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Trial record 2 of 3 for:    PERL and type 1

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Joslin Diabetes Center
Sponsor:
Collaborators:
Juvenile Diabetes Research Foundation
Joslin Diabetes Center
University of Minnesota - Clinical and Translational Science Institute
University of Colorado, Denver
University of Michigan
University of Toronto
Feinberg School of Medicine, Northwestern University
Albert Einstein College of Medicine of Yeshiva University
Steno Diabetes Center
Information provided by (Responsible Party):
Alessandro Doria, Joslin Diabetes Center
ClinicalTrials.gov Identifier:
NCT02017171
First received: December 16, 2013
Last updated: July 19, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Diabetic Nephropathies
Coronary Artery Disease
Drug: Allopurinol
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Official Title: PERL: A Multicenter Clinical Trial of Allopurinol to Prevent GFR Loss in T1D

Resource links provided by NLM:


Further study details as provided by Joslin Diabetes Center:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • eGFR at 4 months of treatment [ Time Frame: 4 months after randomization ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 480
Study Start Date: February 2014
Estimated Study Completion Date: June 2019
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Drug: Allopurinol
Placebo Comparator: Placebo
Oral placebo tablets
Drug: Placebo
Inactive oral tablets identical in appearance to allopurinol tablets.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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, with the upper limit being decreased by 1 ml/min/1.73 m2 for each year over age 60
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02017171

Contacts
Contact: Debbie Conboy, RN, BSN, CDE 617-309-4343 debra.conboy@joslin.harvard.edu
Contact: Ben Flagg 617-309-4506 benjamin.flagg@joslin.harvard.edu

