Diabetic Nephropathies | A Multicenter Clinical Trial of Allopurinol to Prevent Kidney Function Loss in Type 1 Diabetes
Diabetic Nephropathies research study
What is the primary objective of this study?
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.
Who is eligible to participate?
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.
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Coronary Artery Disease
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Drug:PlaceboInactive oral tablets identical in appearance to allopurinol tablets.
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
AllopurinolOral 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
PlaceboOral placebo tablets
Active, not recruiting
Start Date: February 2014
Completed Date: December 31, 2019
Phase: Phase 3
Primary Outcome: iGFR at the end of the wash-out period
Secondary Outcome: eGFR at 4 months of treatment
Study sponsors, principal investigator, and references
Principal Investigator: Alessandro Doria, MD, PhD, MPH
Lead Sponsor: Alessandro Doria
Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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.