CPAT-ISR: COVID Protection After Transplant-Immunosuppression Reduction

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Recruiting
• CT.gov ID: NCT05077254
• Collaborator: PPD (Industry), Johns Hopkins University (Other)
• Enrollment: 400
• Locations: 15
• Arms: 4
• Anticipated Duration (Months): 20.8
• Patients Per Site: 26.7
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

This study will enroll individuals who have:

• Completed, at a minimum, a full 2-dose course but no more than 4 of either the Moderna messenger RNA (mRNA) based coronavirus infectious disease 19 (COVID-19) vaccine or the Pfizer-BioNTech mRNA based COVID-19 vaccine, and

• An antibody response ≤ 250 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.

Condition or Disease	Intervention/Treatment	Phase
Kidney Transplant Recipients; Liver Transplant Recipients	Biological: Pfizer-BioNTech COVID-19 Vaccine Booster; Biological: Moderna COVID-19 Vaccine Booster; Drug: SOC IS Regimen; Drug: SOC IS Reduction	Phase 2

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 ≤ 250 U/mL anti-spike antibody (as measured by the Roche Elecsys® anti-SARS-CoV-2 S assay) after at least two mRNA COVID-19 vaccines.

Participants will be randomized to either:

1. Receive an additional 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 an additional dose (booster) of mRNA-based COVID-19 vaccine.

Duration of study participation for interested and eligible individuals: 13 months.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants will be randomized to: An additional dose of COVID-19 vaccine only, or Immunosuppression (IS) reduction plus an additional dose of COVID-19 vaccine. IS reduction will be based on the participant's IS regimen upon study entry, in accordance with the study's protocol.Participants will be randomized to:An additional dose of COVID-19 vaccine only, or Immunosuppression (IS) reduction plus an additional dose of 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)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Dec 6, 2021
• Anticipated Primary Completion Date: Sep 1, 2022
• Anticipated Study Completion Date: Sep 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pfizer-BioNTech COVID-19 Vaccine Booster + SOC IS Regimen Participants will receive an additional dose (1 dose) of the Pfizer-BioNTech COVID-19 vaccine 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 Booster; Administration: One dose administered intramuscularly.; Other Names: Comirnaty® mRNA COVID-19 vaccine BNT162b2 mRNA COVID-19 vaccine SARS-CoV-2 RNA vaccine ; 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: Standard of Care transplant immunosuppression regimen Immunosuppression (IS) mycophenolate mofetil (MMF) or equivalent tacrolimus
Experimental: Pfizer-BioNTech COVID-19 Vaccine Booster+SOC IS Reduction Participants will receive an additional dose (1 dose) of the Pfizer-BioNTech COVID-19 vaccine, 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 Booster; Administration: One dose administered intramuscularly.; Other Names: Comirnaty® mRNA COVID-19 vaccine BNT162b2 mRNA COVID-19 vaccine SARS-CoV-2 RNA vaccine ; 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: Standard of Care (SOC) transplant immunosuppression regimen Immunosuppression (IS) Reduction mycophenolate mofetil (MMF) or equivalent tacrolimus
Experimental: Moderna COVID-19 Vaccine Booster + SOC IS Regimen Participants will receive an additional dose (1 dose) of the Moderna COVID-19 Vaccine 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 Booster; Administration: One dose administered intramuscularly.; Other Names: mRNA COVID-19 vaccine Moderna COVID-19 vaccine SARS-CoV-2 vaccine ; 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: Standard of Care transplant immunosuppression regimen Immunosuppression (IS) mycophenolate mofetil (MMF) or equivalent tacrolimus
Experimental: Moderna COVID-19 Vaccine Booster +SOC IS Reduction Participants will receive an additional dose (1 dose) of the Moderna COVID-19 vaccine, 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 Booster; Administration: One dose administered intramuscularly.; Other Names: mRNA COVID-19 vaccine Moderna COVID-19 vaccine SARS-CoV-2 vaccine ; 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: Standard of Care (SOC) transplant immunosuppression regimen Immunosuppression (IS) Reduction mycophenolate mofetil (MMF) or equivalent tacrolimus

Outcome Measures

Primary Outcome Measures

1. 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. [Day 30 After Study Vaccination]

   Serum antibody titer will be measured using the Roche Elecsys®) severe acute respiratory syndrome coronavirus type 2 serological (anti-SARS-CoV-2) S assay.

Secondary Outcome Measures

1. Frequency of Solicited Local Reactogenicity Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine [Through Day 7 Post Study Vaccination]

   Safety measure after receipt of the study's COVID-19 mRNA vaccine.

2. Frequency of Solicited Local Allergic Reaction Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine [Through Day 7 Post Study Vaccination]

   Safety measure after receipt of the study's COVID-19 mRNA vaccine.

3. Frequency of Solicited Systemic Reactogenicity Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine [Through Day 7 Post Study Vaccination]

   Safety measure after receipt of the study's COVID-19 mRNA vaccine.

4. Frequency of Solicited Systemic Allergic Reaction Adverse Events (AEs) to the mRNA-Based COVID-19 Vaccine [Through Day 7 Post Study Vaccination]

   Safety measure after receipt of the study's COVID-19 mRNA vaccine.

5. Frequency of Any Serious Adverse Events (SAEs) [Through Day 30 Post Study Vaccination]

   Safety measure after receipt of the study's COVID-19 mRNA vaccine.

6. Frequency of Any Unsolicited Adverse Events (AEs) [Through Day 30 Post Study Vaccination]

   Safety measure. An AE associated with the receipt of the study's COVID-19 mRNA vaccine and/or study mandated procedures.

