm/Group Title Allopurinol / Sham Comparator (Febuxostat) Febuxostat / Sham Comparator (Allopurinol)
    Arm/Group Description Patients will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling Febuxostat will be given with allopurinol Allopurinol: Patients will be titrated up to the dose that will lower to target uric acid levels. Placebo, vehicle control (Febuxostat-shaped): Placebo in the shape of Febuxostat will be given with Allopurinol Febuxostat will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling Allopurinol will be given with Febuxostat Febuxostat: Febuxostat will be titrated up to the dose that will lower to target uric acid levels. Placebo, vehicle control (Allopurinol-shaped): Placebo in the shape of Allopurinol will be given with Febuxostat
    Measure Participants 370 379
    Count of Participants [Participants]
    135
    28.8%
    165
    35%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Allopurinol / Sham Comparator (Febuxostat), Febuxostat / Sham Comparator (Allopurinol)
    Comments One-sided null hypothesis posited that allopurinol was inferior to febuxostat. The proportions of participants with ≥ 1 gout flare during phase 3 were compared between the two treatments.
    Type of Statistical Test Non-Inferiority
    Comments A non-inferiority bound of 8% was established during the trial design; a one-sided alpha level was set at 0.05.
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method t-test, 1 sided
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -7
    Confidence Interval (1-Sided) 95%
    to -1.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame Beginning at informed consent and continuing until the end of participation in the study at 72 weeks, plus 30 days of observation.
    Adverse Event Reporting Description Data on adverse events was collected spontaneously through patient reports, actively elicited during visits through open-ended questioning and examination, and gathered at the time of telephone contact and medical record reviews during the follow-up period.
    Arm/Group Title Allopurinol / Sham Comparator (Febuxostat) Febuxostat / Sham Comparator (Allopurinol)
    Arm/Group Description Patients will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling Febuxostat will be given with allopurinol Allopurinol: Patients will be titrated up to the dose that will lower to target uric acid levels. Placebo, vehicle control (Febuxostat-shaped): Placebo in the shape of Febuxostat will be given with Allopurinol Febuxostat will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling Allopurinol will be given with Febuxostat Febuxostat: Febuxostat will be titrated up to the dose that will lower to target uric acid levels. Placebo, vehicle control (Allopurinol-shaped): Placebo in the shape of Allopurinol will be given with Febuxostat
    All Cause Mortality
    Allopurinol / Sham Comparator (Febuxostat) Febuxostat / Sham Comparator (Allopurinol)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/468 (1.7%) 8/472 (1.7%)
    Serious Adverse Events
    Allopurinol / Sham Comparator (Febuxostat) Febuxostat / Sham Comparator (Allopurinol)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 125/468 (26.7%) 123/472 (26.1%)
    Blood and lymphatic system disorders
    Anaemia 2/468 (0.4%) 5 3/472 (0.6%) 5
    Iron deficiency anaemia 1/468 (0.2%) 1 0/472 (0%) 0
    Spontaneous haematoma 1/468 (0.2%) 1 0/472 (0%) 0
    Cardiac disorders
    Angina unstable 4/468 (0.9%) 4 3/472 (0.6%) 4
    Arrhythmia supraventricular 12/468 (2.6%) 18 8/472 (1.7%) 11
    Atrioventricular block complete 1/468 (0.2%) 1 0/472 (0%) 0
    Bradycardia 3/468 (0.6%) 3 0/472 (0%) 0
    Cardiac failure 27/468 (5.8%) 56 12/472 (2.5%) 19
    Coronary artery disease 3/468 (0.6%) 3 2/472 (0.4%) 2
    Hypertensive cardiomyopathy 0/468 (0%) 0 1/472 (0.2%) 1
    Ischaemic cardiomyopathy 1/468 (0.2%) 1 0/472 (0%) 0
    Mitral valve disease 0/468 (0%) 0 1/472 (0.2%) 1
    Myocardial infarction 4/468 (0.9%) 4 8/472 (1.7%) 8
    Myocardial ischaemia 2/468 (0.4%) 2 0/472 (0%) 0
    Palpitations 0/468 (0%) 0 1/472 (0.2%) 1
    Pulseless electrical activity 0/468 (0%) 0 1/472 (0.2%) 1
    Sinus node dysfunction 1/468 (0.2%) 1 0/472 (0%) 0
    Tachycardia 1/468 (0.2%) 1 0/472 (0%) 0
    Ventricular fibrillation 0/468 (0%) 0 2/472 (0.4%) 3
    Ventricular tachycardia 1/468 (0.2%) 1 2/472 (0.4%) 2
    Endocrine disorders
    Hypothyroidism 1/468 (0.2%) 1 0/472 (0%) 0
    Gastrointestinal disorders
    Abdominal discomfort 0/468 (0%) 0 1/472 (0.2%) 1
    Abdominal pain 2/468 (0.4%) 2 2/472 (0.4%) 3
    Ascites 1/468 (0.2%) 1 0/472 (0%) 0
    Diarrhoea 1/468 (0.2%) 1 1/472 (0.2%) 1
    Duodenal ulcer haemorrhage 1/468 (0.2%) 1 0/472 (0%) 0
    Erosive oesophagitis 0/468 (0%) 0 1/472 (0.2%) 1
    Gastrointestinal angiodysplasia 0/468 (0%) 0 1/472 (0.2%) 1
    Gastrointestinal haemorrhage 3/468 (0.6%) 3 2/472 (0.4%) 2
    Gastrooesophageal reflux disease 0/468 (0%) 0 1/472 (0.2%) 1
    Glossitis 1/468 (0.2%) 1 0/472 (0%) 0
    Haematemesis 1/468 (0.2%) 1 0/472 (0%) 0
    Ileus 1/468 (0.2%) 1 0/472 (0%) 0
    Incarcerated umbilical hernia 1/468 (0.2%) 1 0/472 (0%) 0
    Inguinal hernia 1/468 (0.2%) 1 0/472 (0%) 0
    Melaena 1/468 (0.2%) 1 0/472 (0%) 0
    Pancreatitis 2/468 (0.4%) 2 1/472 (0.2%) 1
    Pancreatitis chronic 1/468 (0.2%) 1 0/472 (0%) 0
    Rectal haemorrhage 1/468 (0.2%) 1 0/472 (0%) 0
    Small intestinal obstruction 1/468 (0.2%) 1 0/472 (0%) 0
    Vomiting 0/468 (0%) 0 1/472 (0.2%) 1
    General disorders
    Adverse drug reaction 1/468 (0.2%) 1 0/472 (0%) 0
    Asthenia 1/468 (0.2%) 1 0/472 (0%) 0
    Cardiac death 1/468 (0.2%) 1 0/472 (0%) 0
    Chest pain 5/468 (1.1%) 5 4/472 (0.8%) 4
    Non-cardiac chest pain 0/468 (0%) 0 1/472 (0.2%) 2
    Hepatobiliary disorders
    Cholecystitis 5/468 (1.1%) 5 2/472 (0.4%) 2
    Cholelithiasis 0/468 (0%) 0 1/472 (0.2%) 1
    Hepatic cirrhosis 1/468 (0.2%) 1 1/472 (0.2%) 1
    Liver injury 1/468 (0.2%) 1 0/472 (0%) 0
    Immune system disorders
    Anaphylactic reaction 1/468 (0.2%) 1 1/472 (0.2%) 1
    Infections and infestations
    Abdominal abscess 0/468 (0%) 0 1/472 (0.2%) 1
    Abscess limb 0/468 (0%) 0 1/472 (0.2%) 1
    Acute haemorrhagic conjunctivitis 0/468 (0%) 0 1/472 (0.2%) 1
    Anal abscess 1/468 (0.2%) 1 0/472 (0%) 0
    Appendicitis 2/468 (0.4%) 2 0/472 (0%) 0
    Arthritis bacterial 1/468 (0.2%) 1 0/472 (0%) 0
    Bacteraemia 2/468 (0.4%) 2 0/472 (0%) 0
    Bacterial infection 0/468 (0%) 0 1/472 (0.2%) 1
    Bronchitis 1/468 (0.2%) 1 2/472 (0.4%) 2
    Bursitis infective 1/468 (0.2%) 1 0/472 (0%) 0
    COVID-19 0/468 (0%) 0 2/472 (0.4%) 2
    Cellulitis 6/468 (1.3%) 6 12/472 (2.5%) 15
    Diabetic foot infection 1/468 (0.2%) 1 0/472 (0%) 0
    Diverticulitis 0/468 (0%) 0 3/472 (0.6%) 3
    Gangrene 0/468 (0%) 0 1/472 (0.2%) 1
    Gastroenteritis 1/468 (0.2%) 1 2/472 (0.4%) 2
    Groin abscess 1/468 (0.2%) 1 0/472 (0%) 0
    Infection 0/468 (0%) 0 1/472 (0.2%) 1
    Influenza 2/468 (0.4%) 2 2/472 (0.4%) 2
    Liver abscess 1/468 (0.2%) 1 0/472 (0%) 0
    Localised infection 0/468 (0%) 0 1/472 (0.2%) 1
    Osteomyelitis 2/468 (0.4%) 4 3/472 (0.6%) 3
    Pneumonia 10/468 (2.1%) 11 9/472 (1.9%) 10
    Postoperative wound infection 3/468 (0.6%) 3 0/472 (0%) 0
    Respiratory syncytial virus infection 1/468 (0.2%) 1 0/472 (0%) 0
    Sepsis 2/468 (0.4%) 2 6/472 (1.3%) 8
    Tonsillitis 0/468 (0%) 0 1/472 (0.2%) 1
    Upper respiratory tract infection 1/468 (0.2%) 1 0/472 (0%) 0
    Urinary tract infection 0/468 (0%) 0 7/472 (1.5%) 8
    Urosepsis 0/468 (0%) 0 1/472 (0.2%) 1
    Injury, poisoning and procedural complications
    Chest injury 1/468 (0.2%) 1 0/472 (0%) 0
    Fall 6/468 (1.3%) 6 3/472 (0.6%) 3
    Hip fracture 0/468 (0%) 0 1/472 (0.2%) 1
    Post procedural haemorrhage 2/468 (0.4%) 2 0/472 (0%) 0
    Road traffic accident 1/468 (0.2%) 1 0/472 (0%) 0
    Skin laceration 0/468 (0%) 0 1/472 (0.2%) 1
    Subdural haematoma 1/468 (0.2%) 1 0/472 (0%) 0
    Traumatic haematoma 1/468 (0.2%) 1 0/472 (0%) 0
    Vascular pseudoaneurysm 1/468 (0.2%) 1 0/472 (0%) 0
    Wound 0/468 (0%) 0 1/472 (0.2%) 1
    Wound necrosis 1/468 (0.2%) 1 0/472 (0%) 0
    Investigations
    Electrocardiogram abnormal 0/468 (0%) 0 1/472 (0.2%) 1
    International normalised ratio increased 1/468 (0.2%) 1 0/472 (0%) 0
    Metabolism and nutrition disorders
    Dehydration 0/468 (0%) 0 1/472 (0.2%) 1
    Diabetic ketoacidosis 0/468 (0%) 0 1/472 (0.2%) 1
    Electrolyte imbalance 0/468 (0%) 0 3/472 (0.6%) 3
    Failure to thrive 1/468 (0.2%) 1 0/472 (0%) 0
    Fluid overload 3/468 (0.6%) 3 0/472 (0%) 0
    Gout 3/468 (0.6%) 3 2/472 (0.4%) 2
    Hyperglycaemia 2/468 (0.4%) 2 5/472 (1.1%) 5
    Hyperkalaemia 2/468 (0.4%) 2 4/472 (0.8%) 4
    Hypoglycaemia 1/468 (0.2%) 1 4/472 (0.8%) 4
    Hypokalaemia 0/468 (0%) 0 1/472 (0.2%) 1
    Hyponatraemia 1/468 (0.2%) 1 0/472 (0%) 0
    Hypovolaemia 1/468 (0.2%) 1 1/472 (0.2%) 1
    Malnutrition 1/468 (0.2%) 1 0/472 (0%) 0
    Obesity 1/468 (0.2%) 1 0/472 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 0/468 (0%) 0 1/472 (0.2%) 1
    Flank pain 0/468 (0%) 0 1/472 (0.2%) 1
