A Multicenter Clinical Trial of Allopurinol to Prevent Kidney Function Loss in Type 1 Diabetes (PERL)

General Description

Despite improvements during the past 20 years in blood glucose and blood pressure control, diabetic kidney disease remains one of the leading 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 was to see whether a medication called allopurinol may help prevent loss of kidney function among people with type 1 diabetes (T1D). Allopurinol has been used for many years to decrease high blood uric acid and treat gout. 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, a double-blinded, international clinical trial was conducted with patients with type 1 diabetes that had an increased risk of developing kidney disease. Participants were randomly assigned to take allopurinol or placebo (inactive pill) for three years, during which they were followed through periodical visits. Kidney function was measured at the beginning and at the end of the treatment period to assess whether patients taking allopurinol experienced a slower loss of kidney function over time compared to those taking the inactive pill.

Objectives

To determine whether lowering serum uric acid by means of allopurinol early in the course of kidney disease is effective in preventing or slowing the decline of renal function in T1D patients.

Outcome Measure

Primary outcome measure: Glomerular filtration rate (GFR) at the end of the 2-month washout period following the 3-year treatment period, measured by the plasma disappearance of non-radioactive iohexol (iGFR) and adjusted for the iGFR at baseline.

Secondary outcome measures:

• iGFR at the end of the 3-year treatment period (before the washout period)
  adjusted for the iGFR at baseline
• iGFR time trajectory estimated from periodical iGFR measurements
• Estimated glomerular filtration rate (eGFR) at 4 months estimated from serum
  creatinine and cystatin C and adjusted for the eGFR at baseline
• eGFR time trajectory estimated from quarterly serum creatinine and cystatin
  C measurements
• Time to serum creatinine doubling or end stage renal disease (ESRD)
• Albumin excretion rate (AER) at the end of the 2-month washout period
  following the 3-year treatment period, adjusted for the AER at baseline
• AER at the end of the 3-year treatment period, adjusted for the AER at
  baseline
• Time to fatal or non-fatal cardiovascular events

Criteria

Inclusion criteria:

• Male or female T1D patients continuously treated with insulin within one year
  from diagnosis
• Duration of T1D greater than or equal to 8 years
• Age 18-70 years
• History or presence of microalbuminuria or moderate macroalbuminuria, or
  evidence of declining kidney function (eGFR decline ≥3.0 ml/min/1.73 m2/year
  in the previous 3-5 years), regardless of history or presence of albuminuria
  and/or RAS Blocker treatment
• eGFR based on serum creatinine between 40 and 99.9 ml/min/1.73 m2 at
  screening
• Serum UA greater than or equal to 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
• Systolic blood pressure (SBP) > 160 or diastolic blood pressure (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)

Outcome

Despite achieving full enrollment and participant completion targets and a sustained 35% serum urate reduction throughout 3-years of treatment, PERL did not find evidence of clinically meaningful benefit of allopurinol on the primary outcome measure (iGFR at the end of the washout period period). Pre-specified subgroup analyses did not show heterogeneity in the effect of allopurinol on the primary outcome. Results were similarly neutral for secondary outcomes such as iGFR and eGFR slopes, and time to serum creatinine doubling or end-stage kidney disease.