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Open Access Highly Accessed Research

Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial

Kassoum Kayentao1, Ogobara K Doumbo1, Louis K Pénali2, André T Offianan2, Kirana M Bhatt3, Joshua Kimani3, Antoinette K Tshefu4, Jack HT Kokolomami4, Michael Ramharter567, Pablo Martinez de Salazar56, Alfred B Tiono8, Alphonse Ouédraogo8, Maria Dorina G Bustos9, Frederick Quicho9, Isabelle Borghini-Fuhrer10*, Stephan Duparc10, Chang-Sik Shin11 and Lawrence Fleckenstein12

Author Affiliations

1 Malaria Research and Training Center, Faculté de Médecine de Pharmacie et d’Odonto-Stomatologie, Bamako, Mali

2 Malariology Department, Institut Pasteur, Abidjan, Côte d'Ivoire

3 UNITID, College of Health Sciences, University of Nairobi, Nairobi, Kenya

4 Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa, Kinshasa, Democratic Republic of Congo

5 Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon

6 Institute of Tropical Medicine, Tübingen, Germany

7 Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria

8 Center National de Recherche et de Formation sur le Paludisme, Ministère de la Santé, Ouagadougou, Burkina Faso

9 Research Institute for Tropical Medicine, Department of Health, FICC, Alabang, Muntinlupa City, Metro Manila, Philippines

10 Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, PO Box 1826, CH-1215, Geneva 15, Switzerland

11 Shin Poong Pharmaceutical, Seoul, South Korea

12 University of Iowa, Iowa City, IA, USA

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Malaria Journal 2012, 11:364  doi:10.1186/1475-2875-11-364

Published: 31 October 2012

Abstract

Background

Children are most vulnerable to malaria. A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria.

Methods

This phase III, multi-center, comparative, open-label, parallel-group, controlled clinical trial included patients aged ≤12 years, bodyweight ≥5 to <25 kg, with a reported history of fever at inclusion or in the previous 24 h and microscopically-confirmed uncomplicated P. falciparum malaria. Patients were randomized (2:1) to pyronaridine-artesunate granules (60/20 mg) once daily or artemether-lumefantrine crushed tablets (20/120 mg) twice daily, both dosed by bodyweight, orally (liquid suspension) for three days.

Results

Of 535 patients randomized, 355 received pyronaridine-artesunate and 180 received artemether-lumefantrine. Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using polymerase chain reaction (PCR) genotyping (per-protocol population) was 97.1% (329/339; 95% CI 94.6, 98.6) for pyronaridine-artesunate; 98.8% (165/167; 95% CI 95.7, 99.9) for artemether-lumefantrine. The primary endpoint was achieved: pyronaridine-artesunate PCR-corrected day-28 ACPR was statistically significantly >90% (P < .0001). Pyronaridine-artesunate was non-inferior to artemether-lumefantrine: treatment difference -1.8% (95% CI -4.3 to 1.6). The incidence of drug-related adverse events was 37.2% (132/355) with pyronaridine-artesunate, 44.4% (80/180) with artemether-lumefantrine. Clinical biochemistry results showed similar mean changes versus baseline in the two treatment groups. From day 3 until study completion, one patient in each treatment group had peak alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and peak total bilirubin >2xULN (i.e. within the Hy’s law definition).

Conclusions

The pyronaridine-artesunate pediatric granule formulation was efficacious and was non-inferior to artemether-lumefantrine. The adverse event profile was similar for the two comparators. Pyronaridine-artesunate should be considered for inclusion in paediatric malaria treatment programmes.

Trial registration

ClinicalTrials.gov: identifier NCT00541385

Keywords:
Pyronaridine-artesunate; Artemether-lumefantrine; Malaria; Plasmodium falciparum; Pediatric