Background

Recent studies raise concerns that resistance against commonly used ACTs for the treatment of malaria in African countries may be emerging. Residual parasitaemia after treatment was found to be common in Western Kenya and associated with increased gametocyte carriage, a higher transmission potential and  an increased risk on recurrent parasitaemia. Therefore, not only the extensive monitoring of clearance dynamics is important, but also 1. the development and evaluation of alternative treatments and 2. the development of fast, easy-to-perform and sensitive diagnostics, capable of following parasite survival during and after treatment.

One of these alternative treatments could be the combination of pyronaridine and artesunate (Shin Poong Pharmaceuticals). A child-friendly granule formulation (Pyramax) was developed for patients from the age of 3 months between 5 and 20 kg and has been shown to be well-tolerated and efficacious for the treatment of uncomplicated malaria in a phase III multicenter trial. dB-PCR-NALFIA is suggested as a suitable molecular tool to follow-up patients after treatment, as it is fast, sensitive and can be done in semi-field conditions.

Objectives

Our objectives are:

1. To determine the efficacy of pyronaridine-artesunate (PA) compared to artemether-lumefantrine (AL), for the treatment of uncomplicated falciparum malaria in Kenyan children (primary objective);

2. To determine parasite clearance time after treatment by PA, compared to AL;

3. To determine the duration of gametocyte carriage after treatment by PA, compared to AL;

4. To determine the rate of gametocyte transmission to mosquitos after treatment by PA, compared to AL;

5. To determine the accuracy of dB-PCR-NALFIA compared to microscopy and real-time PCR;

6. To determine treatment efficacy and predict treatment outcome by dB-PCR-NALFIA, compared to real-time PCR and microscopy;

7. To determine the safety of pyronaridine-artesunate for the treatment of uncomplicated falciparum malaria in Kenyan children compared to that of artemether-lumefantrine.

Methods

The main study concerns a single-blind, randomised controlled non-inferiority trial in Mbita, Western Kenya. Children aged 6 months (and ≥5 kg) to 12 years will be randomly allocated to receive either PA or AL, and will be followed for 42 days. Finger-prick blood will be collected on day 0, 1, 2, 3, 7, 14, 28, and 42. On day 7, for children aged ≥2 years and only when additional informed consent is obtained, a 3ml venous blood sample will be collected instead of a finger-prick to determine transmission potential (objective 4). It is planned to include 225 children per intervention group. With this sample size it is possible to evaluate non-inferiority of PA compared to AL with a margin of 7% (corresponding to the absolute difference between groups), a one-sided alpha of 0.05 and a power of 91%. In the primary analysis non-inferiority of the PA group regarding the PCR-corrected ACPR-rate at day-28 compared to the AL group will be tested.