Optimisation of Controlled Human Malaria Infection Using Sporozoites Administered by Needle and Syringe

Study Overview
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Brief Summary
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This is an open label, human pilot study to optimise controlled human malaria infection (CHMI) administered by Plasmodium falciparum sporozoites (PfSPZ. Volunteers will be inoculated with PfSPZ Challenge. The route of administration and dose will vary in order to identify the optimal regimen that achieves the greatest infection rate in volunteers with Plasmodium falciparum. All volunteers recruited will be healthy adults aged between 18 and 45 years. Safety and infectivity data will be collected for each of the regimens.

Detailed Description
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Studies involving CHMI are a powerful tool for investigating malaria vaccine and prophylactic drug efficacy.CHMI has now become established as a key tool to assess the efficacy of novel malaria vaccines and drugs. As CHMI trials are carried out in a controlled environment, they allow unprecedented detailed evaluation of parasite growth and immunological responses, providing essential information for vaccine and drug development. Out of three currently available methods of performing experimental human malaria infections (blood stage infection, mosquito bites and sporozoite infection), experimental injection directly by needle and syringe using aseptic, purified, cryopreserved sporozoites is, in principle, the most accurate and practical way of dosing sporozoites for challenge studies. Recently, Sanaria Inc have been able to overcome the technical issues associated with the production of aseptic, purified, cryopreserved Plasmodium falciparum sporozoites. As a result, an Investigational New Drug application (IND) was submitted to the U.S. Food and Drug Administration in February 2009, and a Phase 1 clinical trial with experimental challenge of volunteers was initiated in April 2009. Another trial sponsored by Sanaria to find the dose of aseptic, purified, cryopreserved sporozoites that should be used for experimental human malaria infections is currently ongoing with collaboration with the Radboud University Nijmegen Medical Center, The Netherlands. This trial will be the first time aseptic, purified, cryopreserved P. falciparum sporozoites have been administered intramuscularly to humans.

Official Title
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A Pilot Study to Optimise Controlled Human Malaria Infections Using Plasmodium Falciparum Sporozoites Administered by Needle and Syringe

Conditions
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Malaria, Plasmodium Falciparum

Intervention / Treatment
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* Biological: Plasmodium falciparum sporozoites 2sites
* Biological: Plasmodium falciparum sporozoites 1 site
* Biological: Plasmodium falciparum sporozoites 1site


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women only: Must practice continuous effective contraception for the duration of the study. Agreement to refrain from blood donation during the course of the study and for at least 3 years after the end of their involvement in the study. Written informed consent to undergo CHMI. Reachable (24/7) by mobile phone during the whole study period. Willingness to take a curative anti-malaria regimen. For volunteers not living in Oxford: agreement to stay in a hotel room close to the trial centre during a part of the study (At least Day 6.5 post inoculation until 2 days after treatment commenced). Answer all questions on the informed consent quiz correctly. Exclusion Criteria: History of clinical P. falciparum malaria. Travel to a malaria endemic region during the study period or within the preceding six months with positive P. falciparum serology at screening. Use of systemic antibiotics with known antimalarial activity within 30 days of study enrolment (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones and azithromycin) Receipt of an investigational product in the 30 days preceding enrollment, or planned receipt during the study period. Prior receipt of an investigational malaria vaccine. Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed). Use of immunoglobulins or blood products within 3 months prior to enrollment. History of sickle cell anemia, sickle cell trait, thalassemia or thalassemia trait. Pregnancy, lactation or intention to become pregnant during the study A history of allergic disease or reactions likely to be exacerbated by malaria infection. Contraindications to the use of all three proposed anti-malarial medications; Malarone, Riamet and Chloroquine. History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ). History of serious psychiatric condition that may affect participation in the study. Any other serious chronic illness requiring hospital specialist supervision. Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 42 units every week. Suspected or known injecting drug abuse in the 5 years preceding enrollment. Seropositive for hepatitis B surface antigen (HBsAg). Seropositive for hepatitis C virus (antibodies to HCV). An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system.39 Positive family history in 1st and 2nd degree relatives < 50 years old for cardiac disease. Volunteers unable to be closely followed for social, geographic or psychological reasons. Any clinically significant abnormal finding on biochemistry or haematology blood tests, urinalysis or clinical examination. Any other significant disease, disorder or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plasmodium falciparum sporozoites 2sites<br>2,500 sporozoites intradermally | Biological: Plasmodium falciparum sporozoites 2sites<br>* Aseptic, purified, cryopreserved Plasmodium falciparum sporozoites, 2,500 sporozoites, 50ulx2, 2 intradermal injection sites<br>|
| Experimental: Plasmodium falciparum sporozoites 1 site<br>2,500 sporozoites intramuscularly | Biological: Plasmodium falciparum sporozoites 1 site<br>* Aseptic, purified, cryopreserved Plasmodium falciparum sporozoites, 2,500 sporozoites, 50ulx2, 2 intramuscular injection sites<br>|
| Experimental: Plasmodium falciparum sporozoites 1site<br>25,000 sporozoites intramuscularly | Biological: Plasmodium falciparum sporozoites 1site<br>* Aseptic, purified, cryopreserved Plasmodium falciparum sporozoites, 25,000 sporozoites, 50ulx2, 2 intramuscular injection sites<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Infected | To determine the infectivity rates of PfSPZ Challenge administered in various regimens by thick film microscopy and highly sensitive PCR for Plasmodium falciparum DNA. | 21 days post administration of PfSPZ Challenge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency, Incidence and Nature of Adverse Events and Serious Adverse Events Arising. | To assess the safety of PfSPZ Challenge administered in various regimens by analysing actively and passively collected data from clinical review of volunteers and laboratory measurements, including lab reports and adverse events. | Participants will be followed for the duration of the study, an expected average of 3 months | 
| Dynamics of Plasmodium Falciparum Parasite Growth Following PfSPZ Challenge Administered in Various Regimens | To determine the parasite growth dynamics of PfSPZ Challenge administered in various regimens using highly sensitive PCR for Plasmodium falciparum DNA. | 21 days post administration of PfSPZ Challenge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Protozoan Infections, Parasitic Diseases, Malaria Challenge