Diabetic NephropathiesPhase 3NCT02017171
A Multicenter Clinical Trial of Allopurinol to Prevent Kidney Function Loss in Type 1 Diabetes
A Phase 3 study testing Allopurinol in people with Diabetic Nephropathies and Coronary Artery Disease, run by Alessandro Doria at 30 sites in 3 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Diabetic Nephropathies, Coronary Artery Disease
- What is being tested?
- Allopurinol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 530 participants
- Where
- 30 sitesin 3 countries
- Study dates
- Feb 2014to 31 Aug 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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).
Show all 19Show fewer
- 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.
Trial locations and contacts
30 sites in 3 countries.
30 sites in 3 countries
United States23 sites
Brehm Center for Diabetes Research / University of Michigan
Ann Arbor, Michigan, 48105
Emory University - Grady Memorial Hospital
Atlanta, Georgia, 30303
Atlanta Diabetes Associates
Atlanta, Georgia, 30318
Barbara Davis Center / University of Colorado Denver
Aurora, Colorado, 80045
Massachusetts General Hospital
Boston, Massachusetts, 02114
Joslin Diabetes Center
Boston, Massachusetts, 02215
Northwestern University Feinberg School of Medicine
Chicago, Illinois, 60611
University of Texas Southwestern
Dallas, Texas, 75390
Kaiser Permanente Colorado Institute of Health Research
Denver, Colorado, 80231
Henry Ford Health System
Detroit, Michigan, 48202
Gunderson Health System
La Crosse, Wisconsin, 54601
Winthrop-University Hospital
Mineola, New York, 11501
University of Minnesota
Minneapolis, Minnesota, 55455
ICAHN School of Medicine at Mount Sinai
New York, New York, 10029
Weill Cornell Medical Center
New York, New York, 10065
Virginia Mason Medical Center
Seattle, Washington, 98101
University of Washington
Seattle, Washington, 98105
Providence Sacred Heart Medical Center
Spokane, Washington, 99204
Washington University
St Louis, Missouri, 63110
SUNY Upstate Medical University
Syracuse, New York, 13210
Albert Einstein College of Medicine / Montefiore Medical Center
The Bronx, New York, 10461
Jacobi Medical Center
The Bronx, New York, 10461
University of Massachusetts Memorial Health Care
Worcester, Massachusetts, 01655
Canada6 sites
University of Calgary
Calgary, Alberta, T2T 5C7
Alberta Diabetes Institute
Edmonton, Alberta, T6G 2E1
LMC Diabetes and Endocrinology
Toronto, Ontario, M4G 3E8
Mount Sinai Hospital / University of Toronto
Toronto, Ontario, M5G 2C4
Toronto General Hospital
Toronto, Ontario, M5G 2N2
BC Diabetes
Vancouver, British Columbia, V5Y 3W2
About this study
Official title: PERL: A Multicenter Clinical Trial of Allopurinol to Prevent GFR Loss in T1D
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.
Read the detailed description
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.
- Conditions
- Diabetic Nephropathies, Coronary Artery Disease
- Being tested
- Allopurinol, Placebo
- Keywords
- Kidney Diseases, Diabetic Nephropathies, Diabetes Mellitus, Diabetes Complications, Uric acid, Allopurinol, Glomerular filtration rate, Coronary artery disease
- Medical subject headings
- Diabetic Nephropathies, Coronary Artery Disease, Kidney Diseases, Diabetes Mellitus, Diabetes Complications
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AllopurinolDrug
PlaceboDrug
Inactive oral tablets identical in appearance to allopurinol tablets.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Drug: Allopurinol |
| Placebo | Placebo comparator | Oral placebo tablets Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Glomerular filtration rate (GFR) at 4 months after randomization, estimated from serum creatinine and cystatin C and adjusted for the eGFR at baseline.
Measured: 4 months after randomization (week 16)
iGFR the End of Treatment Period
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.
Measured: End of the 3-yr treatment period (week 156)
iGFR Time Trajectory
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.
Measured: Weeks 0, 80, 156, and 164 (from baseline to the end of washout period)
eGFR Time Trajectory
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.
Measured: 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)
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).
Measured: Up to the end of the 2-month wash-out period following the 3-year treatment period (Week 0 to Week 164)
AER at the End of the Wash-out Period
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.
Measured: End of the 2-month wash-out period following the 3-year treatment period (week 164)
AER at the End of the Treatment Period
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.
Measured: Last three months of treatment period (Weeks 142 and 156)
Fatal or Non-fatal Cardiovascular Events
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).
