Clinical trial NCT05077254: COVID Protection After Transplant-Immunosuppression Reduction
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Kidney Transplant Recipients
Liver Transplant Recipients
Keywords: 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
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: PPD Development, LP
name: Johns Hopkins University
First posted: 2021-10-14
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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:

1. Receive a study dose of mRNA based COVID-19 vaccine (booster) with no change in their immunosuppressive regimen, or
2. 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.

Eligibility criteria: Inclusion Criteria:

Individuals who meet all the following criteria are eligible for enrollment as study participants-

1. Able to understand and provide informed consent
2. Individual ≥18 years of age.
3. Recipient of a kidney or liver transplant ≥12 months prior to enrollment, without allograft rejection in the 6 months preceding enrollment
4. Negative for anti-donor human leukocyte antigens (HLA) antibodies at screening (Central Lab Test Determination).
5. 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
6. Received a minimum of 3 doses of either the Moderna coronavirus infectious disease 19 (COVID-19) vaccine or Pfizer-BioNTech COVID-19 vaccine
7. 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.
8. 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.
9. 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-

1. 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
2. Recipient of any allograft other than a kidney or liver
3. Participant is pregnant
4. Any past history of Donor Specific Antibody (DSA) using local site standards
5. Prior receipt of the Moderna COVID-19 Vaccine 2023-2024 or Pfizer-BioNTech COVID-19 Vaccine 2023-2024.
6. Currently taking any systemic immunosuppressive agent, other than their prescribed transplant immunosuppression
7. Known history of severe allergic reaction to any component of an authorized or licensed COVID-19 vaccine
8. Thrombotic events, myocarditis, or pericarditis temporally associated with a prior dose of COVID-19 vaccine
9. History of heparin-induced thrombocytopenia
10. Any change in transplant immunosuppression regimen (drug or dose) in response to suspected or proven rejection within the last 6 months
11. More than minimal graft dysfunction, in accordance with study definition
12. Receipt of any cellular depleting agent (e.g. antithymocyte globulins (ATG), rituximab, alemtuzumab, Cyclophosphamide) within 12 months preceding enrollment
13. Concurrent autoimmune disease at risk for exacerbation with immunosuppression reduction
14. Any untreated active infection including BK viremia \>10\^4 copies
15. Infection with human immunodeficiency virus (HIV)
16. 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)
17. Treatment or prophylaxis of COVID-19 with a monoclonal antibody product or convalescent plasma within 6 months preceding enrollment, or
18. 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.

Primary outcomes:
measure: 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.
timeFrame: Day 30 After Study Vaccination
Secondary outcomes:
measure: Frequency of Solicited Local Reactogenicity Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine
timeFrame: Through Day 7 Post Study Vaccination
measure: Frequency of Solicited Local Allergic Reaction Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine
timeFrame: Through Day 7 Post Study Vaccination
measure: Frequency of Solicited Systemic Reactogenicity Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine
timeFrame: Through Day 7 Post Study Vaccination
measure: Frequency of Solicited Systemic Allergic Reaction Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine
timeFrame: Through Day 7 Post Study Vaccination
measure: Frequency of Any Serious Adverse Events (SAEs)
timeFrame: Through Day 30 Post Study Vaccination
measure: Frequency of Any Unsolicited Adverse Events (AEs)
timeFrame: Through Day 30 Post Study Vaccination
measure: Frequency of Any Serious Adverse Events (SAEs)
timeFrame: Through Day 60 Post Study Vaccination
measure: Frequency of Any Serious Adverse Events (SAEs)
timeFrame: Through Day 365 Post Study Vaccination
measure: Frequency of Any Unsolicited Adverse Events (AEs)
timeFrame: Through Day 365 Post Study Vaccination
measure: Proportion of Participants Treated for Acute Cell-Mediated and/or Antibody-Mediated Allograft Rejection
timeFrame: Through Day 60 Post Study Vaccination
measure: Proportion of Participants who Develop de Novo Donor-Specific Anti-Human Leukocyte Antigens (HLA) Antibody
timeFrame: Through Day 60 Post Study Vaccination
measure: Proportion of Participants with Graft Loss
timeFrame: Through Day 60 Post Study Vaccination
measure: Occurrence of Death Among Participants
timeFrame: Through Day 60 Post Study Vaccination
measure: Frequency of Positive SARS-CoV-2 Test Results Using Real-Time Polymerase Chain Reaction (RT-PCR)
timeFrame: Baseline (Day 0, Prior to Study Vaccination), Month 1, 3, 6, 9 and 12
measure: Occurrence of Symptomatic COVID-19
timeFrame: Through Day 365 Post Study Vaccination
measure: Occurrence of COVID-19 Requiring Hospitalization
timeFrame: Through Day 365 Post Study Vaccination
measure: Change from Baseline in Anti-SARS-CoV-2 Antibody Levels at Day 30
timeFrame: Baseline (Day 0, Prior to Study Vaccination),Day 30 After Study Vaccination
measure: Change from Baseline in SARS-CoV-2 Antibody Levels
timeFrame: From Baseline (Day 0, Prior to Study Vaccination) to Day 365 Post Study Vaccination
measure: Fold Increase in SARS-CoV-2 Antibody Levels: Limited to Participants With Detectable Antibody Levels at Baseline (Day 0)
timeFrame: Baseline (Day 0, Prior to Receipt of COVID-19 Study Vaccination), Day 30 After Study Vaccination
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Health
state: California
city: Atlanta
country: United States
facility: Emory Healthcare
state: Georgia
city: Chicago
country: United States
facility: University of Illinois Health
state: Illinois
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals
state: Iowa
city: New Orleans
country: United States
facility: Ochsner Health
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Institute for Clinical and Translational Research: Broadway Adult Outpatient Clinical Research Unit
state: Maryland
city: New York
country: United States
facility: NYU Langone Transplant Institute
state: New York
city: New York
country: United States
facility: Mt. Sinai Hospital
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: Houston Methodist
state: Texas
city: Madison
country: United States
facility: University of Wisconsin-Madison
state: Wisconsin
Study officials:
affiliation: Transplant Surgery, Johns Hopkins University School of Medicine
name: Dorry L. Segev, MD, PhD
role: STUDY_CHAIR
affiliation: Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai
name: Peter S. Heeger, MD
role: STUDY_CHAIR
affiliation: Emory Transplant Center, Emory University School of Medicine
name: Christian P. Larsen, MD, DPhil
role: STUDY_CHAIR
References:
citation: Werbel WA, Boyarsky BJ, Ou MT, Massie AB, Tobian AAR, Garonzik-Wang JM, Segev DL. Safety and Immunogenicity of a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series. Ann Intern Med. 2021 Sep;174(9):1330-1332. doi: 10.7326/L21-0282. Epub 2021 Jun 15. No abstract available.