Effect of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine with and without azithromycin versus monthly sulfadoxine-pyrimethamine on adverse pregnancy outcomes in Africa: a double-blind randomised, partly placebo-controlled trial.

"Declaration of interests We declare no competing interests."

"AcknowledgmentsThis study received financial support from the European & Developing Countries Clinical Trials Partnership 2 (EDCTP2) programme supported by the EU (grant number TRIA-2015-1076-IMPROVE to the Liverpool School of Tropical Medicine [LSTM], Liverpool, UK) and the UK Joint Global-Health-Trials (JGHT) Scheme funded by the Department of Health and Social Care, Foreign, Commonwealth and Development Office, Medical Research Council, and Wellcome (grant reference MR/P006914/1 to LSTM), and from the Bill & Melinda Gates Foundation (INV-002781). We thank Montserrat Blázquez-Domingo from EDCTP2 for her support in managing the grant on behalf of EDCTP2 and JGHT. Eurartesim was provided free of charge by AlfaSigma. We thank all the study participants and all the research assistants who did the study. We are grateful to the members of the Trial Steering Committee (Laurence Slutsker, Matthew Cairns, Miriam Laufer, Grant Dorsey, and Per Ashorn) and the Data Safety and Monitoring Board (Andy Stergachis, Kathleen Wannemuehler, Ib Christian Bygbjerg, William Ngasala, and Christian Funck-Brentano) for their expertise and guidance in conducting the trial and independent review of the safety data, study protocol, and statistical analysis plan. We thank Franklin Mosha for hosting the study at the Kilimanjaro Clinical Research Institute and Kilimanjaro Christian Medical University College, Moshi, Tanzania. We also thank Tracy Seddon, Helen Wong, and Katie Davies in Liverpool, UK; Benta Kamire and Sheila Nyarinda in Kisumu, Kenya; Christopher Masaka in Dar es Salaam and Amina Farah in Moshi, Tanzania; and Zainab Longwe, Jones Chakholoma, and Palinji Mungoni in Blantyre, Malawi for their managerial and administrative support. We thank Kelly Byrne from the Global Health Trials Unit at LSTM for trial management and pharmacovigilance support. We also thank the Directors of Ahero sub-County Hospital, Rabuor sub-County Hospital, Homa Bay County Referral Hospitals, and Akala Health Centre in Siaya for accommodating the study in Kenya; the Medical Officers in charge of Korogwe District Hospital (Magunga), Handeni District Hospital, and Bombo Referral Regional hospitals for accommodating the study in Tanzania; and the Directors and staff of Blantyre, Chikwawa, Mangochi, and Zomba District Health Offices for accommodating the study in Malawi. We thank Jane Mallewa in Malawi and Gerald Yonga in Kenya for providing support with the cardiac monitoring component, and Nickline Kuya Ashitiba and Evelyne Delylah Ondieki for trial coordination in Kenya. We thank Atusaye Ngwira in Malawi; Henry Aura and Micah June in Kenya; and Mohamed Mapondela, Joyce Mbwana, and Edwin Nyale in Tanzania for technical support and internal monitoring; John Chabuka and John Lino for external monitoring oversight; and Bernard Owino and Martina Oneko for safety monitoring. We also thank Tao Chen for supporting the Data Safety and Monitoring Board as the independent statistician with access to the study code and Tony Sang, the lead pharmacist, for support with the preparations of study drugs. This study is published with the permission of the Director of KEMRI. The LSTM was the sponsor. The findings and conclusions in this publication are those of the authors and do not necessarily represent the views of the US Centers for Disease Control and Prevention or the US Department of Health and Human Services."

