A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria
Authors: Adoke Yeka , Zoleko-Manego Rella , Ouoba Serge , Tiono Alfred B. , Kaguthi Grace , Bonzela Juvêncio Eduardo , Duong Tran Thanh , Nahum Alain , Bouyou-Akotet Marielle , Ogutu Bernhards , Ouedraogo Alphonse , Macintyre Fiona , Jessel Andreas , Laurijssens Bart , Cherkaoui-Rbati Mohammed H. , Cantalloube Cathy , Marrast Anne Claire , Bejuit Raphaël , White David , Wells Timothy N. C. , Wartha Florian , Leroy Didier , Kibuuka Afizi , Mombo-Ngoma Ghyslain , Ouattara Daouda , Mugenya Irène , Phuc Bui Quang , Bohissou Francis , Mawili-Mboumba Denise P. , Olewe Fredrick , Soulama Issiaka , Tinto Halidou ,   the FALCI Study Group, Ramharter Michael , Nahum Diolinda , Zohou Hermione , Nzwili Irène , Ongecha John Michael , Thompson Ricardo , Kiwalabye John , Diarra Amidou , Coulibaly Aboubacar S. , Bougouma Edith C. , Kargougou Désiré G. , Tegneri Moubarak , Castin Vuillerme Catherine , Djeriou Elhadj , Ansary Aziz Filali 
Published: May 2021

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