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Efficiency of Everolimus for the Treatment of Kidney Transplanted Patients Presenting a Missing Self-induced NK-mediated Rejection (STARR)

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ClinicalTrials.gov Identifier: NCT03955172
Recruitment Status : Recruiting
First Posted : May 20, 2019
Last Update Posted : April 26, 2021
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

Study Description
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Brief Summary:

Background:

Long-term success of organ transplantation is limited by the inexorable loss of graft function due to rejection. Prevalent dogma defends that allograft rejection is exclusively mediated by the adaptive immune system: T cells are responsible for cellular rejections and B cells producing Donor Specific Antibodies (DSA) are responsible for humoral rejection. Recently, we demonstrated that innate NK cells could be implicated in the generation of chronic vascular rejections lesions by sensing the absence of expression of self Major Histocompatibility Complex (MHC) class I molecules ("missing self") on graft endothelial cells with their Killer cell immunoglobulin-like (KIR) receptors. Using human in vitro and murine in vivo models, we also showed that Mammalian Target Of Rapamycin (mTOR) inhibitors could efficiently prevent this new kind of rejection.

Objective:

The aim of our project is therefore to test in a cohort of kidney transplanted patients the efficiency of mTOR inhibitors to treat this new kind of rejection

Methods:

A cohort of 20 kidney transplant patients with a missing self on their graft responsible for a NK-mediated rejection will be established prospectively. An mTOR inhibitor will be introduced in these patients for 6 months in association with a calcineurin inhibitor and corticosteroids. Graft function, histological lesions and NK activability will be monitored following this modification of treatment.


Condition or disease Intervention/treatment Phase
Kidney Transplant Failure and Rejection Drug: Everolimus Not Applicable

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficiency of Everolimus for the Treatment of Kidney Transplanted Patients Presenting a Missing Self-induced Natural Killer Cells Mediated (NK-mediated) Rejection
Actual Study Start Date : December 3, 2020
Estimated Primary Completion Date : June 15, 2022
Estimated Study Completion Date : June 15, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Everolimus

Arms and Interventions
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Arm Intervention/treatment
Experimental: Everolimus Drug: Everolimus
Patients will received everolimus (CERTICAN), oral form, at the necessary dose to obtain trough levels between 6 and 8 ng/ml, during 6 months. Everolimus will replace the anti-proliferative drug they have before (azathioprine or mycophenolic acid). Everolimus will be associated with corticosteroids (prednisolone) and a calcineurin inhibitor (tacrolimus or cyclosporin).


Outcome Measures
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Primary Outcome Measures :
  1. Change in Estimated glomerular filtration rate [ Time Frame: 6 months after start of Everolimus treatment ]

    Glomerular filtration rate will be estimated by Chronic Kidney Disease - Epidemiology CollaborationI (CKD-EP) equation.

    Outcome evaluation at 6 months after everolimus treatment introduction (at D0) compared to baseline (between 15 and 30 days before D0).



Secondary Outcome Measures :
  1. Change in the severity of rejection lesions on allograft biopsy [ Time Frame: 6 months after start of Everolimus treatment ]

    Evolution of microvascular inflammation and chronic glomerular and vascular lesions graded according to Banff 2013 classification.

    Outcome evaluation at 6 months after everolimus treatment introduction (at D0) compared to baseline (between 15 and 30 days before D0).


  2. Change in NK cell activability [ Time Frame: 6 months after start of Everolimus treatment ]

    Nk cell activability will be measured by looking at the expression of activation markers (CD107a and MIP1B) on circulating NK cells by flow cytometry.

    Outcome evaluation at 6 months after everolimus treatment introduction (at D0) compared to baseline (between 15 and 30 days before D0).


  3. Change in proteinuria [ Time Frame: 6 months after start of Everolimus treatment ]
    Calculation of proteinuria/urinary creatinin index. Outcome evaluation at 6 months after everolimus treatment introduction (at D0) compared to baseline (between 15 and 30 days before D0).


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Patient aged > 18 years
  • Kidney transplanted patient
  • Having microvascular inflammation lesion on his graft biopsy associated to mild chronic lesions
  • In absence of donor specific antibodies
  • In presence of a missing self

Exclusion Criteria:

  • Proteinuria/urinary creatinin > 100 mg/mmol
  • Antecedent of poor tolerance or hypersensibility to everolimus or sirolimus
  • Severe chronic lesions
  • Presence of donor specific antibodies
Contacts and Locations
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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): NCT03955172


Contacts
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Contact: Alice KOENIG, MD 472110178 ext +33 alice.koenig@chu-lyon.fr
Contact: Daniel SPERANDIO, MD 472116926 ext +33 daniel.sperandio@chu-lyon.fr

Locations
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France
Service de transplantation, néphrologie et immunologie clinique, Hôpital Edouard Herriot (HCL) Recruiting
Lyon, France, 69003
Contact: Alice KOENIG, MD    472110178 ext +33    alice.koenig@chu-lyon.fr   
Contact: Daniel SPERANDIO    472116926 ext +33    daniel.sperandio@chu-lyon.fr   
Principal Investigator: Alice KOENIG, MD         
Sponsors and Collaborators
Hospices Civils de Lyon
More Information
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Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT03955172    
Other Study ID Numbers: 69HCL17_0706
First Posted: May 20, 2019    Key Record Dates
Last Update Posted: April 26, 2021
Last Verified: April 2021

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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 Hospices Civils de Lyon:
Missing self
NK cells
Rejection
mTOR inhibitors
Kidney transplanted patients
Additional relevant MeSH terms:
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Everolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs