COVID Protection After Transplant-Immunosuppression Reduction

Study Overview
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Brief Summary
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This study will enroll individuals who have: Completed primary series of mRNA COVID-19 vaccine, and An antibody response ≤ 2500 U/mL measured at least 30 days after the last dose of vaccine. This group of patients is at high risk for severe COVID-19 disease due to pharmacologic immunosuppression and a high prevalence of non-transplant risk factors such as obesity and diabetes.

Detailed Description
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This study is a randomized, open-label multi-site trial designed to induce an enhanced antibody response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in kidney and liver transplant recipients who have ≤ 2500 U/mL anti-spike antibody (as measured by the Roche Elecsys® anti-SARS-CoV-2 S assay) after a completed primary series (3 doses) of mRNA COVID-19 vaccines. Participants will be randomized to either: Receive a study dose of mRNA based COVID-19 vaccine (booster) with no change in their immunosuppressive regimen, or Undergo a temporary, prescribed reduction in their maintenance immunosuppression (IS) regimen and receive a study dose (booster) of mRNA based COVID-19 vaccine. Protocol Version 8.0 will include a booster dose of either Pfizer-BioNTech COVID-19 Vaccine 2023-2024 or Moderna COVID-19 Vaccine 2023-2024, with or without IS reduction. Duration of study participation for interested and eligible individuals: 13 months.

Official Title
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A Randomized Study to Evaluate Antibody Response to an Additional Dose of SARS-CoV-2 Vaccination With and Without Immunosuppression Reduction in Kidney and Liver Transplant Recipients

Conditions
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Kidney Transplant Recipients, Liver Transplant Recipients

Intervention / Treatment
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* Biological: Pfizer-BioNTech COVID-19 Vaccine 2023-2024
* Biological: Moderna COVID-19 Vaccine 2023-2024
* Drug: SOC IS Regimen
* Drug: SOC IS Reduction


