To identify host risk factors through genetic and immunological screening that may be associated with the development of cardiac SAEs following CHMI. Identification of such factors may on the one hand allow at-risk individuals to be screened out…
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Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Immunological risk factors with significant odds ratios for cardiac SAEs
following CHMI, i.e. in cases compared to controls.
2. Genetic factors/deviations/variants identified in one or more cases which
can (possibly and/or partially) explain why these subjects suffered cardiac
SAEs following CHMI.
Secondary outcome
1. Immunological factors/deviations/variants identified in one or more cases
which can (possibly and/or partially) explain why these subjects suffered
cardiac SAEs following CHMI.
Background summary
Malaria, a disease caused by Plasmodium parasites, is one of the most important
infectious diseases worldwide. After a period of relative success in global
malaria control, progress has stalled since 2015. Resistance to medication is
increasing in endemic areas and a fully efficacious vaccine has still not been
developed. Controlled Human Malaria Infections (CHMI), a model in which study
participants are infected with Plasmodium parasites in a controlled (research)
setting, are an important and established tool in malaria research, especially
in the clinical development of malaria vaccines. CHMI is considered a
reproducible, predictable and safe model and has been performed successfully at
Radboudumc since 1998 in over 500 individuals, resulting in paradigm-shifting
developments such as CPS immunisation. Nevertheless, since 2002 five of these
subjects developed a cardiac Serious Adverse Event (acute coronary syndrome,
often resembling myocarditis) following CHMI at Radboudumc. Cardiac SAEs have
never been described in thousands of participants at other CHMI centres
worldwide, nor after the hundreds of millions of cases of uncomplicated natural
malaria infection that occur each year. Despite inclusion of stricter in- and
exclusion criteria and additional safety controls to subsequent protocols after
each respective event, SAEs have continued to occur sporadically and a clear
cause remains to be identified, although the presentation and timing of these
SAEs suggest a (delayed) abnormal inflammatory response may play a role.
Additional investigation into possible causes is therefore desirable with a
view to further improving safety, either by modifying the overall model or by
excluding at-risk participants. In addition to factors that may be unique to
the CHMI model at Radboudumc, we hypothesize that some subjects are predisposed
(through either genetic background or prior immunological history) to an
abnormal inflammatory reaction following CHMI, leading to these adverse events.
Study objective
To identify host risk factors through genetic and immunological screening that
may be associated with the development of cardiac SAEs following CHMI.
Identification of such factors may on the one hand allow at-risk individuals to
be screened out prior to inclusion and/or suggest modifications to the overall
CHMI in future studies.
Study design
A case-control study; cases and controls are defined in the section 'Study
population'. Cases and controls will be invited for a first study visit,
including medical history, physical examination, blood samples for routine lab
tests and immunological screening and a urine sample for drug screening.
Consent to request medical files from general practitioners will be asked. If
cases consent to this, they will additionally undergo genetic screening (Whole
Exome Sequencing (WES)), under supervision of a clinical geneticist. All
subjects will be invited for a final study visit. One or max. a couple of extra
study visits inc. blood sampling for immunological tests may be necessary,
depending on the initial results.
Study burden and risks
At least two study visits for all study participants, with a total duration of
approximately 1.5 hours. Cases have the possibility to undergo genetic
analysis, which consists of two consultations with a clinical geneticist and
holds the risk of incidental findings. Venous blood samples will be taken at
least once for controls, and at least twice for cases undergoing genetic
screening. No direct health benefit of participation is expected for either
cases or controls, but insight gained should help to improve the safety of CHMI
studies, which in themselves are a markedly valuable tool in the global fight
against malaria.
Geert Grooteplein 28
Nijmegen 6525 GA
NL
Geert Grooteplein 28
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study as a case, a subject must
meet all of the following criteria:
1. Subject must sign written informed consent to participate in the trial.
2. By judgement of the clinical investigator, the subject is able to understand
the planned study procedures and (limited) risks associated with the study,
inc. the risk of incidental findings in genetic analysis.
3. The subject was enrolled in a CHMI study performed by the Radboudumc between
January 1998 and December 2021 and was subjected to a Controlled Human Malaria
Infection. Subject developed a cardiac serious adverse event in the period of
20 days following CHMI. A cardiac SAE is defined as either clinically
significant increased troponin levels and/or diagnosis of myocarditis, acute
coronary syndrome or myocardial infarction by a cardiologist, and meet the
criteria of an SAE as defined in the study protocol.
4. Subjects unwilling and/or unable to participate in genetic analysis, are
still eligible for immunological analysis (and vice versa).
In order to be eligible to participate in this study as a control, a subject
must meet all of the following criteria:
1. The subject has signed written informed consent.
2. The subject is able to understand the study procedures and (limited) risks
associated with the study.
3. The subject was enrolled in a CHMI study performed by the Radboudumc between
January 1998 and December 2021 and was subjected to a Controlled Human Malaria
Infection. Subject did not develop a cardiac serious adverse event in the
period of 20 days following CHMI. A cardiac SAE is defined as either
clinically significant increased troponin levels and/or diagnosis of
myocarditis, acute coronary syndrome or myocardial infarction by a
cardiologist, and meets the criteria of an SAE as defined in the respective
study protocol.
Exclusion criteria
A potential case or control subject who meets any of the following criteria
will be excluded from participation in immunological screening:
1. Subject is HIV-positive or suffers from any other (acute or chronic) disease
as determined by medical history, physical examination or laboratory screening
tests which according to the clinical judgment of the investigator leads to
undesirable interference with the results of the immunological tests. The
clinical investigator will consider whether blood samples without such
interference can be obtained later in the study period (e.g. in case of acute
infectious disease).
2. Use or receipt of
i) immunosuppressive drugs or other immune modifying drugs within three months
prior to blood sampling for immunological screening (inhaled and topical
corticosteroids and oral anti-histamines exempted) OR
ii) use of illicit drugs determined through urine drug screening OR
iii) any vaccinations within 30 days prior to immunology blood sampling
IF use of these drugs or receipt of a vaccination lead to undesirable
interference with the results of the immunological tests according to the
clinical judgment of the investigator. The clinical investigator will consider
whether blood samples without such interference can be obtained later in the
study period.
3. Any history of malaria other than CHMI as part of the Radboudumc trial in
which the subject has previously participated.
A potential case subject who meets any of the following criteria will be
excluded from participation in genetic analysis:
1. A history of bone marrow transplantation.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | Clinicaltrials.gov (nog te registreren) |
| CCMO | NL79934.091.21 |