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Evaluation of Anti-rejection Drug, Tacrolimus, in African-Americans With Kidney Transplant

10 décembre 2020 mis à jour par: Ahmed Osama Gaber, MD, The Methodist Hospital Research Institute

Evaluation of Early Dose Escalation Using Extended-Release Tacrolimus (Envarsus XR®) to Reduce Acute Rejection and Donor Specific Antibodies in African American Renal Transplant Recipients

In spite of conventional immunosuppression with lymphocyte-depleting induction followed by tacrolimus- and mycophenolate-based regimens, African American (AA) renal transplant recipients experience higher rates of acute rejection (AR), donor specific antibodies (DSA), and graft failure. Envarsus Extended-Release (XR)® (ENV) is a novel extended-release formulation of tacrolimus with a favorable pharmacokinetic profile, even in the setting of CYP3A5*1 allele (rapid metabolizers). The investigator will evaluate the safety and efficacy of early dose escalation with ENV in AA recipients. The study hypothesis is that higher tacrolimus target concentrations may be achieved without typical dose-limiting toxicities, and this may ultimately result in lower incidence of early AR, DSA, and graft loss.

Aperçu de l'étude

Statut

Retiré

Les conditions

Intervention / Traitement

Description détaillée

Phase 4 (post-marketing) De novo African American living or deceased donor renal transplant recipients 18 to 65 years of age Number of subjects to be enrolled: 60

All patients will receive standard induction immunosuppression according to institution protocol. Within one week of transplantation, all patients will be converted from immediate-release tacrolimus (TAC) to extended-release tacrolimus (ENV) at 20% reduction in total daily dosage. Patients will be randomized to low-, moderate-, or high-intensity ENV groups, stratified by peak panel reactive antibody (pPRA) greater than or equal to 75%. Target tacrolimus trough concentrations for the first month post-transplant will be 8-10 ng/mL in low-intensity group, 10-12 ng/mL in moderate-intensity group, and 12-14 ng/mL in high-intensity group; likewise from month 1-3 post-transplant, target trough concentrations will be 6-8 ng/mL, 8-10 ng/mL, and 10-12 ng/mL, respectively. Subjects experiencing dose-limiting adverse events (AEs) will be de-escalated as warranted. Following month 3, all patients will be maintained on ENV at target tacrolimus trough concentrations according to institution protocol. Additional maintenance immunosuppression will consist of mycophenolate mofetil (MMF) at a goal dose of 2000 mg daily along with an oral prednisone taper to 5-10 mg daily by the end of month 1. All patients will be followed for 6 months post-transplant.

Type d'étude

Interventionnel

Phase

  • Phase 4

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans à 65 ans (Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

Inclusion Criteria:

  • • Primary live donor or deceased donor renal allograft

    • African American patients aged 18 to 65 years
    • Ability to take oral medications

    • Not currently on medications known to significantly interfere with tacrolimus metabolism, e.g. strong CYP3A4 inducers or inhibitors including but not limited to rifampin, rifabutin, phenytoin, carbamazepine, phenobarbital, protease inhibitors, azole antifungal (voriconazole, itraconazole, posaconazole, ketoconazole)

      o Note: All patients will be discharged on clotrimazole 10 mg three times daily for one month for thrush prophylaxis, a known mild-to-moderate CYP3A4 inhibitor

    • Female subjects of childbearing potential:

      • Not current pregnant
      • Agree not to try to become pregnant during the study period
      • Agree to consistently use two forms of highly effective birth control throughout the study period
    • Provision of signed and dated informed consent form
    • Stated willingness to comply with all study procedures and availability for the duration of the study

Exclusion Criteria:

  • • Presence of a positive T- or B-cell flow cytometry allogeneic crossmatch

    • Presence of pre-formed anti-human leukocyte antigen (HLA) donor-specific antibodies (DSAs)
    • Recipient of an ABO-incompatible organ
    • Receipt of a multi-organ or dual kidney transplant
    • Receipt of pediatric en bloc deceased donor kidneys
    • Receipt of deceased donor kidney with a kidney donor profile index (KDPI) greater than or equal to 85%
    • Has undergone desensitization, or received antibody removal, anti-B-cell, or anti-plasma cell therapy in the 90 days preceding the transplant
    • Planned initiation of antibody removal (i.e. plasmapheresis) within 7 days of the transplant procedure
    • Positive test for latent tuberculosis (TB) and has not previously received adequate anti-microbial therapy or would require TB prophylaxis after transplant
    • Uncontrolled concomitant infection that would not allow for targeting escalated tacrolimus trough concentrations, as deemed by prescriber
    • Known infection or seropositivity for hepatitis B virus (HBV, defined by positive HBsAg, anti-HBcAg, or positive viral load) or hepatitis C virus (HCV) with active viral load
    • Current malignancy
    • Use of an investigational study in the 30 days prior to the transplant procedure

