Multicenter Randomized Two-arms Study Evaluating the BK Viral Clearance in Kidney Transplant Recipients With BK Viremia. (BK EVER)

Multicenter Randomized Two-arms Study Evaluating the BK Viral Clearance in Kidney Transplant Recipients With BK Viremia After Reduction of Immunosuppression Alone vs. Reduction of Immunosuppression and Replacement of Mycophenolate Mofetil by Everolimus

BK virus nephropathy (BKVN), a consequence of the strong immunosuppressive therapy given after kidney transplantation, represents a growing problem in the kidney transplant (KT) setting. In recent cohorts, BKVN concerns up to 10% of kidney transplant recipients and early signs of BK virus (BKV) infection as development of asymptomatic viruria and viremia are even much more frequent (40% and 20% of patients, respectively). In this context, finding strategies to prevent BKV infection or treat patients before the occurrence of BKV nephropathy is challenging. For several years, detection of BKV replication by real-time PCR in urine and/or blood of kidney transplant recipients at early stages of infection allowed adaptation of their therapy. As BKV reactivates essentially in patients with over-immunosuppression, the first step of the treatment is the reduction of immunosuppression. However, reducing immunosuppression (IS) can lead to acute rejection and allograft loss. Other treatments have been proposed (cidofovir, quinolones) but their toxicity profile or their lack of clinical efficacy are now demonstrated. Hence, an efficient and safe strategy against uncontrolled BKV replication is urgently needed. MTor-inhibitors are well known immunosuppressive drugs used in organ transplantation to prevent graft-rejection. They have furthermore anti-viral effects that can be beneficial for prevention of viral infections after transplantation. Recent evidence that inhibition of mTor pathway had an impact on BK infected cells provides additional insight into the observed benefits associated with these drugs. The aim of our study is to evaluate the effect of the mTor inhibitor everolimus on the prevention of severe BKV infection (BKV nephropathy or loss of the allograft) after kidney transplantation compared to the reduction of immunosuppression alone in kidney recipients with BK viremia.

Study Overview

• Status: Active, not recruiting
• Conditions: BK Virus Nephropathy After Kidney Transplantation
• Intervention / Treatment: Drug: everolimus

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • CHU - Hôpital Sud
  • Angers, France, 49033
    • CHRU d'Angers
  • Bois-guillaume, France, 76230
    • CHU - Hôpital de la Cavale Blanche
  • Brest, France, 29609
    • CHU - Hôpital de la Cavale Blanche
  • Caen, France, 14033
    • CHU côte de Nacre
  • Clermont-Ferrand, France, 63000
    • CHU Hôpital Gabriel Montpied
  • Limoges, France, 87042
    • CHU - Hôpital Dupuytren
  • Lyon, France, 69003
    • Hôpital Edouard Herriot
  • Paris, France, 75743
    • AP-HP Hôpital Necker
  • Paris, France, 75908
    • AP-HP - Hôpital Georges Pompidou
  • Poitiers, France, 86021
    • CHU Poitiers - Hopital Jean Bernard
  • Reims, France, 51092
    • CHU - Hôpital Maison Blanche
  • Rennes, France, 35033
    • CHU Rennes - Hôpital Pontchaillou
  • Strasbourg, France, 67000
    • Les Hôpitaux Universitaires
  • Tours, France, 37044
    • CHRU - Hôpital Bretonneau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients
• Kidney transplant recipients
• Patients treated by a calcineurin inhibitor and mycophenolic acid
• Viremia >= 2.8 log UI/ml
• Patients who have given written informed consent
• Negative pregnancy test (blood β-HCG dosage)

Exclusion Criteria:

• Known proved BKV nephropathy
• Hypersensitivity to everolimus, sirolimus or excipient
• Concomitant treatment by leflunomide, cidofovir, sirolimus, Millepertuis (Hypericum Perforatum)
• Pregnant or lactating women
• Women of child bearing potential unless they are using a birth control method

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: IS lowering alone; 50% decrease of the dose of mycophenolic acid at M1 (target AUC 20 mg.h/L)	Drug: everolimus; Patients with viremia above 2.8 log of copies/ml will be randomized (ratio 1:1) into either of 2 groups Group 1 : control group : immunosuppression lowering or Group 2 : experimental group : immunosuppression lowering and replacement of mycophenolate acid by everolimus Evolution of BKV viremia and allograft function will be assessed during 2 years after randomization
Experimental: Everolimus + IS lowering; Stop mycophenolate acid (Cellcept or myfortic) Introduction of everolimus : 2 x 0.75 mg/d per os in patiens treated by ciclosporine	Drug: everolimus; Patients with viremia above 2.8 log of copies/ml will be randomized (ratio 1:1) into either of 2 groups Group 1 : control group : immunosuppression lowering or Group 2 : experimental group : immunosuppression lowering and replacement of mycophenolate acid by everolimus Evolution of BKV viremia and allograft function will be assessed during 2 years after randomization

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The main objective of our study is to evaluate the proportion of patients with BKV clearance 6 months after introduction of everolimus in kidney recipients who develop BKV viremia compared to patients managed with IS reduction alone	The primary end point is the proportion of patients with clearance of BK viremia assessed by blood PCR and functional graft 6 months after modification of immunosuppressive therapy	6 months after randomization

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2018
• Primary Completion (Estimated): November 1, 2023
• Study Completion (Estimated): November 1, 2023

Study Registration Dates

• First Submitted: July 4, 2017
• First Submitted That Met QC Criteria: July 11, 2017
• First Posted (Actual): July 13, 2017

Study Record Updates

• Last Update Posted (Actual): August 21, 2023
• Last Update Submitted That Met QC Criteria: August 18, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Viremia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; MTOR Inhibitors; Everolimus
• Other Study ID Numbers: 6646

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No