Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Versus Mefloquine Prophylaxis

This study has been completed.
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Radboud University
ClinicalTrials.gov Identifier:
NCT01422954
First received: August 23, 2011
Last updated: April 26, 2013
Last verified: April 2013
  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 800.000 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 controlled human malaria infections (CHMIs). CHMIs 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 when risks of complications are virtually absent.

The investigators 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). Interestingly, sterile protection in 100% of the human CPS immunized volunteers was achieved by a relatively miniscule dose, i.e. a total of 45 infectious mosquito bites, strikingly 20-fold more potent than the 1000 bites needed in a model using irradiated mosquitoes. One possible explanation for this efficient induction of protective immunity, is the immune modulating effect of chloroquine. The investigators aim to assess this possible immune modulating effect in CPS immunization by comparing immunization with P. falciparum sporozoites under chloroquine with immunization under mefloquine prophylaxis, which has the same antimalarial effect, but not the immune modulating effects known from chloroquine.


Condition Intervention
Malaria
Plasmodium Falciparum
Drug: Chloroquine prophylaxis
Drug: Mefloquine prophylaxis
Biological: Immunization
Biological: Controlled Human Malaria Infection
Drug: Malarone

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Immunization With Plasmodium Falciparum Sporozoites Under Chloroquine Versus Mefloquine Prophylaxis

Resource links provided by NLM:


Further study details as provided by Radboud University:

Primary Outcome Measures:
  • Duration of prepatent period after challenge infection as measured by microscopy [ Time Frame: 21 days after challenge (day 239 of the study) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Development of parasitemia as measured by PCR [ Time Frame: 21 days after challenge (day 239 of study) ] [ Designated as safety issue: No ]
  • Frequency of signs or symptoms in study groups [ Time Frame: Day 0 - day 358 of study ] [ Designated as safety issue: Yes ]
  • Cellular immune responses between study groups [ Time Frame: Day 0 -day 358 of study ] [ Designated as safety issue: No ]
  • Humoral immune responses between study groups [ Time Frame: Day 0 - 358 ] [ Designated as safety issue: No ]

Enrollment: 20
Study Start Date: January 2012
Study Completion Date: April 2013
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Chloroquine immunisation
This group will receive chloroquine prophylaxis, and three times infected mosquito-bites.
Drug: Chloroquine prophylaxis
Standard prophylactic regime: a loading dose of 300 mg on day 14 and day 17 and then 300 mg once a week, starting on day 21, for a total duration of 13 weeks. On day 0, day 3, day 7 and day 10, this group will receive a placebo.
Biological: Immunization
Group 1 and 2 will receive three immunizations with Plasmodium falciparum infected mosquito-bites. Group 3 will receive an equal number of uninfected mosquito-bites.
Biological: Controlled Human Malaria Infection
Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.
Drug: Malarone
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Other Name: atovaquon/proguanil
Experimental: Mefloquine immunisation
This group will receive mefloquine prophylaxis and infected mosquito-bites.
Drug: Mefloquine prophylaxis
Mefloquine prophylaxis, starting with a loading regime of split doses during the first three weeks: 125 mg on day 0, day 3, day 7, day 10, day 14 and day 17 and 250 mg once a week from day 21 onwards for a total duration of 13 weeks.
Biological: Immunization
Group 1 and 2 will receive three immunizations with Plasmodium falciparum infected mosquito-bites. Group 3 will receive an equal number of uninfected mosquito-bites.
Biological: Controlled Human Malaria Infection
Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.
Drug: Malarone
When thick smear positive, of ar day 21 after challenge, all volunteers will be treated with malarone.
Other Name: atovaquon/proguanil
Placebo Comparator: Mefloquine control
This group will receive mefloquine prophylaxis, and uninfected mosquito-bites.
Drug: Mefloquine prophylaxis
Mefloquine prophylaxis, starting with a loading regime of split doses during the first three weeks: 125 mg on day 0, day 3, day 7, day 10, day 14 and day 17 and 250 mg once a week from day 21 onwards for a total duration of 13 weeks.
Biological: Immunization
Group 1 and 2 will receive three immunizations with Plasmodium falciparum infected mosquito-bites. Group 3 will receive an equal number of uninfected mosquito-bites.
Biological: Controlled Human Malaria Infection
Exposure to the bites of 5 Plasmodium falciparum infected mosquitoes.
Drug: Malarone
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. Signing of the informed consent form, thereby demonstrating understanding of the meaning and procedures of the study
  6. Agreement to inform the general practitioner and to sign a request to release medical information concerning contra-indications for participation in the study
  7. Willingness to undergo a Pf controlled infection through mosquito bites
  8. Agreement to stay in a hotel room close to the trial center during a part of the study (Day 5 after challenge till treatment is finished)
  9. Reachable (24/7) by mobile phone during the whole study period
  10. Available to attend all study visits
  11. Agreement to refrain from blood donation to Sanquin or for other purposes, during the whole study period
  12. Willingness to undergo HIV, hepatitis B and hepatitis C tests
  13. Negative urine toxicology screening test at screening visit and the day before challenge
  14. Willingness to take a prophylactic regime of chloroquine or mefloquine 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 events < 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 20 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. For women: pregnancy or lactation
  17. Volunteers unable to give written informed consent
  18. Volunteers unable to be closely followed for social, geographic or psychological reasons
  19. History of drug or alcohol abuse interfering with normal social function
  20. A history of treatment for psychiatric disease or moderate or severe psychological episode in volunteer
  21. A history of convulsions in volunteer
  22. Severe depression, anxiety disorder of psychosis in first or second degree family
  23. Contra-indications to Malarone®, chloroquine or mefloquine including hypersensitivity or treatment taken by the volunteer that interferes with Malarone®, chloroquine or mefloquine
  24. The use of chronic immunosuppressive drugs, antibiotics, or other immune modifying drugs within three months of study onset (inhaled and topical corticosteroids and oral anti-histaminic are allowed) and during the study period
  25. Any confirmed or suspected immunosuppressive or immunodeficient condition, including asplenia
  26. Co-workers or trainees of the departments of Medical Microbiology, Parasitology, or Internal Medicine of the Leiden University medical Centre
  27. A history of sickle cell anemia, sickle cell trait, thalassemia, thalassemia trait or G6PD deficiency
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01422954

Locations
Netherlands
Leiden University Medical Centre
Leiden, Netherlands, 2333 ZA
Sponsors and Collaborators
Radboud University
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
Principal Investigator: Leo G Visser, MD, PhD Leiden University Medical Centre
  More Information

Additional Information:
No publications provided

Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT01422954     History of Changes
Other Study ID Numbers: ZonMw2
Study First Received: August 23, 2011
Last Updated: April 26, 2013
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

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

ClinicalTrials.gov processed this record on August 18, 2014