E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Kidney transplant patients |
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E.1.1.1 | Medical condition in easily understood language |
Kidney transplant patients |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
In the year 2020, the COVID19 pandemic caused by the Sars-Cov2 virus was responsible for a high mortality rate particularly in solid organ transplant recipients, and especially in kidney transplant patients who are the most frequent among organ solid transplant patients. The recent availability of anti-Sars-Cov2 vaccines could protect them from severe disease. However, it is widely accepted that vaccine responses are much weaker in this populations compared to healthy controls. The primary objective is to assess the immune response to SARS-Cov2 vaccination (vaccine BNT162b2 Comirnaty®; Pfizer- BioNTech) in 80 kidney transplant recipients. Due to new SARS-CoV-2 variants and waning immunity, additional SARSCoV-2 vaccinations may be necessary. This amendment concerns the follow-up of the immune response, both in naïve and previously infected patients, after additional SARS-CoV-2 vaccinations done in the framework of the national vaccination program is highly relevant. |
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E.2.2 | Secondary objectives of the trial |
- to assess the safety of immunization by the vaccine BNT162b2 (Comirnaty®; Pfizer- BioNTech) after two doses - to study the duration of the immune response using serology assays performed on day 28 after the second dose as well as at 6 months after the first dose - to assess in depth the humoral and cellular responses to the vaccine BNT162b2 (Comirnaty®; Pfizer- BioNTech), by measuring the Sars-Cov2 specific T and B cell responses and its evolution and longevity by sampling blood at different time point - To compare the immunogenicity and safety of vaccination in patients previously infected or not by SARS-Cov2 - To assess the safety and efficacy of a third dose of vaccination by BNT162b2 (Comirnaty®; Pfizer- BioNTech) in COVID19 free patients - To assess the immune reponse to additional dose of anti-SARS-CoV2 vaccination - To assess the immune response to new variants in breakthrough cases |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age of 18 years old or older - Patients should met one of the cohort criteria - life expectancy > 12 months - Ability to provide informed consent
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E.4 | Principal exclusion criteria |
- women who are pregnant or breastfeeding.
To reflect the real-world population of kidney transplant patients, the NEPHRO-VAC transplantation project is designed as inclusive as possible. Exclusion criteria are minimal and serve to exclude patients who are not evaluable, or in whom vaccination is considered not safe or not effective. Since baseline blood samples before vaccination will provide an individual reference level of antibody measures, potential bias can be anticipated for. As such, we can still evaluate the immune response induced by the vaccination only. Moreover, At baseline (ie before vaccination) blood samples will be taken. The existence of SARS-Cov-2 antibodies will be examined in the samples in retrospect. As such, based on the baseline antibody levels, we can divide the study population in a COVID+ and COVID- subgroup and perform subgroup analysis to evaluate the effect of this variable. We feel it is not feasible and necessary to exclude patients for the trial based on prevaccination SARS-CoV-2 antibody positivity. First of all the procedures in the study reflect the real life situation. Secondly, analyzing the study results the revaccination antibody levels will be a variable used in the analysis.
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E.5 End points |
E.5.1 | Primary end point(s) |
ELISA RBD antibodies (IgG) 28 days after booster dose. For those with a previous COVID infection, the in house multiplex assay from Sciensano will be performed to discriminate between previous infection and vaccination |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
day 28 after the second vaccination |
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E.5.2 | Secondary end point(s) |
- Safety is accurately followed in kidney transplant patients receiving a vaccine through an autoquestionnary. Patients receive an individual planning for their study visits to the hospital among which also vaccination days are planned. Of course patients are planned to get a vaccine during a study consult on a day also other patients will receive their vaccine. A maximum of 24 patients will receive a vaccination per day. Next to the study nurse, also a doctor will be present for patient monitoring. After the consult, any adverse events, including redness at the injection site, will be followed continuously during each medical visit. It will be noticed each “Adverse event (AEs), serious adverse events (SAEs) and adverse events of special interest (AESI)” and if there is a suspected relationship between AE and vaccin. Each suSAR will be reported in the SAE-form in the attached document. - ELISA RBD antibodies (IgG) 7 days after booster dose, titer of neutralizing antibodies 7 and 28 days after booster dose. Both total and neutralizing antibodies against SARS-Cov-2 will be assessed. The total amount of anti- SARS-Cov-2 IgG antibodies will be studied using an ELISA in which the binding capacities against SARS-CoV-2 spike protein – full S (S1 and S2) as well as against the receptor-binding domain of SARS-CoV-2 protein are tested. Furthermore, a multiplex immune assay will be used for simultaneously testing of the presence of different SARS-CoV-2 binding IgG antibodies. To measure the titers of neutralizing antibodies against SARS-Cov-2 spike protein and nucleocapsid protein, the capacity of the antibodies to neutralize an infection with SARSCoV-2 or pseudoviral particles in vitro will be tested. These methodologies are established and available at the laboratory of Sciensano. Both simple and multi parametric analyses will be performed. The aim is to have these answers within the first month after day 28 of the boost. - Additional endpoints: B-cell immunity seven days after booster dose, measuring memory B cells. T-cell immunity 28 days after boost. - After additional dose: humoral and cellular responses will be analyzed at two supplementary timepoints: just before the additional dose and 28 days after additional dose. - In case of breakthrough case: a blood sample during the 5 first days of symptoms and at day 21, in addition to a nasopharyngeal swab with PCR is planned, for humoral response assessment.
Measurements of the geometric mean concentrations will be calculated for the SARS-CoV-2 specific IgG antibodies. If a serological correlate of protection for COVID-19 based IgG antibody levels (in IU/mL) will be known before data analysis the definition of a responder will be based on having serum concentration of IgG antibodies on day 28 after second vaccination above this cut-off. If no cut-off is established at time of data analysis, we will use a seroconversion (a ≥ 4-fold increase of the geometric mean concentration (GMC) of SARS-CoV-2 specific IgG antibodies over baseline). Titers will be expressed as GMCs with 95% CIs for each cohort, for each time point. Patients will be classified as responders or non-responders. As mentioned in the protocol, the statistical analysis is indeed descriptive. This means that the data resulting from the NEPHRO-VAC will be summarized in an organized manner by describing the immune response in a population of cancer patients. Box plots will be used for interpreting descriptive data in graphical form. This is a vital first step before making inferential statistical comparisons between different cohorts. This will include estimates of variance and comparisons between the different patient cohorts. The most robust appropriate statistical tests will be applied. Full transparency about the analysis and presentation of all individual data points will be available. All analyses will be performed in R (R Core Team (2018), available from https://www.R-project.org/), STATA or SAS. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
day 28, day 49, day 180 and day 365 (end of the study) AND the day of the third dose, day7, day 28, day 180, day 365 after the third dose AND before an additional dose and 28 days after an additional dose. In case of breakthrough case: during the 5 first days of symptoms and at day 21 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |