The ASAP Study - Therapeutic Efficacy of Atovaquone-proguanil vs. Artesunate-atovaquone-proguanil in Cambodia

Study Overview
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Brief Summary
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This is a two-arm, randomized, open label Treatment Study evaluating the therapeutic efficacy, safety, tolerability and pharmacokinetics of a three-day course of Atovaquone-Proguanil (AP) or a three-day course of Atovaquone-Proguanil combined with 3 days of Artesunate (ASAP) in patients with uncomplicated Plasmodium falciparum malaria at selected sites in Cambodia. Atovaquone-proguanil, soon to adopted as a first line antimalarial agent by the National Malaria Control Program (CNM) in Cambodia in provinces with confirmed multidrug resistance, will be given with or without artesunate (AS) as a directly observed, standard three-day fixed dose combination treatment to all volunteers enrolled. The efficacy and safety of both drug combination as well as evidence for in vivo and in vitro resistance to their components will be monitored during the treatment period. All volunteers will receive a single dose of 15mg of primaquine as recommended by WHO with the first dose of AP or ASAP to block the transmission of malaria to mosquitoes. Resistance to AP and ASAP will be assessed by a combination of clinical, pharmacologic, and parasitological parameters including genomic signatures of selection during careful weekly follow-up visits for 6 weeks. Investigators will also be able to evaluate the effects of primaquine on the sexual stages of malaria (gametocytes).

Official Title
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Therapeutic Efficacy of Atovaquone-proguanil and Artesunate-atovaquone-proguanil for the Treatment of Uncomplicated P. Falciparum Malaria in Areas of Multidrug Resistance in Cambodia.

Conditions
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Malaria

Intervention / Treatment
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* Drug: atovaquone-proguanil
* Drug: artesunate-atovaquone-proguanil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female with uncomplicated P. falciparum malaria (volunteers with mixed P. falciparum and P. vivax infections may be enrolled), 18-65 years of age Baseline asexual parasite density between 100-200,000 parasites/microL Able to provide informed consent Available and agree to follow-up for anticipated study duration including 3 day treatment course at the Medical Treatment Facility, and weekly follow-up for the 42-day period. Exclusion Criteria: Allergic reaction or medical contraindication to atovaquone, proguanil, artesunate or primaquine, to include a calculated serum creatinine clearance estimate of less than 30mL/min Significant acute comorbidity requiring urgent medical intervention Signs/symptoms and parasitological confirmation of severe malaria Use of any anti-malarial within the past 7 days, or atovaquone-proguanil in the past 30 days Use of the following concomitant medications within 7 days, which may cause or be volunteers to significant drug-drug interactions with study drug - tetracycline, metoclopramide, rifampin, rifabutin, zidovudine or etoposide. Pregnant or lactating female, or female of childbearing age, up to 50 years of age, who does not agree to use an acceptable form of contraception during the study Judged by the investigator to be otherwise unsuitable for study participation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: atovaquone-proguanil (AP)<br>A standard fixed-dose 3 day regimen of Atovaquone-proguanil (AP) for treatment of uncomplicated P. falciparum malaria. | Drug: atovaquone-proguanil<br>* A daily fixed dose combination of 4 tablets containing atovaquone 250mg and proguanil hydrochloride 100mg (total 1000mg/400mg respectively)<br>|
| Active Comparator: artesunate-atovaquone-proguanil (ASAP)<br>A standard fixed-dose 3 day regimen of Atovaquone-proguanil (AP) plus 3 days of artesunate (200mg per day) for treatment of uncomplicated P. falciparum malaria. | Drug: artesunate-atovaquone-proguanil<br>* A daily fixed dose combination of 4 tablets containing atovaquone 250mg and proguanil hydrochloride 100mg (total 1000mg/400mg daily respectively) in addition to 4 tablets containing 50mg artesunate (200mg daily)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy at 42 days (with 95% confidence intervals) for AP with and without artesunate for uncomplicated P. falciparum diagnosed by positive PCR-corrected malaria microscopy. |  | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy at 28 days (with 95% confidence intervals) for atovaquone-proguanil and artesunate-atovaquone-proguanil for uncomplicated P. falciparum diagnosed by positive PCR-corrected malaria microscopy. |  | 4 weeks | 
| Rates of sexual stage infections at days 1, 4, week 1 and week 2 based on a combined endpoint of light microscopy and PCR analysis for detection of gametocyte maturity. |  | 2 weeks | 
| Comparative rates, duration and intensity of treatment-related adverse drug events, and total adverse events in each treatment group. |  | 6 weeks |