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BMC Med. 2017 Oct 9;15(1):181. doi: 10.1186/s12916-017-0940-3.

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.

Author information

1
Medicines for Malaria Venture, Geneva, Switzerland.
2
Infectious Diseases Research Collaboration, Tororo Hospital, Tororo, Uganda.
3
Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso.
4
National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam.
5
Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon.
6
Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany.
7
Universite des Sciences de la Sante Gabon, Département de Parasitology, Malaria Clinical and Operational Research Unit, Melen Hospital, Libreville, Gabon.
8
Institut de Recherche en Sciences de la Santé - Unité de Recherche Clinique de Nanoro, Ouagadougou, Burkina Faso.
9
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
10
Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique.
11
ICREA, Pg. Lluís Companys 23, 08010, Barcelona, Spain.
12
Pediatric Infectious Diseases Unit, Pediatrics Department, Hospital Sant Joan de Déu (University of Barcelona), Barcelona, Spain.
13
Universidad Europea de Madrid, Madrid, Spain.
14
Centre de Recherche sur le Paludisme Associé à la Grossesse et l'Enfance, Faculte Des Sciences De La Sante, Cotonou, Benin.
15
BEL Pharm Consulting, Chambonas, France.
16
Centre de Recherche du Centre Hospitalier de Mont Amba, Kinshasa School of Public Health, University of Kinshasa, Kinshasa, Democratic Republic of the Congo.
17
QuintilesIMS, Department: Biostatistics, Bloemfontein, South Africa.
18
Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon. michael.ramharter@uni-tuebingen.de.
19
Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany. michael.ramharter@uni-tuebingen.de.
20
Department of Medicine I, Division of Infectious Diseases, Medical University of Vienna, Vienna, Austria. michael.ramharter@uni-tuebingen.de.
21
Bernhard Nocht Hospital for Tropical Diseases, Bernhard Nocht Institute for Tropical Medicine and University Medical Center Hamburg-Eppendorf, Hamburg, Germany. michael.ramharter@uni-tuebingen.de.

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

PMID:
28988541
PMCID:
PMC5632828
DOI:
10.1186/s12916-017-0940-3
[Indexed for MEDLINE]
Free PMC Article

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