- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01236612
Experimental Human Malaria Infection After Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Prophylaxis (EHMI9)
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, Plasmodium falciparum (P.falciparum) malaria can be radically cured at the earliest stages of blood infection where risks of complications are virtually absent.
The investigators have shown previously, that healthy human volunteers can be protected from a malaria mosquito challenge by immunization with mosquito-bites under chloroquine prophylaxis (CPS immunization). However, it is unknown whether this protection is based on immunity directed towards the liver- or the blood stage of the disease. For future development of vaccines and understanding of protective immunity to malaria, it is important to investigate at which level protective immunity is generated by CPS immunization. Therefore, we aim to investigate whether CPS immunization confers protection to a blood-stage challenge.
Study Overview
Status
Conditions
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Nijmegen, Netherlands, 6500 HB
- Radboud University Nijmegen Medical Centre
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age > 18 and < 35 years healthy volunteers (males or females)
- Good health based on history and clinical examination
- Negative pregnancy test
- Use of adequate contraception for females
- All volunteers must sign the informed consent form demonstrating their understanding of the meaning and procedures of the study
- Volunteer agrees to inform the general practitioner and agrees to sign a request to release medical information concerning contra-indications for participation in the study
- Willingness to undergo a Pf mosquito or blood stage challenge
- For volunteers not living in Nijmegen: agreement to stay in a hotel room close to the trial center during a part of the study (for groups 1 and 3 from challenge day till 3 days after treatment, for groups 2 and 4 from 5 days after challenge till 3 days after treatment)
- Reachable (24/7) by mobile phone during the whole study period
- Living with a third party that could contact the clinicians in case of alteration of consciousness or agreement to stay in a hotel room close to the trial center during a part of the study (for groups 1 and 3 from challenge day till 3 days after treatment, for groups 2 and 4 from 5 days after challenge till 3 days after treatment)
- Available to attend all study visits
- Agreement to refrain from blood donation to Sanquin or for other purposes, during the study period until 393
- Willingness to undergo HIV, hepatitis B and hepatitis C tests
- Negative urine toxicology screening test at screening visit and day before challenge
- Willingness to take a prophylactic regime of chloroquine and curative regimen of Malarone®
Exclusion Criteria:
- History of malaria
- Plans to travel to malaria endemic areas during the study period
- Plans to travel outside of the Netherlands during the challenge period
- Previous participation in any malaria vaccine study and/or positive serology for Pf
- Symptoms, physical signs and laboratory values suggestive of systemic disorders including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, psychiatric, and other conditions which could interfere with the interpretation of the study results or compromise the health of the volunteers
- History of diabetes mellitus or cancer (except basal cell carcinoma of the skin)
- History of arrhythmias or prolonged QT-interval
- Positive family history in 1st and 2nd degree relatives for cardiac disease < 50 years old
- An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system
- Clinically significant abnormalities in electrocardiogram (ECG) at screening
- Body Mass Index (BMI) below 18 or above 30 kg/m2
- Any clinically significant deviation from the normal range in biochemistry or hematology blood tests or in urine analysis
- Positive HIV, HBV or HCV tests
- Participation in any other clinical study within 30 days prior to the onset of the study
- Enrollment in any other clinical study during the study period
- Pregnant or lactating women
- Volunteers unable to give written informed consent
- Volunteers unable to be closely followed for social, geographic or psychological reasons
- Previous history of drug or alcohol abuse interfering with normal social function during a period of one year prior to enrolment in the study
- A history of psychiatric disease
- Known hypersensitivity to anti-malaria drugs
- 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
- Contra-indications to Malarone® or chloroquine including treatment taken by the volunteer that interferes with Malarone® or chloroquine
- Any confirmed or suspected immunosuppressive or immunodeficient condition, including asplenia
- Co-workers of the departments of Medical Microbiology or Internal Medicine of the RUNMC
- A history of sickle cell anemia, sickle cell trait, thalassemia, thalassemia trait or G6PD deficiency
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Immunization + bloodstage challenge
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The chloroquine dose used will be 300mg for the first two days, followed by 300mg per week, for 13 weeks.
