Elsevier

The Lancet

Volume 372, Issue 9652, 22–28 November 2008, Pages 1819-1827
The Lancet

Articles
Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial

https://doi.org/10.1016/S0140-6736(08)61492-0Get rights and content

Summary

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.

Introduction

Plasmodium falciparum malaria is one of the commonest causes of morbidity and mortality in large areas of the world. Most deaths happen in children in sub-Saharan Africa.1, 2, 3 Efforts to fight this disease are based on the combined use of preventive and therapeutic measures, including the adequate use of available antimalarial drugs, which are under constant threat from the emergence and spread of drug resistance of P falciparum. WHO now recommends combination treatments, preferably including an artemisinin derivative, to improve efficacy and prevent the emergence of parasite drug resistance.4 Artemisinin-based combination therapy is highly effective against multidrug-resistant P falciparum malaria in Asia and Africa,3, 5 and has been used in southeast Asia for more than 10 years. Sub-Saharan African countries are currently implementing artemisinin-based combination therapies as first-line or second-line treatments.5, 6

Artemether-lumefantrine (Coartem, Novartis Pharma AG, Basel, Switzerland) became the first fixed-dose combination therapy that was prequalified by WHO in April, 2004. A tablet consists of 20 mg artemether and 120 mg lumefantrine. A 3-day, six-dose regimen of artemether-lumefantrine is efficacious and safe in both adults and children,7, 8 and is recommended for infants and children weighing 5–35 kg, and adults weighing more than 35 kg. Many countries in sub-Saharan Africa have already adopted artemether-lumefantrine as first-line treatment for uncomplicated malaria, or have initiated the implementation process.6 Studies in animals5 suggested that artemisinin derivatives might have neurotoxic effects, although these findings have never been reproduced in people. Artemether-lumefantrine was reported to cause audiometric changes; however, that study has been much criticised.9 Furthermore, the chemical similarity of lumefantrine and halofantrine, which prolongs corrected QT interval (QTc), has generated concern that artemether-lumefantrine might have cardiac adverse effects. To date, no clinically significant cardiovascular toxic effects have been seen with the combination.10

In African children, efficacy of artemether-lumefantrine at day 28 after treatment is consistently more than 90%,11, 12, 13, 14, 15, 16 even with unsupervised administration.17, 18 However, many young children cannot swallow whole tablets, and the bitter taste of the crushed commercial tablet added to water could compromise tolerability. Also, crushing tablets is an inefficient procedure, which could result in loss of drug and reduced dose ingested. To overcome these problems, a sweetened cherry-flavoured dispersible formulation has been developed for young children. Dispersible tablets contain the same amounts of artemether and lumefantrine as crushed tablets. We compared the efficacy and safety of the new dispersible formulation of artemether-lumefantrine with the crushed one in children with uncomplicated P falciparum malaria. Our primary aim was to show non-inferiority of the new formulation compared with the conventional one on day-28 PCR-corrected cure rates. Major secondary and exploratory outcomes included time to fever clearance and the day-42 PCR-corrected cure rate. Additionally, safety and tolerability profiles (including QTc changes) were compared between the two groups.

Section snippets

Patients

We recruited infants and children with microscopically confirmed acute uncomplicated P falciparum malaria from eight health-care facilities in five malaria-endemic countries: one centre each in Benin, Mali, Mozambique, Tanzania mainland, and Zanzibar, and three in Kenya. Except one site in Kenya, study centres were located in rural and periurban areas. At these locations, malaria transmission is intense and perennial, with the exception of the two study sites in Mozambique and Zanzibar, where

Results

Overall, 899 patients were randomly assigned to the two treatment groups (figure 1; 447 to dispersible tablets and 452 to crushed tablets; 110 in Benin, 193 in Kenya, 225 in Mali, 102 in Mozambique, 240 in Tanzania mainland, and 29 in Zanzibar). More than 85% of patients in each treatment group completed the study. 4% of patients withdrew during the 3-day treatment period (16 of 447 in the dispersible formulation group and 17 of 452 in the crushed formulation group). 886 (99%) and 804 (89%) of

Discussion

The dispersible formulation of artemether-lumefantrine was not inferior in efficacy to crushed tablets in children with acute uncomplicated P falciparum malaria, and had a similar safety profile. PCR-corrected day-28 cure rates were high for both formulations in children. No differences were seen in the response to treatment across the various bodyweight groups, or between the two formulations in terms of clearance of asexual parasites and fever, which was rapid for both treatments.

Multiple

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