Prospective Randomized Trial of Everolimus Replacing MMF/MP Acid by the RECOVAC Consortium to Increase VACcine Response in Kidney Transplant Patients
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 110
- 试验地点
- 7
- 主要终点
- Virus-neutralizing capacity of SARS-CoV-2 antibodies
研究概览
简要总结
Objective: To investigate whether replacement of MMF/MPA by everolimus in kidney transplant recipients results in superior immunogenicity of COVID-19 vaccination as measured by neutralizing antibody titer against the Omicron XBB.1.5 strain.
Trial design: Multicentre, open-label randomized controlled clinical trial, for a duration of at least 10 weeks with an optional extension to 18 weeks.
Trial population: Kidney transplant recipients, 18 years or older, who are at least 6 months after transplantation, with a functioning kidney transplant, using MMF/MPA in combination with at least one other immunosuppressant including a calcineurin inhibitor (CNI), with at least 3 previous COVID-19 vaccinations (=basic COVID-19 immunisation).
Interventions:
Patients will be randomized into one of two equally sized groups, with either continuation of their current immunosuppressive regimen including MMF/MPA or replacement of MMF/MPA by everolimus during at least six weeks before until four weeks after the last vaccination. Patients will receive a repeated COVID-19 vaccination with the monovalent Omicron XBB.1.5 vaccine, 28 days thereafter they can opt to also receive two herpes zoster vaccinations with the Recombinant Zoster Vaccine (RZV) with an interval between the first and second dose of 28 days.
Main trial endpoints:
The neutralizing antibody titer against the Omicron XBB.1.5. strain 28 days after monovalent Omicron XBB.1.5 COVID-19 vaccination in patients continuing MMF/MPA compared to patients who switched to everolimus.
Secondary trial endpoints:
- SARS-CoV-2 specific anti-S1 antibody level at 28 and 56 days after COVID-19 vaccination
- Varicella zoster specific anti-gE antibody level 28 days after 1st and 2nd herpes zoster vaccination
- SARS-CoV-2 specific T-cell response 28 days after COVID-19 vaccination
- Varicella zoster specific T-cell response 28 days after 2nd herpes zoster vaccination
- Safety in terms of incidence of acute rejection, kidney function decline, SAEs, AESIs and solicited local and systemic AEs after COVID-19 and herpes zoster vaccination
详细描述
Rationale: The immunogenicity after vaccination against SARS-CoV-2 and other pathogens is diminished in kidney transplant recipients. This patient group therefore remains extremely vulnerable for viral infections despite vaccination. This impaired immune response is related to the use of immunosuppressive agents, especially Mycophenolate Mofetil/Mycophenolic Acid (MMF/MPA). Patients that use everolimus instead of MMF/MPA elicit a higher immune response after vaccination.
Objective
Primary objective:
To investigate whether replacement of MMF/MPA by everolimus in kidney transplant recipients results in superior immunogenicity of COVID-19 vaccination as measured by neutralizing antibody titer against the Omicron XBB.1.5 strain.
Secondary objectives:
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
- •≥6 months after kidney transplantation
- •Maintenance immunosuppressive therapy consisting of either triple or dual therapy including MMF/MPA with a minimum daily dose of 1000 mg (MMF) or 720 mg (MPA) and a CNI
- •Eligible for the vaccinations as described by the instructions of the manufacturers of the vaccines (e.g. received 3 previous COVID-19 vaccinations as part of the primary COVID-19 immunisation)
- •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
排除标准
- •Previous CNI trough levels not sufficient according to the discretion of the treating physician
- •More than two previous kidney transplantations
- •Calculated level of panel reactive antibodies prior to last transplantation above 85%
- •Evidence of DSAs
- •Signs of acute rejection during the preceding year
- •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)
- •Contra-indications for use of everolimus according to the opinion of the treating physician
- •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
- •Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection
- •Subjects with severe systemic infections, current or within the two weeks prior to randomisation
- •Subjects with severe restrictive or obstructive pulmonary disorders
- •Subjects with severe hypercholesterolemia or hypertriglyceridemia that cannot be controlled
- •Subjects with white blood cell (WBC) count ≤ 2,000/mm3 or with platelet count ≤ 50,000/mm3 at last outpatient clinic visit
- •Proteinuria > 1 gram/day at last outpatient clinic visit
- •Simultaneous participation in another interventional study that will likely influence the study outcomes
- •Subject who are actively trying to get pregnant or are pregnant
- •Additional exclusion criteria for Part 2:
- •Active varicella or herpes zoster disease
- •Herpes zoster vaccination with the live attenuated vaccine (Zostavax) or varicella vaccination (Provarivax) during the conduct of the study
- •Previous herpes zoster vaccination with the RZV
研究组 & 干预措施
Continue immunosuppressive therapy with MMF/MPA
Kidney transplant recipients with maintenance therapy, receiving the monovalent Omicron XBB.1.5 COVID-19 mRNA vaccine (Comirnaty, I.M.). Optional to receive the Recombinant Zoster Vaccine (Shingrix, I.M.).
干预措施: COVID-19 vaccination (Biological)
Replace immunosuppressive therapy with MMF/MPA by everolimus
Kidney transplant recipients replacing MMF/MPA by everolimus for at least six weeks, receiving the monovalent Omicron XBB.1.5 COVID-19 mRNA vaccine (Comirnaty, I.M.). Optional to receive the Recombinant Zoster Vaccine (Shingrix, I.M.).
干预措施: COVID-19 vaccination (Biological)
结局指标
主要结局
Virus-neutralizing capacity of SARS-CoV-2 antibodies
时间窗: 28 days after COVID-19 vaccination
The neutralizing antibody titer against the Omicron XBB.1.5 strain
次要结局
- SARS-CoV-2 specific T-cell response(28 days after COVID-19 vaccination)
- Solicited local and systemic adverse events(Within 7 days after vaccination)
- Serious adverse events(Within 84 days after COVID-19 vaccination)
- SARS-CoV-2 antibody concentration(28 days after COVID-19 vaccination)
- Varicella Zoster specific antibodies(28 days after second Varicella Zoster vaccination)
- Varicella Zoster specific T-cell Response(28 days after second Varicella Zoster vaccination)
- Safety of kidney transplant(From enrollment to 84 days after COVID-19 vaccination)