NCT05030974

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

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
336

participants targeted

Target at P50-P75 for phase_4 covid19

Timeline
Completed

Started Oct 2021

Shorter than P25 for phase_4 covid19

Geographic Reach
1 country

4 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

August 20, 2021

Completed
12 days until next milestone

First Posted

Study publicly available on registry

September 1, 2021

Completed
2 months until next milestone

Study Start

First participant enrolled

October 21, 2021

Completed
5 months until next milestone

Primary Completion

Last participant's last visit for primary outcome

March 12, 2022

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

March 12, 2022

Completed
Last Updated

March 29, 2022

Status Verified

March 1, 2022

Enrollment Period

5 months

First QC Date

August 20, 2021

Last Update Submit

March 14, 2022

Conditions

Covid19Kidney DiseasesVaccine Response ImpairedSARS-CoV2 Infection

Outcome Measures

Primary Outcomes (1)

  • 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 Outcomes (6)

  • SARS-CoV-2 antibody concentration

    28 days after vaccination

  • Virus-neutralizing capacity of SARS-CoV-2 antibodies

    28 days after vaccination

  • Mucosal SARS-CoV-2 antibodies

    28 days after vaccination

  • SARS-CoV-2 specific T cell response

    28 days after vaccination

  • Solicited local and systemic adverse events

    within 7 days after vaccination

  • +1 more secondary outcomes

Other Outcomes (8)

  • Relation between age and immune response

    28 days after vaccination

  • Relationship between time after transplant and immune response

    28 days after vaccination

  • Relationship between immunosuppressive medication and immune response

    28 days after vaccination

  • +5 more other outcomes

Study Arms (5)

stratum A1 - one extra dose of mRNA-1273

ACTIVE COMPARATOR

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

stratum A2 - one extra dose of mRNA-1273 with discontinuation of MMF/MPA

ACTIVE COMPARATOR

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

stratum B1 - 3rd dose of mRNA-1273

ACTIVE COMPARATOR

patients treated with any combination of immunosuppressive drugs, receiving a 3rd dose of mRNA-1273 (100 μg, i.m)

Biological: mRNA-1273

statum B2 - 3rd double dose of mRNA-1273

ACTIVE COMPARATOR

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

stratum B3 - Ad26.COV2.S vaccine

ACTIVE COMPARATOR

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

Interventions

mRNA-1273BIOLOGICAL

SARS-CoV-2 vaccination

statum B2 - 3rd double dose of mRNA-1273stratum A1 - one extra dose of mRNA-1273stratum A2 - one extra dose of mRNA-1273 with discontinuation of MMF/MPAstratum B1 - 3rd dose of mRNA-1273
Ad26.COV2.S vaccineBIOLOGICAL

SARS-CoV-2 vaccination

stratum B3 - Ad26.COV2.S vaccine

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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
  • 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

You may not qualify if:

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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (4)

Radboud umc

Nijmegen, Gelderland, Netherlands

Location

Amsterdam UMC

Amsterdam, North Holland, Netherlands

Location

Erasmus mc

Rotterdam, South Holland, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Related Publications (3)

  • Vervoort JPM, Konijn WS, Jansen DEMC, Boersma C, de Zeeuw J, Ho-Dac-Pannekeet MM, Gansevoort RT, Messchendorp AL, Sanders JSF, de Wildt-Liesveld R. Patient engagement as a collaborative process in a large Dutch COVID-19 vaccination study (RECOVAC) - insight into the contribution of patient engagement and learnings for the future. Res Involv Engagem. 2024 Sep 13;10(1):96. doi: 10.1186/s40900-024-00622-x.

    PMID: 39272117DERIVED

  • Malahe SRK, den Hartog Y, Rietdijk WJR, van Baarle D, de Kuiper R, Reijerkerk D, Ras AM, Geers D, Diavatopoulos DA, Messchendorp AL, van der Molen RG, Imhof C, Frolke SC, Bemelman FJ, Gansevoort RT, Hilbrands LB, Sanders JF, GeurtsvanKessel CH, Kho MML, de Vries RD, Reinders MEJ, Baan CC; On behalf of RECOVAC Consortium. Repeated COVID-19 Vaccination Drives Memory T- and B-cell Responses in Kidney Transplant Recipients: Results From a Multicenter Randomized Controlled Trial. Transplantation. 2024 Dec 1;108(12):2420-2433. doi: 10.1097/TP.0000000000005119. Epub 2024 Nov 21.

    PMID: 38902860DERIVED

  • Kho MML, Messchendorp AL, Frolke SC, Imhof C, Koomen VJ, Malahe SRK, Vart P, Geers D, de Vries RD, GeurtsvanKessel CH, Baan CC, van der Molen RG, Diavatopoulos DA, Remmerswaal EBM, van Baarle D, van Binnendijk R, den Hartog G, de Vries APJ, Gansevoort RT, Bemelman FJ, Reinders MEJ, Sanders JF, Hilbrands LB; RECOVAC collaborators. Alternative strategies to increase the immunogenicity of COVID-19 vaccines in kidney transplant recipients not responding to two or three doses of an mRNA vaccine (RECOVAC): a randomised clinical trial. Lancet Infect Dis. 2023 Mar;23(3):307-319. doi: 10.1016/S1473-3099(22)00650-8. Epub 2022 Oct 27.

    PMID: 36354032DERIVED

MeSH Terms

Conditions

COVID-19Kidney Diseases

Interventions

2019-nCoV Vaccine mRNA-1273Ad26COVS1

Condition Hierarchy (Ancestors)

Pneumonia, ViralPneumoniaRespiratory Tract InfectionsInfectionsVirus DiseasesCoronavirus InfectionsCoronaviridae InfectionsNidovirales InfectionsRNA Virus InfectionsLung DiseasesRespiratory Tract DiseasesUrologic DiseasesFemale Urogenital DiseasesFemale Urogenital Diseases and Pregnancy ComplicationsUrogenital DiseasesMale Urogenital Diseases

Intervention Hierarchy (Ancestors)

mRNA VaccinesNucleic Acid-Based VaccinesVaccines, SyntheticRecombinant ProteinsProteinsAmino Acids, Peptides, and ProteinsVaccinesBiological ProductsComplex MixturesCOVID-19 VaccinesViral VaccinesAntigensBiological Factors

Study Officials

  • Jan-Stephan F Sanders, MD PhD

    University Medical Center Groningen

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 4
Allocation
RANDOMIZED
Masking
NONE
Purpose
PREVENTION
Intervention Model
PARALLEL
Model Details: 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.)
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
MD PhD

Study Record Dates

First Submitted

August 20, 2021

First Posted

September 1, 2021

Study Start

October 21, 2021

Primary Completion

March 12, 2022

Study Completion

March 12, 2022

Last Updated

March 29, 2022

Record last verified: 2022-03

Data Sharing

IPD Sharing
Will not share

The data of this study will be available from the principal investigator, upon reasonable request.

Locations

NL(4)