Efficacy and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial

Abstract

Background: The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) in African regions with moderate to high malaria transmission. However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed. This study tested the efficacy, tolerability, and safety of a fixed-dose combination azithromycin-chloroquine (AZCQ; 250 mg AZ/155 mg CQ base) for IPTp relative to IPTp-SP.

Methods and findings: A randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days) or SP (each course 1,500/75 mg SP QD for 1 day) at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28-42). The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight [LBW, <2,500 g], premature birth [<37 weeks], still birth [>28 weeks], abortion [≤28 weeks], lost to follow-up prior to observation of pregnancy outcome, or missing birth weight). The study was terminated early after recruitment of 2,891 of the planned 5,044 participants, due to futility observed in a pre-specified 35% interim analysis. In the final intent-to-treat dataset, 378/1,445 (26.2%) participants in the AZCQ and 342/1,445 (23.7%) in the SP group had sub-optimal pregnancy outcomes, with an estimated risk ratio (RR) of 1.11 (95% CI: 0.97, 1.25; p = 0.12). There was no significant difference in the incidence of LBW between treatment groups (57/1138 [5.0%] in the AZCQ group, 68/1188 [5.7%] in the SP group, RR 0.87 [95% CI: 0.62, 1.23]; p = 0.44). IPTp-AZCQ was less well-tolerated in mothers than IPTp-SP. Occurrences of congenital anomalies, deaths, and serious adverse events were comparable in neonates for both groups. Limitations included the open-label design and early study termination.

Conclusions: IPTp-AZCQ was not superior to IPTp-SP in this study and alternatives for IPTp-SP remain to be identified. The proportions of sub-optimal pregnancy outcomes and LBW were lower than expected, which may be linked to insecticide-treated bednet use throughout the study. Reduced incidences of symptomatic malaria infection and peripheral parasitemia in the AZCQ group relative to SP suggest that AZCQ warrants further investigation as an alternative treatment of uncomplicated malaria.

Trial registration: ClinicalTrials.gov (NCT01103063).

Conflict of interest statement

Competing Interests: Drs. A. Ayoub, R. Rojo, J. Robbins, P. Vandenbroucke, and Mr. R. Orrico are employees of the sponsor, Pfizer. Dr. S. Duparc is an employee of Medicines for Malaria Venture, who co-funded this study. Dr. J. Kimani was a principal investigator on this study. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Participant flow chart.

aThe reasons why study participants were no longer willing to participate included: no specific reason provided, n = 17; family, social, or personal issues, n = 17; experience of AEs, n = 16; no longer willing to take study drug, n = 6; relocation, n = 3; stillbirth, n = 1. bThe reasons why study participants were no longer willing to participate included: family, social, or personal issues, n = 10; relocation, n = 3; no specific reason provided, n = 2. cThe AEs leading to discontinuation were combinations of nausea, vomiting, asthenia, spontaneous abortion, imminent abortion, and restlessness. dThe AE leading to discontinuation was premature rupture of membranes/stillbirth/umbilical cord abnormality. eThe causes of deaths were meningitis; postpartum hemorrhage and uterine rupture; and eclampsia. fThe death was due to peritonitis and intestinal perforation. gThe ‘other’ reasons for discontinuation were: relocation, n = 9; family, social, or personal issues, n = 5; non-compliance with study procedures, n = 2. hThe ‘other’ reasons for discontinuation were: relocation, n = 5; family, social, or personal issues, n = 5; no specific reason provided, n = 1.

Fig 2. Incidence of secondary outcomes in the ITT population.

aDenominators are the number of subjects with a premature or full-term live birth and a non-missing birth weight. bDenominators are the number of pregnancy outcomes, excluding those that were unknown/missing. cIncluding neonatal death and congenital malformations. dDenominators are the number of subjects with a premature or full-term live birth. eDenominators are the number of subjects with available measurements. fSTI = sexually transmitted infection between first dose and Week 36 to 38 of gestation including T. pallidum, N. gonorrhoeae, C. trachomatis (diagnosed based on clinical presentation prior to week 36–38 and/or positive lab test results between week 36–38). gDiagnosed based on positive result at week 36 to 38 of gestation. hBetween first dose and delivery