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Graft Acute Kidney Injury: Vitamin B3 to Facilitate Renal Recovery In the Early Life of a Transplant (GABRIEL)

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ClinicalTrials.gov Identifier: NCT05513807
Recruitment Status : Not yet recruiting
First Posted : August 24, 2022
Last Update Posted : October 18, 2022
Sponsor:
Collaborators:
Institut National de la Santé Et de la Recherche Médicale, France
Centre National de la Recherche Scientifique, France
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Delayed Graft Function Drug: Nicotinamide treatment Drug: Placebo treatment Phase 3

Detailed Description:

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 :

  1. Verify the safety profile of NAM (liver toxicity and tacrolimus trough levels to detect an interaction)
  2. Evaluate the effect of NAM on the rate of delayed graft function defined conventionally as the need for dialysis before POD7.
  3. Evaluate the effect of NAM on renal graft function 3 months after transplantation.
  4. Evaluate the effect of NAM on serum NAM levels (difference between NAM at POD2 and NAM at baseline)
  5. Evaluate the effect of NAM on the biopsy-proven rejection rate within three months after transplantation.
  6. 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.
  7. Evaluate the effect of NAM serum concentration at baseline on the level of risk of DGF.
  8. Cost-effectiveness of NAM after transplantation of a kidney from a deceased donor.
  9. 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.

A quality of life questionnaire EQ5D will be completed by the patient at V0 after inclusion and before transplantation ; and others EQ5D questionnaires will be completed at POD7 and last study visit M3.

It is expected that this study will inform on the effect of NAM on early graft function, and help to define its potential place in the management of a subset if not all kidney transplant patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 204 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Graft Acute Kidney Injury: Vitamin B3 to Facilitate Renal Recovery In the Early Life of a Transplant - GABRIEL
Estimated Study Start Date : November 2022
Estimated Primary Completion Date : August 2023
Estimated Study Completion Date : November 2023


Arm Intervention/treatment
Experimental: Nicotinamide Drug: Nicotinamide treatment
3g Nicotinamide orally (1g immediately pre transplant, then 1g post-transplant in the recovery room and 1g 24 hours later)
Other Name: NICOBION

Placebo Comparator: Placebo Drug: Placebo treatment
3g Placebo orally (1g immediately pre transplant, then 1g post-transplant in the recovery room and 1g 24 hours later)




Primary Outcome Measures :
  1. 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. [ Time Frame: 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.


Secondary Outcome Measures :
  1. Verify the safety profile of NAM (liver toxicity and tacrolimus trough levels to detect an interaction) [ Time Frame: Post-Operative Day 7 ]
    Proportion of patients with at least one increase of ALAT concentrations > 2N between V0 and POD7 (mild and reversible liver toxicity has been described with high dose NAM treatment ; and proportion of patients with inadequately high tacrolimus trough levels (> 15 ng/mL) at POD2, and POD7.

  2. Evaluate the effect of NAM on the rate of delayed graft function defined conventionally as the need for dialysis before POD7 [ Time Frame: Post-Operative Day 7 ]
    Rate of DGF (Delayed Graft Function), as defined by the need of at least one dialysis between engraftment and POD7

  3. Evaluate the effect of NAM on renal graft function 3 months after transplantation [ Time Frame: 3 months after transplantation ]

    Correlation between CRR2 and :

    1. eGFR 3 months after transplantation among patients with no renal event such as, rejection, pyelonephritis and obstruction.
    2. Urinary quinolinate/tryptophan ratio measured by mass spectrometry at 3 months after transplantation among patients with no renal event such as, rejection, pyelonephritis and obstruction

  4. Evaluate the effect of NAM on serum NAM levels (difference between NAM at POD2 and NAM at baseline) [ Time Frame: Post-Operative Day 2 ]
    Comparison of NAM concentration variation from baseline to POD2.

  5. Evaluate the effect of NAM on the biopsy-proven rejection rate within three months after transplantation. [ Time Frame: 3 months after transplantation ]
    Proportion of patients with at least one episode of biopsy-proven rejection (T-cell or antibody mediated) as per the Banff's 2017 classification criteria (48) within 3 months after transplantation

  6. 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 [ Time Frame: Post-operative Day 2 ]
    Urinary quinolinate/tryptophan ratio measured by mass spectrometry at POD2 where we expect an increase in patients with DGF and also at M3, to determine the reversibility of the metabolic abnormalities.

  7. Evaluate the effect of NAM serum concentration at baseline on the level of risk of DGF [ Time Frame: 3 months after transplantation ]
    Serum concentration of NAM at baseline (before pre transplant NAM dose), measured by mass spectrometry

  8. Cost-effectiveness and cost utility of NAM after transplantation of a kidney from a deceased donor [ Time Frame: Baseline ]
    Incremental cost effectiveness ratio of NAM compared to placebo, measured by the difference in costs of healthcare divided by the difference in rate of 3-month renal events defined as rejection, pyelonephritis and obstruction and incremental cost utility analysis using quality adjusted life years

  9. Comparison of different separation techniques (LC, HILIC, IC, EC) for MS quantification of uQ/T and serum NAM [ Time Frame: 3 months after transplantation ]
    Reproductibility of the quantification of urinary quinolinate/tryptophan ratio and serum concentration of NAM, measured by mass spectrometry



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • Preemptive transplant,
  • Pregnancy,
  • Liver disease defined by the necessity for a specialized follow-up by an hepatologist or by elevated liver enzymes > 3N (ALAT, 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05513807


Contacts
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Contact: Pierre GALICHON, Doctor 0142177201 pierre.galichon@aphp.fr
Contact: Alexandre HERTIG, Professor 0146251020 a.hertig@hopital-foch.com

Locations
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France
Department of Renal Transplantation - Hospital Pitié Salpétrière
Paris, France, 75013
Contact: Pierre GALICHON, Md, PhD    0142177229    pierre.galichon@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Institut National de la Santé Et de la Recherche Médicale, France
Centre National de la Recherche Scientifique, France
Investigators
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Principal Investigator: Pierre GALICHON, Doctor Assistance Publique - Hôpitaux de Paris
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT05513807    
Other Study ID Numbers: APHP200036
First Posted: August 24, 2022    Key Record Dates
Last Update Posted: October 18, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Kidney Transplantation
Delayed Graft Function
Niacinamide
Acute Kidney Injury
Acute Tubular Necrosis
creatinine reduction ratio
Nicotinamide Adenine Dinucleotide
Quinolinate
urinary quinolinate / tryptophane
Additional relevant MeSH terms:
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Acute Kidney Injury
Delayed Graft Function
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Pathologic Processes
Niacinamide
Niacin
Nicotinic Acids
Vitamin B Complex
Vitamins
Micronutrients
Physiological Effects of Drugs
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Vasodilator Agents