Weekly Dosing of Malarone ® for Prevention of Malaria

Study Overview
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Brief Summary
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The purpose of this study is to determine whether Malarone ®, which is a drug approved to prevent malaria when taken daily, will still effectively prevent malaria if taken weekly.

Detailed Description
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In this study, two groups of volunteers will be exposed to malaria through the bites of infected mosquitoes. In one group, volunteers will be randomly assigned to one of 5 arms. Each of these arms will receive a different dose of Malarone®, a drug known to prevent malaria when taken daily. Each of these doses will be lower than the maximum approved dose of this medicine. The other group will not be treated with any drug that could prevent symptoms or infection. After exposure, both groups will be monitored for a period of approximately 3 months to see if they develop symptoms of malaria. Any subjects who do so will be treated with appropriate medications. Subjects in both groups will have their blood checked regularly during this period for the presence of malaria parasites. At the completion of the study, results will be analyzed to determine whether any of the doses of Malarone might effectively prevent malaria if taken weekly rather than daily.

Official Title
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Pilot Evaluation of Weekly Dosing of Atovaquone/Proguanil (Malarone ®) for Malaria Chemoprophylaxis

Conditions
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Malaria

Intervention / Treatment
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* Drug: Atovaquone Proguanil
* Other: Procedure - malaria challenge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A male or non-pregnant, non-lactating female 18 to 50 years of age (inclusive) at the time of screening Free of clinically significant health problems Baseline ECG before entering into the study Available to participate for duration of study (approximately 4 months, not including screening period) If the participant is female, not pregnant or lactating and willing to use contraception to prevent pregnancy BMI between 19 and 30 Exclusion Criteria: History of malaria or travel to a malarious country within the previous 12 months History of participation in a study in which potential exposure to malaria or vaccination against malaria occurred. Planned travel to malarious areas during the study period. History of malaria chemoprophylaxis within 60 days prior to time of study entry. Chronic use of antibiotics with anti-malarial effects Chronic use (defined as more than 14 days)of immunosuppressants or other immune-modifying drugs within six months of study entry. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination, ECG or laboratory screening tests Significant unexplained anemia History of sickle cell disease or sickle cell trait Seropositive for hepatitis B or hepatitis C History of splenectomy Pregnant or lactating female, or female who intends to become pregnant during the study Suspected or known current alcohol abuse as defined by the American Psychiatric Association in DSM IV History of a neuropsychiatric disorder (anxiety, depression, psychosis, schizophrenia) Chronic or active illicit and/or intravenous drug use History of allergy to atovaquone, proguanil or chloroquine History of psoriasis Concurrent participation in other research studies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug<br>5 groups, each group receiving Malarone tablet(s) (250/100mg)prior to challenge. Group 1 - 1 tablet 1 day before challenge Group 2 - 1 tablet 4 days before challenge Group 3 - 1 tablet 7 days before challenge Group 4 - 2 tablets 7 days before challenge Group 5 - 4 tablets 7 days before challenge | Drug: Atovaquone Proguanil<br>* Volunteers will receive doses of atovaquone/proguanil (Malarone) or matching sugar pills.<br>* Other names: Challenge;Other: Procedure - malaria challenge<br>* 2) Procedure- Malaria Challenge- Volunteers will be exposed to bites of infectious mosquitoes with the intention of causing malaria infection. Volunteers infected with malaria will undergo approved treatments for malaria.<br>* Other names: Challenge;|
| Placebo Comparator: Control -no prophylaxis<br> | Other: Procedure - malaria challenge<br>* 2) Procedure- Malaria Challenge- Volunteers will be exposed to bites of infectious mosquitoes with the intention of causing malaria infection. Volunteers infected with malaria will undergo approved treatments for malaria.<br>* Other names: Challenge;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prophylactic Efficacy of 3 Different Doses of Atovaquone/Proguanil (Malarone@) Given 1 Week Before Infectious Sporozoite Challenge Using the P. Falciparum Human Challenge Model. | Number of participants with prophylactic efficacy was determined by the absence of cases of malaria parasitemia, defined as microscopically detectable parasitemia by Giemsa-stained thick smears, in those receiving any dose of Malarone as compared to the control (no treatment) group | Days 6-20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measured Concentrations of Plasma Atovaquone With Determinations of T1/2. | Plasma concentrations (ng/ml) were used to determine the elimination half life (t1/2) of atovaquone (days). | 7, 6, 5, and 1 day prior to challenge; on the day of the challenge; 1, 4, 5, 6, 7, 8, 10and 14 days after the challenge; and on the day parasitemia develops., | 
| Measured Concentrations of Plasma Atovaquone With Determinations of Area Under the Curve | Plasma concentrations were used to determine the pharmacokinetic curves with determinations of area under the curve (AUC).The smallest AUC Day 0-6.5 associated with protection from detectable parasitemia, and the highest AUC Day 0-6.5 observed in any cases of malaria (prophylactic failures) were to be reported. | 7, 6, 5, and 1 day prior to challenge; on the day of the challenge; 1, 4, 5, 6, 7, 8, 10and 14 days after the challenge; and on the day parasitemia develops., | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Prophylaxis, Atovaquone, Malarone, Challenge