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: 10668324
• 负责人: SHALENDER BHASIN
• 金额: $ 86.81万
• 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/10668324
• 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; disability; effective therapy; efficacy evaluation; 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.

烟酰胺腺嘌呤二核苷酸 (NAD) 依赖性脱乙酰酶的沉默调节蛋白家族充当代谢能量传感器，介导热量限制对寿命的一些有益影响，并且是衰老过程的重要调节因子。通过施用烟酰胺单核苷酸 (NMN) 等 NAD 前体来增强 NAD，可以预防或逆转许多与衰老相关的疾病，包括糖尿病和糖尿病肾病，并提高有氧运动能力。肾脏中 NAD 水平降低与小鼠和人类糖尿病肾病 (DKD) 的发病机制密切相关，补充 NMN 可以预防 DKD 的发展并降低 DKD 小鼠模型的死亡率。这些数据支持这样的假设：通过 NMN 给药增加 NAD 将降低尿白蛋白与肌酐比值 (UACR)，这是 DKD 的一个标志，可预测肾脏和心血管结局。尽管有许多有效的 DKD 治疗方法，但发展为终末期肾病的巨大残余风险仍然存在；因此，需要采取新的办法，通过针对不同的机制来进一步减少风险。 Sirtuin-NAD 激活剂之所以有吸引力，是因为：1）它们的作用机制与目前批准的药物不同； 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状况。我们建议对 60 岁或以上、患有 2 型糖尿病、UACR > 100 mg/g 肌酐和估计肾小球滤过率的老年人进行 2a 期、随机、安慰剂对照、双盲、平行组试验（ eGFR) > 30 mL/min/ /1.73m2。参与者将被随机分配接受 1.0 g NMN 或安慰剂，每天两次，持续 6 个月，按性别和年龄（60-75，>75 岁）分层。主要结果是 6 个月期间 UACR 的变化。次要结局包括 6 个月内相对于基线的以下变化： UACR 降低 30% 或以上的参与者比例；血清肌酐和 eGFR 的变化；血糖控制（血红蛋白 A1c、空腹血糖）；血压;衰老和肾损伤的生物标志物；自我报告（晚期生命功能和残疾指数 - 计算机自适应技术版本）和基于表现的身体功能测量（以 VO2peak 测量的有氧能力；6 分钟步行距离）； NMN 及其代谢物的循环水平以及 NAD 水平。我们还将确定治疗完成后 3 个月内 PBMC 中 NAD 水平的增加和 UACR 的改善是否持续（遗留效应）。本次试验的严谨性和创新性通过使用高质量的 NMN 结晶配方而得以体现；通过仔细进行的药代动力学研究确定的剂量方案；严格的样品采集程序，确保分析前的稳定性；强有力的科学前提建立在令人信服的临床前和人体研究的基础上，即 NAD 消耗在 DKD 中的重要作用。