Primary Objective: To determine if two thirds or one third of the CPS immunization dose still induces complete protection against an experimental malaria challenge. Secondary Objectives: • To study and compare parasitemia and kinetics of parasitemia…
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Source
Brief title
Condition
- Protozoal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study endpoint: Duration of prepatent period as measured by microscopy
Other main study endpoints:
• Parasitemia and kinetics of parasitemia as measured by PCR
• Frequency of signs or symptoms in study groups
Secondary outcome
• Antibody production between groups 1, 2, 3 and 4
• Cellular immune response between groups 1, 2, 3 and 4
• Cytokine profile in groups 1, 2, 3 and 4
Background summary
Malaria is one of the major infectious diseases in the world with a tremendous
impact on the quality of life significantly contributing to the ongoing poverty
in endemic countries. It causes almost one million deaths per year, the
majority of which are children under the age of five. The malaria parasite
enters the human body through the skin, by the bite of an infected mosquito.
Subsequently, it invades the liver and develops and multiplies inside the
hepatocytes. After a week, the hepatocytes burst open and the parasites are
released in the blood stream, causing the clinical phase of the disease.
As a unique opportunity to study malaria immunology and efficacy of
immunisation strategies, a protocol has been developed in the past to conduct
experimental human malaria infections (EHMIs). EHMIs generally involve small
groups of malaria-naïve volunteers infected via the bites of P. falciparum
infected laboratory-reared Anopheline mosquitoes. Although potentially serious
or even lethal, P. falciparum malaria can be radically cured at the earliest
stages of blood infection where risks of complications are virtually absent.
We have shown previously that healthy human volunteers can be protected from a
malaria mosquito (sporozoite) challenge by immunization with sporozoites (by
mosquito bites) under chloroquine prophylaxis (CPS immunization). However, it
is unknown how many mosquito bites are necessary to confer protection.
Moreover, as all volunteers were protected in this study, no correlates of
protection could be established. For future development of vaccines and
understanding of protective immunity to malaria, it is important to investigate
the lowest dose of CPS immunization that confers 100% protection and to find
correlates of protection. Therefore, the present study aims to make the CPS
immunization protocol more sensitive by lowering the number of infected
mosquito bites, in order to study the underlying mechanisms of protection.
Study objective
Primary Objective: To determine if two thirds or one third of the CPS
immunization dose still induces complete protection against an experimental
malaria challenge.
Secondary Objectives:
• To study and compare parasitemia and kinetics of parasitemia after challenge
between study groups
• To analyze and compare the immune responses between study groups
Exploratory objectives:
To explore the pathophysiology of early malaria, with specific attention
endothelial activation and VAR gene expression.
Study design
single centre, double-blind randomized controlled clinical trial.
Intervention
All groups will receive chloroquine prophylaxis for the duration of three
months. In these months, they will be exposed to mosquito-bites at days 8, 36
and 64. The volunteers will be divided into four groups at random. Group 1
(n=5, positive control) will receive three CPS immunizations by 15 mosquitoes
infected with P. falciparum sporozoites. Group 2 (n=10) will receive three
times 10 bites from infected mosquitoes and 5 bites from uninfected mosquitoes.
Group 3 (n=10) will receive three times 5 bites from infected mosquitoes and 10
bites from uninfected mosquitoes. Group 4 (n=5, negative control) will receive
three placebo immunizations with 15 bites of uninfected mosquitoes.
Fifteen weeks after discontinuation of chloroquine, all volunteers will be
challenged by the bites of five P. falciparum infected mosquitoes. After
challenge, volunteers will be treated with a curative regimen of Malarone®
(each tablet containing 250 mg atovaquone and 100 mg proguanil). Volunteers
will be checked for parasites by thick smear at least twice after treatment.
Study burden and risks
Benefits: No benefit can be claimed for any of the volunteers. Even though
immunized volunteers might be protected to P. falciparum in this challenge,
these effects may not apply to field situations. Therefore, volunteers will be
advised to take regular malaria prophylaxis when travelling to malaria endemic
areas in the future.
