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    Summary
    EudraCT Number:2022-002594-28
    Sponsor's Protocol Code Number:APHP200036
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2022-07-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2022-002594-28
    A.3Full title of the trial
    Graft Acute kidney injury: vitamin B3 to facilitate renal Recovery In the Early Life of a transplant
    Insuffisance Rénale Aigue du Transplant: vitamine B3 pour améliorer la reprise précoce de fonction du greffon rénal
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Graft Acute kidney injury: vitamin B3 to facilitate renal Recovery In the Early Life of a transplant
    Insuffisance Rénale Aigue du Transplant: vitamine B3 pour améliorer la reprise précoce de fonction du greffon rénal
    A.3.2Name or abbreviated title of the trial where available
    GABRIEL
    GABRIEL
    A.4.1Sponsor's protocol code numberAPHP200036
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorASSISTANCE PUBLIQUE-HOPITAUX DE PARIS (AP-HP)
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDGOS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE-HOPITAUX DE PARIS (AP-HP)
    B.5.2Functional name of contact pointPôle Promotion-DRCI
    B.5.3 Address:
    B.5.3.1Street AddressDRCI-Hôpital Saint Louis, 1 av. Claude Vellefau
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number+331 40 27 57 27
    B.5.5Fax number+33 1 44 84 17 01
    B.5.6E-mailcarla.vandenabele@aphp.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name NICOBION 500mg
    D.2.1.1.2Name of the Marketing Authorisation holderTEOFARMA S.R.L.
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNICOTAMIDE 500mg
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNicotinamide
    D.3.9.3Other descriptive nameNicotinamide
    D.3.9.4EV Substance CodeSUB09246MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with end-stage renal failure treated with extrarenal purification (hemodialysis using a catheter or a fistula, or peritoneal dialysis), registered on the national kidney donation waiting list and contacted by their monitoring center for a kidney transplant from a deceased donor
    Patients ayant une insuffisance rénale terminale traités par épuration extrarénale (hémodialyse à l'aide d'un cathéter ou d'une fistule, ou dialyse péritonéale), inscrits sur la liste d’attente nationale de dons de reins et contactés par leur centre de suivi pour une greffe rénale issue de donneur décédé
    E.1.1.1Medical condition in easily understood language
    Patients with end-stage renal failure treated with extrarenal purification registered on the national kidney donation waiting list
    Patients ayant une insuffisance rénale terminale traités par épuration extrarénale inscrits sur la liste d’attente nationale de dons de reins
    E.1.1.2Therapeutic area Body processes [G] - Chemical Phenomena [G02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10023438
    E.1.2Term Kidney transplant
    E.1.2System Organ Class 100000004865
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to assess the efficacy of 3 doses of NAM given orally at 1g/dose pre transplant and during the first 2 post-operative days of renal transplantation versus placebo, on the early graft function, assessed by CRR2.
    L’objectif principal est d’évaluer l'efficacité de 3 doses de nicotinamide (NAM) administrées par voie orale à 1g/dose avant la transplantation et pendant les 2 premiers jours post-opératoires de la transplantation rénale par rapport à un placebo, sur la fonction précoce du greffon, évaluée par CRR2.
    E.2.2Secondary objectives of the trial
    1.Verify the safety profile of NAM
    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. This time point is usually a nadir for graft function.
    4. Evaluate the effect of NAM on serum NAM levels
    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.
    1. Vérifier le profil de sécurité du NAM .
    2. Evaluer l'effet du NAM sur le taux de reprise retardée de fonction du greffon.
    3. Evaluer l'effet du NAM sur la fonction du greffon rénal 3 mois après la transplantation.
    4. Evaluer l'effet du NAM sur les taux sériques de NAM
    5. Evaluer l'effet de la NAM sur le taux de rejet prouvé par biopsie dans les trois mois suivant la transplantation.
    6. Précision de la mesure, et valeur prédictive positive du rapport quinolinate/ tryptophane urinaire mesuré tôt après la transplantation (à POD2) pour le CRR2, la RRF, et la fonction du greffon estimé par MDRD à 3 mois.
    7. Evaluer l'effet de la concentration sérique de NAM au départ sur le niveau de risque de retard de fonctionnement du greffon.
    8. Rapport coût-efficacité et coût utilité de la NAM après la transplantation
    9. Comparaison de différentes techniques de séparation (LC, HILIC, IC, EC) pour la quantification par spectrométrie de masse du Q/T urinaire et du NAM sérique.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age ≥ 18 years
    - ESRD with ongoing renal replacement therapy (hemodialysis using a catheter or a fistula, or peritoneal dialysis)
    - Allocated a renal allograft from a deceased donor of any origin (brain death, programed cardiac death / Maastricht 3)
    - Written informed consent of the recipient
    - Affiliation to French social security (“AME” excepted)
    -Âge ≥ 18 ans.
    -Patients ayant une insuffisance rénale terminale avec traitement de substitution rénale en cours (hémodialyse à l'aide d'un cathéter ou d'une fistule, ou dialyse péritonéale)
    -Attribution d'une allogreffe rénale provenant d'un donneur décédé de toute origine (mort cérébrale ou mort cardiaque programmée / Maastricht 3).
    -Affiliation à un régime de sécurité sociale française (hors AME)
    -Recueil du consentement éclairé écrit du receveur
    E.4Principal exclusion criteria
    - Pre-emptive kidneys transplantation (because the diagnosis of DGF is made difficult or inaccurate by the pre-existing residual renal function of native kidneys) and other transplantation;
    - Liver disease defined by the necessity for a specialized follow-up by a hepatologist or by elevated liver enzymes > 3N (ALAT, gamma GT) on the day of transplantation;
    - Pregnancy
    - Multiple organ transplantation.
    - Hypersensibility to nicotinamide or one of its excipients (lactose, povidone, corn starch, cellulose, magnesium stearate, hydromellose, macrogol 6000, tinanium dioxide)
    - Inclusion in another interventional study (RIPH 1)
    - Patient under legal protection measure (tutorship or curatorship) and patient deprived of freedom.
    -Transplantation rénale préemptive
    -Grossesse
    -Maladie hépatique définie par la nécessité d'un suivi spécialisé par un hépatologue ou par des enzymes hépatiques élevées > 3N (ALAT, gamma GT) le jour de la transplantation
    -Transplantation d'organes multiples
    -Hypersensibilité à la nicotinamide ou à l'un de ses excipients
    -Participation à une autre recherche interventionnelle RIPH 1
    -Patient sous protection juridique (tutelle, curatelle) ou privé de liberté
    E.5 End points
    E.5.1Primary end point(s)
    The creatinine decrease ratio calculated at POD2 (2nd post-operative day) according to the following formula:

    CRR2(%)=(([Cr1 -Cr2]x 100))/Cr1
    Cr1 and Cr2 correspond to morning serum creatinine on day 1 and day 2 post-operatively.
    Le ratio de diminution de la créatinine calculé à POD2 (2ème jour post- opératoire) selon la formule suivante:

    CRR2(%)=(([Cr1 -Cr2]x 100))/Cr1
    Cr1 et Cr2 correspondent à la créatinine sérique du matin au jour 1 et au jour 2 post-opératoire.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 2
    Jour 2
    E.5.2Secondary end point(s)
    1. a) 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;
    b) Proportion of patients with inadequately high tacrolimus trough levels (> 15 ng/mL) at POD2, and POD7.
    2. Rate of DGF (Delayed Graft Function), as defined by the need of at least one dialysis between engraftment and POD7.
    3. Correlation between CRR2 and
    a) eGFR 3 months after transplantation among patients with no renal event such as, rejection, pyelonephritis and obstruction.
    b) 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. Comparison of NAM concentration variation from baseline to POD2.

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

    8. 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. Reproductibility of the quantification of urinary quinolinate/tryptophan ratio and serum concentration of NAM, measured by mass spectrometry
    1. Vérifier le profil de sécurité du NAM (toxicité hépatique et dosages résiduels de tacrolimus pour détecter une interaction).
    2. Evaluer l'effet du NAM sur le taux de reprise retardée de fonction du greffon.
    3. Evaluer l'effet du NAM sur la fonction du greffon rénal 3 mois après la transplantation.
    4. Evaluer l'effet du NAM sur les taux sériques de NAM (différence entre POD2 et le taux basal).
    5. Evaluer l'effet de la NAM sur le taux de rejet prouvé par biopsie dans les trois mois suivant la transplantation.
    6. Précision de la mesure, et valeur prédictive positive du rapport quinolinate/ tryptophane urinaire mesuré tôt après la transplantation (à POD2) pour le CRR2, la RRF, et la fonction du greffon estimé par MDRD à 3 mois.
    7. Evaluer l'effet de la concentration sérique de NAM au départ sur le niveau de risque de retard de fonctionnement du greffon.
    8. Rapport coût-efficacité et coût utilité de la NAM après la transplantation
    9. Comparaison de différentes techniques de séparation (LC, HILIC, IC, EC) pour la quantification par spectrométrie de masse du Q/T urinaire et du NAM sérique.

    Critères d’évaluation:
    1. a) Proportion de patients avec au moins un épisode d'élévation ALAT (alanine aminotransferase) supérieure à deux fois la norme haute du laboratoire entre V0 and POD7 (une toxicité hépatique légère et réversible a été décrite avec de fortes doses de NAM);
    b) Proportion de patients avec une résiduelle élevée de tacrolimus (> 15 ng/mL) à POD2, ou POD7.
    2. Taux de reprise retardée de fonction du greffon : au moins une dialyse après transplantation effectuée entre la greffe et le POD7.

    3. Corrélation entre CRR2 et :
    o le DFGe, 3 mois après la transplantation chez les patients sans événement rénal tel que rejet, pyélonéphrite et obstruction.
    o Rapport quinolinate/tryptophane urinaire mesuré par spectrométrie de masse 3 mois après la transplantation chez les patients sans événement rénal.
    4. Comparaison de la variation de la concentration de NAM entre les 2 groupes randomisés, mesurée au départ et au POD2.
    5. Proportion de patients présentant au moins un épisode de rejet prouvé par biopsie selon les critères de classification de Banff 2017 dans les 3 mois suivant la transplantation.
    6. Rapport quinolinate/tryptophane urinaire mesuré par spectrométrie de masse à POD2 et à M3.

    7. Concentration sérique de NAM au départ (avant l'administration de NAM immédiatement avant la transplantation), mesurée par spectrométrie de masse.
    8. Rapport coût-efficacité de la NAM après la transplantation d'un rein provenant d'un donneur décédé. Il est mesuré par la différence des coûts liés à la durée de l'hospitalisation et au coût des soins de santé, divisée par la différence du taux d'événements rénaux à 3 mois (rejet, pyélonéphrite et obstruction).
    9. Reproductibilité de la quantification du rapport quinolinate/tryptophane urinaire et de la concentration sérique de NAM, mesurée par spectrométrie de masse.

    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 0 to Day 90
    Jour 0 à J90
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned11
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last Visit of the Last Subject
    Dernière Visite du dernier patient inclus
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 155
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 49
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state204
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-09-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-10-05
    P. End of Trial
    P.End of Trial StatusCompleted
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