Locations
United States, Colorado
Barbara Davis Center / University of Colorado Denver Recruiting
Aurora, Colorado, United States, 80045
Contact: Victoria Gage, RN, BSN, CDE    303-724-8369    Victoria.Gage@ucdenver.edu   
Principal Investigator: David Maahs, MD, PhD         
Kaiser Permanente Colorado Institute of Health Research Recruiting
Denver, Colorado, United States, 80231
Contact: Jennifer McCance    303-764-8532    jennifer.a.mccance@kp.org   
Principal Investigator: Emily Schroeder, MD, PhD         
United States, Illinois
Northwestern University Feinberg School of Medicine Recruiting
Chicago, Illinois, United States, 60611
Contact: Elaine Massaro    312-926-9628    e-massaro@northwestern.edu   
Contact: Daphne Adelman    312-908-9002    d-adelman@northwestern.edu   
Principal Investigator: Mark Molitch, MD         
United States, Massachusetts
Joslin Diabetes Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Ben Flagg    617-309-4506    benjamin.flagg@joslin.harvard.edu   
Principal Investigator: Allison Goldfine, MD         
Principal Investigator: Alessandro Doria, MD, PhD, MPH         
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact    617-726-1847    lbissett@partners.org   
Sub-Investigator: Enrico Cagliero, MD         
University of Massachusetts Memorial Health Care Recruiting
Worcester, Massachusetts, United States, 01655
Contact: Celia Hartigan, RN, MPH    508-856-3676    celia.hartigan@umassmed.edu   
Principal Investigator: Michael Thompson, MD         
United States, Michigan
Brehm Center for Diabetes Research / University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48105
Contact: Ginny Leone, MA    734-936-8656    vleone@med.umich.edu   
Contact: Cynthia Plunkett, RNC, CCRC       cplunket@med.umich.edu   
Principal Investigator: Rodica Pop-Busui, MD, PhD         
United States, Minnesota
Essentia Health Not yet recruiting
Duluth, Minnesota, United States, 55805
Contact: Nichole Haithcock, BA, RN, CCRC    218-786-1220    nhaithcock@eirh.org   
Principal Investigator: Michael Slag, MD         
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Lauri Schafer    612-301-2103    PERL-T1D@umn.edu   
Principal Investigator: Maria Luiza Caramori, MD, PhD         
United States, Missouri
Washington University Not yet recruiting
St. Louis, Missouri, United States, 63110
Contact: Carol Recklein, RN, MHS, CDE    314-362-8606    crecklein@dom.wustl.edu   
Principal Investigator: Janet McGill, MD         
United States, New York
Albert Einstein College of Medicine / Montefiore Medical Center Recruiting
Bronx, New York, United States, 10461
Contact: Danielle Powell, MPH    718-405-8271    PERL@einstein.yu.edu   
Principal Investigator: Jill Crandall, MD         
Jacobi Medical Center Recruiting
Bronx, New York, United States, 10461
Contact: Jeanne Russo    718-918-6039    jeanne.russo@nbhn.net   
Principal Investigator: Ulrich Schubart, MD         
Winthrop-University Hospital Recruiting
Mineola, New York, United States, 11501
Contact: Marilyn Richardson    516-663-9582    clinicaltrials@winthrop.org   
Principal Investigator: Micahel Radin, MD         
Beth Israel Medical Center, Friedman Diabetes Institute Recruiting
New York, New York, United States, 10003
Contact: Kamala Mantha-Thaler    212-420-3569    KMantha@chpnet.org   
Principal Investigator: Augustin Busta, MD         
ICAHN School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Joanna Lis    212-824-8562    joanna.lis@mssm.edu   
Principal Investigator: Carol Levy, MD         
Weill Cornell Medical Center Recruiting
New York, New York, United States, 10065
Contact: Karen S. Hyams, RD, CDE    212-746-6922    khyams@med.cornell.edu   
Principal Investigator: Naina Sinha Gregory, MD         
SUNY Upstate Medical University Recruiting
Syracuse, New York, United States, 13210
Contact: Suzan Bzdick, RN, CCRC    315-464-9006    bzdicks@upstate.edu   
Contact: Jane Bulger, MS, CCRC    (315) 464-9008    bulgerj@upstate.edu   
Principal Investigator: Ruth Weinstock, MD         
United States, Wisconsin
University of Wisconsin - Madison Not yet recruiting
Madison, Wisconsin, United States, 53717-2656
Contact: Constance B. Trantow, MS, CCRC    608-263-4797    cbt@clinicaltrials.wisc.edu   
Canada, Ontario
Mount Sinai Hospital / University of Toronto Recruiting
Toronto, Ontario, Canada, M5G 2C4
Contact: Andrej Orszag    416-586-4800 ext 7625    PERLstudy@lunenfeld.ca   
Contact: Holly Tschirhart    (416) 586-4800 ext 4436    tschirhart@lunenfeld.ca   
Principal Investigator: Bruce Perkins, MD, MPH         
Toronto General Hospital Recruiting
Toronto, Ontario, Canada, M5G 2N2
Contact: Andrej Orszag    416-586-4800 ext 7625    andrej.orszag@uhn.ca   
Contact    416-586-4800 ext 7187      
Principal Investigator: David Cherney, MD         
Denmark
Steno Diabetes Center Recruiting
Gentofte, Denmark, DK-2820
Contact: Sascha Pilemann-Lyberg, MD    +45 30792090    sply@steno.dk   
Contact: Frederik Persson, MD    +45 3968 0800    frip@steno.dk   
Principal Investigator: Peter Rossing, MD         
Sponsors and Collaborators
Alessandro Doria
Juvenile Diabetes Research Foundation
Joslin Diabetes Center
University of Minnesota - Clinical and Translational Science Institute
University of Colorado, Denver
University of Michigan
University of Toronto
Feinberg School of Medicine, Northwestern University
Albert Einstein College of Medicine of Yeshiva University
Steno Diabetes Center
Investigators
Principal Investigator: Alessandro Doria, MD, PhD, MPH Joslin Diabetes Center
Principal Investigator: Michael Mauer, MD University of Minnesota - Clinical and Translational Science Institute
  More Information

Additional Information:
Publications:
Responsible Party: Alessandro Doria, Investigator, Joslin Diabetes Center
ClinicalTrials.gov Identifier: NCT02017171     History of Changes
Other Study ID Numbers: DK101108, UC4DK101108-01
Study First Received: December 16, 2013
Last Updated: July 19, 2014
Health Authority: United States: Food and Drug Administration
Canada: Canadian Institutes of Health Research
Denmark: Danish Medicines Agency

Keywords provided by Joslin Diabetes Center:
Kidney Diseases
Diabetic Nephropathies
Diabetes Mellitus
Diabetes Complications
Uric acid
Allopurinol
Glomerular filtration rate
Coronary artery disease

Additional relevant MeSH terms:
Coronary Artery Disease
Coronary Disease
Diabetic Nephropathies
Kidney Diseases
Myocardial Ischemia
Arterial Occlusive Diseases
Arteriosclerosis
Cardiovascular Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Heart Diseases
Urologic Diseases
Vascular Diseases
Allopurinol
Antimetabolites
Antioxidants
Antirheumatic Agents
Enzyme Inhibitors
Free Radical Scavengers
Gout Suppressants
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014