Risks: Risks for volunteers are related to exposure to (early) P. falciparum
malaria infection and side-effects of chloroquine prophylaxis and Malarone®
treatment.
Burden: The study is associated with an immunization period of three months in
which the volunteers receive immunization with mosquito bites in every first
week of the month, and have to visit the trial centre five times in the second
week. During these three months, they have to take weekly chloroquine
prophylaxis. After challenge there will be a short period (35 days) of intense
clinical monitoring with frequent site visits and blood examinations. As it is
unpredictable if and/or when subjects will develop a positive thick blood
smear, it is impossible to state the exact number of site visits and blood
examinations. However, the maximum number (in case a subject does not develop a
positive blood smear) of site visits and blood examinations will be 65 with a
maximum amount of collected blood of 500 mL. In addition periodical physical
examinations will be performed and the subject is asked to complete a diary.
Geert Grooteplein 28
6525 GA Nijmegen
NL
Geert Grooteplein 28
6525 GA Nijmegen
NL
Listed location countries
Age
Inclusion criteria
1. Age > 18 and < 35 years healthy volunteers (males or females)
2. General good health based on history and clinical examination
3. Negative pregnancy test
4. Use of adequate contraception for females
5. All volunteers have to sign the informed consent form following proper understanding of the meaning and procedures of the study
6. Volunteer agrees to inform the general practitioner and agrees to sign a request for medical information concerning contra-indications for participation in the study
7. Willingness to undergo a P. falciparum sporozoite challenge
8. For volunteers not living in Leiden: agreement to stay in a hotel room close to the trial center during a part of the study (Day 5 after challenge till 3 days after treatment)
9. Reachable by mobile phone during the whole study period
10. Availability to attend all study visits
11. Agreement to refrain from blood donation to Sanquin or for other purposes, during the course of the study
12. Willingness to undergo an HIV, hepatitis B and C test
13. Negative urine toxicology screening test at screening visit and day before challenge
14. Willingness to take a prophylactic regime of chloroquine and curative regimen of Malarone
Exclusion criteria
1. History of malaria
2. Plans to travel to malaria endemic areas during the study period
3. Previous participation in any malaria vaccine study and/or positive serology for Pf
4. Symptoms, physical signs and laboratory values suggestive of systemic disorders which could interfere with the interpretation of the study results or compromise the health of the volunteers
5. History of diabetes mellitus or cancer (except basal cell carcinoma of the skin)
6. History of arrhythmias or prolonged QT-interval
7. Positive family history in 1st and 2nd degree relatives for cardiac disease < 50 years old
8. An estimated, ten year risk of fatal cardiovascular disease of >=5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system
9. Clinically significant abnormalities in electrocardiogram (ECG) at screening
10. Body Mass Index (BMI) below 18 or above 30 kg/m2
11. Any clinically significant deviation from the normal range in biochemistry or hematology blood tests or in urine analysis
12. Positive HIV, HBV or HCV tests
13. Participation in any other clinical study within 30 days prior to the onset of the study
14. Enrollment in any other clinical study during the study period
15. Pregnant or lactating women
16. Volunteers unable to give written informed consent
17. Volunteers unable to be closely followed for social, geographic or psychological reasons
18. Previous history of drug or alcohol abuse interfering with normal social function during a period of one year prior to enrolment in the study
19. A history of psychiatric disease
20. Known hypersensitivity to Malarone® or chloroquine
21. The use of chronic immunosuppressive drugs, antibiotics, or other immune modifying drugs within three months of study onset (inhaled and topical corticosteroids are allowed) and during the study period
22. Contra-indications to Malarone® or chloroquine including treatment taken by the volunteer that interferes with Malarone® or chloroquine
23. Any confirmed or suspected immunosuppressive or immunodeficient condition, including asplenia
24. Co-workers of the departments of Medical Microbiology, Parasitology, or Internal Medicine of the Leiden University medical Centre
25. A history of sickle cell anemia, sickle cell trait, thalassemia, thalassemia trait or G6PD deficiency
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 |
|---|---|
| ClinicalTrials.gov | NCT01218893 |
| CCMO | NL33904.091.10 |