Experimental Human Malaria Infection After Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Prophylaxis (EHMI9)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Radboud University
ClinicalTrials.gov Identifier:
NCT01236612
First received: November 4, 2010
Last updated: January 20, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention
Plasmodium Falciparum Malaria
Drug: Chloroquine prophylaxis
Biological: Immunization
Biological: Plasmodium falciparum Bloodstage challenge
Biological: Plasmodium falciparum mosquito challenge
Drug: Malarone treatment

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Experimental Human Malaria Infection After Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Prophylaxis

Resource links provided by NLM:


Further study details as provided by Radboud University:

Primary Outcome Measures:
  • Duration of prepatent period as measured by microscopy [ Time Frame: 21 days after challenge ] [ Designated as safety issue: No ]
  • Parasitemia and kinetics of parasitemia as measured by PCR [ Time Frame: 21 days after challenge ] [ Designated as safety issue: No ]
  • Frequency of signs or symptoms in study groups [ Time Frame: 21 days after challenge ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Antibody production in groups 1, 2, 3 and 4 [ Time Frame: 393 days ] [ Designated as safety issue: No ]
  • Cellular immune response in groups 1, 2, 3 and 4 [ Time Frame: 393 days ] [ Designated as safety issue: No ]
  • Cytokine profile in groups 1, 2, 3 and 4 [ Time Frame: 393 days ] [ Designated as safety issue: No ]

Enrollment: 25
Study Start Date: April 2011
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Immunization + bloodstage challenge Drug: Chloroquine prophylaxis
The chloroquine dose used will be 300mg for the first two days, followed by 300mg per week, for 13 weeks.
Biological: Immunization
Groups 1 and 2 will be immunized with 3 times 15 bites of Pf infected mosquitoes under chloroquine prophylaxis.
Biological: Plasmodium falciparum Bloodstage challenge
Groups 1 and 3 will be challenged by intravenous administration of Plasmodium falciparum infected erythrocytes.
Drug: Malarone treatment
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Other Name: atovaquon/proguanil
Active Comparator: Immunization + mosquito challenge Drug: Chloroquine prophylaxis
The chloroquine dose used will be 300mg for the first two days, followed by 300mg per week, for 13 weeks.
Biological: Immunization
Groups 1 and 2 will be immunized with 3 times 15 bites of Pf infected mosquitoes under chloroquine prophylaxis.
Biological: Plasmodium falciparum mosquito challenge
Groups 2 and 4 will be challenged by the bites of 5 Plasmodium falciparum infected mosquitoes.
Drug: Malarone treatment
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Other Name: atovaquon/proguanil
Placebo Comparator: Control - Bloodstage challenge Biological: Plasmodium falciparum Bloodstage challenge
Groups 1 and 3 will be challenged by intravenous administration of Plasmodium falciparum infected erythrocytes.
Drug: Malarone treatment
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Other Name: atovaquon/proguanil
Placebo Comparator: Control - Mosquito challenge Biological: Plasmodium falciparum mosquito challenge
Groups 2 and 4 will be challenged by the bites of 5 Plasmodium falciparum infected mosquitoes.
Drug: Malarone treatment
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Other Name: atovaquon/proguanil

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Age > 18 and < 35 years healthy volunteers (males or females)
  2. Good health based on history and clinical examination
  3. Negative pregnancy test
  4. Use of adequate contraception for females
  5. All volunteers must sign the informed consent form demonstrating their understanding of the meaning and procedures of the study
  6. 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
  7. Willingness to undergo a Pf mosquito or blood stage challenge
  8. 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)
  9. Reachable (24/7) by mobile phone during the whole study period
  10. 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)
  11. Available to attend all study visits
  12. Agreement to refrain from blood donation to Sanquin or for other purposes, during the study period until 393
  13. Willingness to undergo HIV, hepatitis B and hepatitis C tests
  14. Negative urine toxicology screening test at screening visit and day before challenge
  15. 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. Plans to travel outside of the Netherlands during the challenge period
  4. Previous participation in any malaria vaccine study and/or positive serology for Pf
  5. 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
  6. History of diabetes mellitus or cancer (except basal cell carcinoma of the skin)
  7. History of arrhythmias or prolonged QT-interval
  8. Positive family history in 1st and 2nd degree relatives for cardiac disease < 50 years old
  9. An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system
  10. Clinically significant abnormalities in electrocardiogram (ECG) at screening
  11. Body Mass Index (BMI) below 18 or above 30 kg/m2
  12. Any clinically significant deviation from the normal range in biochemistry or hematology blood tests or in urine analysis
  13. Positive HIV, HBV or HCV tests
  14. Participation in any other clinical study within 30 days prior to the onset of the study
  15. Enrollment in any other clinical study during the study period
  16. Pregnant or lactating women
  17. Volunteers unable to give written informed consent
  18. Volunteers unable to be closely followed for social, geographic or psychological reasons
  19. Previous history of drug or alcohol abuse interfering with normal social function during a period of one year prior to enrolment in the study
  20. A history of psychiatric disease
  21. Known hypersensitivity to anti-malaria drugs
  22. 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
  23. Contra-indications to Malarone® or chloroquine including treatment taken by the volunteer that interferes with Malarone® or chloroquine
  24. Any confirmed or suspected immunosuppressive or immunodeficient condition, including asplenia
  25. Co-workers of the departments of Medical Microbiology or Internal Medicine of the RUNMC
  26. A history of sickle cell anemia, sickle cell trait, thalassemia, thalassemia trait or G6PD deficiency
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01236612

Locations
Netherlands
Radboud University Nijmegen Medical Centre
Nijmegen, Netherlands, 6500 HB
Sponsors and Collaborators
Radboud University
Investigators
Principal Investigator: Robert W Sauerwein, MD, PhD Radboud University
  More Information

Publications:
Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT01236612     History of Changes
Other Study ID Numbers: EHMI9
Study First Received: November 4, 2010
Last Updated: January 20, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Radboud University:
Plasmodium
falciparum
malaria
chloroquine
immunity

Additional relevant MeSH terms:
Malaria
Malaria, Falciparum
Parasitic Diseases
Protozoan Infections
Chloroquine
Chloroquine diphosphate
Amebicides
Analgesics
Analgesics, Non-Narcotic
Anthelmintics
Anti-Infective Agents
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antimalarials
Antinematodal Agents
Antiparasitic Agents
Antiprotozoal Agents
Antirheumatic Agents
Central Nervous System Agents
Filaricides
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014