What is the aim of this review?
We wanted to find out about the potential benefits and harms of child-friendly formulations of artemisinin-based combination therapy (ACT) to treat uncomplicated malaria in children. We searched for studies that investigated the use of child-friendly formulations of ACTs, compared with the usual ACT tablet formulations, to treat uncomplicated malaria in children aged under 14 years. We looked for randomized controlled studies, in which the treatments the children received were decided at random. This type of study usually gives the most reliable evidence about the effects of a treatment. We found three relevant studies of two child-friendly formulations.
Key messages
Child-friendly formulations of ACT probably work as well as crushed tablets to treat uncomplicated malaria in children, and probably cause fewer unwanted effects.
What was studied in this review?
Malaria is a tropical disease spread by mosquitoes infected with Plasmodium parasites. The most common, and most serious, type of malaria is caused by Plasmodium falciparum. This parasite causes high levels of illness and death, particularly in young children in regions where malaria is widespread.
Malaria can be a mild illness, but is sometimes severe and life-threatening if not treated soon enough or with the right medicines.
Medicines based on artemisinin, a compound derived from a plant (Artemisia annua), are commonly taken by mouth (orally) to treat malaria in combination with other drugs. The World Health Organization recommends treating uncomplicated malaria with oral artemisinin-based combination therapy (called ACT).
Oral ACT tablets are often crushed to help make them easier for children to swallow. New formulations of oral ACTs have been developed especially for children, such as syrups, and granules, powders or tablets that can be dissolved in water, and which may be flavoured.
What are the main results of this review?
We found three relevant studies in 1306 children (aged 6 months to 11 years) with uncomplicated malaria. The studies were conducted in sub-Saharan Africa between 2006 and 2015. All studies were funded by pharmaceutical companies that made child-friendly formulations of the ACTs.
The studies compared crushed ACT tablets to child-friendly formulations of ACTs: these were dissolvable tablets of artemether-lumefantrine or dihydroartemisinin-piperaquine, or artemether-lumefantrine syrup.
We were interested in:
· whether children remained cured of malaria after 28 days (measured by absence of Plasmodium parasites in the blood); and
· whether the medicines caused any unwanted effects.
None of the studies looked at how any of the medicine formulations were accepted by children.
There may be little or no difference between the child-friendly formulations of ACTs (dissolvable tablets or syrup) and the usual crushed tablets for how many children:
· were successfully treated after 28 days; or
· experienced serious unwanted effects.
The crushed ACT tablets and the child-friendly formulations successfully treated most cases of uncomplicated malaria. After 28 days the rates of treatment failure were similar in both groups. On average, 59 of every 1000 children taking crushed ACT tablets and 62 of every 1000 children taking dissolvable tablets would still have Plasmodium infection (2 studies; 1139 children).
Similar numbers of serious unwanted effects were reported for the usual crushed tablets and the dissolvable tablets (2 studies; 1197 children) or syrup (1 study; 267 children), therefore differences as a result of the formulation are unlikely.
A dissolvable tablet probably reduces unwanted effects of the medicine, including vomiting (throwing up), compared with the usual crushed tablets. Children taking dissolvable tablets had fewer unwanted effects associated with the medicine (139 of every 1000 children) than those taking crushed tablets (178 of every 1000 children).
There was no difference in the number of unwanted effects found in the study with the syrup formulation compared with the usual crushed tablets.
Our confidence in our results is low to moderate. The results come from a small number of studies. All studies were supported by manufacturers of the child-friendly formulations, which could have affected how the studies were designed, conducted, and reported.
How up-to-date is this review?
We searched for studies that had been published up to 11 December 2019.
Trials did not demonstrate a difference in efficacy between paediatric dispersible or suspension ACT when compared with the respective crushed tablet ACT for treating uncomplicated P falciparum malaria in children. However, the evidence is of low to moderate certainty due to limited power. There appeared to be fewer drug-related adverse events with dispersible ACT compared to crushed tablet ACT. None of the included studies assessed acceptability of paediatric ACT formulation.
In endemic malarial areas, young children have high levels of malaria morbidity and mortality. The World Health Organization recommends oral artemisinin-based combination therapy (ACT) for treating uncomplicated malaria. Paediatric formulations of ACT have been developed to make it easier to treat children.
To evaluate evidence from trials on the efficacy, safety, tolerability, and acceptability of paediatric ACT formulations compared to tablet ACT formulations for uncomplicated P falciparum malaria in children up to 14 years old.
We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; the Latin American and Caribbean Health Science Information database (LILACS); ISI Web of Science; Google Scholar; Scopus; and the metaRegister of Controlled Trials (mRCT) to 11 December 2019.
We included randomised controlled clinical trials (RCTs) of paediatric versus non-paediatric formulated ACT in children aged 14 years or younger with acute uncomplicated malaria.
Two authors independently assessed eligibility and risk of bias, and carried out data extraction. We analyzed the primary outcomes of efficacy, safety and tolerability of paediatric versus non-paediatric ACT using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were: treatment failure on the last day of observation (day 42), fever clearance time, parasite clearance time, pharmacokinetics, and acceptability.
Three trials met the inclusion criteria. Two compared a paediatric dispersible tablet formulation against crushed tablets of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQ), and one trial assessed artemether-lumefantrine formulated as powder for suspension compared with crushed tablets. The trials were carried out between 2006 and 2015 in sub-Saharan Africa (Benin, Mali, Mozambique, Tanzania, Kenya, Democratic Republic of the Congo, Burkina Faso, and The Gambia).
In all three trials, the paediatric and control ACT achieved polymerase chain reaction (PCR)-adjusted treatment failure rates of < 10% on day 28 in the per-protocol (PP) population.
For the comparison of dispersible versus crushed tablets, the two trials did not detect a difference for treatment failure by day 28 (PCR-adjusted PP population: RR 1.35, 95% CI 0.49 to 3.72; 1061 participants, 2 studies, low-certainty evidence). Similarly, for the comparison of suspension versus crushed tablet ACT, we did not detect any difference in treatment failure at day 28 (PCR-adjusted PP population: RR 1.64, 95% CI 0.55 to 4.87; 245 participants, 1 study).
We did not detect any difference in serious adverse events for the comparison of dispersible versus crushed tablets (RR 1.05, 95% CI 0.38 to 2.88; 1197 participants, 2 studies, low-certainty evidence), or for the comparison of suspension versus crushed tablet ACT (RR 0.74, 95% CI 0.17 to 3.26; 267 participants, 1 study).
In the dispersible ACT arms, drug-related adverse events occurred in 9% of children in the AL study and 34% of children in the DHA-PQ study. In the control arms, drug-related adverse events occurred in 12% of children in the AL study and in 42% of children in the DHA-PQ study. Drug-related adverse events were lower in the dispersible ACT arms (RR 0.78, 95% CI 0.62 to 0.99; 1197 participants, 2 studies, moderate-certainty evidence).
There was no detected difference in the rate of drug-related adverse events for suspension ACT versus crushed tablet ACT (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study).
Drug-related vomiting appeared to be less common in the dispersible ACT arms (RR 0.75, 95% CI 0.56 to 1.01; 1197 participants, 2 studies, low-certainty evidence) and in the suspension ACT arm (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study), but both analyses were underpowered.
No study assessed acceptability.