PREPARE-iVAC Trial (PREPARE-iVAC)

Prospective Randomized Trial of Everolimus Replacing MMF/MP Acid by the RECOVAC Consortium to Increase VACcine Response in Kidney Transplant Patients

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Radboud University Medical Center, Erasmus Medical Center, UMC Utrecht, Leiden University Medical Center, Maastricht University Medical Center, ZonMw: The Netherlands Organisation for Health Research and Development

Objective: To investigate whether replacement of MMF/MPA by everolimus in kidney transplant recipients results in superior immunogenicity of COVID-19 vaccination as measured by neutralizing antibody titer against the Omicron BA.5 strain. Trial design: Multicentre, open-label randomized controlled clinical trial, for a duration of at least 10 weeks with an optional extension to 18 weeks. Trial population: Kidney transplant recipients, 18 years or older, who are at least 6 months after transplantation, with a functioning kidney transplant, using MMF/MPA in combination with at least one other immunosuppressant including a calcineurin inhibitor (CNI), with at least 3 previous COVID-19 vaccinations (=basic COVID-19 immunisation). Interventions: Patients will be randomized into one of two equally sized groups, with either continuation of their current immunosuppressive regimen including MMF/MPA or replacement of MMF/MPA by everolimus during at least six weeks before until four weeks after the last vaccination. Patients will receive a repeated COVID-19 vaccination with the bivalent (original-BA.4/5) vaccine, 28 days thereafter they can opt to also receive two herpes zoster vaccinations with the Recombinant Zoster Vaccine (RZV) with an interval between the first and second dose of 28 days. Main trial endpoints: The neutralizing antibody titer against the Omicron BA.5 strain 28 days after bivalent (original-BA.4/5) COVID-19 vaccination in patients continuing MMF/MPA compared to patients who switched to everolimus. Secondary trial endpoints: SARS-CoV-2 specific anti-S1 antibody level at 28 and 56 days after COVID-19 vaccination Varicella zoster specific anti-gE antibody level 28 days after 1st and 2nd herpes zoster vaccination SARS-CoV-2 specific T-cell response 28 days after COVID-19 vaccination Varicella zoster specific T-cell response 28 days after 2nd herpes zoster vaccination Safety in terms of incidence of acute rejection, kidney function decline, SAEs, AESIs and solicited local and systemic AEs after COVID-19 and herpes zoster vaccination

Rationale: The immunogenicity after vaccination against SARS-CoV-2 and other pathogens is diminished in kidney transplant recipients. This patient group therefore remains extremely vulnerable for viral infections despite vaccination. This impaired immune response is related to the use of immunosuppressive agents, especially Mycophenolate Mofetil/Mycophenolic Acid (MMF/MPA). Patients that use everolimus instead of MMF/MPA elicit a higher immune response after vaccination. Objective Primary objective: To investigate whether replacement of MMF/MPA by everolimus in kidney transplant recipients results in superior immunogenicity of COVID-19 vaccination as measured by neutralizing antibody titer against the Omicron BA.5 strain. Secondary objectives: To investigate whether replacement of MMF/MPA by everolimus in kidney transplant recipients results in superior humoral immunogenicity of COVID-19 vaccination as measured by SARS-CoV-2 specific anti-S1 antibody levels herpes zoster vaccination as measured by varicella zoster specific anti-gE antibody levels To investigate whether replacement of MMF/MPA by everolimus in kidney transplant recipients results in superior cellular immunogenicity of COVID-19 vaccination as measured by SARS-CoV-2 specific T-cell response herpes zoster vaccination as measured by varicella zoster specific T-cell response To evaluate safety of replacement of MMF/MPA by everolimus in terms of incidence of treated acute rejection, kidney function decline, incidence of serious adverse events (SAEs) incidence of adverse events of special interest (AESI) of immunosuppression incidence of solicited adverse events (AEs) of COVID-19 vaccination incidence of solicited AEs of herpes zoster vaccination This is a multicentre, open-label, controlled, randomized study to evaluate replacement of MMF/MPA by everolimus in KTR on immunogenicity and safety after vaccination. The seven participating study sites are Amsterdam UMC, Erasmus MC, Leiden UMC, Maastricht UMC+, Radboudumc, UMC Groningen and UMC Utrecht. At the first study visit, eligibility for study participation will be checked, blood will be drawn, and participants will subsequently be 1:1 randomised to: Continue immunosuppressive therapy with MMF/MPA Replace immunosuppressive therapy with MMF/MPA by everolimus After randomisation, the study will continue in 2 parts: Part 1 - Run-in and COVID-19 vaccination (≥6 weeks + 28 days) The aim of this phase is to first ensure complete washout of MMF/MPA and attaining optimal trough levels of everolimus in patients randomized to everolimus. To monitor tolerability, safety and trough levels, participants will be invited at week 1 and week 3 after randomisation for a blood withdrawal and spot urine collection. At least 6 weeks after randomisation, patients will receive the COVID-19 vaccination (=baseline visit). After 28 days patients will be invited for a study visit for blood withdrawal. Part 2 (optional) - Herpes zoster vaccination (+56 days) Patients that opted to participate in this part of the study will continue their randomised treatment for the next 56 days. During this period patients will receive 2 herpes zoster vaccinations with an interval of 28 days between each vaccination. At 28 days after the second vaccination patients will be invited for the last study visit for blood withdrawal. After completion of the study (either 28 days after COVID-19 vaccination or 28 days after the last herpes zoster vaccination) patients will be offered the option to continue everolimus instead of MMF/MPA as part of shared clinical decision making.

