A Multicenter Clinical Trial of Allopurinol to Prevent Kidney Function Loss in Type 1 Diabetes
Condition: Diabetic Nephropathies; Coronary Artery Disease
MeSH terms: Kidney Diseases; Diabetic Nephropathies; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
Intervention: Allopurinol; Placebo
Intervention description: Inactive oral tablets identical in appearance to allopurinol tablets.
Intervention MeSH terms: Allopurinol
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 530.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Kidney Diseases; Diabetic Nephropathies; Diabetes Mellitus; Diabetes Complications; Uric acid; Allopurinol; Glomerular filtration rate; Coronary artery disease

Summary:

      Despite improvements during the past 20 years in blood glucose and blood pressure control,
      diabetic kidney disease remains one of the most important causes of health problems in
      patients with diabetes. Novel treatments to complement blood glucose and blood pressure
      control are urgently needed. The goal of this study is to see whether a medication called
      allopurinol may help prevent loss of kidney function among people with type 1 diabetes.
      Allopurinol has been used for many years to decrease high blood uric acid and treat gout - a
      disease characterized by arthritis, especially of the foot joints. There is evidence
      suggesting that allopurinol might also be useful in people with diabetes who have normal or
      moderately impaired kidney function to decrease the risk of developing advanced kidney
      disease in the future. To prove this beneficial effect of allopurinol, we will be conducting
      an international clinical trial at eight diabetes centers, enrolling approximately 480
      patients with type 1 diabetes who are at increased risk of developing kidney disease.
      Participants will be randomly assigned to take allopurinol or placebo (inactive pill) for
      three years, during which they will be followed through periodical visits. To prevent any
      possible bias, neither the participants nor the clinical staff knows who is taking
      allopurinol and who is taking the placebo. Kidney function will be measured at the beginning
      and at the end of the treatment period to see whether patients taking allopurinol experience
      a slower loss of kidney function over time as compared to those taking the inactive pill. If
      this trial is successful, the reduction in health problems resulting from the prevention or
      delay of kidney function loss due to the use of allopurinol would have a major impact on the
      lives of type 1 diabetic patients as well as on society at large, significantly reducing the
      human and financial costs associated with diabetic kidney disease. Because of the emphasis on
      early intervention, the proposed trial, if successful, will establish a new paradigm in
      treatments to slow or prevent progression towards end stage kidney disease in type 1 diabetes
      far beyond anything achieved to date.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female subjects with type 1 diabetes continuously treated with insulin within
             one year from diagnosis

          -  Duration of T1D ≥ 8 years

          -  Age 18-70 years

          -  History or presence of microalbuminuria or moderate macroalbuminuria, or evidence of
             declining kidney function regardless of history or presence of albuminuria and/or RAS
             Blocker treatment. Micro- or moderate macroalbuminuria will be defined as at least two
             out of three consecutive urinary albumin excretion rates [AERs] or albumin creatinine
             ratios [ACRs] taken at any time during the two years before screening or at screening
             in the 30-5000 mg/24 hr (20-3333 ug/min) or 30-5000 mg/g range, respectively, if not
             on RASB agents, or in the 18-5000 mg/24 hr (12-3333 ug/min) or 18-5000 mg/g range,
             respectively, if on RASB agents). Evidence of declining kidney function will be
             defined as an eGFR (CKD-EPI) decline ≥3.0 ml/min/1.73 m2/year, estimated from the
             slope derived from all the available serum creatinine measurements (including the one
             at screening assessment) from the previous 3 years. If at least 3 serum creatinine
             measures are not available in the previous 3 years, then the slope can be derived from
             creatinine values from the previous 5 years.

          -  Estimated GFR (eGFR) based on serum creatinine between 40 and 99.9 ml/min/1.73 m2 at
             screening. The upper and the lower limits should be decreased by 1 ml/min/1.73 m2 for
             each year over age 60 (with a lower limit of 35 ml/min/1.73m2) and by 10 ml/min/1.73
             m2 for strict vegans.

          -  Serum UA (UA) ≥ 4.5 mg/dl at screening

        Exclusion Criteria:

          -  History of gout or xanthinuria or other indications for uric acid lowering therapy
             such as cancer chemotherapy.

          -  Recurrent renal calculi.

          -  Use of urate-lowering agents within 2 months before screening.

          -  Current use of azathioprine, 6-mercaptopurine, didanosine, warfarin, tamoxifen,
             amoxicillin/ampicillin, or other drugs interacting with allopurinol.

          -  Known allergy to xanthine-oxidase inhibitors or iodine containing substances.

          -  HLA B*58:01 positivity (tested before randomization).

          -  Renal transplant.

          -  Non-diabetic kidney disease.

          -  SBP>160 or DBP >100 mmHg at screening or SBP>150 or DBP>95 mmHg at the end of the
             run-in period.

          -  Cancer treatment (excluding non-melanoma skin cancer treated by excision) within two
             years before screening.

          -  History of clinically significant hepatic disease including hepatitis B or C and/or
             persistently elevated serum liver enzymes at screening and/or history of HBV/HCV
             positivity.

          -  History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV)
             infection.

          -  Hemoglobin concentration <11 g/dL (males), <10 g/dL (females) at screening.

          -  Platelet count <100,000/mm3 at screening.

          -  History of alcohol or drug abuse in the past 6 months.

          -  Blood donation in the 3 months before screening.

          -  Breastfeeding or pregnancy or unwillingness to be on contraception throughout the
             trial.

          -  Poor mental function or any other reason to expect patient difficulty in complying
             with the requirements of the study.

          -  Serious pre-existing medical problems other than diabetes, e.g. congestive heart
             failure, pulmonary insufficiency.