A Phase III, Randomized, Non-Inferiority Trial to Assess the Efficacy and Safety of Dihydroartemisinin-Piperaquine in Comparison with Artesunate-Mefloquine in Patients with Uncomplicated Plasmodium falciparum Malaria in Southern Laos

We conducted an open, randomized clinical trial of oral dihydroartemisinin-piperaquine (DP) versus artesunate-mefloquine (AM) in 300 patients in Laos with uncomplicated Plasmodium falciparum malaria as part of a multicentre study in Asia. Survival analysis and adjustment for re-infection showed that the 63-day cure rates (95% confidence interval [CI]) were 100% for AM and 99.5% (96.4–99.8%) for DP. The 63-day cure rates per protocol were 99% (97 of 98) for AM and 99.5% (196 of 197) for DP (P = 0.55). The difference (AM minus DP) in cure rates (95% CI) was −0.5% (−5.1 to 2.0%), which is within the 5% non-inferiority margin. The median fever and parasite clearance times were also similar for AM and DP. The proportion of patients with at least one recorded potential adverse event was significantly higher in the AM group (38 of 87, 44%) than in the DP group (57 of 182, 31%) (relative risk = 0.6, 95% CI = 0.4–0.9; P = 0.04). Dihydroartemisinin-piperaquine is not inferior to AM in the treatment of uncomplicated P. falciparum malaria in Laos and is associated with fewer adverse effects. The results of this study were similar to those of the larger multicentre study.

[1]  F. Nosten,et al.  A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[2]  P. Newton,et al.  Randomized comparison of chloroquine plus sulfadoxine-pyrimethamine versus artesunate plus mefloquine versus artemether-lumefantrine in the treatment of uncomplicated falciparum malaria in the Lao People's Democratic Republic. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  T. Jelínek,et al.  Therapeutic efficacy of artemether‐lumefantrine and artesunate‐mefloquine for treatment of uncomplicated Plasmodium falciparum malaria in Luang Namtha Province, Lao People's Democratic Republic , 2004, Tropical medicine & international health : TM & IH.

[4]  M. Fukuda,et al.  Evidence of artemisinin-resistant malaria in western Cambodia. , 2008, The New England journal of medicine.

[5]  P. Newton,et al.  A comparison of artesunate alone with combined artesunate and quinine in the parenteral treatment of acute falciparum malaria. , 2001, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[6]  R. Price,et al.  Dihydroartemisinin-piperaquine versus artesunate-amodiaquine: superior efficacy and posttreatment prophylaxis against multidrug-resistant Plasmodium falciparum and Plasmodium vivax malaria. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[7]  P. Rosenthal,et al.  Artemether-lumefantrine versus dihydroartemisinin-piperaquine for falciparum malaria: a longitudinal, randomized trial in young Ugandan children. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[8]  S. Omar,et al.  O38 A randomized trial to monitor the efficacy and effectiveness by QT-NASBA of artemether–lumefantrine versus dihydroartemisinin–piperaquine for treatment and transmission control of uncomplicated Plasmodium falciparum malaria in western Kenya , 2009 .

[9]  T. Davis,et al.  Safety evaluation of fixed combination piperaquine plus dihydroartemisinin (Artekin) in Cambodian children and adults with malaria. , 2003, British journal of clinical pharmacology.

[10]  I. Versteeg,et al.  A randomized trial to monitor the efficacy and effectiveness by QT-NASBA of artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment and transmission control of uncomplicated Plasmodium falciparum malaria in western Kenya , 2008, Malaria Journal.

[11]  R. Price,et al.  Electrocardiographic safety evaluation of dihydroartemisinin piperaquine in the treatment of uncomplicated falciparum malaria. , 2007, The American journal of tropical medicine and hygiene.

[12]  G. Brittenham,et al.  Comparative clinical trial of two-fixed combinations dihydroartemisinin-napthoquine-trimethoprim (DNP) and artemether-lumefantrine (Coartem/Riamet) in the treatment of acute uncomplicated falciparum malaria in Thailand. , 2003, The Southeast Asian journal of tropical medicine and public health.

[13]  W. Gropp,et al.  Does increased aromatase activity in adipose fibroblasts cause low sexual desire in patients with HIV lipodystrophy? , 2002, Sexually transmitted infections.

[14]  N. White,et al.  Randomized Comparison of Artemether-Benflumetol and Artesunate-Mefloquine in Treatment of MultidrugResistant Falciparum Malaria , 1998, Antimicrobial Agents and Chemotherapy.

[15]  C. Dolecek,et al.  Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial , 2004, The Lancet.

[16]  N. White.  Cardiotoxicity of antimalarial drugs. , 2007, The Lancet. Infectious diseases.

[17]  P. Newton,et al.  Safety and Efficacy of Dihydroartemisinin-Piperaquine in Falciparum Malaria: A Prospective Multi-Centre Individual Patient Data Analysis , 2009, PloS one.

[18]  Q. Bassat,et al.  Dihydroartemisinin-Piperaquine and Artemether-Lumefantrine for Treating Uncomplicated Malaria in African Children: A Randomised, Non-Inferiority Trial , 2009, PloS one.

[19]  K. Stepniewska,et al.  Some considerations in the design and interpretation of antimalarial drug trials in uncomplicated falciparum malaria , 2006, Malaria Journal.

