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Clinical Therapeutics

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

Jessica Manning, Pattaraporn Vanachayangkul, Chanthap Lon, Michele Spring, Mary So, Darapiseth Sea, Youry Se, Sok Somethy, Sut-Thang Phann, Soklyda Chann, Sabaithip Sriwichai, Nillawan Buathong, Worachet Kuntawunginn, Mashamon Mitprasat, Raveewan Siripokasupkul, Paktiya Teja-Isavadharm, Eugene Soh, Ans Timmermans, Charlotte Lanteri, Jaranit Kaewkungwal, Montida Auayporn, Douglas Tang, Char Meng Chour, Satharath Prom, Mark Haigney, Louis Cantilena, David Saunders
Jessica Manning
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Pattaraporn Vanachayangkul
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Chanthap Lon
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Michele Spring
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Mary So
cRoyal Cambodian Armed Forces, Phnom Penh, Cambodia
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Darapiseth Sea
bNational Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
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Youry Se
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Sok Somethy
cRoyal Cambodian Armed Forces, Phnom Penh, Cambodia
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Sut-Thang Phann
bNational Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
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Soklyda Chann
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Sabaithip Sriwichai
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Nillawan Buathong
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Worachet Kuntawunginn
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Mashamon Mitprasat
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Raveewan Siripokasupkul
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Paktiya Teja-Isavadharm
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Eugene Soh
dF. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
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Ans Timmermans
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Charlotte Lanteri
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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Jaranit Kaewkungwal
eCenter for Excellence in Bioinformatics (BIOPHICS), Mahidol University, Bangkok, Thailand
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Montida Auayporn
eCenter for Excellence in Bioinformatics (BIOPHICS), Mahidol University, Bangkok, Thailand
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Douglas Tang
fFast Track Biologics, Bethesda, Maryland, USA
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Char Meng Chour
bNational Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
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Satharath Prom
cRoyal Cambodian Armed Forces, Phnom Penh, Cambodia
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Mark Haigney
dF. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
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Louis Cantilena
dF. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
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David Saunders
aDepartment of Immunology and Medicine, Armed Forces Research Institute of Medical Science, Bangkok, Thailand
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DOI: 10.1128/AAC.02667-14
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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.)

FOOTNOTES

    • Received 27 February 2014.
    • Returned for modification 22 March 2014.
    • Accepted 18 July 2014.
    • Accepted manuscript posted online 4 August 2014.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.02667-14.

  • Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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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
Jessica Manning, Pattaraporn Vanachayangkul, Chanthap Lon, Michele Spring, Mary So, Darapiseth Sea, Youry Se, Sok Somethy, Sut-Thang Phann, Soklyda Chann, Sabaithip Sriwichai, Nillawan Buathong, Worachet Kuntawunginn, Mashamon Mitprasat, Raveewan Siripokasupkul, Paktiya Teja-Isavadharm, Eugene Soh, Ans Timmermans, Charlotte Lanteri, Jaranit Kaewkungwal, Montida Auayporn, Douglas Tang, Char Meng Chour, Satharath Prom, Mark Haigney, Louis Cantilena, David Saunders
Antimicrobial Agents and Chemotherapy Sep 2014, 58 (10) 6056-6067; DOI: 10.1128/AAC.02667-14

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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
Jessica Manning, Pattaraporn Vanachayangkul, Chanthap Lon, Michele Spring, Mary So, Darapiseth Sea, Youry Se, Sok Somethy, Sut-Thang Phann, Soklyda Chann, Sabaithip Sriwichai, Nillawan Buathong, Worachet Kuntawunginn, Mashamon Mitprasat, Raveewan Siripokasupkul, Paktiya Teja-Isavadharm, Eugene Soh, Ans Timmermans, Charlotte Lanteri, Jaranit Kaewkungwal, Montida Auayporn, Douglas Tang, Char Meng Chour, Satharath Prom, Mark Haigney, Louis Cantilena, David Saunders
Antimicrobial Agents and Chemotherapy Sep 2014, 58 (10) 6056-6067; DOI: 10.1128/AAC.02667-14
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