Optimal Chemopreventive Regimens to Prevent Malaria and Improve Birth Outcomes in Uganda

This trial tests the hypothesis that intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) + dihydroartemisin-piperaquine (DP) will significantly reduce the risk of adverse birth outcomes compared to IPTp with SP alone or DP alone. This double-blinded randomized controlled phase III trial of 2757 HIV uninfected pregnant women enrolled at 12-20 weeks gestation will be randomized in equal proportions to one of three IPTp treatment arms: 1) SP given every 4 weeks, or 2) DP given every 4 weeks, or 3) SP+DP given every 4 weeks. SP or DP placebos will be used to ensure adequate blinding is achieved in the study and follow-up will end 28 days after giving birth.

Malaria in pregnancy remains a major challenge in Africa, where approximately 50 million women are at risk for P. falciparum infection during pregnancy each year. Among pregnant women living in malaria endemic areas symptomatic disease is uncommon, but infection with malaria parasites is associated with maternal anemia and adverse birth outcomes including abortions, stillbirth, preterm birth, low birth weight (LBW), and infant mortality. The World Health Organization (WHO) recommends the use of long-lasting insecticidal nets (LLINs) and intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) for the prevention of malaria in pregnancy in endemic areas of Africa. However, there is concern for diminishing efficacy of these interventions due to the spread of vector resistance to the pyrethroid insecticides used in LLINs and parasite resistance to SP. Thus, there is an urgent need for new strategies for the prevention of malaria in pregnancy and improving birth outcomes. Artemisinin-based combination therapies (ACTs) are now the standard treatment for malaria in Africa. Dihydroartemisin-piperaquine (DP) is a fixed-dose ACT and an attractive alternative to SP for IPTp. DP is highly efficacious, and the long half-life of piperaquine provides at least 4 weeks of post-treatment prophylaxis. Recent randomized controlled trials showed that, compared to IPTp with SP, IPTp with DP dramatically reduced risks of malaria-specific outcomes but there were minimal differences between the SP and DP groups in risks of adverse birth outcomes. The key question for this study is why IPTp with either SP or DP is associated with similar risks of adverse birth outcomes despite the far superior antimalarial activity of DP. The likely explanation is that SP, a broad-spectrum antibiotic, protects against non-malarial causes of LBW and preterm birth. The central hypothesis is that SP improves birth outcomes independent of its antimalarial activity and that IPTp with a combination of SP+DP will offer antimalarial and non-antimalarial benefits, thus providing superior prevention of adverse birth outcomes compared to either drug used alone. To test this hypothesis, a double-blinded randomized clinical trial will conducted in a rural area of Uganda with very high malaria transmission intensity, where there is already an established infrastructure for clinical research. Specific aims will be (1) to compare the risk of adverse birth outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, (2) To compare safety and tolerability of IPTp regimens among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP, and (3) to compare risks of malaria-specific and non-malarial outcomes among pregnant women randomized to receive monthly IPTp with SP vs. DP vs. SP+DP. This study will be the first to evaluate the efficacy and safety of a novel combination of well-studied drugs for improving birth outcomes and findings may well have important policy implications, with a change in standard practice for millions of pregnant women in Africa.

dihydroartemisinin-piperaquine, sulfadoxine-pyrimethamine, IPTp, reproductive tract infection, microbiome, drug resistance

Placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two drugs on day 1 (SP and placebo or DP and placebo or SP and DP) followed by one drug on days 2 and 3 (DP or placebo). Two placebos will be used, one that mimics the appearance of SP and one that mimics the appearance of DP. A randomization list will be computer generated by a member of the project who will not be directly involved in the conduct of the study. The randomization list will include consecutive treatment numbers with corresponding random treatment assignments. Randomized codes will correspond to the 3 treatment arms using permuted variable sized blocks of 6 and 9.

SP (Kamsidar) will be supplied by Kampala Pharmaceutical Industries (KPI), Uganda. SP will be given as a single dose consisting of 3 full strength tablets.

DP (Duo-Cotecxin) will be supplied by Holley-Cotec, Beijing, China. DP will consist of 3 full strength tablets given once a day for 3 consecutive days.

Composite adverse birth outcome defined as the occurrence of any of the following: Spontaneous abortion: Fetal loss at < 28 weeks gestational age Stillbirth: Infant born deceased at > 28 weeks gestational age Low Birth Weight (LBW): Live birth with birth weight < 2500 gm Preterm birth: Live birth at < 37 weeks gestational age Small-for-gestational age (SGA): Live birth with weight-for-gestational age < 10th percentile of reference population Neonatal death: Live birth with neonatal death within the first 28 days of life

Day study drugs are first given until when study participants reach 28 days postpartum or early study termination

Composite adverse birth outcome defined as the occurrence of any of the following: Spontaneous abortion: Fetal loss at < 28 weeks gestational age Stillbirth: Infant born deceased at > 28 weeks gestational age LBW: Live birth with birth weight < 2500 gm Preterm birth: Live birth at < 37 weeks gestational age SGA: Live birth with weight-for-gestational age < 10th percentile of reference population Neonatal death: Live birth with neonatal death within the first 28 days of life

Day study drugs are first given until when study participants reach 28 days postpartum or early study termination

Grade 3-4 AEs possibly or definitely related to study drug defined by the July 2017 NIH DAIDS Toxicity Tables

Day study drugs are first given until when study participants reach 28 days postpartum or early study termination

Every 28 days study participants will receive one course of study drugs consisting of once a day dosing for 3 consecutive days. Day 1 of study drug administration will be directly observed in the study clinic where vomiting will be assessed. Vomiting of days 2 of 3 of study drugs administered at home will be done at the time of each subsequent routine clinic visit using a standardized assessment.

Every 28 days study participants will receive one course of study drugs consisting of once a day dosing for 3 consecutive days. Day 1 of study drug administration will be directly observed in the study clinic. Adherence to days 2 of 3 of study drugs administered at home will be done at the time of each subsequent routine clinic visit using a standardized assessment.

Inclusion Criteria: Viable singleton pregnancy confirmed by ultrasound Estimated gestational age between 12-20 weeks Confirmed to be HIV- uninfected by rapid test 16 years of age or older Residency within Busia District of Uganda Provision of informed consent Agreement to come to the study clinic for any febrile episode or other illness and avoid medications given outside the study protocol Willing to deliver in the hospital Exclusion Criteria: History of serious adverse event to SP or DP Active medical problem requiring inpatient evaluation at the time of screening Intention of moving outside of Busia District Uganda Chronic medical condition requiring frequent medical attention Prior chemopreventive therapy or any other antimalarial therapy during this pregnancy Early or active labor (documented by cervical change with uterine contractions) Multiple pregnancies (i.e. twins/triplets)