[20]  N. Thanh,et al.  Open label randomized comparison of dihydroartemisinin–piperaquine and artesunate–amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in central Vietnam , 2009, Tropical medicine & international health : TM & IH.

[21]  R. Snow,et al.  Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria , 2003 .

[22]  P. Newton,et al.  An Open-Label, Randomised Study of Dihydroartemisinin-Piperaquine Versus Artesunate-Mefloquine for Falciparum Malaria in Asia , 2010, PloS one.

[23]  J. Philpott,et al.  Severe falciparum malaria. , 1987, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[24]  K. Stepniewska,et al.  Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison , 2006, The Lancet.

[25]  M. Newell.  Vertical transmission of HIV-1 infection. , 2000, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[26]  R. Newcombe,et al.  Interval estimation for the difference between independent proportions: comparison of eleven methods. , 1998, Statistics in medicine.

[27]  P. Newton,et al.  A randomized comparison of oral chloroquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria in Laos. , 2003, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[28]  S. Krudsood,et al.  A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. , 2001, The American journal of tropical medicine and hygiene.

[29]  P. Siba,et al.  A trial of combination antimalarial therapies in children from Papua New Guinea. , 2008, The New England journal of medicine.

[30]  C. Karema,et al.  Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. , 2006, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[31]  S. Merhar,et al.  Letter to the editor , 2005, IEEE Communications Magazine.

[32]  N. White,et al.  Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria. , 1999, The American journal of tropical medicine and hygiene.

[33]  S. Krudsood,et al.  An open randomized clinical trial of Artekin vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria. , 2005, The Southeast Asian journal of tropical medicine and public health.

[34]  S. Krudsood,et al.  An open randomized clinical trial of Artecom vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria in Thailand. , 2002, The Southeast Asian journal of tropical medicine and public health.

[35]  F. Nosten,et al.  Dihydroartemisinin-piperaquine rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report. , 2008, The American journal of tropical medicine and hygiene.

[36]  F. Nosten,et al.  Randomized, controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. , 2004, The Journal of infectious diseases.

[37]  P. Rosenthal,et al.  Randomized comparison of amodiaquine plus sulfadoxine-pyrimethamine, artemether-lumefantrine, and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Burkina Faso. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[38]  G. Brittenham,et al.  Dose ranging studies of new artemisinin-piperaquine fixed combinations compared to standard regimens of artemisisnin combination therapies for acute uncomplicated falciparum malaria. , 2007, The Southeast Asian journal of tropical medicine and public health.

[39]  P. Rosenthal,et al.  Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treatment of Malaria: A Randomized Trial , 2007, PLoS clinical trials.

[40]  P. Newton,et al.  An open, randomized comparison of artesunate plus mefloquine vs. dihydroartemisinin–piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Lao People's Democratic Republic (Laos) , 2006, Tropical medicine & international health : TM & IH.

[41]  K. Silamut,et al.  Artemisinin resistance in Plasmodium falciparum malaria. , 2009, The New England journal of medicine.

[42]  Jianping Song,et al.  A randomized, controlled trial of artemisinin-piperaquine vs dihydroartemisinin-piperaquine phosphate in treatment of falciparum malaria , 2009, Chinese journal of integrative medicine.

[43]  S. Satpathy,et al.  Severe falciparum malaria , 2004, Indian journal of pediatrics.

[44]  T. Butler,et al.  QT prolongation and sudden cardiac death in patients with alcoholic liver disease , 1993, The Lancet.

[45]  U. d’Alessandro,et al.  A Randomised Controlled Trial to Assess the Efficacy of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Falciparum Malaria in Peru , 2007, PloS one.

[46]  S. Hewitt,et al.  Efficacy and safety of dihydroartemisinin-piperaquine (Artekin) in Cambodian children and adults with uncomplicated falciparum malaria. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[47]  P. Newton,et al.  Chloroquine versus sulfadoxine-pyrimethamine for treatment of Plasmodium falciparum malaria in Savannakhet Province, Lao People's Democratic Republic: an assessment of national antimalarial drug recommendations. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[48]  F. Nosten,et al.  Application of genetic markers to the identification of recrudescent Plasmodium falciparum infections on the northwestern border of Thailand. , 1999, The American journal of tropical medicine and hygiene.

[49]  B. Hongvanthong,et al.  High heterogeneity in Plasmodium falciparum risk illustrates the need for detailed mapping to guide resource allocation: a new malaria risk map of the Lao People's Democratic Republic , 2010, Malaria Journal.

[50]  E. Ashley,et al.  A randomized open study to assess the efficacy and tolerability of dihydroartemisinin–piperaquine for the treatment of uncomplicated falciparum malaria in Cambodia , 2007, Tropical medicine & international health : TM & IH.

[51]  P. Kager,et al.  CV8, a new combination of dihydroartemisinin, piperaquine, trimethoprim and primaquine, compared with atovaquone–proguanil against falciparum malaria in Vietnam , 2004, Tropical medicine & international health : TM & IH.

[52]  P. Rosenthal,et al.  Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treating Uncomplicated Malaria: A Randomized Trial to Guide Policy in Uganda , 2008, PloS one.