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RECOVAC Repeated Vaccination Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05030974
Recruitment Status : Completed
First Posted : September 1, 2021
Last Update Posted : March 29, 2022
Sponsor:
Collaborators:
Radboud University Medical Center
Erasmus Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
J.S.F. Sanders, University Medical Center Groningen

Brief Summary:

Rationale: The humoral and cellular immune response after two mRNA vaccinations is severely attenuated in kidney transplant patients compared to controls, especially when their immunosuppressive regimen contains mycophenolate mofetil (MMF) / mycophenolic acid (MPA). A repeated dose strategy is therefore required to improve the efficacy of vaccination.

Objective: To investigate the immunogenicity of third or fourth dose SARS-CoV-2 vaccination strategies in kidney transplant patients.

Study design: Prospective, multicentre, open-label randomized clinical trial

Study population: Patients with a functioning kidney transplant who did not seroconvert after two or three doses of a mRNA vaccine (either mRNA-1273 (Moderna) or BNT162b2 (Pfizer) or any combination of both)

Procedures:

Based on their immunosuppressive treatment, patients can participate in one of the following strata:

  • stratum A: patients receiving triple immunosuppressive therapy, consisting of a calcineurin inhibitor, MMF/MPA, and steroids In stratum A, patients will be randomized to one of two equally sized groups. Patients will receive a third or fourth vaccination of the mRNA-1273 vaccine (100 μg, i.m), with either continuation of MMF/MPA (A1) or discontinuation of MMF/MPA during one week before and one week after the third or fourth dose, respectively (A2).
  • stratum B: patients receiving any combination of immunosuppressive drugs. In stratum B, patients will be randomized to one of three equally sized groups. Patients will receive another dose (100 μg, i.m) of the mRNA-1273 vaccine (B1), or two single doses of mRNA-1273 into the left and the right upper arm (2 x 100 μg, i.m; B2), or the Ad26.COV2.S vaccine (Janssen, 5x1010 viral particles, i.m; B3).

Main study parameters/endpoints:

The primary endpoint is the proportion of patients with an anti-S1 antibody concentration higher than 10 BAU/mL established at 28 days after the third or fourth vaccine administration. Within each stratum different vaccination strategies will be compared.

Secondary endpoints include:

  • concentration of anti-S1 antibodies in serum at 28 days after the 3rd or 4th vaccine administration
  • concentration of virus-neutralizing antibodies in serum
  • SARS-CoV-2 specific T cell responses
  • safety in terms of incidence of acute rejection and solicited local and systemic adverse events (AEs) after vaccination.
  • antibody (IgG and IgA) responses in nasal mucosal fluid

Condition or disease Intervention/treatment Phase
Covid19 Kidney Diseases Vaccine Response Impaired SARS-CoV2 Infection Biological: mRNA-1273 Biological: Ad26.COV2.S vaccine Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 336 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Based on their immunosuppressive treatment, patients will participate in one of the following strata:

  • stratum A: patients treated with triple immunosuppressive therapy consisting of a calcineurin inhibitor, MMF/MPA, and steroids,
  • stratum B: patients treated with any combination of immunosuppressive drugs.

In stratum A, patients will be randomized to one of two third or fourth vaccination strategies:

  • A1: one extra dose of mRNA-1273 (100 μg, i.m)
  • A2: one extra dose of mRNA-1273 (100 μg, i.m), with temporary discontinuation of MMF/MPA during one week before and one week after the 3rd dose

In stratum B, patients will be randomized to one of three third vaccination strategies:

  • B1: 3rd dose of mRNA-1273 (100 μg, i.m)
  • B2: 3rd dose of mRNA-1273 (100 μg, i.m) in both upper arms
  • B3: Ad26.COV2.S vaccine (Janssen, 5x1010 viral particles i.m.)
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Optimal Repeated Dose Strategy for SARS-CoV-2 Vaccination in Kidney Transplant Patients A Prospective, Randomized Multicenter Study by the REnal Patients COVID-19 VACcination (RECOVAC) Consortium
Actual Study Start Date : October 21, 2021
Actual Primary Completion Date : March 12, 2022
Actual Study Completion Date : March 12, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vaccines

