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
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 336
- 试验地点
- 4
- 主要终点
- Positive SARS-CoV-2 seroresponse
研究概览
简要总结
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
详细描述
- OBJECTIVES
Primary objective:
To assess the immunogenicity (expressed as percentage of responders) of various COVID-19 third or fourth vaccination strategies in kidney transplant patients that failed to mount a sufficient antibody response after two or three primary doses of a mRNA vaccine (either mRNA-1273 (Moderna) or BNT162b2 (Pfizer) or any combination of both).
Secondary Objectives:
- To measure the concentration of SARS-CoV-2 spike S1-specific IgG antibodies in serum at 28 days after the 3rd or 4th vaccine administration
- To measure the presence and titer of neutralizing anti-SARS-CoV-2 antibodies after third or fourth vaccination
- To evaluate SARS-CoV-2 specific T cell responses
- To measure anti-S1 antibody (IgG and IgA) responses and neutralizing capacity of these antibodies in nasal mucosal fluid
- To evaluate vaccine safety in terms of incidence of solicited local and systemic adverse events (AEs) graded according to severity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18 years or older
- •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.
- •At least 6 months after kidney transplantation
- •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.
- •Eligible for COVID-19 vaccination as described by the instructions of the manufacturers of the vaccine (Moderna and Janssen)
- •Capable of understanding the purpose and risks of the study, fully informed and given written informed consent (signed informed consent form has been obtained)
- •Willing to adhere to the protocol and be available during the study period
- •Additional inclusion criteria to be eligible for stratum A:
- •Maintenance immunosuppressive therapy consisting of a calcineurin inhibitor (tacrolimus or cyclosporine), MMF/MPA, and prednisone
- •In case of tacrolimus treatment: last tacrolimus pre-dose level while on current dosage above 4 μg/l
- •In case of cyclosporine treatment: last cyclosporine pre-dose level while on current dosage above 75 μg/l
- •Prednisone dose at least 5 mg/day
- •First or second transplantation
- •Calculated level of panel reactive antibodies prior to last transplantation below 85%
- •No signs of acute rejection during the preceding year
排除标准
- •Multi-organ transplant recipient
- •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).
- •Previous or active COVID-19 disease
- •Active malignancy, except non-melanoma skin cancer
- •Inherited immune deficiency
- •Infection with Human Immunodeficiency Virus (HIV)
- •Administration of T cell, B cell, or plasma cell depleting antibodies during the last 6 months
- •Any vaccination within a week before enrolment
- •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:
- •History of recurrent venous thrombosis or venous thrombosis <2 years before baseline
- •Immune-mediated diseases associated with thrombocytopenia such as ITP and aHUS
结局指标
主要结局
Positive SARS-CoV-2 seroresponse
时间窗: 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
次要结局
- Mucosal SARS-CoV-2 antibodies(28 days after vaccination)
- SARS-CoV-2 specific T cell response(28 days after vaccination)
- Serious adverse events(within 28 days after vaccination)
- SARS-CoV-2 antibody concentration(28 days after vaccination)
- Virus-neutralizing capacity of SARS-CoV-2 antibodies(28 days after vaccination)
- Solicited local and systemic adverse events(within 7 days after vaccination)
研究者
J.S.F. Sanders
MD PhD
University Medical Center Groningen