NAD Augmentation to Treat Diabetic Kidney Disease: A Randomized Controlled Trial

NAD 增强治疗糖尿病肾病：一项随机对照试验

• 批准号: 10430705
• 负责人: SHALENDER BHASIN
• 金额: $ 89.97万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10430705
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adult; Aerobic; Affect; Aftercare; Age; Aging; Albumins; Albuminuria; Anabolism; Bioenergetics; Biological Assay; Biological Markers; Blood Pressure; Caloric Restriction; Cardiac Surgery procedures; Cardiovascular system; Chronic Kidney Failure; Computers; Consensus; Creatinine; Data; Deacetylase; Development; Diabetes Mellitus; Diabetic Nephropathy; Dose; Double-Blind Method; Drug Kinetics; Elderly; End stage renal failure; Ensure; Epigenetic Process; F2-Isoprostanes; Failure; Family; Formulation; Glomerular Filtration Rate; Glycosylated hemoglobin A; Human; IL6 gene; Impairment; Injury to Kidney; Insulin-Like Growth Factor I; Kidney; Kidney Failure; Link; Longevity; Measures; Mediating; Metabolic; Mitochondria; Modification; Mus; Muscle; Niacinamide; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patient Self-Report; Patients; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Physical Function; Placebo Control; Placebos; Plasma; Play; Pre-Clinical Model; Prevalence; Procedures; Process; Public Health; Randomized; Randomized Controlled Trials; Regimen; Residual state; Risk; Risk Reduction; Rodent Model; Role; Running; SIRT1 gene; Sample Size; Serum; Signal Transduction; Sirtuins; Stratification; Supplementation; Technology; Walking; Withholding Treatment; age related; attenuation; base; crystallinity; disability; effective therapy; fasting glucose; glycemic control; healthspan; improved; indexing; innovation; insulin sensitivity; mortality; mouse model; novel strategies; overexpression; performance based measurement; phase I trial; phase III trial; preclinical study; prevent; primary outcome; sample collection; secondary outcome; sensor; sex; urinary

The sirtuin family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases act as metabolic energy sensors, mediate some of the beneficial effects of caloric restriction on lifespan, and are important regulators of the aging process. NAD augmentation by administration of NAD precursors, such as nicotinamide mononucleotide (NMN), prevents or reverses a number of aging-related conditions, including diabetes and diabetic nephropathy, and improves aerobic performance. Reduced NAD levels in the kidney are closely linked to the pathogenic mechanisms of diabetic kidney disease (DKD) in mice as well as in humans, and NMN supplementation prevents the development of DKD and reduces mortality in a mouse model of DKD. These data support the hypothesis that NAD augmentation by NMN administration will reduce urinary albumin to creatinine ratio (UACR), a hallmark of DKD that is predictive of renal and cardiovascular outcomes. Despite the availability of a number of effective therapies for DKD, substantial residual risk to develop end-stage kidney disease still remains; thus, there is a need for new approaches that provide additional risk reduction by targeting different mechanisms. The sirtuin-NAD activators are attractive because: 1) they act by a mechanism distinct from that of currently approved drugs; and 2) they target aging mechanisms and have the potential to improve physical function and other age-related conditions. We propose to conduct a Phase 2a, randomized, placebo-controlled, double-blind, parallel group trial in older adults, 60 years or older, with type 2 diabetes mellitus, UACR > 100 mg/g creatinine, and estimated glomerular filtration rate (eGFR) > 30 mL/min/ /1.73m2. Participants will be randomized to receive either 1.0 g NMN or placebo twice daily for 6 months, stratified by sex and age (60-75, >75 years). The primary outcome is the change in UACR over the 6-month period. Secondary outcomes include change from baseline over 6-months in the following: the proportion of participants with 30% or greater reduction in UACR; change in serum creatinine and eGFR; glycemic control (hemoglobin A1c, fasting glucose); blood pressure; biomarkers of aging and kidney injury; self-reported (Late Life Function and Disability Index - Computer Adaptive Technology Version) and performance-based measures of physical function (aerobic capacity measured as VO2peak; 6-minute walking distance); and circulating levels of NMN and its metabolites, and NAD levels. We will also determine whether the increases in NAD levels in the PBMCs and improvements in UACR persist 3 months after treatment completion (legacy effect). The rigor and innovation in this trial is underscored by the use of a high-quality crystalline formulation of NMN; a dose-regimen informed by carefully performed pharmacokinetic studies; rigorous sample collection procedures to ensure preanalytical stability; and strong scientific premise founded on compelling preclinical and human studies of the important role of NAD depletion in DKD.

烟酰胺腺苷二核苷酸（NAD）依赖性脱乙酰基酶的Sirtuin家族充当代谢能传感器，介导了热量限制对寿命的某些有益作用，并且是衰老过程的重要调节剂。通过给药NAD前体（例如烟酰胺单核苷酸（NMN））的NAD增强可防止或逆转许多与衰老相关的疾病，包括糖尿病和糖尿病性肾病，并改善有氧性能。肾脏中的NAD水平降低与小鼠和人类中糖尿病肾脏疾病（DKD）的致病机制密切相关，而补充NMN可以防止DKD的发展并降低DKD小鼠模型中的死亡率。这些数据支持以下假设：NMN给药的NAD扩大将降低尿白蛋白与肌酐比率（UACR），DKD的标志可预测肾脏和心血管结局。尽管对DKD有许多有效的疗法，但仍存在末期肾脏疾病的实质性残留风险。因此，有必要通过针对不同的机制来降低风险的新方法。 Sirtuin-NAD激活剂很有吸引力，因为：1）它们采用与当前批准的药物不同的机制； 2）它们针对衰老机制，并有可能改善身体机能和其他与年龄相关的疾病。我们建议在老年人中进行2A期，随机，安慰剂对照，双盲，平行组试验，60岁或60岁，含2型糖尿病，UACR> 100 mg/g肌酐和估计的肾小球过滤率（EGFR）> 30 mL/min/lein///////1.73m2。参与者将被随机接受1.0 g NMN或每天两次安慰剂，共6个月，按性别和年龄分层（60-75，> 75岁）。主要结果是UACR在6个月期间的变化。次要结果包括以下6个月以上的基线变化：UACR降低30％或更高的参与者比例；更改血清肌酐和EGFR；血糖控制（血红蛋白A1c，禁食葡萄糖）；血压;衰老和肾脏损伤的生物标志物；自我报告（晚期生活功能和残疾指数 - 计算机自适应技术版本）和基于绩效的身体功能措施（有氧能力以VO2PEAK测量；步行距离为6分钟）； NMN及其代谢产物的循环水平以及NAD水平。我们还将确定PBMCS中NAD水平的升高以及治疗完成后3个月的UACR持续性（遗产效应）的提高。该试验中的严格和创新是通过使用NMN的高质量晶体配方强调的。通过精心进行的药代动力学研究告知的剂量调节；严格的样品收集程序，以确保放分析稳定性；以及强大的科学前提是基于令人信服的临床前和人类研究，该研究是NAD耗竭在DKD中的重要作用。