Parasitological Clearance Rates and Drug Concentrations of a Fixed Dose Combination of Azithromycin-Chloroquine in Asymptomatic Pregnant Women with Plasmodium Falciparum Parasitemia: An Open-Label, Non-Comparative Study in Sub-Saharan Africa

RESEARCH ARTICLE a11111 Parasitological Clearance Rates and Drug Concentrations of a Fixed Dose Combination of Azithromycin-Chloroquine in Asymptomatic Pregnant Women with Plasmodium Falciparum Parasitemia: An Open-Label, Non-Comparative Study in SubSaharan Africa Kamija Phiri1*, Joshua Kimani2, George A. Mtove3, Qinying Zhao4, Ricardo Rojo4, Jeffery Robbins4, Stephan Duparc5, Ayman Ayoub6, Pol Vandenbroucke7 OPEN ACCESS Citation: Phiri K, Kimani J, Mtove GA, Zhao Q, Rojo R, Robbins J, et al. (2016) Parasitological Clearance Rates and Drug Concentrations of a Fixed Dose Combination of AzithromycinChloroquine in Asymptomatic Pregnant Women with Plasmodium Falciparum Parasitemia: An Open-Label, Non-Comparative Study in SubSaharan Africa. PLoS ONE 11(11): e0165692. doi:10.1371/journal.pone.0165692 Editor: Aric Gregson, University of California Los Angeles, UNITED STATES Received: June 10, 2015 Accepted: October 14, 2016 Published: November 18, 2016 Copyright: © 2016 Phiri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: Data described in this article are available on the clinicaltrials.gov registry at the following url: https://clinicaltrials.gov/ct2/ show/results/NCT01103713. In addition to posting clinical trial results on the clinicaltrials.gov registry, Pfizer provides secure access to anonymized patient-level data to qualified researchers in response to scientifically valid research proposals. Further detail can be found at: http://www.pfizer. 1 College of Medicine, University of Malawi, Blantyre, Malawi, 2 College of Health Sciences, University of Nairobi, Nairobi, Kenya, 3 National Institute for Medical Research, Amani Medical Research Centre, Tanga, Tanzania, 4 Pfizer Inc., Groton, Connecticut, United States of America, 5 Medicines for Malaria Venture, Geneva, Switzerland, 6 Pfizer Inc., Sandwich, Kent, United Kingdom, 7 Pfizer Inc., New York, New York, United States of America * Abstract Background Malaria remains one of the most important causes of morbidity and mortality in pregnant women and their newborn babies in sub-Saharan Africa. Intermittent preventive treatment in pregnancy (IPTp) is recommended by the World Health Organization (WHO) to reduce the burden of disease and improve maternal and neonatal survival and general health. Due to the growing resistance to sulfadoxine-pyrimethamine (SP), the current WHO-recommended drug for IPTp, identification of new and effective drugs is an urgent priority. Methods and Findings This was an open-label, non-comparative study (NCT01103713) in 5 countries in East and sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) to assess parasitological response and drug concentrations of a single, 3-day course of four tablets of a fixeddose combination of azithromycin-chloroquine (AZCQ) 250/155 mg given during the second or third trimester to women with asymptomatic Plasmodium falciparum parasitemia in their first or second pregnancy. Parasitemia was determined by microscopy and molecular genotyping was performed to characterize parasites relative to the baseline infection. Weekly follow-up visits took place until day 42 after first dose and additional follow-up occurred after delivery. Systemic concentrations of azithromycin (AZ), chloroquine (CQ), and the CQ metabolite, desethyl CQ (DECQ) were evaluated at Day 0 (pre-dose), at Day 2 (pre-dose, 2 PLOS ONE | DOI:10.1371/journal.pone.0165692 November 18, 2016 1 / 15 Parasitological Cure Rates with Azithromycin-Chloroquine in Pregnant Women with Asymptomatic Malaria com/research/clinical_trials/trial_data_and_results/ data_requests. Funding: Pfizer and the Medicines for Malaria Venture (MMV) funded this trial and were involved in study design, data analysis, data interpretation, and writing of the study report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. Medical writing and editorial support was provided by Paul Hassan, PhD, of Engage Scientific and was funded by Pfizer. Competing Interests: Drs. K. Phiri, J. Kimani, and G. Mtove were investigators in this study. Drs. A. Ayoub, R. Rojo, J. Robbins, P. Vandenbroucke and Q. Zhao are employees of the sponsor, Pfizer. Dr. S. Duparc is an employee of Medicines for Malaria Venture, who co-funded this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Abbreviations: AE, adverse event; AZCQ, azithromycin-chloroquine; CI, confidence interval; CV, coefficient of variation; DECQ, desethyl-CQ; IPTp, intermittent preventive treatment in pregnancy; ITT, intention to treat; LBW, low birth weight; MITT, modified intention to treat; PCR, polymerase chain reaction; PP, per protocol; SD, standard deviation; SP, sulfadoxinepyrimethamine; TEAE, treatment emergent adverse event. and 8 hours) and randomly at Days 7 and 14. Systemic concentrations of CQ and DECQ were also measured randomly at Day 21 and Day 28. In total, 404 women were screened for eligibility and 168 were treated, 155 of whom completed the study. PCR-adjusted parasitological response in the modified intent-to-treat population at day 28 (the primary efficacy endpoint) was estimated by the Kaplan-Meier method as 99.35% (95% confidence interval [CI]: 97.76, 100.00). PCR-adjusted parasitological response remained high at day 42 (95.19%; 95% CI: 91.35, 99.03). In general, the mean concentrations of serum AZ, plasma CQ, and plasma DECQ showed large CV% values (ranges of 33–156%, 42–228%, and 57– 109%, respectively). There were 157 live births, three stillbirths, and eight pregnancies of unknown outcome: 7 due to withdrawal of participant consent and 1 lost to follow-up. The most frequent treatment-emergent adverse events were vomiting (20.8%) and dizziness (19.6%). Conclusions These results suggest that a 3-day course of AZCQ can lead to an adequate 28-day parasitological response. Introduction Malaria is a serious infection caused by protozoan parasites of the Plasmodium species that are transmitted when infected female anopheline mosquitoes bite a human host to consume a blood meal [1]. The characteristic clinical signs and symptoms of malaria include recurrent attacks of fever, paroxysm, hemolytic anemia, and jaundice [2]. Asymptomatic malaria, in which individuals are infected but exhibit few signs and symptoms of disease presents substantial challenges in terms of eradication or control strategies [3]. Although malaria cases occur in all the major tropical and sub-tropical regions of the world, Africa has the greatest number of people at risk of contracting the disease and has the greatest number of deaths related to malaria [4]. The World Health Organization (WHO) World Malaria Report 2013 states that there were (...truncated)