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals who meet all the following criteria are eligible for enrollment as study participants- Able to understand and provide informed consent Individual ≥18 years of age. Recipient of a kidney or liver transplant ≥12 months prior to enrollment, without allograft rejection in the 6 months preceding enrollment Negative for anti-donor human leukocyte antigens (HLA) antibodies at screening (Central Lab Test Determination). Currently taking one of the following tacrolimus-based immunosuppressive regimens: Tacrolimus plus Mycophenolate Mofetil (MMF) or Mycophenolic Acid (MPA), with or without a corticosteroid Tacrolimus with trough ≥ 5ng/mL with or without ≤5 mg of prednisone or equivalent Received a minimum of 3 doses of either the Moderna coronavirus infectious disease 19 (COVID-19) vaccine or Pfizer-BioNTech COVID-19 vaccine Participant must be ≥ 60 days after completion of primary vaccination or receipt of the most recent booster dose with any authorized or approved monovalent or bivalent COVID-19 vaccine at the time of study vaccine. Serum antibody negative or low (titer ≤ 2500 U/mL) at ≥ 30 days from the last dose of mRNA COVID-19 vaccine and ≥ 30 days following receipt of a monoclonal antibody product or convalescent plasma for COVID-19, measured using the Roche Elecsys® anti-SARS-CoV-2 S assay. Participant's transplant physician or midlevel practitioner who is clinically licensed to prescribe and manage immunosuppression must confirm the participant's eligibility based on medical history. Exclusion Criteria: Individuals who meet any of these criteria are not eligible for enrollment as study participants- Currently on an immunosuppressive regimen different from the three regimens described in the Inclusion Criteria, for example (but not limited to) those including sirolimus, everolimus, belatacept, or azathioprine Recipient of any allograft other than a kidney or liver Participant is pregnant Any past history of Donor Specific Antibody (DSA) using local site standards Prior receipt of the Moderna COVID-19 Vaccine 2023-2024 or Pfizer-BioNTech COVID-19 Vaccine 2023-2024. Currently taking any systemic immunosuppressive agent, other than their prescribed transplant immunosuppression Known history of severe allergic reaction to any component of an authorized or licensed COVID-19 vaccine Thrombotic events, myocarditis, or pericarditis temporally associated with a prior dose of COVID-19 vaccine History of heparin-induced thrombocytopenia Any change in transplant immunosuppression regimen (drug or dose) in response to suspected or proven rejection within the last 6 months More than minimal graft dysfunction, in accordance with study definition Receipt of any cellular depleting agent (e.g. antithymocyte globulins (ATG), rituximab, alemtuzumab, Cyclophosphamide) within 12 months preceding enrollment Concurrent autoimmune disease at risk for exacerbation with immunosuppression reduction Any untreated active infection including BK viremia >10^4 copies Infection with human immunodeficiency virus (HIV) Recent (within one year) or ongoing treatment for malignancy with the exception of: Non- melanomatous skin cancer definitively treated by local therapy, and Definitively treated carcinoma-in-situ of the cervix (Stage 0 cervical cancer) Treatment or prophylaxis of COVID-19 with a monoclonal antibody product or convalescent plasma within 6 months preceding enrollment, or Any past or current medical problems, treatments, or findings which, in the opinion of the investigator, may: pose additional risks from participation in the study, interfere with the candidate's ability to comply with study requirements, or impact the quality or interpretation of the data obtained from the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized to: A study dose of mRNA COVID-19 vaccine only, or Immunosuppression (IS) reduction plus a study dose of mRNA COVID-19 vaccine. IS reduction will be based on the participant's IS regimen upon study entry, in accordance with the study's protocol.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pfizer-BioNTech COVID-19 Vaccine 2023-2024 + SOC IS Regimen<br>Participants will receive a study dose (1 dose) of the Pfizer-BioNTech COVID-19 Vaccine 2023-2024 and will continue to take their standard of care transplant immunosuppressive medications without alterations in schedule and dosing. SOC IS: Standard of Care transplant immunosuppression regimen | Biological: Pfizer-BioNTech COVID-19 Vaccine 2023-2024<br>* Administration: One dose administered intramuscularly.<br>* Other names: Comirnaty;Drug: SOC IS Regimen<br>* Participants will continue to take their prescribed immunosuppression (IS) medications without alterations in schedule and dosing, per protocol instruction.<br>* Other names: tacrolimus;|
| Experimental: Pfizer-BioNTech COVID-19 Vaccine 2023-2024 + SOC IS Reduction<br>Participants will receive an additional dose (1 dose) of the Pfizer-BioNTech COVID-19 Vaccine 2023-2024, with concurrent reduction of their standard of care transplant immunosuppression regimen (IS), per protocol. SOC IS Reduction: Standard of Care transplant immunosuppression regimen reduction, per protocol | Biological: Pfizer-BioNTech COVID-19 Vaccine 2023-2024<br>* Administration: One dose administered intramuscularly.<br>* Other names: Comirnaty;Drug: SOC IS Reduction<br>* Participants will reduce their standard of care immunosuppression medications (IS) before and after the COVID-19 vaccine booster (1 dose), per protocol instruction.<br>* Other names: tacrolimus;|
