ABSTRACT.
malaria, deaths, malaria infection, neutropenia
RECRUITMENT, NEUTROPENIA, MALARIA, ADVERSE EVENTS, ADVERSE EVENT, EVENT, TERATOGENICITY, MALARIA
Financial support: The study was funded, designed, conducted, and analyzed by Medicines for Malaria Venture. Medicines for Malaria Venture is funded by several donors. Unrestricted funding comes from several donors, including the Foreign Commonwealth and Development Office, German Ministry for Education and Research, Bill & Melinda Gates Foundation, Ireland Department of Foreign Affairs and Trade (IrishAid), Australia Department of Foreign Affairs and Trade, Swiss Agency for Development and Cooperation, and the Principality of Monaco. These funders had no role in the design, conduct, or analysis of the trial.This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation (grant number INV-007155). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.Data availability: Anonymised subject data are available on reasonable request from the corresponding author.Disclosure: A.C.M., C.D., and S.D. are employees of Medicines for Malaria Venture. H.J. is a former independent consultant for Medicines for Malaria Venture.Authors’ addresses: Rezika Mohammed and Mezgebu Silamsaw Asres, Department of Internal Medicine, University of Gondar Hospital, Gondar, Ethiopia, E-mails: An open label, phase IIa study conducted in Ethiopia evaluated the efficacy, safety, tolerability, and pharmacokinetics of a single 120-mg dose of the phosphatidylinositol 4-kinase inhibitor MMV390048 in Malaria remains major threat to global health.MMV390048 is a phosphatidylinositol 4-kinase inhibitor with in vitro activity against all This open label, adaptive, phase IIa study was designed to evaluate the efficacy, safety, tolerability, and pharmacokinetics of a single 120-mg dose of MMV390048 in adult patients with uncomplicated malaria. The study was conducted between October 6, 2017 and January 5, 2018 at two hospitals in Ethiopia (in Gondar and Jimma). Recruitment was suspended on December 4, 2017 to allow assessment of a teratogenicity signal in a concurrent investigation in rodents.The study protocol was approved by the independent Ethics Committees of the College of Public Health and Medical Sciences, Jimma University (now the Institute of Health Institutional Review Board), the Institutional Review Board of the University of Gondar, Ethiopia, and the Ethiopian National Research Ethics Review Committee and Ethiopian Food and Drug Administration, Addis Ababa, and was registered with ClinicalTrials.gov (NCT02880241). Study conduct conformed to the national regulatory requirements of Ethiopia and the Declaration of Helsinki.Planned enrollment was for three Eligible patients were adults aged 18–55 years, weighing 40–90 kg with microscopically confirmed Giemsa-stained thick and thin blood films for parasite identification and enumeration were prepared using standard methods.The primary outcome for The eight enrolled patients were males, self-defined as black, mean age 24.5 years (range 20–50 years), with a mean (SD) body mass index of 18.1 (1.2) kg/mThe primary endpoint of ACPR at day 14 was 100% (8/8). Asexual parasites were cleared by 24 hours postdose in four patients, by 48 hours in two patients, and by 66 hours in the remaining two patients (Parasite counts for Gametocytes were detected in all patients at baseline and were cleared by 24 hours postdose in four patients, by 30 hours in two patients, and by 78 hours in two patients (Using qPCR, parasite clearance was achieved between 20 and 161 hours (MMV390048 pharmacokinetic parameters are shown in Plasma pharmacokinetic parameters for a single 120-mg dose of MMV390048 in adult patients with Values are geometric mean (coefficient of variation), except for The reported There were no deaths, serious adverse events, or adverse events leading to study discontinuation. A total of 27 adverse events were reported during the study across all eight patients (Adverse events of any causeAdverse event of special interest.There were three adverse events of special interest occurring in two patients. One patient had neutropenia, considered possibly drug related. This event started on day 2 (baseline neutrophil count 3.39 × 10Clinical laboratory tests showed no drug-related trends. Baseline low platelet and hemoglobin levels, consistent with malaria infection, tended to improve throughout the study. There were no other safety concerns.In summary, a single oral dose of 120-mg MMV390048 rapidly cleared asexual parasites and gametocytes in eight male patients with 