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

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:

• 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

Study Overview

• Status: Completed
• Conditions: Vaccine Response; Immunosuppression; COVID-19 Vaccines; Varicella Zoster Vaccine
• Intervention / Treatment: Biological: COVID-19 vaccination

Detailed Description

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

  • 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:

1. Continue immunosuppressive therapy with MMF/MPA
2. 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.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands
    • University Medical Center Groningen
  • Utrecht, Netherlands
    • University Medical Center Utrecht
  • Gelderland
    • Nijmegen, Gelderland, Netherlands
      • Radboud University Medical Center
  • Limburg
    • Maastricht, Limburg, Netherlands
      • Maastricht University Medical Center
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands
      • Amsterdam University Medical Center
  • Zuid-Holland
    • Leiden, Zuid-Holland, Netherlands
      • Leiden University Medical Center
    • Rotterdam, Zuid-Holland, Netherlands
      • Erasmus Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 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
• Simultaneous participation in another interventional study that will likely influence the study outcomes
• Subject who are actively trying to get pregnant or are pregnant

Additional exclusion criteria for Part 2:

• Active varicella or herpes zoster disease
• 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

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
Active Comparator: Continue immunosuppressive therapy with MMF/MPA; 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; Vaccination; Other Names: the monovalent Omicron XBB.1.5 COVID-19 mRNA vaccination
Active Comparator: Replace immunosuppressive therapy with MMF/MPA by everolimus; 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; Other Names: the monovalent Omicron XBB.1.5 COVID-19 mRNA vaccination

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virus-neutralizing capacity of SARS-CoV-2 antibodies	The neutralizing antibody titer against the Omicron XBB.1.5 strain	28 days after COVID-19 vaccination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SARS-CoV-2 antibody concentration	SARS-CoV-2 specific anti-S1 antibody concentrations in serum	28 days after COVID-19 vaccination
SARS-CoV-2 specific T-cell response	SARS-CoV-2 specific T-cell response	28 days after COVID-19 vaccination
Varicella Zoster specific antibodies	Concentrations of Varicella Zoster specific anti-gE antibodies	28 days after second Varicella Zoster vaccination
Varicella Zoster specific T-cell Response	Varicella Zoster specific T-cell response	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	Within 7 days after 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.	From enrollment to 84 days after COVID-19 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.	Within 84 days after COVID-19 vaccination

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	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	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.	28 days after vaccination

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Radboud University Medical Center; Maastricht University Medical Center; UMC Utrecht; Erasmus Medical Center; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Leiden University Medical Center; ZonMw: The Netherlands Organisation for Health Research and Development; Dutch Kidney Foundation
• Investigators: Principal Investigator: Jan-Stephan F Sanders, MD PhD, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2023
• Primary Completion (Actual): December 29, 2023
• Study Completion (Actual): February 27, 2024

Study Registration Dates

• First Submitted: June 20, 2023
• First Submitted That Met QC Criteria: June 20, 2023
• First Posted (Actual): June 29, 2023

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Everolimus; Mycophenolate Mofetil; Varicella Zoster Vaccine; COVID-19 vaccines; Kidney Transplant Recipients
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; DNA Virus Infections; Herpesviridae Infections; Varicella Zoster Virus Infection; COVID-19; Herpes Zoster; Chickenpox
• Other Study ID Numbers: 11442; 2023-503894-39-00 (Other Identifier: EUCTnumber)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The data of this study will be available from the principal investigator, upon reasonable request.

Drug and device information, study documents

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