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

NCT02017171 | Completed Phase 3 Results DMC

• 2 other identifiers: DK101108UC4DK101108-01
• Study Type: interventional
• Target: 530
• Locations: 3 countries
• Sites: 30

Brief 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.

Conditions

Diabetic Nephropathies; Coronary Artery Disease

Keywords

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

Outcome Measures

Primary Outcomes (1)

• iGFR at the End of the Wash-out Period

  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.

  End of the 2-month wash-out period following the 3-year treatment period (week 164)

Secondary Outcomes (8)

• eGFR at 4 Months of Treatment

  4 months after randomization (week 16)

• iGFR the End of Treatment Period

  End of the 3-yr treatment period (week 156)

• iGFR Time Trajectory

  Weeks 0, 80, 156, and 164 (from baseline to the end of washout period)

• eGFR Time Trajectory

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

• Serum Creatinine Doubling or End Stage Renal Disease (ESRD)

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

Study Arms (2)

Allopurinol

EXPERIMENTAL

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

Drug: Allopurinol

Placebo

PLACEBO COMPARATOR

Oral placebo tablets

Drug: Placebo

Interventions

Allopurinol DRUG

Allopurinol

Placebo DRUG

Inactive oral tablets identical in appearance to allopurinol tablets.

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (30)

Barbara Davis Center / University of Colorado Denver

Aurora, Colorado, 80045, United States

Location

Kaiser Permanente Colorado Institute of Health Research

Denver, Colorado, 80231, United States

Location

Emory University - Grady Memorial Hospital

Atlanta, Georgia, 30303, United States

Location

Atlanta Diabetes Associates

Atlanta, Georgia, 30318, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Joslin Diabetes Center

Boston, Massachusetts, 02215, United States

Location

University of Massachusetts Memorial Health Care

Worcester, Massachusetts, 01655, United States

Location

Brehm Center for Diabetes Research / University of Michigan

Ann Arbor, Michigan, 48105, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Winthrop-University Hospital

Mineola, New York, 11501, United States

Location

ICAHN School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Weill Cornell Medical Center

New York, New York, 10065, United States

Location

SUNY Upstate Medical University

Syracuse, New York, 13210, United States

Location

Albert Einstein College of Medicine / Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

Jacobi Medical Center

The Bronx, New York, 10461, United States

Location

University of Texas Southwestern

Dallas, Texas, 75390, United States

Location

Virginia Mason Medical Center

Seattle, Washington, 98101, United States

Location

University of Washington

Seattle, Washington, 98105, United States

Location

Providence Sacred Heart Medical Center

Spokane, Washington, 99204, United States

Location

Gunderson Health System

La Crosse, Wisconsin, 54601, United States

Location

University of Calgary

Calgary, Alberta, T2T 5C7, Canada

Location

Alberta Diabetes Institute

Edmonton, Alberta, T6G 2E1, Canada

Location

BC Diabetes

Vancouver, British Columbia, V5Y 3W2, Canada

Location

LMC Diabetes and Endocrinology

Toronto, Ontario, M4G 3E8, Canada

Location

Mount Sinai Hospital / University of Toronto

Toronto, Ontario, M5G 2C4, Canada

Location

Toronto General Hospital

Toronto, Ontario, M5G 2N2, Canada

Location

Steno Diabetes Center

Gentofte Municipality, DK-2820, Denmark

Location

Related Publications (7)

• 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.

  PMID: 20332356 BACKGROUND

• 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.

  PMID: 19411615 BACKGROUND

• 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.

  PMID: 20064950 BACKGROUND

• 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.

  PMID: 23649945 BACKGROUND

• Ang L, Gunaratnam S, Huang Y, Dillon BR, Martin CL, Burant A, Reiss J, Blakely P, Vasbinder A, Zhao L, Mizokami-Stout K, Tang Y, Feldman EL, Doria A, Spino C, Banerjee M, Hayek SS, Pop-Busui R. Inflammatory Markers and Measures of Cardiovascular Autonomic Neuropathy in Type 1 Diabetes. J Am Heart Assoc. 2025 Jan 7;14(1):e036787. doi: 10.1161/JAHA.124.036787. Epub 2024 Dec 27.

  PMID: 39727210 DERIVED

• Keum Y, Caramori ML, Cherney DZ, Crandall JP, de Boer IH, Lingvay I, McGill JB, Polsky S, Pop-Busui R, Rossing P, Sigal RJ, Mauer M, Doria A. Albuminuria and Rapid Kidney Function Decline as Selection Criteria for Kidney Clinical Trials in Type 1 Diabetes Mellitus. Clin J Am Soc Nephrol. 2025 Jan 1;20(1):62-71. doi: 10.2215/CJN.0000000000000567. Epub 2024 Nov 18.

  PMID: 39423023 DERIVED

• 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.

  PMID: 32579810 DERIVED

Related Links

• Study website

MeSH Terms

Conditions

Diabetic Nephropathies; Coronary Artery Disease; Kidney Diseases; Diabetes Mellitus; Diabetes Complications

Interventions

Allopurinol

Condition Hierarchy (Ancestors)

Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Endocrine System Diseases; Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Alessandro Doria (Sponsor and PI of the study)
• Organization: Joslin Diabetes Center

alessandro.doria@joslin.harvard.edu

617-319-0970

Study Officials

• Alessandro Doria, MD, PhD, MPH

  Joslin Diabetes Center

  PRINCIPAL INVESTIGATOR

• Michael Mauer, MD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Investigator

Study Record Dates

• First Submitted: December 16, 2013
• First Posted: December 20, 2013
• Study Start: February 1, 2014
• Primary Completion: July 15, 2019
• Study Completion: August 31, 2019
• Last Updated: December 4, 2020
• Results First Posted: November 20, 2020

Record last verified: 2020-10

Locations

CA (6); DK (1); US (23)