Primary objectives:1) To evaluate the safety of four different CHMI-trans protocols in healthy malaria-naïve volunteers challenged with Plasmodium falciparum by sporozoite challenge. 2) To determine the best CHMI-trans protocol for induction of…
ID
Source
Brief title
Condition
- Protozoal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Frequency and magnitude of adverse events in the CHMI-trans model in study
groups.
- Prevalence of gametocytes in the CHMI-trans model in study groups.
Secondary outcome
- Peak density and time-point of peak density of gametocytes by qRT-PCR.
- The area under the curve of gametocyte density versus time.
- Assessment of the dynamics of gametocyte commitment, maturation and
sex-ratio.
Background summary
Malaria is one of the most devastating infectious diseases worldwide. Despite
all the progress that has been made in reducing the malaria burden, in 2013
there were still ~200 million cases and ~0.6 million deaths, mainly in children
less than five years of age[1]. In addition to the intolerable clinical burden,
malaria forms a profound economic burden for the affected countries, which are
already struggling with poverty. The urgency of the situation is further
emphasized by the waning effectiveness of all currently registered
anti-malarials due to fast emergence and spread of resistance and the absence
of an highly effective vaccine[2].
Malaria transmission blocking vaccines (TBVs) and transmission-blocking drugs
aim to interrupt the development of parasites in the mosquito[3]. TBVs will
play a central role in efforts to reduce the malaria burden, to contain drug
resistance and to move towards malaria elimination[2, 4].
The clinical development of such transmission blocking interventions will be
greatly accelerated by a suitable model for their evaluation.
Controlled Human Malaria Infections (CHMI) are an established model for
evaluation of malaria candidate vaccines and drugs targeting pre-erythrocytic
or asexual blood stages.
The primary aim of this project is to develop a controlled human malaria
infection transmission model (*CHMI-trans*) or *challenge model* to evaluate
the capacity of vaccines, biologics (monoclonal antibodies, or mAbs), and drugs
to block malaria parasite transmission by assessing infectiousness of
Plasmodium falciparum (Pf) gametocyte carriers for Anopheles mosquitoes.
Study objective
Primary objectives:
1) To evaluate the safety of four different CHMI-trans protocols in healthy
malaria-naïve volunteers challenged with Plasmodium falciparum by sporozoite
challenge.
2) To determine the best CHMI-trans protocol for induction of stable
gametocytaemia at densities detectable by qRT-PCR
Secondary objectives:
3) To determine the dynamics of gametocyte commitment, maturation and sex ratio
by molecular markers of sexual stage development.
4) To determine the time-point of peak density of gametocytaemia in the
CHMI-trans model.
Study design
Single center, open label, randomized, sporozoite challenge study.
A total of 32 volunteers will be randomly assigned to four groups (n=8) and
subjected to a standard controlled human malaria infection (CHMI) delivered by
five Pf-infected mosquitoes (3D7 clone) (see Figure 1, section 3). Treatment is
subsequently initiated to induce gametocytaemia (treatment 1, DT1) and to clear
pathogenic asexual parasites whilst leaving gametocytes unaffected (treatment
2, DT2). At the end of the study, treatment of all parasite stages is provided
following national treatment guidelines (end treatment, ET).
Once malaria infections are detected by 18S qPCR positive at a density of 5,000
par/ml (day of treatment 1 [DT1]), groups 1 and 2 will be treated with a course
of subcurative sulfadoxine-pyrimethamine (SP) (SP low, 500mg/25mg). Groups 3
and 4 will receive piperaquine (Pip) in a low-dose (Pip low, 480 mg). Daily
blood samples will allow detailed quantification of gametocytes, gametocyte sex
ratio and ex vivo assessments of gametocyte fitness. Using blood samples taken
twice daily, the initial clearance of parasitaemia will be carefully monitored.
After DT1, volunteers will receive a curative treatment (DT2) when a
recrudescence of asexual parasitaemia occurs or on day 21 post challenge
infection, whichever comes first. Recrudescence of asexual parasitaemia will be
carefully monitored until parasite densities reach 1,500 par/ml by 18S qPCR, at
which time participants will receive the curative treatment (DT2). Volunteers
in group 1 (SP low/SP high) will be treated with sulfadoxine-pyrimethamine
(1000mg/50mg) and group 2 (SP low/Pip high) with piperaquine (960mg).
Volunteers in group 3 (Pip low/Pip high) will be treated with piperaquine
(960mg) and group 4 (Pip low/SP high) with sulfadoxine-pyrimethamine
(1000mg/50mg). These treatment regimens for DT2 have been shown to cure asexual
parasitaemia while leaving immature and mature gametocytes unaffected[5]. To
ensure the radical clearance of all parasite stages, all volunteers will
receive a final treatment (ET) according to national guidelines with
atovaquone/proguanil (Malarone®) on day 42. In case a volunteer remains 18S
qPCR and Pfs25 qRT-PCR negative for 7 days after DT1, final treatment with
Malarone® will also be initiated and end of study will apply for the volunteer.
Intervention
All volunteers will be subjected to a standard controlled human malaria
infection (CHMI) delivered by bites of five Pf-infected mosquitoes (3D7 clone).