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Other Names:
Groups 1 and 2 will be immunized with 3 times 15 bites of Pf infected mosquitoes under chloroquine prophylaxis.
Groups 1 and 3 will be challenged by intravenous administration of Plasmodium falciparum infected erythrocytes.
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Active Comparator: Immunization + mosquito challenge
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The chloroquine dose used will be 300mg for the first two days, followed by 300mg per week, for 13 weeks.
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Other Names:
Groups 1 and 2 will be immunized with 3 times 15 bites of Pf infected mosquitoes under chloroquine prophylaxis.
Groups 2 and 4 will be challenged by the bites of 5 Plasmodium falciparum infected mosquitoes.
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Placebo Comparator: Control - Bloodstage challenge
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When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Other Names:
Groups 1 and 3 will be challenged by intravenous administration of Plasmodium falciparum infected erythrocytes.
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Placebo Comparator: Control - Mosquito challenge
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When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Other Names:
Groups 2 and 4 will be challenged by the bites of 5 Plasmodium falciparum infected mosquitoes.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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Duration of prepatent period as measured by microscopy
Time Frame: 21 days after challenge
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21 days after challenge
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Parasitemia and kinetics of parasitemia as measured by PCR
Time Frame: 21 days after challenge
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21 days after challenge
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Frequency of signs or symptoms in study groups
Time Frame: 21 days after challenge
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21 days after challenge
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Antibody production in groups 1, 2, 3 and 4
Time Frame: 393 days
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393 days
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Cellular immune response in groups 1, 2, 3 and 4
Time Frame: 393 days
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393 days
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Cytokine profile in groups 1, 2, 3 and 4
Time Frame: 393 days
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393 days
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Collaborators and Investigators
Investigators
- Principal Investigator: Robert W Sauerwein, MD, PhD, Radboud University Medical Center
Publications and helpful links
General Publications
- Roestenberg M, McCall M, Hopman J, Wiersma J, Luty AJ, van Gemert GJ, van de Vegte-Bolmer M, van Schaijk B, Teelen K, Arens T, Spaarman L, de Mast Q, Roeffen W, Snounou G, Renia L, van der Ven A, Hermsen CC, Sauerwein R. Protection against a malaria challenge by sporozoite inoculation. N Engl J Med. 2009 Jul 30;361(5):468-77. doi: 10.1056/NEJMoa0805832.
- Nahrendorf W, Scholzen A, Bijker EM, Teirlinck AC, Bastiaens GJ, Schats R, Hermsen CC, Visser LG, Langhorne J, Sauerwein RW. Memory B-cell and antibody responses induced by Plasmodium falciparum sporozoite immunization. J Infect Dis. 2014 Dec 15;210(12):1981-90. doi: 10.1093/infdis/jiu354. Epub 2014 Jun 25.
- Bijker EM, Bastiaens GJ, Teirlinck AC, van Gemert GJ, Graumans W, van de Vegte-Bolmer M, Siebelink-Stoter R, Arens T, Teelen K, Nahrendorf W, Remarque EJ, Roeffen W, Jansens A, Zimmerman D, Vos M, van Schaijk BC, Wiersma J, van der Ven AJ, de Mast Q, van Lieshout L, Verweij JJ, Hermsen CC, Scholzen A, Sauerwein RW. Protection against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7862-7. doi: 10.1073/pnas.1220360110. Epub 2013 Apr 18.
- Coffeng LE, Hermsen CC, Sauerwein RW, de Vlas SJ. The Power of Malaria Vaccine Trials Using Controlled Human Malaria Infection. PLoS Comput Biol. 2017 Jan 12;13(1):e1005255. doi: 10.1371/journal.pcbi.1005255. eCollection 2017 Jan.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Infections
- Vector Borne Diseases
- Parasitic Diseases
- Protozoan Infections
- Malaria
- Malaria, Falciparum
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antirheumatic Agents
- Antimetabolites
- Antiprotozoal Agents
- Antiparasitic Agents
- Antimalarials
- Amebicides
- Chloroquine
- Proguanil
- Atovaquone, proguanil drug combination
Other Study ID Numbers
- EHMI9
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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