Yeka Adoke1, Rella Zoleko-Manego2,3, Serge Ouoba4, Alfred B Tiono5, Grace Kaguthi6, Juvêncio Eduardo Bonzela7, Tran Thanh Duong8, Alain Nahum9, Marielle Bouyou-Akotet10, Bernhards Ogutu11, Alphonse Ouedraogo12, Fiona Macintyre13, Andreas Jessel14, Bart Laurijssens15, Mohammed H Cherkaoui-Rbati13, Cathy Cantalloube16, Anne Claire Marrast13, Raphaël Bejuit16, David White17, Timothy N C Wells13, Florian Wartha13, Didier Leroy13, Afizi Kibuuka18, Ghyslain Mombo-Ngoma2,3,19, Daouda Ouattara5, Irène Mugenya6, Bui Quang Phuc8, Francis Bohissou9, Denise P Mawili-Mboumba10, Fredrick Olewe11, Issiaka Soulama12, Halidou Tinto4. 1. Infectious Diseases Research Collaboration (IDRC), Nakasero Hill Road, P.O. Box 7475, Kampala, Uganda. yadoke@yahoo.com. 2. Centre de Recherches Médicales de Lambaréné (CERMEL), BP 142, Lambaréné, Gabon. 3. Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine & I. Dep. of Medicine, University Medical Centre Hamburg-Eppendorf, Bernhard Nocht Straße 74, 20359, Hamburg, Germany. 4. Unité de Recherche Clinique de Nanoro, Institut de Recherche en Sciences de La Santé, Nanoro, Burkina Faso. 5. Unité de Recherche Clinique de Banfora, C/H Régional de Banfora, Centre National de Recherche Et de Formation Sur Le Paludisme (CNRFP), Ouagadougou, Province de la Comoé, Burkina Faso. 6. Kenya Medical Research Institute-Centre for Respiratory Diseases Research (KEMRI-CRDR), P.O. Box 47855-00100, Nairobi, Kenya. 7. Chokwe Health Research and Training Centre, 1 Bairro, Zona Do Orli, CP 30, Chokwe, Mozambique. 8. National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam. 9. Centre de Recherche Entomologique de Cotonou (CREC) and Hôpital La Croix de Zinvié, 06 BP 2604, Cotonou, Benin. 10. Département de Parasitologie-Mycologie-Médecine Tropicale, Faculté de Médecine Et Des Sciences de La Santé, Université Des Sciences de La Santé, BP 4009, Libreville, Gabon. 11. Kenya Medical Research Institute, Kisumu, Kenya. 12. Unité de Recherche Clinique de Niangoloko, S/C Centre Medical de Niangoloko, Centre National de Recherche Et de Formation Sur Le Paludisme (CNRFP), BP 37, Niangoloko, Burkina Faso. 13. Medicines for Malaria Venture (MMV), Route de Pré-Bois 20, Post Box 1826, 1215, Geneva 15, Switzerland. 14. Sanofi Research and Development, 55 Corporate Drive, Bridgewater, NJ, 08807, USA. 15. BEL Pharm Consulting, 116 Chemin du Moulin d'Ozil, 07140, Chambonas, France. 16. Sanofi Research and Development, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France. 17. IQVIA CEVA, 4820 Emperor Boulevard, Durham, NC, 27703, USA. 18. Infectious Diseases Research Collaboration (IDRC), Nakasero Hill Road, P.O. Box 7475, Kampala, Uganda. 19. Institute for Tropical Medicine, University of Tübingen, Wilhelmstraße 27, 72074, Tübingen, Germany.
Abstract
BACKGROUND: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia. METHODS: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure-response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored. RESULTS: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures. CONCLUSION: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1.
RCT Entities:
BACKGROUND: For uncomplicated Plasmodium falciparummalaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia. METHODS: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure-response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored. RESULTS: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures. CONCLUSION: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1.