COVID Protection After Transplant-Immunosuppression Reduction (CPAT-ISR)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Liver Transplant Recipients; Kidney Transplant Recipients
• Intervention / Treatment: Drug: SOC IS Regimen; Drug: SOC IS Reduction; Biological: Pfizer-BioNTech COVID-19 Vaccine 2023-2024; Biological: Moderna COVID-19 Vaccine 2023-2024

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.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92093
      • University of California, San Diego
    • San Francisco, California, United States, 94143
      • University of California San Francisco Health
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Healthcare
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois Health
    • Evanston, Illinois, United States, 60208
      • Northwestern University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Health
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Institute for Clinical and Translational Research: Broadway Adult Outpatient Clinical Research Unit
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medicine
    • New York, New York, United States, 10029
      • Mt. Sinai Hospital
    • New York, New York, United States, 10016
      • NYU Langone Transplant Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist
  • Wisconsin
    • Madison, Wisconsin, United States, 53706
      • University of Wisconsin-Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pfizer-BioNTech COVID-19 Vaccine 2023-2024 + SOC IS Regimen; 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	Drug: SOC IS Regimen; Participants will continue to take their prescribed immunosuppression (IS) medications without alterations in schedule and dosing, per protocol instruction.; Other Names: tacrolimus; Standard of Care transplant immunosuppression regimen; Immunosuppression (IS); mycophenolate mofetil (MMF) or equivalent; Biological: Pfizer-BioNTech COVID-19 Vaccine 2023-2024; Administration: One dose administered intramuscularly.; Other Names: Comirnaty; SARS-CoV-2 RNA vaccine; mRNA COVID-19 vaccine; BNT162b2 mRNA COVID-19 vaccine
Experimental: Pfizer-BioNTech COVID-19 Vaccine 2023-2024 + SOC IS Reduction; 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	Drug: SOC IS Reduction; Participants will reduce their standard of care immunosuppression medications (IS) before and after the COVID-19 vaccine booster (1 dose), per protocol instruction.; Other Names: tacrolimus; mycophenolate mofetil (MMF) or equivalent; Standard of Care (SOC) transplant immunosuppression regimen; Immunosuppression (IS) Reduction; Biological: Pfizer-BioNTech COVID-19 Vaccine 2023-2024; Administration: One dose administered intramuscularly.; Other Names: Comirnaty; SARS-CoV-2 RNA vaccine; mRNA COVID-19 vaccine; BNT162b2 mRNA COVID-19 vaccine
Experimental: Moderna COVID-19 Vaccine 2023-2024 + SOC IS Regimen; 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	Drug: SOC IS Regimen; Participants will continue to take their prescribed immunosuppression (IS) medications without alterations in schedule and dosing, per protocol instruction.; Other Names: tacrolimus; Standard of Care transplant immunosuppression regimen; Immunosuppression (IS); mycophenolate mofetil (MMF) or equivalent; Biological: Moderna COVID-19 Vaccine 2023-2024; Administration: One dose administered intramuscularly.; Other Names: Moderna COVID-19 vaccine; Spikevax; mRNA COVID-19 vaccine; SARS-CoV-2 vaccine
Experimental: Moderna COVID-19 Vaccine 2023-2024 + SOC IS Reduction; 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	Drug: SOC IS Reduction; Participants will reduce their standard of care immunosuppression medications (IS) before and after the COVID-19 vaccine booster (1 dose), per protocol instruction.; Other Names: tacrolimus; mycophenolate mofetil (MMF) or equivalent; Standard of Care (SOC) transplant immunosuppression regimen; Immunosuppression (IS) Reduction; Biological: Moderna COVID-19 Vaccine 2023-2024; Administration: One dose administered intramuscularly.; Other Names: Moderna COVID-19 vaccine; Spikevax; mRNA COVID-19 vaccine; SARS-CoV-2 vaccine

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Johns Hopkins University; PPD
• Investigators: Study Chair: Dorry L. Segev, MD, PhD, Transplant Surgery, Johns Hopkins University School of Medicine; Study Chair: Peter S. Heeger, MD, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai; Study Chair: Christian P. Larsen, MD, DPhil, Emory Transplant Center, Emory University School of Medicine

Publications and helpful links

General Publications

• 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.

Helpful Links

• Division of Allergy, Immunology, and Transplantation
• National Institute of Allergy and Infectious Diseases

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2021
• Primary Completion (Actual): February 28, 2024
• Study Completion (Estimated): March 4, 2025

Study Registration Dates

• First Submitted: October 12, 2021
• First Submitted That Met QC Criteria: October 12, 2021
• First Posted (Actual): October 14, 2021

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: COVID-19; SARS-CoV-2 antibody response; immunosuppression (IS); mRNA COVID-19 vaccines; coronavirus infectious disease 19; severe acute respiratory syndrome coronavirus type 2; SARS-CoV-2 protection
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Vaccines; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: DAIT COVID19-TB-03; U01AI138897 (U.S. NIH Grant/Contract); NIAID CRMS ID#: 38892 (Other Identifier: DAIT NIAID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
• IPD Sharing Time Frame: On average, within 24 months after database lock for the trial.
• IPD Sharing Access Criteria: Open access.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No