Measured: Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Dec 2013 (estimated)
- Study startFeb 2014
- Primary completion15 Jul 2019
- Study completion31 Aug 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Diabetic NephropathiesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 530 participants (actual)
Sponsor and investigators
- Lead sponsor
- Alessandro Doria
- Sponsor type
- University, hospital or other
- Collaborators
- 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, 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
- Responsible party
- Sponsor-investigator, Alessandro Doria, Joslin Diabetes Center
- Investigators
- Alessandro Doria, MD, PhD, MPH, Principal investigator, Joslin Diabetes CenterMichael Mauer, MD, Principal investigator, University of Minnesota
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02017171
- Sponsor's protocol ID
- DK101108
- Other IDs
- UC4DK101108-01
- Status last verified
- Oct 2020
- First submitted
- 16 Dec 2013
- Last updated
- 4 Dec 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 20332356Hovind 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.
PubMed 19411615Jalal 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.
PubMed 20064950Maahs 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.
PubMed 23649945Ang 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.
PubMed 39727210Keum 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.
PubMed 39423023Doria 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.
PubMed 32579810
Study at a glance
From the registry record, last updated by the sponsor on 4 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- PERL: A Multicenter Clinical Trial of Allopurinol to Prevent GFR Loss in T1D
- ClinicalTrials.gov ID
- NCT02017171
- Acronym / sponsor ID
- DK101108
- Conditions
- Diabetic Nephropathies, Coronary Artery Disease
- Keywords
- Kidney Diseases, Diabetic Nephropathies, Diabetes Mellitus, Diabetes Complications, Uric acid, Allopurinol, Glomerular filtration rate, Coronary artery disease
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 530 participants (actual)
- Lead sponsor
- Alessandro DoriaUniversity, hospital or other
- Collaborators
- 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, 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
- Study start
- Feb 2014 (actual)
- Primary completion
- 15 Jul 2019 (actual)
- Study completion
- 31 Aug 2019 (actual)
- First posted
- 20 Dec 2013 (estimated)
- Results
- Posted 20 Nov 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Allopurinol | Experimental | Drug: 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 |
| Placebo | Placebo comparator | Drug: PlaceboOral placebo tablets |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (19 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Allopurinol | Drug | Allopurinol |
| PlaceboInactive oral tablets identical in appearance to allopurinol tablets. | Drug | Placebo |
Primary outcome
iGFR at the End of the Wash-out Period
Time frame: End of the 2-month wash-out period following the 3-year treatment period (week 164)
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.
8 secondary outcomes
eGFR at 4 Months of Treatment
Time frame: 4 months after randomization (week 16)
iGFR the End of Treatment Period
Time frame: End of the 3-yr treatment period (week 156)
iGFR Time Trajectory
Time frame: Weeks 0, 80, 156, and 164 (from baseline to the end of washout period)
eGFR Time Trajectory
Time frame: 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)
Time frame: Up to the end of the 2-month wash-out period following the 3-year treatment period (Week 0 to Week 164)
AER at the End of the Wash-out Period
Time frame: End of the 2-month wash-out period following the 3-year treatment period (week 164)
AER at the End of the Treatment Period
Time frame: Last three months of treatment period (Weeks 142 and 156)
Fatal or Non-fatal Cardiovascular Events
Time frame: Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Dec 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 20332356Ficociello 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.
- Background: PubMed 19411615Hovind 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.
- Background: PubMed 20064950Jalal 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.
- Background: PubMed 23649945Maahs 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.
- Derived from this study: PubMed 39727210Ang 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.
- Derived from this study: PubMed 39423023Keum 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.
- Derived from this study: PubMed 32579810Doria 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.
- Study websiteLink provided by the sponsor.
Related trials for Diabetic Nephropathies
Not yet recruitingObservational study
Beta-2-Trace Protein in Diabetic Nephropathy
Diabetic Nephropathy Type 2, Type 2 Diabetes Mellitus
Active, not recruitingObservational study
Family Investigation of Nephropathy and Diabetes (F.I.N.D.)
Diabetic Nephropathy, Diabetes Mellitus
Active, not recruitingPhase 4
Pentoxifylline in Diabetic Kidney Disease
Diabetic Kidney Disease
Active, not recruitingPhase 2
A Study on the Safety and Clinical Efficacy of Guominkang in the Treatment of Diabetic Kidney Disease
Diabetic Kidney Disease (DKD), Type 2 Diabetes
Not yet recruitingObservational study
Relationship Between Insulin Dose and Complications in Type 1 Diabetes
Diabetes Mellitus, Type 1 Diabetes, Cardiovascular Diseases (CVD)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alessandro Doria, MD, PhD, MPH principal investigator
Joslin Diabetes Center
Michael Mauer, MD principal investigator
University of Minnesota
30 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Allopurinol in people with Diabetic Nephropathies and Coronary Artery Disease, run by Alessandro Doria at 30 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 30 sites in United States, Canada, Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Nov 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
iGFR at the End of the Wash-out Period (time frame: End of the 2-month wash-out period following the 3-year treatment period (week 164)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02017171, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Dec 2020.