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PERL: A multi-center clinical trial of allopurinol to prevent GFR loss in T1D

PERL：别嘌呤醇预防 T1D 患者 GFR 损失的多中心临床试验

基本信息

批准号：
9738022
负责人：
Alessandro Doria
金额：
$ 25万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9738022
关键词：
Adherence Alberta province Albumins Allopurinol Canada Chronic Kidney Failure Clinical Clinical Trials Cohort Studies Colorado Complement Complications of Diabetes Mellitus Conduct Clinical Trials Data Data Analyses Denmark Diabetes Mellitus Diabetic Nephropathy Double-Blind Method Early Intervention End stage renal failure Excretory function Financial cost Funding Glomerular Filtration Rate Goals Grant Hemodialysis Human Incidence Increased Uric Acid Level Insulin-Dependent Diabetes Mellitus Intervention Iohexol Kidney Kidney Transplantation Manuscripts Measures Medicine Michigan Minnesota Morbidity - disease rate Multi-Institutional Clinical Trial Names National Institute of Diabetes and Digestive and Kidney Diseases Participant Patients Persons Pharmaceutical Preparations Placebos Plasma Prevention Protocols documentation Public Health Randomized Recording of previous events Renal function Renin-Angiotensin System Research Personnel Residual state Risk Serum Site Societies Testing United States National Institutes of Health Universities Urate Uric Acid Visit Washington Writing blood pressure regulation college cost functional decline high risk loss of function mortality novel therapeutics outreach participant retention prevent primary outcome recruit treatment duration urinary

项目摘要

SUMMARY Despite improvements in the past 20 years in glycemia and blood pressure (BP) control, and the introduction of “renoprotective” drugs such as renin-angiotensin system blockers (RASB), the overall incidence of end- stage renal disease (ESRD) in type 1 diabetes (T1D) is not declining. Novel therapies to complement these interventions are urgently needed. Convincing evidence from multiple cohort studies indicates that higher serum uric acid levels (SUA) predict a substantial increase in the risk of chronic kidney disease (CKD) and accelerated glomerular filtration rate (GFR) loss among persons with T1D. To study whether SUA lowering can reduce GFR loss in T1D, we established a unique consortium of investigators from 16 academic centers in the US, Canada, and Denmark. Led by co-PIs, Drs. Doria from the Joslin Kidney Study, and Mauer, formerly PI of the Renin Angiotensin System Study (RASS) clinical trial, the Consortium has been named PERL (Preventing Early Renal Function Loss in Diabetes) to emphasize its focus on intervening relatively early in the course of CKD in T1D, when renal damage is more likely to be arrestable or reversible and interventions are thus more likely to be effective. With the support of NIH grants R03 DK094484, R34 DK097808, UC4 DK101108, and a JDRF grant, the PERL Consortium is currently conducting a multi-center, double-blind, clinical trial in which 530 patients with T1D of ≥8 years of duration, mild to moderate decrease in GFR, moderately increased SUA (≥4.5 mg/dl), and a history of either elevated urinary excretion of albumin or accelerated GFR decline were randomized to receive the urate-lowering drug allopurinol (200 to 400 mg per day depending on renal function) or placebo for three years. The primary outcome is the GFR (as measured by iohexol plasma disappearance) at the end of a 2-month wash-out period after the 3-year intervention. PERL successfully completed randomization of the 530 participants (10% more than the initial recruitment goal) in May 2016, with the last participant visit planned for June 2019. PERL participant retention and adherence have been excellent. The purpose of this application is to renew NIH grant UC4 DK101108, which currently supports all aspects of the trial and is projected to cover costs until October 2017. Funding after that date will allow completion of the 3-year treatment period for all PERL subjects, this being necessary for adequate power to answer the trial's questions as delineated in the protocol approved by NIDDK and the DSMB. This grant renewal will also provide support for data analysis and manuscript writing upon trial completion. If PERL demonstrates that allopurinol can halt or slow the rate of GFR decline in persons with T1D, it would provide a simple, safe, and inexpensive intervention to prevent or delay ESRD in T1D that can be applied at the earliest clinically detectable stages of renal functional decline. It is difficult to overstate how significant this would be, both from the perspective of public health and that of persons with diabetes, adding an estimated 8-10 years free of hemodialysis or kidney transplant to their lives.

摘要尽管过去20年在血糖和血压(BP)控制方面有所改善，而且引入了在肾素-血管紧张素系统阻滞剂(RASB)等肾脏保护药物中，终末期肾病的总发生率 1型糖尿病(T1D)的肾病分期(ESRD)没有下降。补充这些的新疗法迫切需要干预。来自多个队列研究的令人信服的证据表明，血清尿酸水平(SUA)预测慢性肾脏疾病(CKD)风险的大幅增加 T1D患者肾小球滤过率(GFR)加速丢失。研究血尿酸是否降低为了减少T1D的GFR损失，我们成立了一个由来自16个学术中心的研究人员组成的独特联盟在美国、加拿大和丹麦。由共同PI、Joslin Kidney研究的Doria博士和Mauer领导，该联盟以前是肾素血管紧张素系统研究(RASS)临床试验的PI，现已被命名为 Perl(预防糖尿病早期肾功能丧失)强调相对干预的重点在T1D的CKD病程早期，肾损害更有可能是可阻止或可逆的，因此，干预更有可能是有效的。在NIH拨款的支持下R03 DK094484，R34 DK097808、UC4 DK101108和JDRF赠款，Perl财团目前正在进行一项多中心，双盲临床试验，其中530名T1D患者的≥疗程为8年，轻至中度肾小球滤过率降低，血尿酸中度升高(≥4.5mgdl)，并有尿量升高的病史白蛋白排泄或肾小球滤过率加速下降随机接受降尿酸药物治疗别嘌醇(根据肾功能，每天200至400毫克)或安慰剂，为期三年。初级阶段结果是在2个月的洗脱期结束时的肾小球滤过率(用碘海醇血浆消失率来衡量)。经过3年的干预。Perl成功地完成了对530名参与者的随机化(多10% 2016年5月)，最后一次参与者访问计划于2019年6月进行。Perl 参与者的留存率和忠诚度一直很高。此申请的目的是续订NIH 授予UC4 DK101108，目前支持试验的所有方面，预计将覆盖成本至2017年10月。该日期之后的资助将允许完成所有Perl的3年治疗期受试者，这对于有足够的权力回答议定书中描述的审判问题是必要的由NIDDK和dsmb批准。这笔赠款续期还将为数据分析和审判结束后的手稿写作。如果Perl证明别嘌醇可以阻止或减缓在T1D患者中，GFR下降，它将提供一种简单、安全和廉价的干预措施，以防止或在T1D中延迟ESRD，可在临床上可检测到的肾功能下降的最早阶段应用。它无论从公共卫生的角度还是从糖尿病患者，估计使他们的寿命增加8-10年，不进行血液透析或肾移植。