Type 1 diabetes, microalbuminuria or macroalbuminuria and mildly impaired kidney function. MedDRA version: 19.1 Level: LLT Classification code 10037827 Term: Raised serum uric acid System Organ Class: 100000004848
Conditions
Interventions
Trade Name: Allopurinol (Hexanurat)
Product Name: Hexanurat
Pharmaceutical Form:
INN or Proposed INN: ALLOPURINOL
Other descriptive name
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female T1D patients. 2. T1D continuously treated with insulin within one year from diagnosis. If the onset was after age 35, the presence of one or more of the following will also be required: • documentation of the presence of circulating T1D-associated autoantibodies at diagnosis or at any other time • history of hospitalization for DKA • plasma C-peptide below the limit of detection with standard assay (with concurrent blood glucose >100 mg/dl) 3. Duration of T1D = 8 years. 4. Age 18-70 years. 5. 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 ?g/min) or 30-5000 mg/g range, respectively, if not on RASB agents, or in the 18-5000 mg/24 hr (12-3333 ?g/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. 6. 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. 7. Serum UA (UA) = 4.5 mg/dl at screening. 8. Valid baseline (Visit 4) iGFR measurement. OR 9. Being an active participant in the PERL Pilot Study. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 480 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 70
Exclusion criteria
Exclusion criteria: 1. History of gout or xanthinuria or other indications for uric acid lowering therapy such as cancer chemotherapy. 2. Recurrent renal calculi. 3. Use of urate-lowering agents within 2 months before screening. 4. Current use of azathioprine, 6-mercaptopurine, didanosine, warfarin, tamoxifen, amoxicillin/ampicillin, or other drugs interacting with allopurinol. 5. Known allergy to xanthine-oxidase inhibitors or iodine containing substances. 6. HLA B*58:01 positivity (tested before randomization). 7. Renal transplant. 8. Non-diabetic kidney disease. 9. SBP>160 or DBP >100 mmHg at screening or SBP>150 or DBP>95 mmHg at the end of the run-in period. 10. Cancer treatment (excluding non-melanoma skin cancer treated by excision) within two years before screening. 11. 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. 12. History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV) infection. 13. Hemoglobin concentration <11 g/dL (males), <10 g/dL (females) at screening. 14. Platelet count <100,000/mm3 at screening. 15. History of alcohol or drug abuse in the past 6 months. 16. Blood donation in the 3 months before screening. 17. Breastfeeding or pregnancy or unwillingness to be on contraception throughout the trial. 18. Poor mental function or any other reason to expect patient difficulty in complying with the requirements of the study. 19. Serious pre-existing medical problems other than diabetes, e.g. congestive heart failure, pulmonary insufficiency.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To determine whether lowering serum uric acid by means of allopurinol early in the course of kidney disease may be effective in preventing or slowing the decline of renal function in T1D patients. ; Secondary Objective: 2.Time to serum creatinine doubling or ESRD in the two treatment groups 3.The effect of treatment on the AER at the end of the wash-out period, based on the geometric mean of two AER measured at this time point and adjusted for the geometric mean of AER at baseline investigated in a linear regression model framework. 4.The effect of treatment on the AER at the end of the treatment period, based on the geometric mean of the AER measures 5.Time to fatal or non-fatal cardiovascular events will be analyzed as proposed for time to serum creatinine doubling or ESRD. ;Primary end point(s): GFR at the end of washout (Visit 17) of the 3-year intervention measured by the plasma clearance of non-radioactive iohexol (iGFR) and adjusted for the GFR at baseline;Timepoint(s) of evaluation of this end point: GFR at the end of washout (Visit 17) of the 3-year intervention | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Treatment differences in: 1. iGFR the end of the 3-yr treatment period (before the washout period) adjusted for the iGFR at baseline. 2. iGFR time trajectory estimated from periodical iGFR measurements. 3. eGFR at 4 months estimated from serum creatinine and cystatin C and adjusted for the eGFR at baseline. 4. eGFR time trajectory estimated from quarterly serum creatinine and cystatin C measurements (eGFR). 5. Time to serum creatinine doubling or end stage renal disease (ESRD). 6. AER at the end of the 2-month wash-out following the 3-yr treatment period, adjusted for the AER at baseline. 7. AER at the end of the 3-yr treatment period, adjusted for the AER at baseline. 8. Time to fatal or non-fatal cardiovascular events. ;Timepoint(s) of evaluation of this end point: Multiple timepoints as stated in E.5.2 throughout the study | — |
Countries
Canada, Denmark, United States
Contacts
Public ContactSection on Genetics and Epidemiolog
Joslin Diabetes Center
Outcome results
None listed