Arm Intervention/treatment
Active Comparator: stratum A1 - one extra dose of mRNA-1273
Patients treated with triple immunosuppressive therapy consisting of a calcineurin inhibitor, MMF/MPA, and steroids, receiving a 3rd or 4th dose of mRNA-1273 (100 μg, i.m)
Biological: mRNA-1273
SARS-CoV-2 vaccination

Active Comparator: stratum A2 - one extra dose of mRNA-1273 with discontinuation of MMF/MPA
patients treated with triple immunosuppressive therapy consisting of a calcineurin inhibitor, MMF/MPA, and steroids, receiving a 3rd or 4th dose of mRNA-1273 (100 μg, i.m), with temporary discontinuation of MMF/MPA during one week before and one week after the extra dose
Biological: mRNA-1273
SARS-CoV-2 vaccination

Active Comparator: stratum B1 - 3rd dose of mRNA-1273
patients treated with any combination of immunosuppressive drugs, receiving a 3rd dose of mRNA-1273 (100 μg, i.m)
Biological: mRNA-1273
SARS-CoV-2 vaccination

Active Comparator: statum B2 - 3rd double dose of mRNA-1273
patients treated with any combination of immunosuppressive drugs, receiving a 3rd dose of mRNA-1273 (100 μg, i.m) in both upper arms
Biological: mRNA-1273
SARS-CoV-2 vaccination

Active Comparator: stratum B3 - Ad26.COV2.S vaccine
patients treated with any combination of immunosuppressive drugs, receiving a 3rd COVID vaccination with Ad26.COV2.S vaccine (Janssen, 5x1010 viral particles i.m.)
Biological: Ad26.COV2.S vaccine
SARS-CoV-2 vaccination




Primary Outcome Measures :
  1. Positive SARS-CoV-2 seroresponse [ Time Frame: 28 days after third vaccination ]
    The percentage of subjects with a serum anti-S1 IgG concentration ≥10 BAU/mL after the third or fourth vaccine administration


Secondary Outcome Measures :
  1. SARS-CoV-2 antibody concentration [ Time Frame: 28 days after vaccination ]
    SARS-CoV-2 anti-S1 IgG concentration in serum after third or fourth vaccine administration

  2. Virus-neutralizing capacity of SARS-CoV-2 antibodies [ Time Frame: 28 days after vaccination ]
    The titer of neutralizing anti-SARS-CoV-2 antibodies after third or fourth vaccine administration

  3. Mucosal SARS-CoV-2 antibodies [ Time Frame: 28 days after vaccination ]
    Concentrations of SARS-CoV-2 specific antibodies (IgG and IgA) in nasal fluid after third or fourth vaccine administration

  4. SARS-CoV-2 specific T cell response [ Time Frame: 28 days after vaccination ]
    1. Interferon-gamma concentration in whole blood after ex vivo stimulation with SARS-CoV-2 specific peptides
    2. Ex vivo production of T cell related cytokines by peripheral blood mononuclear cells (PBMC) in ELISpot assays after third vaccine administration

  5. Solicited local and systemic adverse events [ Time Frame: within 7 days after vaccination ]
    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 third or fourth vaccine administration

  6. Serious adverse events [ Time Frame: within 28 days after vaccination ]
    Percentage of participants with serious adverse events after third or fourth vaccine administration


Other Outcome Measures:
  1. Relation between age and immune response [ Time Frame: 28 days after vaccination ]
    The association between age and development of an antibody and/or T cell response after third or fourth vaccine administration

  2. Relationship between time after transplant and immune response [ Time Frame: 28 days after vaccination ]
    The association between time after transplantation and development of an antibody and/or T cell response after third or fourth vaccine administration

  3. Relationship between immunosuppressive medication and immune response [ Time Frame: 28 days after vaccination ]
    The association between baseline immunosuppressive medication and development of an antibody and/or T cell response after third or fourth vaccine administration