    Gouty arthritis 1/468 (0.2%) 1 0/472 (0%) 0
    Myalgia 1/468 (0.2%) 1 0/472 (0%) 0
    Myopathy toxic 0/468 (0%) 0 1/472 (0.2%) 1
    Neck pain 0/468 (0%) 0 1/472 (0.2%) 1
    Osteoarthritis 2/468 (0.4%) 2 1/472 (0.2%) 1
    Spinal osteoarthritis 1/468 (0.2%) 1 0/472 (0%) 0
    Spinal stenosis 0/468 (0%) 0 1/472 (0.2%) 1
    Vertebral column mass 1/468 (0.2%) 1 0/472 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Astrocytoma 1/468 (0.2%) 1 0/472 (0%) 0
    Bladder cancer recurrent 0/468 (0%) 0 1/472 (0.2%) 1
    Hepatocellular carcinoma 0/468 (0%) 0 1/472 (0.2%) 1
    Invasive ductal breast carcinoma 0/468 (0%) 0 1/472 (0.2%) 1
    Lung adenocarcinoma 0/468 (0%) 0 1/472 (0.2%) 1
    Lung neoplasm malignant 0/468 (0%) 0 1/472 (0.2%) 1
    Metastatic malignant melanoma 0/468 (0%) 0 1/472 (0.2%) 1
    Metastatic squamous cell carcinoma 1/468 (0.2%) 1 0/472 (0%) 0
    Myelofibrosis 1/468 (0.2%) 1 0/472 (0%) 0
    Pancreatic carcinoma metastatic 0/468 (0%) 0 1/472 (0.2%) 1
    Prostate cancer 2/468 (0.4%) 2 3/472 (0.6%) 3
    Squamous cell carcinoma 1/468 (0.2%) 1 1/472 (0.2%) 1
    Tracheal cancer 0/468 (0%) 0 1/472 (0.2%) 1
    Nervous system disorders
    Carotid artery stenosis 2/468 (0.4%) 2 2/472 (0.4%) 2
    Cerebrovascular accident 2/468 (0.4%) 2 7/472 (1.5%) 7
    Dementia 1/468 (0.2%) 1 0/472 (0%) 0
    Dizziness 0/468 (0%) 0 1/472 (0.2%) 1
    Encephalopathy 0/468 (0%) 0 3/472 (0.6%) 3
    Generalised tonic-clonic seizure 0/468 (0%) 0 1/472 (0.2%) 1
    Headache 1/468 (0.2%) 1 0/472 (0%) 0
    IIIrd nerve paresis 1/468 (0.2%) 1 0/472 (0%) 0
    Migraine 1/468 (0.2%) 1 0/472 (0%) 0
    Myasthenia gravis 0/468 (0%) 0 1/472 (0.2%) 1
    Radiculopathy 2/468 (0.4%) 2 0/472 (0%) 0
    Syncope 2/468 (0.4%) 3 1/472 (0.2%) 1
    Transient ischaemic attack 0/468 (0%) 0 2/472 (0.4%) 2
    Psychiatric disorders
    Alcohol withdrawal syndrome 0/468 (0%) 0 1/472 (0.2%) 1
    Alcoholism 2/468 (0.4%) 2 2/472 (0.4%) 2
    Delirium 1/468 (0.2%) 1 0/472 (0%) 0
    Depression 0/468 (0%) 0 1/472 (0.2%) 1
    Post-traumatic stress disorder 0/468 (0%) 0 1/472 (0.2%) 1
    Substance abuse 0/468 (0%) 0 1/472 (0.2%) 1
    Substance use disorder 1/468 (0.2%) 1 1/472 (0.2%) 1
    Suicidal ideation 2/468 (0.4%) 5 0/472 (0%) 0
    Suicide attempt 1/468 (0.2%) 1 0/472 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 19/468 (4.1%) 24 12/472 (2.5%) 12
    Nephrolithiasis 1/468 (0.2%) 1 0/472 (0%) 0
    Renal failure 2/468 (0.4%) 2 0/472 (0%) 0
    Renal impairment 0/468 (0%) 0 1/472 (0.2%) 1
    Renal mass 1/468 (0.2%) 1 0/472 (0%) 0
    Urinary tract obstruction 1/468 (0.2%) 1 0/472 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration 1/468 (0.2%) 1 0/472 (0%) 0
    Asthma 0/468 (0%) 0 1/472 (0.2%) 3
    Chronic obstructive pulmonary disease 7/468 (1.5%) 10 4/472 (0.8%) 6
    Cough 0/468 (0%) 0 1/472 (0.2%) 1
    Dyspnoea 2/468 (0.4%) 2 1/472 (0.2%) 1
    Epistaxis 1/468 (0.2%) 1 0/472 (0%) 0
    Haemoptysis 1/468 (0.2%) 1 0/472 (0%) 0
    Interstitial lung disease 0/468 (0%) 0 1/472 (0.2%) 1
