A Phase 4 interventional study of COVID-19 vaccination in COVID-19 Vaccines, Varicella Zoster Vaccine and Vaccine Response, sponsored by University Medical Center Groningen. Completed at 7 sites in Netherlands. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-03-04.
Sponsored by University Medical Center Groningen · Phase 4, Interventional, and Prevention
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 XBB.1.5 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 monovalent Omicron XBB.1.5 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 XBB.1.5. strain 28 days after monovalent Omicron XBB.1.5 COVID-19 vaccination in patients continuing MMF/MPA compared to patients who switched to everolimus.
Secondary trial endpoints:
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 XBB.1.5 strain.
Secondary objectives:
To investigate whether replacement of MMF/MPA by everolimus in kidney transplant recipients results in superior humoral immunogenicity of
To investigate whether replacement of MMF/MPA by everolimus in kidney transplant recipients results in superior cellular immunogenicity of
To evaluate safety of replacement of MMF/MPA by everolimus in terms of
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:
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.
Exclusion Criteria:
Additional exclusion criteria for Part 2:
Kidney transplant recipients with maintenance therapy, receiving the monovalent Omicron XBB.1.5 COVID-19 mRNA vaccine (Comirnaty, I.M.). Optional to receive the Recombinant Zoster Vaccine (Shingrix, I.M.).
Biological: COVID-19 vaccination
Kidney transplant recipients replacing MMF/MPA by everolimus for at least six weeks, receiving the monovalent Omicron XBB.1.5 COVID-19 mRNA vaccine (Comirnaty, I.M.). Optional to receive the Recombinant Zoster Vaccine (Shingrix, I.M.).
Biological: COVID-19 vaccination
Vaccination
Also known as: the monovalent Omicron XBB.1.5 COVID-19 mRNA vaccination
Virus-neutralizing capacity of SARS-CoV-2 antibodies
The neutralizing antibody titer against the Omicron XBB.1.5 strain
Time frame: 28 days after COVID-19 vaccination
SARS-CoV-2 antibody concentration
SARS-CoV-2 specific anti-S1 antibody concentrations in serum
Time frame: 28 days after COVID-19 vaccination
SARS-CoV-2 specific T-cell response
SARS-CoV-2 specific T-cell response
Time frame: 28 days after COVID-19 vaccination
Varicella Zoster specific antibodies
Concentrations of Varicella Zoster specific anti-gE antibodies
Time frame: 28 days after second Varicella Zoster vaccination
Varicella Zoster specific T-cell Response
Varicella Zoster specific T-cell response
Time frame: 28 days after second Varicella Zoster vaccination
Solicited local and systemic adverse events
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
Time frame: Within 7 days after vaccination
Serious adverse events
Percentage of participants with serious adverse events after COVID-19 and both Varicella Zoster vaccines administration, with special interest in treatment of acute rejection.
Time frame: Within 84 days after COVID-19 vaccination
Safety of kidney transplant
Change in estimated glomerular filtration rate and proteinuria during the study including creatinine measurements in blood and protein measurements in spot urine.
Time frame: From enrollment to 84 days after COVID-19 vaccination
Relationship between previous COVID-19 infection and immune responses
The association between immunological outcomes and the timing of a previous COVID-19 infection and COVID-19 severity will be investigated
Time frame: 28 days after vaccination
Virus neutralizing capacity of SARS-CoV-2 antibodies
Neutralizing antibody titers against the most common SARS-CoV-2 variant at the moment of study conduct
Time frame: 28 days after COVID-19 vaccination
Delayed SARS-CoV-2 antibody response
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
Time frame: 56 days after COVID-19 vaccination
Relationship between baseline clinical features and immune responses
Compare/relate baseline clinical features and antibody/T cell responses to the level of induced antibody and T cell responses after vaccination.
Time frame: 28 days after vaccination
Plan to share: No — The data of this study will be available from the principal investigator, upon reasonable request.
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This study is completed, as verified in Mar 2024. You cannot join it, but the record below documents what was studied.
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University Medical Center Groningen