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
Study type: Interventional
Phase: Phase 3

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.
    

Detailed description: 
      Despite improvements in the past 20 years in glycemic and blood pressure control and the
      introduction of 'renoprotective' drugs such as renin-angiotensin system blockers, the
      incidence of end-stage renal disease (ESRD) in type 1 diabetes (T1D) is not declining. Novel
      therapies to complement these interventions are urgently needed. Mounting evidence from
      prospective studies indicates that moderately elevated serum uric acid is a strong,
      independent predictor of an increased risk of chronic kidney disease and increased rates of
      loss of kidney function among T1D persons. To study whether uric acid lowering can reduce
      glomerular filtration rate (GFR) loss in T1D, we have established the PERL (Preventing Early
      Renal Function Loss in Diabetes) Consortium including investigators from Joslin Diabetes
      Center, the Universities of Minnesota, Colorado, Toronto, and Michigan, Northwestern
      University, Albert Einstein College of Medicine, and the Steno Diabetes Center in Denmark.
      With the support of NIH grant R03 DK094484, the Consortium has designed a three-year,
      multi-center, double-blind, placebo-controlled, randomized clinical trial with the specific
      aim of evaluating the efficacy of the urate-lowering drug allopurinol, as compared to
      placebo, in reducing kidney function loss among subjects with T1D. The trial is targeted to
      T1D patients with microalbuminuria or moderate macroalbuminuria or ongoing kidney function
      decline and serum uric acid levels ≥ 4.5 mg/dl, since these are the patients who are at very
      high risk of having rapid GFR decline and might benefit most from reductions in uric acid
      levels. Study subjects will be required to have a GFR between 40 and 99 ml/min/1.73 m2,
      consistent with the goal of intervening relatively early in the course of clinical DN rather
      than at later stages when structural changes are far advanced and a very large proportion of
      kidney function has already been lost. The primary endpoint of the study will be the GFR (as
      measured by iohexol plasma disappearance) at the end of a 2-month wash-out period after the
      3-year intervention. Sample size calculations under various dropout and non-adherence
      scenarios suggest that 240 subjects in each treatment arm would provide at least 80% power to
      detect a clinically meaningful and achievable reduction in GFR decline in the allopurinol vs.
      the placebo group.If we demonstrate that allopurinol can halt or slow down GFR decline in T1D
      subjects, we will provide a safe and inexpensive intervention to prevent or delay kidney
      failure in T1D that can be applied at the earliest clinically detectable stages of renal
      injury. It is difficult to overstate how significant this finding would be, both from the
      perspective of public health and that of persons with diabetes.

      Thirty-one of the 530 participants in this study were recruited as part of a pilot study
      (JDRF 17-2012-377, NCT01575379) and transferred to the main study (NCT02017171) when this was
      funded. Eligibility criteria for the pilot study were the same as those for the main study,
      with the exception of a wider estimated GFR interval at entry in the run-in period
      (eGFR=35-109) ml/min/1.73 m2) and the additional requirement of a measured GFR (iGFR) between
      45 and 99 ml/min/1.73 m2 at the end of the run-in period. Pilot subjects joined the main
      study at a time point corresponding to the time elapsed from randomization in the pilot.
      Thus, they were exposed to the study medication for the same length of time (3 years) as
      participants who were directly enrolled in the main study. Outcomes measures were those of
      the main study, regardless of whether participants were transferred from the pilot or were
      directly enrolled in the main study.
    

Intervention name(s): Allopurinol; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Inactive oral tablets identical in appearance to allopurinol tablets.
Intervention MeSH terms: Allopurinol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Kidney Diseases; Diabetic Nephropathies; Diabetes Mellitus; Diabetes Complications; Uric acid; Allopurinol; Glomerular filtration rate; Coronary artery disease