Study burden and risks
The study is associated with a period of intense clinical monitoring with daily
site visits and bloodexaminations.The exact number of site visits and blood
examinations per volunteers depends on the time to positive qPCR and potential
recrudescence - with a maximum number of 50 study visits and a maximum of 500
mL collected blood. In addition periodical physical examinations will be
performed and the subject is asked to complete a diary.
Geert Grooteplein 28
Nijmegen 6525 GA
NL
Geert Grooteplein 28
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
1. Subject is aged * 18 and * 35 years and in good health. ;2. Subject has adequate understanding of the procedures of the study and is able and willing (in the investigator*s opinion) to comply with all study requirements.;3. Subject is willing to complete an informed consent questionnaire and is able to answer all questions correctly. ;4. Subject is able to communicate well with the investigator and is available to attend all study visits, lives in proximity to the trial centre (<10 km) or (if >10km) is willing to stay in a hotel close to the trial centre during part of the study (from day 5 post-infection until DT1+4 provided that the subject has had 2 consecutive negative 18S qPCR tests (at least 24 hours apart) following DT1 treatment; or until day DT2+3). ;5. The subject will remain within the Netherlands during the challenge period, will not travel to a malaria-endemic area during the study period, and is reachable (24/7) by mobile telephone throughout the entire study period. ;6. Subject agrees to their general practitioner being informed and contacted about their participation in the study and agrees to sign a form to request the release by their General Practitioner (GP), and medical specialist when necessary, to the investigator(s), of any relevant medical information concerning possible contra-indications for participation in the study. ;7. The subject agrees to refrain from blood donation to Sanquin or for other purposes throughout the study period and for a defined period thereafter according to current Sanquin guidelines. ;8. For female subjects: subject agrees to use continuous adequate contraception** and not to breastfeed for the duration of study. ;9. Subject agrees to refrain from intensive physical exercise (disproportionate to the subjects usual daily activity or exercise routine) during the malaria challenge period. ;10. Subject has signed written informed consent to participate in the trial.;(*Acceptable forms of contraception include: established use of oral, injected or implanted hormonal contraceptives; intrauterine device or intrauterine system; barrier methods (condoms or diaphragm with additional spermicide); male partner*s sterilisation (with appropriate post-vasectomy documentation of absence of sperm in the ejaculate); true abstinence when this is in line with the preferred and usual lifestyle of the subject; Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.)
Exclusion criteria
1. Any history, or evidence at screening, of clinically significant symptoms, physical signs or abnormal laboratory values suggestive of systemic conditions, such as cardiovascular, pulmonary, renal, hepatic, neurological, dermatological, endocrine, malignant, haematological, infectious, immunodeficient, psychiatric and other disorders, which could compromise the health of the volunteer during the study or interfere with the interpretation of the study results. These include, but are not limited to, any of the following. ;1.1. Body weight <50 kg or Body Mass Index (BMI) <18 or >30 kg/m2 at screening. ;1.2. A heightened risk of cardiovascular disease, as determined by: an estimated ten year risk of fatal cardiovascular disease of *5% at screening, as determined by the Systematic Coronary Risk Evaluation (SCORE); history, or evidence at screening, of clinically significant arrhythmia*s, prolonged QT-interval or other clinically relevant ECG abnormalities; or a positive family history of cardiac events in 1st or 2nd degree relatives <50 years old. ;1.3. A medical history of functional asplenia, sickle cell trait/disease, thalassaemia trait/disease or G6PD-deficiency. ;1.4. History of epilepsy in the period of five years prior to study onset, even if no longer on medication. ;1.5. Screening tests positive for Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) ;1.6. Chronic use of i) immunosuppressive drugs, ii) antibiotics, iii) or other immune modifying drugs within three months prior to study onset (inhaled and topical corticosteroids and oral anti-histamines exempted) or expected use of such during the study period. ;1.7. Any recent or current systemic therapy with an antibiotic or drug with potential anti-malarial activity (chloroquine, doxycycline, tetracycline, piperaquine, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, erythromycin, hydroxychloroquine, etc.) (allowable timeframe for use at the Investigator*s discretion).;1.8. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years. ;1.9. Any history of treatment for severe psychiatric disease by a psychiatrist in the past year. ;1.10. History of drug or alcohol abuse interfering with normal social function in the period of one year prior to study onset, positive urine toxicology test for cocaine or amphetamines at screening or at inclusion, or positive urine toxicology test for cannabis at inclusion. ;2. For female subjects: positive urine pregnancy test at screening and/or at the baseline visit. ;3. Any history of malaria, positive serology for P. falciparum, or previous participation in any malaria (vaccine) study. ;4. Known hypersensitivity to or contra-indications (including co-medication) for use of sulfadoxine-pyrimethamine, piperaquine, chloroquine, Malarone, artemether-lumefantrine, primaquine or history of severe (allergic) reactions to mosquito bites. ;5. Participation in any other clinical study in the 30 days prior to the start of the study or during the study period. ;6. Being an employee or student of the department of Medical Microbiology of the Radboudumc or the department of Internal Medicine. ;7. Any other condition or situation that would, in the opinion of the investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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In other registers
Register | ID |
---|---|
EudraCT | EUCTR2016-001379-66-NL |
CCMO | NL56659.091.16 |
Other | will follow |