A head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomized trial - PubMed (original) (raw)

Randomized Controlled Trial

A head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomized trial

Four Artemisinin-Based Combinations (4ABC) Study Group. PLoS Med. 2011 Nov.

Abstract

Background: Artemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated malaria cases. However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial drug policies are scarce.

Methods and findings: Between 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6-59 mo old with uncomplicated Plasmodium falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed up until day 28, and then passively followed up for the next 6 mo. At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37-0.94); DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41-1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI: 0.28-0.92). For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27, 95% CI: 0.21-0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30-0.53), while DHAPQ (92.2%) had higher efficacy than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26-0.48). CD+A was significantly less efficacious than the other three treatments. Day 63 results were similar to those observed at day 28.

Conclusions: This large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL, ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid option for the treatment of uncomplicated P. falciparum malaria.

Trial registration: ClinicalTrials.gov NCT00393679; Pan African Clinical Trials Registry PACTR2009010000911750

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Conflict of interest statement

Prof. Umberto d‚Alessandro has received research funding from Sigma Tau and Sanofi-Aventis. Dr. Quique Bassat has received in the past three years speaker fees and travel grants from Sigma Tau SP, Pomezia, Rome, Italy. All other authors declare no competing interests.

Figures

Figure 1

Figure 1. Trial profile up to day 28.

Adj TF, adjusted treatment failure; Unadj TF, unadjusted treatment failure.

Figure 2

Figure 2. Proportion of patients whose treatment was failure-free by day of follow-up.

ITT population; data pooled over all sites.

Figure 3

Figure 3. Six pair-wise comparisons at day 28 and day 63.

OR (circles), 95% CI (horizontal bars), and non-inferiority limit (vertical bars) for each pair-wise analysis for PCR-unadjusted (left panel) and -adjusted (right panel) ACPR at days 28 (filled circles) and 63 (open circles) (ITT population). An OR and 95% CI<1 indicate a significantly higher efficacy of the second versus the first treatment of the pair-wise comparison. The non-inferiority limits (day 28 only) correspond to a 10% difference in efficacy, recalculated to an OR scale. Non-inferiority is established if the 95% CI lies completely above the non-inferiority limit.

Figure 4

Figure 4. Treatment efficacy by pair-wise comparison and by site.

Risk difference and 95% CI for three pair-wise analyses by site for PCR-unadjusted (left panel) and -adjusted (right panel) ACPR at days 28 (filled circles) and 63 (open circles) (ITT population) (A) ASAQ versus DHAPQ; (B) AL versus ASAQ; (C) AL versus DHAPQ. BF, Burkina Faso; GA, Gabon; MZ, Mozambique; NG, Nigeria; RW, Rwanda; UG, Uganda; ZM, Zimbabwe.

Figure 5

Figure 5. Gametocyte prevalence by treatment and day of follow-up.

(A) All patients regardless of gametocytemia at enrollment; (B) patients with gametocytes at enrollment excluded.

Figure 6

Figure 6. Hematological recovery by treatment and day of follow-up.

Hematological recovery determined by Hb changes compared to day 0. The boxplots contain the following information: median (bold line), first and third quartile (box), whiskers extending to 1.5× interquartile range, and all more extreme values.

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