TY - JOUR
T1 - Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria
T2 - a randomised, single-blind, multicentre trial
AU - Abdulla, Salim
AU - Sagara, Issaka
AU - Borrmann, Steffen
AU - D'Alessandro, Umberto
AU - González, Raquel
AU - Hamel, Mary
AU - Ogutu, Bernhards
AU - Mårtensson, Andreas
AU - Lyimo, John
AU - Maiga, Hamma
AU - Sasi, Philip
AU - Nahum, Alain
AU - Bassat, Quique
AU - Juma, Elizabeth
AU - Otieno, Lucas
AU - Björkman, Anders
AU - Beck, Hans Peter
AU - Andriano, Kim
AU - Cousin, Marc
AU - Lefèvre, Gilbert
AU - Ubben, David
AU - Premji, Zulfikarali
N1 - Funding Information:
We thank the study population and local staff, without whom the present study would not have been possible. The local staff consisted of: C Membi, A Mohammed, A Abdallah (Ifakara Health Institute, Dar es Salaam, Tanzania); E G Rotllant, H Makame (Zanzibar Malaria Research Unit of the Karolinska Institute, Tanzania); M Bashraheil, P K Klouwenberg, A Salim (Kenya Medical Research Institute, Kifili, Kenya); DAhounou, D Bonou, A Massougbodji, M Bancolé, T Hounhouedo, C Agbowaï (Centre de Recherche Entomologique de Cotonou, Cotonou, Bénin); C Menéndez (CRESIB, Barcelona Centre for International Health Research); S Machevo, M Renom, I Mandomando (Manhiça Health Research Centre, Manhiça, Mozambique); V Owira, M Polhemus, N Otsyula (Walter Reed Project and Kenya Medical Research Institute, Kisumu, Kenya); A Djimde, O B Traore, M Tekete, Z I Traore, N Diallo, S Dama, N Ouologuem, O Doumbo (Malaria Research and Training Centre, University of Bamako, Bamako, Mali); IA Coovadia (Novartis, South Africa); P Ibarra de Palacios, A C Marrast (Novartis Pharma, Switzerland); N Mulure (Novartis, Kenya); O Nwaiwu (Novartis, Nigeria). We also thank P Kremsner and K Dietz from the University of Tübingen (Germany) for their participation in the data monitoring board. Statistical analysis was carried out by DATAMAP GmbH (Freiburg, Germany). We acknowledge the dedicated work of M Wibberg, T Widmayer, and J Lilienthal. Drafting of the manuscript was done by E A Mueller (3P Consulting, Bad Krozingen, Germany). Novartis Pharma sponsored this trial as part of the clinical development programme for the new paediatric formulation investigated. The trial was cosponsored by Medicines for Malaria Venture (MMV). S Borrmann is funded by a German Research Foundation Junior Group grant (SFB 544, A7).
PY - 2008
Y1 - 2008
N2 - Background: Combination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent Plasmodium falciparum drug resistance. Our aim was to show non-inferiority of a new dispersible formulation of artemether-lumefantrine to the conventional crushed tablet in the treatment of young children with uncomplicated malaria. Methods: We did a randomised non-inferiority study on children weighing 5-35 kg with uncomplicated P falciparum malaria in Benin, Kenya, Mali, Mozambique, and Tanzania. The primary outcome measure was PCR-corrected 28-day parasitological cure rate. We aimed to show non-inferiority (with a margin of -5%) of dispersible versus crushed tablet. We constructed an asymptotic one-sided 97·5% CI on the difference in cure rates. A computer-generated randomisation list was kept centrally and investigators were unaware of the study medication administered. We used a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00386763. Findings: 899 children aged 12 years or younger were randomly assigned to either dispersible (n=447) or crushed tablets (n=452). More than 85% of patients in each treatment group completed the study. 812 children qualified for the modified intention-to-treat analysis (n=403 vs n=409). The PCR-corrected day-28 cure rate was 97·8% (95% CI 96·3-99·2) in the group on dispersible formulation and 98·5% (97·4-99·7) in the group on crushed formulation. The lower bound of the one-sided 97·5% CI was -2·7%. The most common drug-related adverse event was vomiting (n=33 [7%] and n=42 [9%], respectively). No signs of ototoxicity or relevant cardiotoxicity were seen. Interpretation: A six-dose regimen of artemether-lumefantrine with the new dispersible formulation is as efficacious as the currently used crushed tablet in infants and children, and has a similar safety profile. Funding: Novartis Pharma, Basel, Switzerland, and Medicines for Malaria Venture (MMV), Geneva, Switzerland.
AB - Background: Combination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent Plasmodium falciparum drug resistance. Our aim was to show non-inferiority of a new dispersible formulation of artemether-lumefantrine to the conventional crushed tablet in the treatment of young children with uncomplicated malaria. Methods: We did a randomised non-inferiority study on children weighing 5-35 kg with uncomplicated P falciparum malaria in Benin, Kenya, Mali, Mozambique, and Tanzania. The primary outcome measure was PCR-corrected 28-day parasitological cure rate. We aimed to show non-inferiority (with a margin of -5%) of dispersible versus crushed tablet. We constructed an asymptotic one-sided 97·5% CI on the difference in cure rates. A computer-generated randomisation list was kept centrally and investigators were unaware of the study medication administered. We used a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00386763. Findings: 899 children aged 12 years or younger were randomly assigned to either dispersible (n=447) or crushed tablets (n=452). More than 85% of patients in each treatment group completed the study. 812 children qualified for the modified intention-to-treat analysis (n=403 vs n=409). The PCR-corrected day-28 cure rate was 97·8% (95% CI 96·3-99·2) in the group on dispersible formulation and 98·5% (97·4-99·7) in the group on crushed formulation. The lower bound of the one-sided 97·5% CI was -2·7%. The most common drug-related adverse event was vomiting (n=33 [7%] and n=42 [9%], respectively). No signs of ototoxicity or relevant cardiotoxicity were seen. Interpretation: A six-dose regimen of artemether-lumefantrine with the new dispersible formulation is as efficacious as the currently used crushed tablet in infants and children, and has a similar safety profile. Funding: Novartis Pharma, Basel, Switzerland, and Medicines for Malaria Venture (MMV), Geneva, Switzerland.
UR - http://www.scopus.com/inward/record.url?scp=56549110631&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(08)61492-0
DO - 10.1016/S0140-6736(08)61492-0
M3 - Article
C2 - 18926569
AN - SCOPUS:56549110631
SN - 0140-6736
VL - 372
SP - 1819
EP - 1827
JO - The Lancet
JF - The Lancet
IS - 9652
ER -
