• Primary objective: To achieve a 100% infection rate of human volunteers by intradermal injection of aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge). • Secondary objective: To compare parasite kinetics between different doses of…
ID
Source
Brief title
Condition
- Protozoal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• 100% thick smear positivity of all volunteers from one group
Secondary outcome
• A significant difference in time of thick smear positivity between the groups
of volunteers
• A significant quantitative difference in parasitemia as measured by
retrospective RTQ-PCR between the groups of volunteers
• A significant difference in kinetics of parasitemia between the groups of
volunteers as measured by retrospective RTQ-PCR.
• A difference in occurrence and/or intensity of signs or symptoms between the
groups of volunteers
Background summary
Experimental human malaria infections are generally accepted to be a powerful
tool for evaluation of potential malaria vaccine and drug efficacies. Until
now, experimental infections have been performed exclusively using infectious
mosquitoes. Recently, Sanaria has been able to overcome the technical issues
associated with the production of aseptic, purified, cryopreserved Plasmodium
falciparum (Pf) sporozoites (PfSPZ). Performing experimental human malaria
infections with aseptic, purified, cryopreserved sporozoites clearly provides
advantages over infectious mosquitoes, in terms of dose determination and
standardisation and overcoming batch differences when performing sequential
clinical trials. This trial is designed to find the dose of aseptic, purified,
cryopreserved sporozoites (PfSPZ Challenge) that should be used for
experimental human malaria infections.
Study objective
• Primary objective: To achieve a 100% infection rate of human volunteers by
intradermal injection of aseptic, purified, cryopreserved Pf sporozoites (PfSPZ
Challenge).
• Secondary objective: To compare parasite kinetics between different doses of
intradermal injection of PfSPZ Challenge.
• Tertiary objective: To compare immune responses in volunteers experimentally
infected by different doses of intradermally injected PfSPZ Challenge.
• Exploratory objectives: To explore the pathophysiology of early malaria, with
specific attention to coagulation, endothelial activation, complement
activation and VAR gene expression.
Study design
single center, open label, with varying doses.
Intervention
Groups of 6 volunteers will be intradermally injected with PfSPZ Challenge.
Groups will be injected 21 days apart. Three different doses of PfSPZ Challenge
will be administered according to the scheme below.
Criteria for treatment with a curative regimen of Malarone® (each tablet
containing 250 mg atovaquone and 100 mg proguanil) are as follows:
• Positive thick smear during regular check-up
• Symptoms consistent with malaria and positive thick smear
• By decision of study doctor or the safety monitor
• On request of the volunteer
• On day 21 post challenge, if the volunteer has remained thick smear negative
• When hs Troponine T (Roche) > 0.1 µg/ml and on recommendation of the
cardiologist
• When thrombocytes < 75 x 109/l
• Depending on abnormal values for LDH, D-dimer, ADAMTS13 and fragmentocytes
•
Dosing will be as follows: once daily 4 tablets of Malarone® (each tablet
containing 250 mg atovaquone and 100 mg proguanil), during three days,
according to SWAB guidelines. 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. Volunteers will
be advised to take regular malaria prophylaxis when traveling to malaria
endemic areas in the future.
Risks: Risks for volunteers are related to exposure to (early) P. falciparum
malaria and side-effects of Malarone® treatment.
Burden: The study is associated with a short period (35 days) of intense
clinical monitoring with frequent site visits (up to three times a day) and
blood examinations. As it is unpredictable if and/or when subjects will develop
a positive thick 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 43 with a maximum amount of blood collected being 500 mL. In addition
periodic physical examinations will be performed and the subject will be asked
to complete a diary.
9800 Medical Center Dr., Suite A209
Rockville MD 20850
US
9800 Medical Center Dr., Suite A209
Rockville MD 20850
US
Listed location countries
Age
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 sporozoite 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 (Day 5 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 (Day 5 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 day 140.
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 curative regimen of Malarone®
Exclusion criteria
1. History of malaria
2. Plans to travel to malaria endemic areas during the 140 day study period
3. Plans to travel outside of the Netherlands during day 0-28 of the study
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® including treatment taken by the volunteer that interferes with Malarone®
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 Radboud University Nijmegen Medical Centre or Sanaria Inc.
26. A history of sickle cell anemia, sickle cell trait, thallasemia, thallasemia 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 |
|---|---|
| EudraCT | EUCTR2010-019300-23-NL |
| ClinicalTrials.gov | NCT01086917 |
| CCMO | NL31858.091.10 |