In children with uncomplicated P. falciparum malaria treated with pyronaridine-artesunate granules, day-28 PCR-corrected ACPR was 97.1% (95% CI 94.6, 98.6) in the per-protocol population. This is consistent with the high efficacy rates reported with pyronaridine-artesunate tablets in Phase III trials conducted in children and adults with P. falciparum malaria [5, 6]. Introduction of a new anti-malarial requires an efficacy of >95% . Statistically this trial was powered to show whether a cure rate of >90% was achieved. This was because of practical reasons in determining a reasonable sample size and the assumption that cure rates would be around 95%. Reaching an actual cure rate of 95% with a confidence interval of 95% ± Δ only allows you to demonstrate that the cure rate is >95% – Δ. Thus, with an actual cure rate of 95% it was deemed realistic to demonstrate that the cure rate is >90%. The sample size calculation was based on these assumptions.
Pyronaridine-artesunate was highly efficacious across all seven study centers and was equally effective across all age groups (Additional file 1). However, the primary efficacy outcome was not quite met in the youngest age group (81.8%; 95% CI 48.2–97.7), though only 11 children <1 year old were analyzed in the per-protocol population for pyronaridine-artesunate. In children aged 1–5 years, outcomes were similar to the older children and met the primary endpoint. Thus, further data are needed to assess to efficacy of pyronaridine-artesunate in very young children (<1 year old). Studies in very young children should only be conducted after more extensive clinical use in older children and adults to demonstrate safety. A study protocol could be envisaged where adults/older children are first recruited, and once a safety review of that population is complete, recruitment could be extended to a cohort of children more than two years of age and if safety is satisfactory in this group, finally, a cohort of very young children from 6 months old could be included in the study.
The data suggested an improved efficacy with pyronaridine-artesunate doses higher than 8.5:2.8 mg/kg/day, using PCR-corrected cure rates. These data are in contrast to a Phase II trial, in which PCR-corrected efficacy was 100% for pyronaridine-artesunate dose groups of 6:2 mg/kg, 9:3 mg/kg and 12:4 mg/kg . Population pharmacokinetic data for pyronaridine indicate a larger volume of distribution in children versus adults, resulting in lower concentrations over time (author’s unpublished data). The limited immunity of children under 5 years of age to P. falciparum could also make this population more sensitive to dose–response effects. These findings will be examined more closely in a report on the population pharmacokinetics across the Phase III trials.
Pyronaridine-artesunate efficacy in children was non-inferior to that of artemether-lumefantrine; consistent with previous findings in children and adults . There were no differences between treatment groups in the rate of recrudescence or re-infection (Figure 2). In the previous Phase III study (tablet formulation), pyronaridine-artesunate showed a significantly greater post-treatment prophylactic effect versus artemether-lumefantrine at day 42 (P = .007) . This might result from differences in transmission rates between the two studies, or because in the previous study 56.7% of patients were >12 years old with no children under 5 years. Their greater immunity to P. falciparum may have contributed to a more sustained prophylactic effect.
As expected, both treatments reduced parasitemia rapidly. Parasite clearance time was shorter with pyronaridine-artesunate versus artemether-lumefantrine (P = .02). This was seen previously , and in studies of other forms of ACT containing dihydroartemisinin or artesunate compared with artemether [17, 18]. Artesunate is converted more rapidly and completely than artemether to the active form dihydroartemisinin and has greater oral availability on the first day of treatment .
The effect of fat for optimizing artemether-lumefantrine absorption is well known and in this study we allowed each center to follow their local recommendations with regard to food or milk at the point of administration. Although this potentially introduces some variability, artemether-lumefantrine efficacy was high across all centers included in the study. There is no significant food effect with pyronaridine-artesunate which can be given regardless of food intake.
Both study treatments were generally well tolerated. Adverse events with pyronaridine-artesunate were consistent with those observed for both components given as monotherapy [20–23], and with previous clinical trials of the fixed-dose combination [5–7, 11]. There were no clinically relevant differences in adverse events according to drug treatment or age group.
The incidence of peak ALT >3xULN plus peak total bilirubin >2xULN was 0.3% (1/355) in the pyronaridine-artesunate group and 0.6% (1/180) in the artemether-lumefantrine group. ALT elevations with increased bilirubin have been observed with pyronaridine-artesunate tablets at a similar incidence in two Phase III studies in P. falciparum in 5/1925 (0.3%) patients [5, 6]. All cases were in adolescents or adults (14, 23, 25, 39 and 43 years old) and there were no clinical symptoms or evidence of liver injury [5, 6]. There were no such cases in a trial of pyronaridine-artesunate in P. vivax.
Meta-analysis has suggested that pediatric ACT formulations have lower rates of drug-related gastrointestinal adverse events versus tablets . Drug-related gastrointestinal adverse events were more common in a previous trial of adults and children receiving pyronaridine-artesunate tablets (vomiting 3.3%, other gastrointestinal 6.6%) versus artemether-lumefantrine (1.9%, 5.2%, respectively) . This trend was reversed in the current study with pyronaridine-artesunate pediatric granules (vomiting 2.0%, other gastrointestinal 2.0%) versus artemether-lumefantrine crushed tablets (3.3% and 3.9%, respectively).
Pyronaridine-artesunate pediatric granules were efficacious and well tolerated in this study of children under 12 years of age with uncomplicated P. falciparum malaria. Considering these data and those of the other Phase III trials [5, 6], pyronaridine-artesunate appears to be a valuable new ACT for use in both adults and children with P. falciparum malaria.
In addition to the named authors, the following co-investigators contributed to this study: Bakary Sidibé, Abdoulaye Djimdé (Mali); Berenger A. A. Ako, Aristide M'Lanhoro Coulibaly (Ivory Coast); Moses Omwoyo, Jacqueleen Wanjiru (Kenya); Nsengi Ntamabyaliro, Raoul Mpoyi Ngambua (Democratic Republic of Congo); Sabine Bélard, Florian Kurth (Gabon); Désiré Kargougou, David T. Kangoye (Burkina Faso); Jennifer Rabang (Philippines).
Presentation: This study was presented in part at the 5th MIM Pan-African Malaria Conference, Nairobi, Kenya 2–6 November, 2009. Kassoum Kayentao et al. Phase III pivotal trial of pyronaridine artesunate versus artemether lumefantrine in paediatric patients with acute uncomplicated Plasmodium falciparum malaria. Abstract MIM16689330.