    Laryngeal stenosis 0/468 (0%) 0 1/472 (0.2%) 1
    Lung hernia 0/468 (0%) 0 1/472 (0.2%) 1
    Pulmonary embolism 1/468 (0.2%) 2 3/472 (0.6%) 3
    Pulmonary hypertension 1/468 (0.2%) 2 0/472 (0%) 0
    Respiratory failure 5/468 (1.1%) 5 4/472 (0.8%) 5
    Skin and subcutaneous tissue disorders
    Angioedema 1/468 (0.2%) 1 0/472 (0%) 0
    Drug eruption 2/468 (0.4%) 2 0/472 (0%) 0
    Surgical and medical procedures
    Alcohol detoxification 1/468 (0.2%) 1 0/472 (0%) 0
    Aneurysm repair 0/468 (0%) 0 1/472 (0.2%) 1
    Cardiac ablation 2/468 (0.4%) 2 0/472 (0%) 0
    Cholecystectomy 1/468 (0.2%) 1 0/472 (0%) 0
    Haemorrhoid operation 0/468 (0%) 0 1/472 (0.2%) 1
    Hip arthroplasty 2/468 (0.4%) 2 2/472 (0.4%) 2
    Knee arthroplasty 2/468 (0.4%) 2 4/472 (0.8%) 4
    Lung lobectomy 0/468 (0%) 0 1/472 (0.2%) 1
    Metabolic surgery 1/468 (0.2%) 1 0/472 (0%) 0
    Nephrectomy 0/468 (0%) 0 1/472 (0.2%) 1
    Pancreaticosplenectomy 0/468 (0%) 0 1/472 (0.2%) 1
    Peripheral artery bypass 1/468 (0.2%) 1 0/472 (0%) 0
    Prostatic operation 1/468 (0.2%) 1 0/472 (0%) 0
    Shoulder arthroplasty 0/468 (0%) 0 1/472 (0.2%) 1
    Skin operation 1/468 (0.2%) 1 0/472 (0%) 0
    Spinal fusion surgery 1/468 (0.2%) 1 0/472 (0%) 0
    Spinal laminectomy 1/468 (0.2%) 1 0/472 (0%) 0
    Spinal operation 0/468 (0%) 0 2/472 (0.4%) 2
    Surgery 1/468 (0.2%) 1 1/472 (0.2%) 1
    Tenoplasty 0/468 (0%) 0 1/472 (0.2%) 1
    Thyroidectomy 0/468 (0%) 0 1/472 (0.2%) 1
    Transurethral prostatectomy 1/468 (0.2%) 1 0/472 (0%) 0
    Vascular disorders
    Aortic aneurysm 1/468 (0.2%) 1 0/472 (0%) 0
    Aortic stenosis 0/468 (0%) 0 1/472 (0.2%) 1
    Deep vein thrombosis 1/468 (0.2%) 1 0/472 (0%) 0
    Dry gangrene 1/468 (0.2%) 1 0/472 (0%) 0
    Haematoma 0/468 (0%) 0 1/472 (0.2%) 1
    Hypertension 5/468 (1.1%) 5 0/472 (0%) 0
    Hypotension 2/468 (0.4%) 2 2/472 (0.4%) 2
    Orthostatic hypotension 1/468 (0.2%) 1 0/472 (0%) 0
    Peripheral ischaemia 1/468 (0.2%) 1 0/472 (0%) 0
    Other (Not Including Serious) Adverse Events
    Allopurinol / Sham Comparator (Febuxostat) Febuxostat / Sham Comparator (Allopurinol)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 36/468 (7.7%) 44/472 (9.3%)
    Gastrointestinal disorders
    Abdominal discomfort 1/468 (0.2%) 1 5/472 (1.1%) 5
    Diarrhoea 4/468 (0.9%) 4 8/472 (1.7%) 9
    Nausea 3/468 (0.6%) 3 6/472 (1.3%) 7
    Investigations
    Alanine aminotransferase increased 18/468 (3.8%) 18 21/472 (4.4%) 22
    Skin and subcutaneous tissue disorders
    Drug eruption 11/468 (2.4%) 11 11/472 (2.3%) 11

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Ryan E. Ferguson, ScD, MPH, Director
    Organization Boston CSP Coordinating Center
    Phone 1-857-364-4201
    Email Ryan.Ferguson@va.gov
    Responsible Party:
    VA Office of Research and Development
    ClinicalTrials.gov Identifier:
    NCT02579096
    Other Study ID Numbers:
    • 594
    First Posted:
    Oct 19, 2015
    Last Update Posted:
    May 17, 2022
    Last Verified:
    Apr 1, 2022