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: Randomisé
  • Modèle interventionnel: Affectation parallèle
  • Masquage: Aucun (étiquette ouverte)

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Comparateur actif: Group 1 - Low-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 2 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 8-10 mg/mL Month 1 to Month 3: 6-8 mg/mL
Médicament: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Autres noms:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP
Comparateur actif: Group 1 - Moderate-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 3 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 10-12 mg/mL Month 1 to Month 3: 8-10 mg/mL
Médicament: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Autres noms:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP
Comparateur actif: Group 1 - High-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 4 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 12-14 mg/mL Month 1 to Month 3: 10-12 mg/mL
Médicament: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Autres noms:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP
Comparateur actif: Group 2 - Low-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 2 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 8-10 mg/mL Month 1 to Month 3: 6-8 mg/mL
Médicament: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Autres noms:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP
Comparateur actif: Group 2 - Moderate-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 3 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 10-12 mg/mL Month 1 to Month 3: 8-10 mg/mL
Médicament: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Autres noms:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP
Comparateur actif: Group 2 - High-Intensity

All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol.

TAC dosing will be 4 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily.

Target Tacrolimus Trough Concentrations:

Week 0 to Week 4: 12-14 mg/mL Month 1 to Month 3: 10-12 mg/mL
Médicament: Envarsus XR
tacrolimus, extended-release tablets, a calcineurin inhibitor
Autres noms:
  • Life Cycle Pharma (LCP)-tacrolimus
  • once-daily extended-release tacrolimus
  • once-daily prolonged-release tacrolimus
  • Tacrolimus-LCP

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
Number of participants reaching the composite endpoint
Délai: 6 months
Composite endpoint of freedom from all of the following: i) biopsy-proven T-cell mediated rejection Banff Grade ≥1A, ii) antibody-mediated rejection, iii) de novo DSA, or iv) immune-mediated graft loss. The endpoint is a binary endpoint (Yes or No) of the composite of all 4 potential outcomes. The presence of any one of the four possible outcomes will be counted as a No for the binary endpoint (no freedom from the composite endpoint). The absence of all 4 possible outcomes will be counted as Yes for freedom from all of the possible outcomes.
6 months

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Proportion of subjects experiencing nephrotoxicity during the study
Délai: 6 months
Increase in serum creatinine of ≥0.3mg/dL
6 months
Proportion of subjects experiencing neurotoxicity during the study
Délai: 6 months
Clinical intolerability including headache or significant tremors that resolve with reduction of the dose of Envarsus
6 months
Proportion of subjects experiencing infectious complications during the study
Délai: 6 months
Participants requiring extended (>2 weeks) reduction in dose of Envarsus due to BK-polyomavirus or cytomegalovirus viral loads at 1, 3, and 6 months post-transplant
6 months
Difference in estimated glomerular filtration rate at 1, 3, and 6 months between groups of enrolled subjects
Délai: 6 months
Assessed as the Chronic Kidney Disease - Epidemiology Collaboration equation
6 months
Difference in immunosuppressant side effects between enrolled subjects
Délai: 6 months
Assessed using the "Immunosuppressant Side Effects Instrument - The Memphis Survey" questionnaire
6 months
Enrolled subject overall survival and Graft survival at 6 months
Délai: 6 months
Freedom from death and from graft loss at 6 months
6 months

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

The Methodist Hospital Research Institute

Collaborateurs

Veloxis Pharmaceuticals

Publications et liens utiles

La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.

Publications générales

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude (Réel)

1 septembre 2018

Achèvement primaire (Anticipé)

31 octobre 2020

Achèvement de l'étude (Anticipé)

31 octobre 2022

Dates d'inscription aux études

Première soumission

2 avril 2019

Première soumission répondant aux critères de contrôle qualité

10 décembre 2020

Première publication (Réel)

11 décembre 2020

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Réel)

11 décembre 2020

Dernière mise à jour soumise répondant aux critères de contrôle qualité

10 décembre 2020

Dernière vérification

1 décembre 2020

Plus d'information

Termes liés à cette étude

Mots clés

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

  • Pro00018836

Plan pour les données individuelles des participants (IPD)

Prévoyez-vous de partager les données individuelles des participants (DPI) ?

NON

Informations sur les médicaments et les dispositifs, documents d'étude

Étudie un produit pharmaceutique réglementé par la FDA américaine

Oui

Étudie un produit d'appareil réglementé par la FDA américaine

Non

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

Essais cliniques sur Rejet aigu de greffe rénale

  • Abramson Cancer Center of the University of Pennsylvania
    Retiré
    ECR d'ACP pour la transplantation
    Patients cancéreux subissant une greffe de cellules souches (RCT of ACP for Transplant)

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