Antimalarial Drug Resistance With Assessment of Transmission Blocking Activity

Study Overview
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Brief Summary
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This is a two-arm, open label Treatment Study comparing the efficacy, safety, tolerability and pharmacokinetics of a three-day course of Dihydroartemisinin-Piperaquine (DP) with or without single-dose primaquine in patients with uncomplicated Plasmodium falciparum malaria. On the last day of DP therapy, volunteers will be randomized to receive either a single 45 mg dose of primaquine (PQ) or DP treatment only (no primaquine).

Detailed Description
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Volunteers with uncomplicated malaria in Cambodia will be enrolled to current standard of care therapy with DHA-piperaquine to monitor therapeutic efficacy and measure resistance. The cardiac safety of piperaquine will be monitored with electrocardiograms during the treatment period. Resistance to DP and DP-PQ will be assessed by a combination of clinical, pharmacologic, and parasitologic parameters including genomic signatures of selection during careful weekly follow-up visits for 42 days. Volunteers will be randomized on day 3 to either a single 45mg dose of primaquine or no sexual stage therapy to evaluate effects of primaquine on the sexual stages of malaria (gametocytes) and potential transmissibility of infection to Anopheles mosquitoes as compared to those not treated with primaquine.

Official Title
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Active Surveillance for P. Falciparum Drug Resistance With Assessment of Transmission Blocking Activity of Single Dose Primaquine in Cambodia

Conditions
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Uncomplicated Plasmodium Falciparum Malaria

Intervention / Treatment
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* Drug: DHA-piperaquine and Primaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Volunteer 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 1,000-200,000 parasites/uL Able to provide informed consent Available and agree to follow-up for anticipated study duration including 3 day treatment course at the MTF and weekly follow-up for the 42-day period Authorized by local commander to participate if active duty military Exclusion Criteria: Allergic reaction or contraindication to DHA, piperaquine or primaquine Significant acute comorbidity requiring urgent medical intervention Signs/symptoms and parasitological confirmation of severe malaria Use of any anti-malarial within the past 14 days. Class I or II G6PD deficiency (defined as severe) as determined at screening 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 Clinically significant abnormal EKG, including a QTcF interval > 500 ms at enrollment. Known or suspected concomitant use of QTc prolonging medications. 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: DHA-piperaquine with Primaquine<br>3-day treatment course of DHA-piperaquine with 45mg single dose primaquine | Drug: DHA-piperaquine and Primaquine<br>* Subject will be enrolled in open label fashion to a 3-day treatment course of DHA-piperaquine (DP) by directly observed therapy (DOT, all patients will receive a total of 9 tablets containing 40mg DHA and 320mg of piperaquine in divided doses at 0, 24 and 48 hours (3 tablets once per day) for the 3 day course. At completion of DP treatment volunteers will be randomized in an open label fashion to receive a single 45 mg dose of primaquine or no therapy.<br>|
| Active Comparator: DHA-piperaquine without Primaquine<br>3-day treatment course of DHA-piperaquine | Drug: DHA-piperaquine and Primaquine<br>* Subject will be enrolled in open label fashion to a 3-day treatment course of DHA-piperaquine (DP) by directly observed therapy (DOT, all patients will receive a total of 9 tablets containing 40mg DHA and 320mg of piperaquine in divided doses at 0, 24 and 48 hours (3 tablets once per day) for the 3 day course. At completion of DP treatment volunteers will be randomized in an open label fashion to receive a single 45 mg dose of primaquine or no therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical efficacy of DP | Efficacy rates at 42 days (with 95% confidence intervals) for DP with and without single dose primaquine for uncomplicated P. falciparum diagnosed by positive PCR-corrected malaria microscopy. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Primaquine to treat sexual stage gametocyte infection and prevent transmission of P. falciparum gametocytes to mosquitoes. | To detect efficacy of a onetime dose of primaquine after completion of therapy for blood stage infection on gametocytemia that may persist after DP treatment by using comparative rates of sexual stage infections between patients dosed with and without primaquine based on a composite endpoint of light microscopy and PCR detection and staging of gamteocytes with mosquito membrane feeding assay to detect oocysts in sterile lab-reared mosquitoes. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Drug resistance, DHA-piperaquine, Cambodia, Transmission Blocking