A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria

Abstract

Background: The clinical development of a single encounter treatment for uncomplicated malaria has the potential to significantly improve the effectiveness of antimalarials. Exploratory data suggested that the combination of artefenomel and piperaquine phosphate (PQP) has the potential to achieve satisfactory cure rates as a single dose therapy. The primary objective of the study was to determine whether a single dose of artefenomel (800 mg) plus PQP in ascending doses is an efficacious treatment for uncomplicated Plasmodium falciparum malaria in the 'target' population of children ≤ 5 years of age in Africa as well as Asian patients of all ages.

Methods: Patients in six African countries and in Vietnam were randomised to treatment with follow-up for 42-63 days. Efficacy, tolerability, safety and pharmacokinetics were assessed. Additional key objectives were to characterise the exposure-response relationship for polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response at day 28 post-dose (ACPR28) and to further investigate Kelch13 mutations. Patients in Africa (n = 355) and Vietnam (n = 82) were included, with 85% of the total population being children < 5 years of age.

Results: ACPR28 in the per protocol population (95% confidence interval) was 70.8% (61.13-79.19), 68.4% (59.13-76.66) and 78.6% (70.09-85.67) for doses of 800 mg artefenomel with 640 mg, 960 mg and 1440 mg of PQP respectively. ACPR28 was lower in Vietnamese than in African patients (66.2%; 54.55-76.62 and 74.5%; 68.81-79.68) respectively. Within the African population, efficacy was lowest in the youngest age group of ≥ 0.5 to ≤ 2 years, 52.7% (38.80-66.35). Initial parasite clearance was twice as long in Vietnam than in Africa. Within Vietnam, the frequency of the Kelch13 mutation was 70.1% and was clearly associated with parasite clearance half-life (PCt1/2). The most significant tolerability finding was vomiting (28.8%).

Conclusions: In this first clinical trial evaluating a single encounter antimalarial therapy, none of the treatment arms reached the target efficacy of > 95% PCR-adjusted ACPR at day 28. Achieving very high efficacy following single dose treatment is challenging, since > 95% of the population must have sufficient concentrations to achieve cure across a range of parasite sensitivities and baseline parasitaemia levels. While challenging, the development of tools suitable for deployment as single encounter curative treatments for adults and children in Africa and to support elimination strategies remains a key development goal.

Trial registration: ClinicalTrials.gov, NCT02083380 . Registered on 7 March 2014.

Keywords: Artefenomel; Children; Dose–response; OZ439; Pharmacokinetics; Phase II B; Piperaquine; Single dose combination treatment; Uncomplicated Plasmodium falciparum malaria; modelling and simulation.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the relevant IEC, national Institutional Review Boards and, where relevant, local regulatory authorities at each of the participating sites. Participants provided written informed consent prior to inclusion. The ethics committees that approved the study are the following:

Comité Nacional Bioética em Saúde (CNBS), Maputo, Mozambique

Departamento Farmacéutico, Ministerio da aúde, Mozambique

The Comité Institutionnel de Bioéthique du CNRFP (CNRFP IRB)

The Comité d’éthique pour la recherche en Santé du Burkina Faso (National ethical committee)

Comité d’Ethique pour la recherche de la santé, Ouagadougou, Burkina Faso

Comité d’Ethique Institutionnel du Centre Muraz Bobo-Dioulasso, Burkina Faso

Ethics Committee of the Kinshasa School of Public Health’s, Kinshasa, Democratic Republic of Congo

Comité National d’Ethique pour la Recherche (CNER), Libreville, Gabon

Ethics Committee, the Uganda National Council of Science and Technology, and the Uganda National Drug Authority, Uganda

Comité National d’Ethique pour la Recherche en Santé, Cotonou, Benin

Ethical Committee of National Institute of Malariology, Parasitology and Entomology, Ha Noi, Vietnam

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Analysis sets and exclusions

Fig. 2

Efficacy: PCR-adjusted ACPR28 in the PP population, a by region (all ages), b by age in African patients, percentage in each category with 95% confidence intervals. The numbers presented above the bars are the percent ACPR28. The majority of treatment failures were late parasitological failures (32.9% across the populations and treatment arms), with one early treatment failure in an African patient > 5 years (PQP 640 mg arm)

Fig. 3

Kaplan–Meier population at risk of recrudescence by region and age group over time (ITT subset). Note that the y-axis is expanded (survival range 0.5–1.0) to clearly visualise the failure rates

Fig. 4

Kaplan–Meier population at risk of new infection by region and age group over time (ITT subset). Note that the y-axis is expanded (survival range 0.5–1.0) to clearly visualise the failure rates

Fig. 5

Association of parasite clearance half-life and Kelch13 Status (PP analysis set). Vietnam (blue circles), Africa (red circles), median (black line), C580Y + P553L polyclonal infection. Note that the plot includes only patients with both genotyping and PCt1/2 results

Fig. 6

Estimated Cday7 for artefenomel (a) and PQP (b) by region/age group. Patients who vomited are included. Median (horizontal line), box (interquartile range) and whiskers represent the most extreme individual point which is not more than 1.5× the length of the box

Fig. 7

Summary of the observed ACPR28 by estimated artefenomel concentration at day 7 together with the logistic regression model predictions. The dots and error bars represent the observed ACPR28 with 90% CI for five artefenomel concentration bins (categories). The lines represent the final logistic regression model predictions taking into account the median artefenomel Cday7, as well as the median piperaquine Cday7 and median baseline parasitaemia, for each bin. Number of patients per bin: Africa ≤ 5 years n = 53, Africa > 5 years n = 15, Asia n = 20

Fig. 8

Estimated exposure–ACPR28 relationship for the combination of artefenomel with piperaquine for a baseline parasitaemia of 10,000 parasites/μL. a African patients, b Vietnamese patients, 3D representation; blue highlights the ACPR28 > 0.95. The shaded area shows the concentrations required to achieve a probability of ACPR28 > 0.95

Fig. 9

Concentrations associated with a probability of ACPR28 of 0.95: model-predicted isobolograms by region and baseline parasitaemia. Asian patients = red, African patients = blue. Baseline parasitaemia 10,000 parasites/μL, solid isobole; baseline parasitaemia 100,000 parasites/μL, dotted isobole. Includes actual estimated individual exposures associated with Cure (ACPR28), open symbol or Failure (recrudescence), closed symbol