Abstract
BackgroundArtemisinin-based combination therapy is currently recommended by the World Health Organization as first-line treatment of uncomplicated malaria. Recommendations were adapted in 2010 regarding rescue treatment in case of treatment failure. Instead of quinine monotherapy, it should be combined with an antibiotic with antimalarial properties; alternatively, another artemisinin-based combination therapy may be used. However, for informing these policy changes, no clear evidence is yet available. The need to provide the policy makers with hard data on the appropriate rescue therapy is obvious. We hypothesize that the efficacy of the same artemisinin-based combination therapy used as rescue treatment is as efficacious as quinine + clindamycin or an alternative artemisinin-based combination therapy, without the risk of selecting drug resistant strains.DesignWe embed a randomized, open label, three-arm clinical trial in a longitudinal cohort design following up children with uncomplicated malaria until they are malaria parasite free for 4 weeks. The study is conducted in both the Democratic Republic of Congo and Uganda and performed in three steps. In the first step, the pre-randomized controlled trial (RCT) phase, children aged 12 to 59 months with uncomplicated malaria are treated with the recommended first-line drug and constitute a cohort that is passively followed up for 42 days. If the patients experience an uncomplicated malaria episode between days 14 and 42 of follow-up, they are randomized either to quinine + clindamycin, or an alternative artemisinin-based combination therapy, or the same first-line artemisinin-based combination therapy to be followed up for 28 additional days. If between days 14 and 28 the patients experience a recurrent parasitemia, they are retreated with the recommended first-line regimen and actively followed up for another 28 additional days (step three; post-RCT phase). The same methodology is followed for each subsequent failure. In any case, all patients without an infection at day 28 are classified as treatment successes and reach a study endpoint. The RCT phase allows the comparison of the safety and efficacy of three rescue treatments. The prolonged follow-up of all children until they are 28 days parasite-free allows us to assess epidemiological-, host- and parasite-related predictors for repeated malaria infection.Trial registrationNCT01374581 and PACTR201203000351114
Highlights
Artemisinin-based combination therapy is currently recommended by the World Health Organization as first-line treatment of uncomplicated malaria
After Polymerase chain reaction (PCR) analysis, over 75% of ASAQ and artemether-lumefantrine (AL) treatment failures have been classified as new infections, while recrudescences have low parasite densities [6]
Efficacy of the six-dose regimen of AL has been demonstrated in semi-immune and non-immune populations in Asia and Africa to be consistently greater than 95%, with rapid parasite and symptom clearance and significant gametocytocidal effect [7]
Summary
Malaria remains one of the great infectious killers in Africa. An estimated 300 to 500 million cases occur each year, causing 1.5 to 2.7 million deaths, primarily in children under the age of 5 years [1]. Rationale Considering the facts that (i) over >75% of treatment failure to ASAQ or AL are new infections, (ii) parasite density is low in case of recrudescence occurring from day 14 onwards, and (iii) in real-life situations patients are retreated with the same first-line drug, there is a need to assess the role of the first-line treatment as rescue treatment This efficacy will be compared to quinine + clindamycin and another ACT treatment in line with the WHO guideline [13]. Post- randomized controlled trial phase All patients included in the RCT phase and presenting a clinical or parasitological failure from day 14 onwards are retreated with the country’s first-line treatment (AL or ASAQ). Relationship of event to study drug, and outcome The severity of a clinical AE is to be scored according to the following scale: 1. Mild: awareness of sign or symptom, but tolerated
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