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

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Juvenile Diabetes Research Foundation, Joslin Diabetes Center, University of Minnesota, University of Colorado, Denver, University of Michigan, University of Toronto, Northwestern University Feinberg School of Medicine, Albert Einstein College of Medicine, Steno Diabetes Center Copenhagen, Washington University School of Medicine, University of Washington, Emory University, University of Calgary, University of Alberta, University of Texas Southwestern Medical Center, BCDiabetes.Ca

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.

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.

Kidney Diseases, Diabetic Nephropathies, Diabetes Mellitus, Diabetes Complications, Uric acid, Allopurinol, Glomerular filtration rate, Coronary artery disease

Oral allopurinol at a dose of 100 mg per day for 4 weeks and then at a dose ranging from 200 to 400 mg per day depending on kidney function

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

Glomerular filtration rate (GFR) at 4 months after randomization, estimated from serum creatinine and cystatin C and adjusted for the eGFR at baseline.

Glomerular filtration rate (GFR) at the end of the 3-year treatment period, measured by the plasma disappearance of non-radioactive iohexol (iGFR) and adjusted for the iGFR at baseline.

Glomerular filtration rate time trajectory estimated from iohexol disappearance GFR (iGFR) measurements at weeks 0, 80, 156, and 164. iGFR slopes were estimated by a linear mixed-effects model for longitudinal iGFR measures using a multiple imputation technique for missing values. Positive values denote increasing GFR over time, negative values denote declining iGFR over time.

Glomerular filtration rate time trajectory from baseline to end of the 2-month wash-out period (week 164) estimated from quarterly serum creatinine measurements (eGFR). eGFR slopes were estimated by a linear mixed-effects model for longitudinal eGFR measures using a multiple imputation technique for missing values. Positive values denote increasing eGFR over time, negative values denote declining eGFR over time.

Weeks 0, 4, 16, 32, 48, 64, 80, 96, 112, 128, 156, and 164 (from baseline to the end of washout period)

Risk of serum creatinine doubling or end stage renal disease (ESRD) in the allopurinol arm as compared to placebo. Results are expressed as the number of participants who experienced an event in each treatment group. The risk of an event in the allopurinol group as compared to the risk in the placebo group is expressed as hazard ratio (estimated by means of proportional hazard regression).

Up to the end of the 2-month wash-out period following the 3-year treatment period (Week 0 to Week 164)

Geometric mean of two urinary albumin excretion (AER) measurements at the end of the 2-month wash-out period following the 3-year treatment period, adjusted for the mean urinary AER at baseline. Results are expressed as least square means of the geometric means in each subject in each group.

Geometric mean of urinary albumin excretion rate (AER) during the last three months of the treatment period (Visits 15 and 16), adjusted for the mean urinary AER at baseline. Results are expressed as least square means of the geometric means in each subject in each group.

Risk of cardiovascular events defined as the composite of CVD death (ICD-10 code I10 to I74.9), myocardial infarction, stroke (ischemic or hemorrhagic), coronary artery bypass grafting, or percutaneous coronary intervention in the allopurinol arm as compared to placebo.Results are expressed as the number of participants who experienced an event in each treatment group. The risk of an event in the allopurinol group as compared to the risk in the placebo group is expressed as hazard ratio (estimated by means of proportional hazard regression).

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.

Ficociello LH, Rosolowsky ET, Niewczas MA, Maselli NJ, Weinberg JM, Aschengrau A, Eckfeldt JH, Stanton RC, Galecki AT, Doria A, Warram JH, Krolewski AS. High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up. Diabetes Care. 2010 Jun;33(6):1337-43. doi: 10.2337/dc10-0227. Epub 2010 Mar 23.

Hovind P, Rossing P, Tarnow L, Johnson RJ, Parving HH. Serum uric acid as a predictor for development of diabetic nephropathy in type 1 diabetes: an inception cohort study. Diabetes. 2009 Jul;58(7):1668-71. doi: 10.2337/db09-0014. Epub 2009 May 1. Erratum In: Diabetes. 2010 Oct;59(10):2695.

Jalal DI, Rivard CJ, Johnson RJ, Maahs DM, McFann K, Rewers M, Snell-Bergeon JK. Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: findings from the Coronary Artery Calcification in Type 1 Diabetes study. Nephrol Dial Transplant. 2010 Jun;25(6):1865-9. doi: 10.1093/ndt/gfp740. Epub 2010 Jan 11.

Maahs DM, Caramori L, Cherney DZ, Galecki AT, Gao C, Jalal D, Perkins BA, Pop-Busui R, Rossing P, Mauer M, Doria A; PERL Consortium. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diab Rep. 2013 Aug;13(4):550-9. doi: 10.1007/s11892-013-0381-0.

Doria A, Galecki AT, Spino C, Pop-Busui R, Cherney DZ, Lingvay I, Parsa A, Rossing P, Sigal RJ, Afkarian M, Aronson R, Caramori ML, Crandall JP, de Boer IH, Elliott TG, Goldfine AB, Haw JS, Hirsch IB, Karger AB, Maahs DM, McGill JB, Molitch ME, Perkins BA, Polsky S, Pragnell M, Robiner WN, Rosas SE, Senior P, Tuttle KR, Umpierrez GE, Wallia A, Weinstock RS, Wu C, Mauer M; PERL Study Group. Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes. N Engl J Med. 2020 Jun 25;382(26):2493-2503. doi: 10.1056/NEJMoa1916624.