Graft Acute Kidney Injury: Vitamin B3 to Facilitate Renal Recovery In the Early Life of a Transplant - GABRIEL
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 204
- 试验地点
- 1
- 主要终点
- Efficacy of 3 doses of NAM given orally at 1g/dose immediately pre transplant and during the first 2 post-operative days of renal transplantation versus placebo, on the early graft function, assessed by CRR2.
研究概览
简要总结
Delayed graft function occurs in more than 20% of kidney transplantations. It is an episode of post-ischemic acute kidney injury with long-term consequences on the allograft's function. Based on preclinical data and on a stage 1 clinical trial, the hypothesize is that an acquired defect in NAD+ biosynthesis is instrumental in delayed graft function and that a treatment with high doses of vitamin B3 (nicotinamide) will improve the early renal graft function.
Thus, it is planned to recruit 204 kidney allograft recipients immediately before transplantation and randomize them to either placebo or nicotinamide treatment for 3 administrations before transplantation, immediately after it and on the next day.
The efficacy of nicotinamide to foster early graft function will be evaluated by comparing the creatinine reduction ratio between the placebo and the nicotinamide treated groups.
Serum will be collected before and 2 days after transplantation and urine 2 days and 3 months after transplantation to study the relationship between biological markers of NAD+ biosynthesis and nicotinamide's effect on early kidney graft function.
详细描述
Delayed graft function (DGF) is a frequent event in kidney transplantation (nationwide, 20.9% if all kinds of donors are included), and is prejudicial to graft survival. DGF is mostly due to acute tubular necrosis (ATN), induced by different cycles of renal ischemia (cold and warm). Until now, ATN has no specific treatment. Nicotinamide (NAM), also known as vitamin PP or as a vitamin B3 analog has recently emerged as a major therapeutic option to prevent ATN and accelerate its recovery. NAM actually allows maintaining mitochondrial function in the context of renal ischemia. In humans, NAM given orally (1 and 3g/day for 3 days) was shown to be effective in a phase I study and was associated with a 35% decreased incidence of AKI in 41 high-risk cardiac surgery patients. It has a well-known and highly favorable safety profile.
The GABRIEL study aims at testing its beneficial properties in the specific context of DGF in phase III study. The early kidney allograft function will be assessed on the creatinine reduction ratio between days 1 and 2 (CRR2, calculated by the following formula: CRR2 (%) = ([Cr1-Cr2]×100)/Cr1, where Cr1 and Cr2 are the morning serum creatinine on post-operative day 1 and day 2 respectively.
The objectives are also to :
- Verify the safety profile of NAM (liver toxicity and tacrolimus trough levels to detect an interaction)
- Evaluate the effect of NAM on the rate of delayed graft function defined conventionally as the need for dialysis before POD7.
- Evaluate the effect of NAM on renal graft function 3 months after transplantation.
- Evaluate the effect of NAM on serum NAM levels (difference between NAM at POD2 and NAM at baseline)
- Evaluate the effect of NAM on the biopsy-proven rejection rate within three months after transplantation.
- Measurement accuracy, and positive predictive value of the urinary quinolinate / tryptophane ratio measured early after transplantation (at POD2) for CRR2, DGF, and graft function estimated by MDRD at 3 months.
- Evaluate the effect of NAM serum concentration at baseline on the level of risk of DGF.
- Cost-effectiveness of NAM after transplantation of a kidney from a deceased donor.
- Comparison of different separation techniques (LC, HILIC, IC, EC) for MS quantification of uQ/T and serum NAM.
Patients called for transplantation will be included if they meet the required criteria. After inclusion and according to randomization, the patient will receive the first dose of treatment (1g NAM or placebo, V0) immediately before surgery, at the time of induction of immunosuppression. The second dose will be given to the patient immediately after recovery room (POD1), and the third dose 24 hours thereafter (POD2). NAM administrations will be no less than 8 and no more than 26 hours apart. The biological samples and anamnestic items will be collected between 6 and 10 AM on the prespecified visits.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years,
- •Patients in end stage renal disease (ESRD) requiring dialysis (hemodialysis or peritoneal dialysis),
- •Kidney transplant with deceased donor (brain death or cardiac death Maastricht 3),
- •Affiliation to French social security ("AME" excepted),
- •Written informed consent
排除标准
- •Preemptive transplant,
- •Pregnancy,
- •Liver disease defined by the necessity for a specialized follow-up by an hepatologist (with liver biological results disturbed) or by elevated liver enzymes > 3N (ALAT and/or gammaGT) on the day of transplantation
- •Transplantation of multiple organs,
- •Hypersensitivity to nicotinamide or one of excipients,
- •Participation to another interventional study (RIPH1),
- •Patient under legal protection measure (tutorship or curatorship) and patient deprived of freedom.
研究组 & 干预措施
Nicotinamide
干预措施: Nicotinamide treatment (Drug)
Placebo
干预措施: Placebo treatment (Drug)
结局指标
主要结局
Efficacy of 3 doses of NAM given orally at 1g/dose immediately pre transplant and during the first 2 post-operative days of renal transplantation versus placebo, on the early graft function, assessed by CRR2.
时间窗: Post-Operative Day 2
The primary endpoint is based on creatinine reduction ratio between days 1 and 2 (CRR2, calculated by the following formula: CRR2 (%) = (\[Cr1-Cr2\]×100)/Cr1, where Cr1 and Cr2 are the morning serum creatinine on post-operative day 1 and day 2 respectively.
次要结局
- Evaluate the effect of NAM on renal graft function 3 months after transplantation(3 months after transplantation)
- Evaluate the effect of NAM on serum NAM levels (difference between NAM at POD2 and NAM at baseline)(Post-Operative Day 2)
- Evaluate the effect of NAM on the biopsy-proven rejection rate within three months after transplantation.(3 months after transplantation)
- Measurement accuracy, and positive predictive value of the urinary quinolinate / tryptophane ratio measured early after transplantation (at POD2) for CRR2, DGF, and graft function estimated by MDRD at 3 months(Post-operative Day 2)
- Comparison of different separation techniques (LC, HILIC, IC, EC) for MS quantification of uQ/T and serum NAM(Baseline, POD2 and 3 months after transplantation)
- Cost-effectiveness and cost utility of NAM after transplantation of a kidney from a deceased donor(Baseline)
- Evaluate the effect of NAM on the rate of delayed graft function defined conventionally as the need for dialysis before POD7(Post-Operative Day 7)
- Verify the safety profile of NAM (liver toxicity and tacrolimus trough levels to detect an interaction)(Post-Operative Day 7)
- Evaluate the effect of NAM serum concentration at baseline on the level of risk of DGF(3 months after transplantation)