Kidney Transplant Recipients, COVID-19 vaccines, Everolimus, Mycophenolate Mofetil, Varicella Zoster Vaccine

Participants will be 1:1 randomised to: Continue immunosuppressive therapy with MMF/MPA Replace immunosuppressive therapy with MMF/MPA by everolimus

Kidney transplant recipients with maintenance therapy, receiving the bivalent original/Omicron BA.4-5 COVID-19 mRNA vaccine (Comirnaty, I.M.). Optional to receive the Recombinant Zoster Vaccine (Shingrix, I.M.).

Kidney transplant recipients replacing MMF/MPA by everolimus for at least six weeks, receiving the bivalent original/Omicron BA.4-5 COVID-19 mRNA vaccine (Comirnaty, I.M.). Optional to receive the Recombinant Zoster Vaccine (Shingrix, I.M.).

Percentage of participants reporting local reactions (pain at the injection site, redness and swelling) and systemic events (fever, fatigue, headache, chills, vomiting, diarrhea, new of worsened muscle pain, and new or worsened joint pain) after COVID-19 and both Varicella Zoster vaccines administration

Percentage of participants with serious adverse events after COVID-19 and both Varicella Zoster vaccines administration, with special interest in treatment of acute rejection, dnDSA.

Change in estimated glomerular filtration rate and proteinuria during the study including creatinine measurements in blood and protein measurements in spot urine.

The association between immunological outcomes and the timing of a previous COVID-19 infection and COVID-19 severity will be investigated

Neutralizing antibody titers against the most common SARS-CoV-2 variant at the moment of study conduct

A potential delayed humoral response after COVID-19 vaccination will be tested by comparing anti-S1 antibody levels at 56 days and 28 days after vaccination

Compare/relate baseline clinical features and antibody/T cell responses to the level of induced antibody and T cell responses after vaccination.

Inclusion Criteria: Age ≥ 18 years ≥6 months after kidney transplantation Maintenance immunosuppressive therapy consisting of either triple or dual therapy including MMF/MPA with a minimum daily dose of 1000 mg (MMF) or 720 mg (MPA) and a CNI Eligible for the vaccinations as described by the instructions of the manufacturers of the vaccines (e.g. received 3 previous COVID-19 vaccinations as part of the primary COVID-19 immunisation) Capable of understanding the purpose and risks of the study, fully informed and given written informed consent (signed informed consent form has been obtained) Willing to adhere to the protocol and be available during the study period Exclusion Criteria: Previous CNI trough levels not sufficient according to the discretion of the treating physician More than two previous kidney transplantations Calculated level of panel reactive antibodies prior to last transplantation above 85% Evidence of DSAs Signs of acute rejection during the preceding year Multi-organ transplant recipient History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g. anaphylaxis) to any component of the study intervention(s) Contra-indications for use of everolimus according to the opinion of the treating physician Active COVID-19 disease Active varicella or herpes zoster disease Active malignancy, except non-melanoma skin cancer Inherited immune deficiency Infection with Human Immunodeficiency Virus (HIV) Administration of T-cell, B-cell, or plasma cell depleting antibodies during the last 6 months Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection Subjects with severe systemic infections, current or within the two weeks prior to randomisation Subjects with severe restrictive or obstructive pulmonary disorders Subjects with severe hypercholesterolemia or hypertriglyceridemia that cannot be controlled Subjects with white blood cell (WBC) count ≤ 2,000/mm3 or with platelet count ≤ 50,000/mm3 at last outpatient clinic visit Proteinuria > 1 gram/day at last outpatient clinic visit Herpes zoster vaccination with the live attenuated vaccine (Zostavax) or varicella vaccination (Provarivax) during the conduct of the study Previous herpes zoster vaccination with the RZV Simultaneous participation in another interventional study that will likely influence the study outcomes Subject who are actively trying to get pregnant or are pregnant