7. Frequency of Any Serious Adverse Events (SAEs) [Through Day 60 Post Study Vaccination]

   Safety measure after receipt of the study's COVID-19 mRNA vaccine.

8. Frequency of Any Serious Adverse Events (SAEs) [Through Day 365 Post Study Vaccination]

   Safety measure after receipt of the study's COVID-19 mRNA vaccine.

9. Frequency of Any Unsolicited Adverse Events (AEs) [Through Day 365 Post Study Vaccination]

   Safety measure. An AE associated with the receipt of of the study's COVID-19 mRNA vaccine and/or study mandated procedures.

10. Proportion of Participants Treated for Acute Cell-Mediated and/or Antibody-Mediated Allograft Rejection [Through Day 60 Post Study Vaccination]

    Safety measure post receipt of the study's COVID-19 mRNA vaccine.

11. Proportion of Participants who Develop de Novo Donor-Specific Anti-Human Leukocyte Antigens (HLA) Antibody [Through Day 60 Post Study Vaccination]

    Safety measure after receipt of the study's COVID-19 mRNA vaccine.

12. Proportion of Participants with Graft Loss [Through Day 60 Post Study Vaccination]

    Safety measure after receipt of the study's COVID-19 mRNA vaccine.

13. Occurrence of Death Among Participants [Through Day 60 Post Study Vaccination]

    Safety measure after receipt of the study's COVID-19 mRNA vaccine.

14. Frequency of Positive SARS-CoV-2 Test Results Using Real-Time Polymerase Chain Reaction (RT-PCR) [Baseline (Day 0, Prior to Study Vaccination), Month 1, 3, 6, 9 and 12]

    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.

15. Occurrence of Symptomatic COVID-19 [Through Day 365 Post Study Vaccination]

    Efficacy measure after receipt of the study's COVID-19 mRNA vaccine.

16. Occurrence of COVID-19 Requiring Hospitalization [Through Day 365 Post Study Vaccination]

    Efficacy measure after receipt of the study's COVID-19 mRNA vaccine.

17. Change from Baseline in Anti-SARS-CoV-2 Antibody Levels at Day 30 [Baseline (Day 0, Prior to Study Vaccination),Day 30 After Study Vaccination]

    Efficacy measure after receipt of the study's COVID-19 mRNA vaccine.

18. Change from Baseline in SARS-CoV-2 Antibody Levels [From Baseline (Day 0, Prior to Study Vaccination) to Day 365 Post Study Vaccination]

    Efficacy measure after receipt of the study's COVID-19 mRNA vaccine.

19. Fold Increase in SARS-CoV-2 Antibody Levels: Limited to Participants With Detectable Antibody Levels at Baseline (Day 0) [Baseline (Day 0, Prior to Receipt of COVID-19 Study Vaccination), Day 30 After Study Vaccination]

    Efficacy measure after receipt of the study's COVID-19 mRNA vaccine.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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. Recipient of a kidney or liver transplant ≥12 months prior to enrollment, without allograft rejection in the 6 months preceding enrollment

3. Negative for anti-donor human leukocyte antigens (HLA) antibodies at screening (Central Lab Test Determination).

4. Currently taking one of the following calcineurin inhibitors (CNI)-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

1. Received a minimum of 2 and no more than 4 doses of either the Moderna coronavirus infectious disease 19 (COVID-19) vaccine or Pfizer-BioNTech COVID-19 vaccine at least 30 days prior to study entry

2. Serum antibody negative or low (titer ≤ 250 U/mL) at ≥ 30 days from the last dose of mRNA COVID-19 vaccine, measured using the Roche Elecsys®) severe acute respiratory syndrome coronavirus type 2 serological (anti-SARS-CoV-2) S assay, and

3. 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. Currently taking any systemic immunosuppressive agent, other than their prescribed transplant immunosuppression

6. Recipients of any COVID-19 vaccine other than the Moderna COVID-19 vaccine or the Pfizer-BioNTech COVID-19 vaccine

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)

1. Treatment or prophylaxis of COVID-19 with a monoclonal antibody product or convalescent plasma within 6 months preceding enrollment, or

2. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	San Diego	California	United States	92093
2	University of California San Francisco Health	San Francisco	California	United States	94143
3	Emory Healthcare	Atlanta	Georgia	United States	30322
4	University of Illinois Health	Chicago	Illinois	United States	60612
5	Northwestern University	Evanston	Illinois	United States	60208
6	University of Iowa Hospitals	Iowa City	Iowa	United States	52242
7	Ochsner Health	New Orleans	Louisiana	United States	70121
8	Johns Hopkins Institute for Clinical and Translational Research: Broadway Adult Outpatient Clinical Research Unit	Baltimore	Maryland	United States	21287
9	NYU Langone Transplant Institute	New York	New York	United States	10016
10	Mt. Sinai Hospital	New York	New York	United States	10029
11	Weill Cornell Medicine	New York	New York	United States	10065
12	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
13	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15260
14	Houston Methodist	Houston	Texas	United States	77030
15	University of Wisconsin-Madison	Madison	Wisconsin	United States	53706

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• PPD
• Johns Hopkins University

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT05077254
• Other Study ID Numbers: DAIT COVID19-TB-03; U01AI138897; NIAID CRMS ID#: 38892
• First Posted: Oct 14, 2021
• Last Update Posted: Jun 22, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): 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
• Additional relevant MeSH terms: Mycophenolic Acid; Vaccines; Tacrolimus

Study Results

No Results Posted as of Jun 22, 2022