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.
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.


RESULTS
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.


BACKGROUND
ClinicalTrials.gov (NCT01103063).
College of Health Sciences, University of Nairobi, Nairobi, Kenya.
Joshua
J
Kimani
College of Medicine, University of Malawi, Blantyre, Malawi.
Kamija
K
Phiri
College of Medicine, University of Malawi, Blantyre, Malawi.
Steve
S
Kamiza
Medicines for Malaria Venture, Geneva, Switzerland.
Stephan
S
Duparc
Pfizer Inc., Sandwich, Kent, United Kingdom.
Ayman
A
Ayoub
Pfizer Inc., Groton, CT, United States of America.
Ricardo
R
Rojo
Pfizer Inc., Groton, CT, United States of America.
Jeffery
J
Robbins
Pfizer Inc., Collegeville, PA, United States of America.
Russell
R
Orrico
Pfizer Inc., New York, NY, United States of America.
Pol
P
Vandenbroucke
D000293:Adolescent; D000328:Adult; D017963:Azithromycin / Q000009:adverse effects* / Q000627:therapeutic use*; D002738:Chloroquine / Q000009:adverse effects* / Q000627:therapeutic use*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D057194:Intention to Treat Analysis; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000517:prevention & control*; D011247:Pregnancy; D011256:Pregnancy Outcome; D011739:Pyrimethamine / Q000009:adverse effects* / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000009:adverse effects* / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D017963:Azithromycin; D013413:Sulfadoxine; D002738:Chloroquine; D011739:Pyrimethamine