  4. Relationship between lymphocytes and immune response [ Time Frame: 28 days after vaccination ]
    The association between baseline lymphocytes and development of an antibody and/or T cell response after third or fourth vaccine administration

  5. Relationship between eGFR and immune response [ Time Frame: 28 days after vaccination ]
    The association between baseline eGFR and development of an antibody and/or T cell response after third or fourth vaccine administration

  6. SARS-CoV-2 reactive CD4+ and CD8+ cells [ Time Frame: 28 days after vaccination ]
    Flow cytometry of PBMC for measuring SARS-CoV-2 reactive CD4+ and CD8+ cells after third or fourth vaccine administration

  7. Early gene expression for SARS-CoV-2 immune response [ Time Frame: 28 days after vaccination ]
    RNA-seq analysis to detect early gene expression that are associated with the development of an antibody and/or T cell response after third or fourth vaccine administration

  8. Incidence of COVID-19 breakthrough infection [ Time Frame: 28 days after vaccination ]
    Measured by questionnaires and SARS-CoV-2 nucleocapsid specific antibodies



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 years or older
  2. Received 2 doses of mRNA-1273 (stratum B) according to the recommended vaccination schedule, with the last administration within the last nine months. For stratum A, also patients who received 2 doses of BNT162b2 and/or a third dose with a mRNA vaccine (mRNA-1273 or BNT162b2) within the last three months are eligible.
  3. At least 6 months after kidney transplantation
  4. Negative seroresponse 14 to 56 days after vaccination, measured by a validated anti-spike IgG assay of which the definition is dependent on the assay that is used.
  5. Eligible for COVID-19 vaccination as described by the instructions of the manufacturers of the vaccine (Moderna and Janssen)
  6. Capable of understanding the purpose and risks of the study, fully informed and given written informed consent (signed informed consent form has been obtained)
  7. Willing to adhere to the protocol and be available during the study period

    Additional inclusion criteria to be eligible for stratum A:

  8. Maintenance immunosuppressive therapy consisting of a calcineurin inhibitor (tacrolimus or cyclosporine), MMF/MPA, and prednisone
  9. In case of tacrolimus treatment: last tacrolimus pre-dose level while on current dosage above 4 μg/l
  10. In case of cyclosporine treatment: last cyclosporine pre-dose level while on current dosage above 75 μg/l
  11. Prednisone dose at least 5 mg/day
  12. First or second transplantation
  13. Calculated level of panel reactive antibodies prior to last transplantation below 85%
  14. No signs of acute rejection during the preceding year

Exclusion Criteria:

  1. Multi-organ transplant recipient
  2. 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).
  3. Previous or active COVID-19 disease
  4. Active malignancy, except non-melanoma skin cancer
  5. Inherited immune deficiency
  6. Infection with Human Immunodeficiency Virus (HIV)
  7. Administration of T cell, B cell, or plasma cell depleting antibodies during the last 6 months
  8. Any vaccination within a week before enrolment
  9. Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection.

    Additional exclusion criteria for stratum B:

  10. History of recurrent venous thrombosis or venous thrombosis <2 years before baseline
  11. Immune-mediated diseases associated with thrombocytopenia such as ITP and aHUS

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05030974


Locations
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Netherlands
Radboud umc
Nijmegen, Gelderland, Netherlands
Amsterdam UMC
Amsterdam, Noord-Holland, Netherlands
Erasmus mc
Rotterdam, Zuid-Holland, Netherlands
University Medical Center Groningen
Groningen, Netherlands
Sponsors and Collaborators
University Medical Center Groningen
Radboud University Medical Center
Erasmus Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
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Principal Investigator: Jan-Stephan F Sanders, MD PhD University Medical Center Groningen
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: J.S.F. Sanders, MD PhD, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT05030974    
Other Study ID Numbers: NL78963.042.21
First Posted: September 1, 2021    Key Record Dates
Last Update Posted: March 29, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: The data of this study will be available from the principal investigator, upon reasonable request.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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COVID-19
Kidney Diseases
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Urologic Diseases