"This study was designed to achieve 80% power to detect at least a 20% reduction in the composite primary endpoint of adverse pregnancy outcomes from 21·3% with IPTp with sulfadoxine–pyrimethamine, , to 17·0% in the IPTp with dihydroartemisinin–piperaquine group or IPTp with dihydroartemisinin–piperaquine plus azithromycin group (risk ratio [RR] 0·80; two-sided α=0·05), which required 4680 participants (1560 per group), allowing for 13·7% loss to follow-up. Statistical analyses were done using Stata (version 17). For the primary and dichotomous secondary endpoints, we used log-binomial regression to obtain RRs and corresponding 95% CIs, and modified Poisson regression in case of non-convergence (). We used linear regression for continuous variables, and results were expressed as mean difference and 95% CIs. The mean differences for estimated fetal weight Z scores were obtained by linear mixed models for repeated measures. We used Poisson regression with a log-link function and follow-up time as an offset for count variables to obtain incidence rate ratios and 95% CIs. The unadjusted (crude) analysis was the primary analysis and included the stratification factors study site and gravidae group in all models. Secondary, covariate-adjusted analyses were done using the following other prespecified baseline covariates in addition to gravidity and site: malaria status (positive vs negative) at enrolment; gestational age (continuous) at enrolment; socioeconomic status (calculated using principal component analysis; continuous); malaria transmission season (based on average rainfall in the last 6 months of pregnancy; continuous); malaria transmission intensity by study site (based on the prevalence of malaria at enrolment); and the degree of sulfadoxine–pyrimethamine resistance by study site (very high vs high based on the prevalence of the Ala581Gly substitutions in the dhps gene >40% vs ≤40%; ). The unadjusted linear mixed models contained visit, study arm, the interaction between visit and study arm, and the stratification factors site and gravidity as fixed effect and participant as random effects to account for the clustering within subject. The adjusted linear mixed models also included the six additional prespecified covariates as fixed effect and participant as random effects. Missing covariates were imputed using simple imputation. These same covariates were also included in subgroup analyses. We used a two-sided p value less than 0·05 to define statistical significance. p values and the widths of the 95% CIs for the primary and secondary endpoints have not been adjusted for multiplicity, so the values should not be used to infer definitive treatment effects. The modified intention-to-treat (ITT) population (ie, all randomised participants who contributed to the endpoint) was used for primary analyses. We did a sensitivity analysis using non-responder imputation to assess the effect of attrition bias (). Per-protocol analyses were done for the composite primary endpoint and its individual components. The per-protocol population included participants who attended every scheduled visit, took all scheduled IPTp courses, did not use prohibited medication, and contributed to the endpoint. For the safety analyses, women were included if they received at least one dose of study drug. All analyses were prespecified (unless otherwise indicated as post hoc) in a statistical analysis plan approved by the data and safety monitoring board. Post-hoc analyses in women were any malaria at delivery (a composite of malaria infection detected by any diagnostic test in either maternal or placental blood); gestational weight gain; and a composite of placental inflammation or chorioamnionitis. Post-hoc analyses in infants were a composite of fetal and neonatal death, early neonatal death, perinatal death, neonatal wasting, and a composite of neonatal wasting or stunting. This trial is registered with ClinicalTrials.gov, NCT03208179. Methods: We did an individually randomised, double-blind, three-arm, partly placebo-controlled trial in areas of high sulfadoxine–pyrimethamine resistance in Kenya, Malawi, and Tanzania. HIV-negative women with a viable singleton pregnancy were randomly assigned (1:1:1) by computer-generated block randomisation, stratified by site and gravidity, to receive monthly IPTp with sulfadoxine–pyrimethamine (500 mg of sulfadoxine and 25 mg of pyrimethamine for 1 day), monthly IPTp with dihydroartemisinin–piperaquine (dosed by weight; three to five tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine once daily for 3 consecutive days) plus a single treatment course of placebo, or monthly IPTp with dihydroartemisinin–piperaquine plus a single treatment course of azithromycin (two tablets containing 500 mg once daily for 2 consecutive days). Outcome assessors in the delivery units were masked to treatment group. The composite primary endpoint was adverse pregnancy outcome, defined as fetal loss, adverse newborn baby outcomes (small for gestational age, low birthweight, or preterm), or neonatal death. The primary analysis was by modified intention to treat, consisting of all randomised participants with primary endpoint data. Women who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT03208179."