A Pilot Study of Allopurinol to Prevent Kidney Function Loss in Type 1 Diabetes

Diabetic Nephropathies Clinical Trial

— PERL  

Official title:

A Pilot Study of Allopurinol to Prevent GFR Loss in Type 1 Diabetes.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01575379
• Other study ID #: JDRF 17-2012-377
• Status: Terminated
• Phase: Phase 4
• First received: April 9, 2012
• Last updated: December 13, 2017
• Start date: September 2012
• Est. completion date: January 31, 2014

Study information

• Verified date: December 2017
• Source: Joslin Diabetes Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Recent evidence from epidemiological studies suggests that serum uric acid levels higher than average predispose diabetic patients to kidney damage. The purpose of this study is to gather preliminary information on whether lowering serum uric acid by means of oral allopurinol (a drug commonly used for the treatment of gout) can be used to prevent or delay the loss of kidney function that may accompany diabetes. The results of this study will help us design a larger study to find out whether this medication can prevent kidney problems, in particular the loss of kidney function, in people with type 1 diabetes.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 30
• Est. completion date: January 31, 2014
• Est. primary completion date: January 31, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Male or female T1D patients between 18 and 60 years of age.

• T1D diagnosed before age 35 and continuously treated with insulin within one year from diagnosis. If the onset was between ages 31 and 35, body mass index (BMI) will be required to be < 26 kg/m2 at the time of diagnosis;

• Duration of T1D = 5 years;

• Presence of microalbuminuria or moderate macroalbuminuria (at least two out of three consecutive urinary albumin excretion rates [AER] or urinary albumin/creatinine ratios (ACR) measured during the preceding two years in the 30-1500 mg/24 hr or the 30-1500 mg/g range, respectively).

• Estimated GFR (based on serum creatinine and the CKD-EPI equation) between 35 and 109 ml/min/1.73 m2 at the screening visit.

• Measured GFR between 45 and 99 ml/min/1.73 m2 at the end of the run-in period;

• Serum UA = 4.5 mg/dl at the screening visit.

• Willing to comply with schedule of events and protocol requirements.

Exclusion Criteria:

• History of gout requiring uric acid lowering therapy or xanthinuria or other indications for uric acid lowering therapy such as cancer chemotherapy or extremely high serum uric acid values (=12 mg/dl)

• Recurrent renal calculi.

• Use of urate-lowering agents within 3 months before enrollment.

• 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 genotype (determined at the time of randomization) indicating increased risk of Stevens-Johnson syndrome in response to allopurinol.

• Renal transplant.

• Non-diabetic kidney disease as indicated by medical history and/or laboratory findings.

• SBP>160 or DBP >100 mmHg at screening or SBP>140 or DBP>90 mmHg at the end of the run-in period.

• Cancer treatment within two years before enrollment.

• History of clinically significant hepatic disease including hepatitis B or C and/or ALT (SGPT) >2.50 x ULN at screening;

• History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV);

• 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 12 months

• Breastfeeding or pregnancy or unwillingness to be on contraception.

• 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.

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1
• Diabetic Nephropathies
• Kidney Diseases

Intervention

Drug:
• Allopurinol
The allopurinol dosage will vary from 200 to 400 mg per day based on GFR. Subjects randomized to allopurinol will initially take 100 mg per day for four weeks. After that, they will be switched to 400 mg per day if their GFR is =50 ml/min/1.73 m2, 300 mg per day if their GFR is in the 25-50 ml/min/1.73 m2 range, and 200 mg per day if the GFR is in the 15-25 ml/min/1.73 m2 range. Allopurinol will be continued at this dosage throughout the study unless the GFR changes, in which case the dosage will be modified to that appropriate for the new GFR class.Subjects will be given four tablets per day to be taken orally following meals, two in the morning and two in the evening. A dosage of 100 mg will be given as a 100 mg tablet plus three placebo tablets, 200 mg as two 100 mg and two placebo tablets, 300 mg as three 100 mg and one placebo tablet, 400 mg as four 100 mg tablets. Subjects randomized to placebo will be given four placebo tablets.
• Placebo
Subjects will be given four placebo (inactive) tablets per day to be taken orally following meals, two in the morning and two in the evening.

Locations

Country	Name	City	State
Denmark	Steno Diabetes Center	Gentofte
United States	Joslin Diabetes Center	Boston	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Alessandro Doria	Steno Diabetes Center, University of Michigan, University of Minnesota - Clinical and Translational Science Institute

Countries where clinical trial is conducted

United States,  Denmark, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Glomerular filtration rate at the end of the treatment period	Glomerular filtration rate (GFR) at the end of the 2-year treatment measured by the plasma clearance of non-radioactive iohexol and adjusted for the GFR at baseline.	2 years from the date of randomization
Secondary	Time to serum creatinine doubling or end stage renal disease	Serum creatinine doubling is in reference to baseline creatinine values. End stage renal disease is defined as measured GFR <= 15 ml/min/1.73 m2 or start of hemodialysis or kidney transplant.	From the date of randomization until the date of the first documented creatinine doubling or the first occurrence of end stage renal disease, whichever comes first, assessed up to 2 years
Secondary	Urinary albumin excretion rate in the last four months of the intervention period.	Median urinary albumin excretion rate during the last four months of the treatment period (measured at 84, 96, 104 weeks) adjusted for the urinary albumin excretion rate at baseline	From 84 to 104 weeks from the date of randomization
Secondary	Time to fatal or non-fatal cardiovascular events	Fatal or non-fatal cardiovascular events are defined as a composite of CVD death (ICD-10 code I10 to I74.9), myocardial infarction, stroke, coronary artery bypass grafting, or percutaneous coronary intervention.	From the date of randomization until the date of first documented event, assessed up to 2 years
Secondary	Glomerular filtration rate trajectory during the treatment period	Glomerular filtration rate (GFR) trajectory (as defined by the slope and intercept) during the entire treatment period estimated from quarterly serum creatinine and cystatin C measurements using the CKD-EPI SCr and the CKD-EPI SCr-SCysC equations.	From the date of randomization to the end of treatment (2 years from randomization)