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

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ClinicalTrials.gov Identifier: NCT02017171
Recruitment Status : Active, not recruiting
First Posted : December 20, 2013
Last Update Posted : August 6, 2019
Sponsor:
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
Feinberg School of Medicine, 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
Information provided by (Responsible Party):
Alessandro Doria, Joslin Diabetes Center

Tracking Information
First Submitted Date  ICMJE December 16, 2013
First Posted Date  ICMJE December 20, 2013
Last Update Posted Date August 6, 2019
Actual Study Start Date  ICMJE February 2014
Actual Primary Completion Date June 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 16, 2013)
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 ]
Glomerular filtration rate (GFR) at the end of the 2-month wash-out period following the 3-year treatment period, measured by the plasma clearance of non-radioactive iohexol (iGFR) and adjusted for the iGFR at baseline.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02017171 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 19, 2014)
  • eGFR at 4 months of treatment [ Time Frame: 4 months after randomization ]
    Glomerular filtration rate (GFR) at 4 months after randomization, estimated from serum creatinine and cystatin C and adjusted for the eGFR at baseline.
  • iGFR the end of treatment period [ Time Frame: End of the 3-yr treatment period (before the washout period) ]
    Glomerular filtration rate (GFR) at the end of the 3-year treatment period, measured by the plasma clearance of non-radioactive iohexol (iGFR) and adjusted for the iGFR at baseline.
  • iGFR time trajectory [ Time Frame: Up to the end of the 2-month wash-out period following the 3-year treatment period ]
    Glomerular filtration rate time trajectory estimated from periodical iohexol clearance GFR measurements
  • eGFR time trajectory [ Time Frame: Up to the end of the 2-month wash-out period following the 3-year treatment period ]
    Glomerular filtration rate time trajectory estimated from quarterly serum creatinine and cystatin C measurements (eGFR).
  • Time to 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 ]
    Time to serum creatinine doubling or end stage renal disease (ESRD)
  • 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 ]
    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.
  • AER at the end of the treatment period [ Time Frame: Last three months of 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.
  • Time to 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 ]
    Time to fatal or non-fatal 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 16, 2013)
  • iGFR at 4 months of treatment [ Time Frame: 4 months after randomization ]
    Glomerular filtration rate (GFR) at 4 months after randomization, measured by the plasma clearance of non-radioactive iohexol (iGFR) and adjusted for the iGFR at baseline.
  • iGFR the end of treatment period [ Time Frame: End of the 3-yr treatment period (before the washout period) ]
    Glomerular filtration rate (GFR) at the end of the 3-year treatment period, measured by the plasma clearance of non-radioactive iohexol (iGFR) and adjusted for the iGFR at baseline.
  • iGFR time trajectory [ Time Frame: Up to the end of the 2-month wash-out period following the 3-year treatment period ]
    Glomerular filtration rate time trajectory estimated from periodical iohexol clearance GFR measurements
  • eGFR time trajectory [ Time Frame: Up to the end of the 2-month wash-out period following the 3-year treatment period ]
    Glomerular filtration rate time trajectory estimated from quarterly serum creatinine and cystatin C measurements (eGFR).
  • Time to 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 ]
    Time to serum creatinine doubling or end stage renal disease (ESRD)
  • 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 ]
    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.
  • AER at the end of the treatment period [ Time Frame: Last three months of 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.
  • Time to 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 ]
    Time to fatal or non-fatal 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Multicenter Clinical Trial of Allopurinol to Prevent Kidney Function Loss in Type 1 Diabetes
Official Title  ICMJE PERL: A Multicenter Clinical Trial of Allopurinol to Prevent GFR Loss in T1D
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • Diabetic Nephropathies
  • Coronary Artery Disease
Intervention  ICMJE
  • Drug: Allopurinol
  • Drug: Placebo
    Inactive oral tablets identical in appearance to allopurinol tablets.
Study Arms  ICMJE
  • Experimental: Allopurinol
    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
    Intervention: Drug: Allopurinol
  • Placebo Comparator: Placebo
    Oral placebo tablets
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 6, 2017)
530
Original Estimated Enrollment  ICMJE
 (submitted: December 16, 2013)
480
Estimated Study Completion Date  ICMJE December 31, 2019
Actual Primary Completion Date June 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Denmark,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02017171
Other Study ID Numbers  ICMJE DK101108
UC4DK101108-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Alessandro Doria, Joslin Diabetes Center
Study Sponsor  ICMJE Alessandro Doria
Collaborators  ICMJE
  • 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
  • Feinberg School of Medicine, 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
Investigators  ICMJE
Principal Investigator: Alessandro Doria, MD, PhD, MPH Joslin Diabetes Center
Principal Investigator: Michael Mauer, MD University of Minnesota
PRS Account Joslin Diabetes Center
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP