Evaluation of the Efficacy of a Treatment by One Single Dose of Rituximab (375mg/m2 ) in the Prevention of the Epstein Barr Virus (EBV) Primary Infection and Post-transplant Lymphoproliferative Disorder in Adult EBV Seronegative Patients Who Received an EBV Seropositive Kidney Allograft (REPLY)

Multicenter Randomized Two Arms Study Evaluating the Efficacy of Prophylactic Rituximab in Adult EBV Negative Kidney Transplant Recipients on Incidence of EBV Primary Infection and Post-transplant Lymphoproliferative Disorders

Epstein Barr virus infects over 90% of human population and persists during lifetime. After infecting B lymphocytes, EBV remains latent in memory B cells. In immunocompromised patients, primary infection could lead to an uncontrolled EBV infected B cells proliferation because of impaired T cell specific cytotoxicity. The latent EBV infection is characterized by expression of restricted latent gene products, which drive cell proliferation and progression to PTLD. As a consequence, EBV seronegativity and EBV mismatch are major risk factors for developing PTLD. The investigators reported in a previous work from the French Registry that the incidence of PTLD was multiplied by ten in adult EBV negative kidney transplant recipients. Moreover, even if the event is relatively rare after transplantation, the prognosis is severe with high morbidity and an overall mortality rate around 50%.

Nowadays, few and inconsistent data exist regarding beneficial preventing strategies like antiviral therapy, reduction of immunosuppression or immunoglobulin infusion in this high-risk population of EBV negative recipients. Therefore, an efficient and safe preventive treatment is still lacking to decrease PTLD incidence.

Rituximab, has been already proposed in stem cell transplant recipients as a preemptive therapy in patients with a persistent EBV viremia independently of their EBV status. A pilot study was performed in EBV negative kidney transplant recipients but in a very small population. Schachtner60 reported the cases of 5 EBV negative recipients receiving kidney from EBV positive donors after a treatment with Rituximab. Only 2 patients showed a seroconversion and no patients developed neither a viremia nor a PTLD after 49 months of follow-up.

The main objective of the investigators study is to evaluate the efficacy of early infusion of Rituximab in the prevention of EBV primary infection and post-transplant lymphoproliferative disorder (PTLD) occurrence in adult EBV negative kidney transplant recipients transplanted with an EBV positive donor.

Study Overview

• Status: Recruiting
• Conditions: Epstein-Barr Virus Infections
• Intervention / Treatment: Drug: Rituximab; Other: control group

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Sophie Ohlmann-Caillard; Phone Number: 0369550511; Email: sophie.caillard@chru-strasboourg.fr

Study Locations

• France
  • Strasbourg, France, 67000
    • Recruiting
    • Les Hôpitaux Universitaires de Strasbourg
    • Contact: Sophie Caillard, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Adult patients (age ≥18 years at transplantation)
• Kidney and kidney pancreas simultaneous transplantation
• EBV seronegative patients (IgG anti EBNA, IgG anti VCA and IgM anti VCA negative) (from 6 months before transplantation to the day of transplantation, included)
• Patient who have given written informed consent
• Negative pregnancy test and use of contraception during all the study
• EBV positive donor
• Patient affiliated to a social security scheme

Exclusion criteria:

• Patient with known HBV active infection
• Allergy to Rituximab
• Severe Immune deficiency
• Severe cardiac insufficiency
• Pregnant or lactating women
• Women of child bearing potential unless they are using a birth control method
• Patient under judicial protection or under guardianship
• Patient currently participating in another clinical trial investigating drugs. Observational studies are not considered as an exclusion criterion
• Any form of substance abuse, psychiatric disorder or condition, which, in the opinion of the investigator, is incompatible with the participation in the study
• Unlikely to comply with the visits scheduled in the protocol.

Exclusion Criteria:

-

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; Prophylactic treatment with Rituximab: one single dose of 375mg/m2 intravenous 7 days before transplantation in case of living donor or at time of transplantation (D0 or D1) in case of transplantation with a deceased donor.	Drug: Rituximab; One single dose of rituximab intravenously (IV)
Active Comparator: control group; Immunosuppression treatment will be given according to the practice of the centers; use of Thymoglobuline is strongly discouraged because of EBV seronegativity and risk of lymphoma. Basiliximab is recommended for induction therapy. Recommended maintenance immunosuppression consists in a calcineurin inhibitor (tacrolimus or ciclosporine), MMF and Steroids	Other: control group; No treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary EBV infection	Infection assessed by a positive blood EBV viral load and/or EBV seroconversion and/or occurrence of a post-transplant lymphoproliferative disorder	1 year post-transplantation

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2021
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: July 15, 2021
• First Submitted That Met QC Criteria: August 3, 2021
• First Posted (Actual): August 4, 2021

Study Record Updates

• Last Update Posted (Actual): August 19, 2024
• Last Update Submitted That Met QC Criteria: August 16, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Immune System Diseases; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; DNA Virus Infections; Tumor Virus Infections; Herpesviridae Infections; Infections; Communicable Diseases; Epstein-Barr Virus Infections; Lymphoproliferative Disorders; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: 7678

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
• product manufactured in and exported from the U.S.: No