title: Randomized, double-blind, placebo-controlled clinical trial of a two-day regimen of dihydroartemisinin-piperaquine for malaria prevention halted for concern over prolonged corrected QT interval.
abstract: Dihydroartemisinin-piperaquine, the current first-line drug for uncomplicated malaria caused by Plasmodium falciparum and Plasmodium vivax in Cambodia, was previously shown to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly 2-day treatment course in the Royal Cambodian Armed Forces. The safety and efficacy of a monthly 2-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in areas along the Thai-Cambodian border where there is a high risk of malaria were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1,440 mg piperaquine within 30 min to 3 h of a meal once per month for a planned 4-month period with periodic electrocardiographic and pharmacokinetic assessment. The study was halted after only 6 weeks (69 of 231 projected volunteers enrolled) when four volunteers met a prespecified cardiac safety endpoint of QTcF (Fridericia's formula for correct QT interval) prolongation of >500 ms. The pharmacodynamic effect on the surface electrocardiogram (ECG) peaked approximately 4 h after piperaquine dosing and lasted 4 to 8 h. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at the maximum concentration of drug in serum (Cmax) on day 2. Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarial agents in Cambodia, compressed 2-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is often unavailable in areas where malaria is endemic, repolarization risk could be mitigated by using conventional 3-day regimens, fasting, and avoidance of repeated dosing or coadministration with other QT-prolonging medications. (This study has been registered at ClinicalTrials.gov under registration no. NCT01624337.).
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Jessica
authors.initials: J
authors.lastname: Manning
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Pattaraporn
authors.initials: P
authors.lastname: Vanachayangkul
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Chanthap
authors.initials: C
authors.lastname: Lon
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Michele
authors.initials: M
authors.lastname: Spring
authors.affiliation: Royal Cambodian Armed Forces, Phnom Penh, Cambodia.
authors.forename: Mary
authors.initials: M
authors.lastname: So
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Darapiseth
authors.initials: D
authors.lastname: Sea
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Youry
authors.initials: Y
authors.lastname: Se
authors.affiliation: Royal Cambodian Armed Forces, Phnom Penh, Cambodia.
authors.forename: Sok
authors.initials: S
authors.lastname: Somethy
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Sut-Thang
authors.initials: ST
authors.lastname: Phann
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Soklyda
authors.initials: S
authors.lastname: Chann
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Sabaithip
authors.initials: S
authors.lastname: Sriwichai
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Nillawan
authors.initials: N
authors.lastname: Buathong
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Worachet
authors.initials: W
authors.lastname: Kuntawunginn
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Mashamon
authors.initials: M
authors.lastname: Mitprasat
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Raveewan
authors.initials: R
authors.lastname: Siripokasupkul
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Paktiya
authors.initials: P
authors.lastname: Teja-Isavadharm
authors.affiliation: F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Soh
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Ans
authors.initials: A
authors.lastname: Timmermans
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lanteri
authors.affiliation: Center for Excellence in Bioinformatics (BIOPHICS), Mahidol University, Bangkok, Thailand.
authors.forename: Jaranit
authors.initials: J
authors.lastname: Kaewkungwal
authors.affiliation: Center for Excellence in Bioinformatics (BIOPHICS), Mahidol University, Bangkok, Thailand.
authors.forename: Montida
authors.initials: M
authors.lastname: Auayporn
authors.affiliation: Fast Track Biologics, Bethesda, Maryland, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Tang
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Char Meng
authors.initials: CM
authors.lastname: Chour
authors.affiliation: Royal Cambodian Armed Forces, Phnom Penh, Cambodia.
authors.forename: Satharath
authors.initials: S
authors.lastname: Prom
authors.affiliation: F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Haigney
authors.affiliation: F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Cantilena
authors.affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand David.Saunders@afrims.org.
authors.forename: David
authors.initials: D
authors.lastname: Saunders
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D037621:Artemisinins / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D055815:Young Adult; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines
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