| Experimental: Moderna COVID-19 Vaccine 2023-2024 + SOC IS Regimen<br>Participants will receive an additional dose (1 dose) of the Moderna COVID-19 Vaccine 2023-2024 and will continue to take their standard of care transplant immunosuppressive medications without alterations in schedule and dosing. SOC IS: Standard of Care transplant immunosuppression regimen | Biological: Moderna COVID-19 Vaccine 2023-2024<br>* Administration: One dose administered intramuscularly.<br>* Other names: Spikevax;Drug: SOC IS Regimen<br>* Participants will continue to take their prescribed immunosuppression (IS) medications without alterations in schedule and dosing, per protocol instruction.<br>* Other names: tacrolimus;|
| Experimental: Moderna COVID-19 Vaccine 2023-2024 + SOC IS Reduction<br>Participants will receive a study dose (1 dose) of the Moderna COVID-19 Vaccine 2023-2024, with concurrent reduction of their standard of care transplant immunosuppression regimen (IS), per protocol. SOC IS Reduction: Standard of Care transplant immunosuppression regimen reduction, per protocol | Biological: Moderna COVID-19 Vaccine 2023-2024<br>* Administration: One dose administered intramuscularly.<br>* Other names: Spikevax;Drug: SOC IS Reduction<br>* Participants will reduce their standard of care immunosuppression medications (IS) before and after the COVID-19 vaccine booster (1 dose), per protocol instruction.<br>* Other names: tacrolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint is the -fold increase in antibody titer (using the Roche Elecsys® anti-SARS-CoV-2 S assay) from before receiving the study dose of vaccine to 30 days after the study dose of vaccine. | Serum antibody titer will be measured using the Roche Elecsys®) severe acute respiratory syndrome coronavirus type 2 serological (anti-SARS-CoV-2) S assay. | Day 30 After Study Vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Solicited Local Reactogenicity Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine | Safety measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 7 Post Study Vaccination | 
| Frequency of Solicited Local Allergic Reaction Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine | Safety measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 7 Post Study Vaccination | 
| Frequency of Solicited Systemic Reactogenicity Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine | Safety measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 7 Post Study Vaccination | 
| Frequency of Solicited Systemic Allergic Reaction Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine | Safety measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 7 Post Study Vaccination | 
| Frequency of Any Serious Adverse Events (SAEs) | Safety measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 30 Post Study Vaccination | 
| Frequency of Any Unsolicited Adverse Events (AEs) | Safety measure. An AE associated with the receipt of the study's COVID-19 mRNA vaccine and/or study mandated procedures. | Through Day 30 Post Study Vaccination | 
| Frequency of Any Serious Adverse Events (SAEs) | Safety measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 60 Post Study Vaccination | 
| Frequency of Any Serious Adverse Events (SAEs) | Safety measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 365 Post Study Vaccination | 
| Frequency of Any Unsolicited Adverse Events (AEs) | Safety measure. An AE associated with the receipt of of the study's COVID-19 mRNA vaccine and/or study mandated procedures. | Through Day 365 Post Study Vaccination | 
| Proportion of Participants Treated for Acute Cell-Mediated and/or Antibody-Mediated Allograft Rejection | Safety measure post receipt of the study's COVID-19 mRNA vaccine. | Through Day 60 Post Study Vaccination | 
| Proportion of Participants who Develop de Novo Donor-Specific Anti-Human Leukocyte Antigens (HLA) Antibody | Safety measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 60 Post Study Vaccination | 
| Proportion of Participants with Graft Loss | Safety measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 60 Post Study Vaccination | 
| Occurrence of Death Among Participants | Safety measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 60 Post Study Vaccination | 
| Frequency of Positive SARS-CoV-2 Test Results Using Real-Time Polymerase Chain Reaction (RT-PCR) | A nasal mid-turbinate swab for SARS-CoV-2 PCR testing will be collected prior to administration of the COVID-19, at specified timepoints after receipt of vaccination and, in any case of suspected COVID-19 infection. | Baseline (Day 0, Prior to Study Vaccination), Month 1, 3, 6, 9 and 12 | 
| Occurrence of Symptomatic COVID-19 | Efficacy measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 365 Post Study Vaccination | 
| Occurrence of COVID-19 Requiring Hospitalization | Efficacy measure after receipt of the study's COVID-19 mRNA vaccine. | Through Day 365 Post Study Vaccination | 
| Change from Baseline in Anti-SARS-CoV-2 Antibody Levels at Day 30 | Efficacy measure after receipt of the study's COVID-19 mRNA vaccine. | Baseline (Day 0, Prior to Study Vaccination),Day 30 After Study Vaccination | 
| Change from Baseline in SARS-CoV-2 Antibody Levels | Efficacy measure after receipt of the study's COVID-19 mRNA vaccine. | From Baseline (Day 0, Prior to Study Vaccination) to Day 365 Post Study Vaccination | 
| Fold Increase in SARS-CoV-2 Antibody Levels: Limited to Participants With Detectable Antibody Levels at Baseline (Day 0) | Efficacy measure after receipt of the study's COVID-19 mRNA vaccine. | Baseline (Day 0, Prior to Receipt of COVID-19 Study Vaccination), Day 30 After Study Vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mRNA COVID-19 vaccines, SARS-CoV-2 antibody response, immunosuppression (IS), coronavirus infectious disease 19, COVID-19, severe acute respiratory syndrome coronavirus type 2, SARS-CoV-2 protection