NCT03726593.

Study name	Drug Combinations of Atovaquone‐Proguanil (AP) With ACT (APACT)
Methods	RCT
Participants	Adults with Plasmodium falciparum malaria Number: 252; randomised 1:1:1 Inclusion criteria: understands Khmer spoken language; male or female (18 to 70 years old); able to take oral medications; haemoglobin on day of enrolment ≥ 9.0 g/dL; agree to follow‐up, including inpatient hospitalization and 6‐weekly follow‐up; written permission for those on active military duty  Exclusion criteria: allergy to study drugs; pregnant/lactating, females of childbearing age who do not agree to use contraception during study period and follow‐up; severe vomiting; severe malaria; abnormal liver function test results; isolated AST or ALT or total bilirubin > 2 x ULN; known significant cardiovascular, liver, or renal abnormality or any other clinically significant illness; treatment for malaria within the last 4 weeks; unable to provide informed consent; judged by the investigator to be otherwise unsuitable for study participation (to include, but not limited to, taking other medications that are known to cause serious drug‐drug interactions with the study drugs, or having suspected medical condition or taking other drugs that may affect test results interpretation or put the volunteer at much higher risk) Diagnosis: microscopic confirmation of asexual stages of P falciparum or mixed infection with P falciparum, with baseline asexual parasite densities between 100/µL and 200,000/µL
Interventions	Artesunate‐pyronaridine: once daily for 3 days, following standard weight‐based dosing per drug label. All volunteers with P falciparum monoinfection will receive single dose of primaquine (PQ) (15 mg) for transmission blocking. Atovaquone‐proguanil (AP) + artesunate‐pyronaridine (ASPY): once daily for 3 days, following standard weight‐based dosing per drug label for each drug. All volunteers with P falciparum monoinfection will receive single dose of PQ (15 mg) for transmission blocking. Atovaquone‐proguanil (AP) + artesunate‐mefloquine (ASMQ): ASMQ once daily for 3 days (D0, D1, D2), following standard weight‐based dosing per drug label. Subsequently, volunteers will continue their treatment with AP once daily starting on day 3, for 3 additional days (D3, 4, 5). All volunteers with P falciparum monoinfection will receive single dose of PQ (15 mg) for transmission blocking.
Outcomes	Primary outcome: ACPR day 42 (PCR‐adjusted) Secondary outcomes:  Prevalence of molecular markers of drug resistance [day of enrolment and day of malaria recurrence up to 8 weeks] Drug susceptibility testing of parasite isolates against standard antimalarial drugs [day of enrolment and day of malaria recurrence up to 8 weeks]. Ex vivo drug susceptibility testing Pharmakokinetics of each study drug ‐ Cmax; AUC; volume of distribution; T1/2 [multiple time points] Kaplan‐Meier survival analysis of asexual blood stage parasitaemia and sexual stage gametocytes [6 weeks] Gametocyte carriage rates on days 0, 1, 2, 3, and weeks 1 through 6  Incidence of hepatotoxicity events [day 3 and week 6] Alanine aminotransferase (ALT) > 5 times the upper limit of normal (ULN) or per cent of volunteers meeting the Hy's law definition (ALT or aspartate aminotransferase (AST) > 3 x ULN and total bilirubin > 2 x ULN) at any postdose time point within 6 weeks of follow‐up Rates of treatment‐related adverse events [6 weeks] Severity of treatment‐related adverse events [6 weeks]. Grade 1 ‐ mild, Grade 2 ‐ moderate, Grade 3 ‐ severe, Grade 4 ‐ life‐threatening Number of participants who say they are willing to take the same drug combination in the future [day 2 and week 6] Point efficacy with 95% confidence interval against blood stage malaria infection classified according to the WHO malaria treatment outcome classifications (ETF, LTF, LCTF, LPTF) [4 weeks, 6 weeks, and 8 weeks] Incidence of glucose‐6‐phosphate dehydrogenase (G6PD) deficiency [enrolment]. Comparative incidence of G6PD deficiency in the study population as determined by G6PD rapid‐diagnostic tests (RDTs) and quantitative tests, to include sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) for each of the point‐of‐care tests against 10%, 30%, and 60% thresholds of normal G6PD activity Number of infected mosquitos following membrane feeding [day 0, day 3, day 7, and on day of malaria recurrence up to 8 weeks]
Starting date	4 October 2018
Contact information	Mariusz Wojnarski (MARIUSZ.WOJNARSKI.MIL@AFRIMS.ORG) Norman Waters (Norman.Waters.mil@afrims.org)
Countries of recruitment	Cambodia
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