Covid19 Clinical Trial
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
Verified date | March 2022 |
Source | University Medical Center Groningen |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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
Status | Completed |
Enrollment | 336 |
Est. completion date | March 12, 2022 |
Est. primary completion date | March 12, 2022 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
Netherlands | Amsterdam UMC | Amsterdam | Noord-Holland |
Netherlands | University Medical Center Groningen | Groningen | |
Netherlands | Radboud umc | Nijmegen | Gelderland |
Netherlands | Erasmus mc | Rotterdam | Zuid-Holland |
Lead Sponsor | Collaborator |
---|---|
University Medical Center Groningen | Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Erasmus Medical Center, Radboud University Medical Center, ZonMw: The Netherlands Organisation for Health Research and Development |
Netherlands,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Relation between age and immune response | The association between age and development of an antibody and/or T cell response after third or fourth vaccine administration | 28 days after vaccination | |
Other | Relationship between time after transplant and immune response | The association between time after transplantation and development of an antibody and/or T cell response after third or fourth vaccine administration | 28 days after vaccination | |
Other | Relationship between immunosuppressive medication and immune response | The association between baseline immunosuppressive medication and development of an antibody and/or T cell response after third or fourth vaccine administration | 28 days after vaccination | |
Other | Relationship between lymphocytes and immune response | The association between baseline lymphocytes and development of an antibody and/or T cell response after third or fourth vaccine administration | 28 days after vaccination | |
Other | Relationship between eGFR and immune response | The association between baseline eGFR and development of an antibody and/or T cell response after third or fourth vaccine administration | 28 days after vaccination | |
Other | SARS-CoV-2 reactive CD4+ and CD8+ cells | Flow cytometry of PBMC for measuring SARS-CoV-2 reactive CD4+ and CD8+ cells after third or fourth vaccine administration | 28 days after vaccination | |
Other | Early gene expression for SARS-CoV-2 immune response | 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 | 28 days after vaccination | |
Other | Incidence of COVID-19 breakthrough infection | Measured by questionnaires and SARS-CoV-2 nucleocapsid specific antibodies | 28 days after vaccination | |
Primary | Positive SARS-CoV-2 seroresponse | The percentage of subjects with a serum anti-S1 IgG concentration =10 BAU/mL after the third or fourth vaccine administration | 28 days after third vaccination | |
Secondary | SARS-CoV-2 antibody concentration | SARS-CoV-2 anti-S1 IgG concentration in serum after third or fourth vaccine administration | 28 days after vaccination | |
Secondary | Virus-neutralizing capacity of SARS-CoV-2 antibodies | The titer of neutralizing anti-SARS-CoV-2 antibodies after third or fourth vaccine administration | 28 days after vaccination | |
Secondary | Mucosal SARS-CoV-2 antibodies | Concentrations of SARS-CoV-2 specific antibodies (IgG and IgA) in nasal fluid after third or fourth vaccine administration | 28 days after vaccination | |
Secondary | SARS-CoV-2 specific T cell response | Interferon-gamma concentration in whole blood after ex vivo stimulation with SARS-CoV-2 specific peptides
Ex vivo production of T cell related cytokines by peripheral blood mononuclear cells (PBMC) in ELISpot assays after third vaccine administration |
28 days after vaccination | |
Secondary | Solicited local and systemic adverse events | 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 | within 7 days after vaccination | |
Secondary | Serious adverse events | Percentage of participants with serious adverse events after third or fourth vaccine administration | within 28 days after vaccination |
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