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Delayed Graft FunctionPhase 3GABRIELNCT05513807

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

A Phase 3 study testing Nicotinamide treatment in people with Delayed Graft Function, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Delayed Graft Function
What is being tested?
Nicotinamide treatment
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
204 participants
Where
1 siteFrance
Study dates
12 Jan 2023to 18 Jun 2024
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country.

France1 site

  • Department of Renal Transplantation - Hospital Pitié Salpétrière

    Paris, 75013

Other trials in France

About this study

Official title: Graft Acute Kidney Injury: Vitamin B3 to Facilitate Renal Recovery In the Early Life of a Transplant - GABRIEL

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.

Read more

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.

Read the 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.

Being tested
Nicotinamide treatment, Placebo treatment
Keywords
Kidney Transplantation, Delayed Graft Function, Niacinamide (NAM), Acute Kidney Injury, Acute Tubular Necrosis, creatinine reduction ratio, Nicotinamide Adenine Dinucleotide, Quinolinate, urinary quinolinate / tryptophane
Medical subject headings
Delayed Graft Function, Acute Kidney Injury, Kidney Cortex Necrosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nicotinamide treatmentDrug

    Also called NICOBION

    3g Nicotinamide orally (1g immediately pre transplant, then immediately 1g post-transplant after the recovery room and 1g 24 hours later)

  • Placebo treatmentDrug

    3g Placebo orally (1g immediately pre transplant, then immediately 1g post-transplant after the recovery room and 1g 24 hours later)

Study groups in NCT05513807
Study groupRoleWhat they receive
NicotinamideExperimentalNot described
Receives: Drug: Nicotinamide treatment
PlaceboPlacebo comparatorNot described
Receives: Drug: Placebo treatment

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    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.

    Measured: Post-Operative Day 2

Secondary outcomes (9)

  1. Verify the safety profile of NAM (liver toxicity and tacrolimus trough levels to detect an interaction)

    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 (> 20 ng/mL) at POD2, and POD7.

    Measured: Post-Operative Day 7

  2. Evaluate the effect of NAM on the rate of delayed graft function defined conventionally as the need for dialysis before POD7

    Rate of DGF (Delayed Graft Function), as defined by the need of at least one dialysis between engraftment and POD7

    Measured: Post-Operative Day 7

  3. Evaluate the effect of NAM on renal graft function 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

    Measured: 3 months after transplantation

  4. Evaluate the effect of NAM on serum NAM levels (difference between NAM at POD2 and NAM at baseline)

    Comparison of NAM concentration variation from baseline to POD2.

    Measured: Post-Operative Day 2

  5. Evaluate the effect of NAM on the biopsy-proven rejection rate within three 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

    Measured: 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

    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.

    Measured: Post-operative Day 2

  7. Evaluate the effect of NAM serum concentration at baseline on the level of risk of DGF

    Serum concentration of NAM at baseline (before pre transplant NAM dose), measured by mass spectrometry

    Measured: 3 months after transplantation

  8. Cost-effectiveness and cost utility of NAM after transplantation of a kidney from a deceased donor

    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

    Measured: Baseline

  9. Comparison of different separation techniques (LC, HILIC, IC, EC) for MS quantification of uQ/T and serum NAM

    Reproductibility of the quantification of urinary quinolinate/tryptophan ratio and serum concentration of NAM, measured by mass spectrometry

    Measured: Baseline, POD2 and 3 months after transplantation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Aug 2022
  2. Study start12 Jan 2023
  3. Primary completion17 Feb 2024
  4. Study completion18 Jun 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
204 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05513807
Sponsor's protocol ID
APHP200036
Acronym
GABRIEL
Status last verified
Jul 2024
First submitted
22 Aug 2022
Last updated
10 Jul 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Biological samples collection : During the study, serum at V0 and POD2, and urine at POD2 and M3 will be aliquoted into three, and stored at -80°C or -20°C. Aliquots will be sent in dry ice to the Biological Resource Center at Pitié-Salpêtrière Hospital (CRB-PSL). * 1 aliquot of each visit (baseline, POD2 and M3) will be send for analysis for the study * The last aliquots will be sent to UMRS1155-INSERM - Maladies Rénales Fréquentes et Rares : des Mécanismes Moléculaires à la Médecine Personnalisée (4 rue de la Chine 75020 Paris) where all study samples will be centrally stored at -80°C under the supervision of Pr. Pierre Galichon in a biological sample collection for further analysis which may be useful for investigation of renal graft functional recovery in light of advances in scientific knowledge, provided the participant is informed and does not oppose this, as stated in the information note/consent form. The total period of conservation couldn't exceed 5 years.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Nicotinamide treatment in people with Delayed Graft Function, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05513807.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2024.

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