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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Malaria

Intervention / Treatment
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* Drug: Sulfadoxine-pyrimethamine (SP)
* Drug: Dihydroartemisinin-piperaquine (DP)


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Double blinded randomized controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SP + DP placebo every 4 weeks<br> | Drug: Sulfadoxine-pyrimethamine (SP)<br>* 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.<br>* Other names: Kamsidar;|
| Active Comparator: DP + SP placebo every 4 weeks<br> | Drug: Dihydroartemisinin-piperaquine (DP)<br>* 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.<br>* Other names: Duo-Cotecxin;|
| Active Comparator: SP + DP given every 4 weeks<br> | Drug: Sulfadoxine-pyrimethamine (SP)<br>* 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.<br>* Other names: Kamsidar;Drug: Dihydroartemisinin-piperaquine (DP)<br>* 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.<br>* Other names: Duo-Cotecxin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Risk of having a composite adverse birth outcome | 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 | Time of delivery up to 28 days postpartum | 
| Incidence of any grade 3-4 Adverse Events (AE) or Serious Adverse Events (SAE) per time at risk | Grade 3-4 AEs as 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of individual composite adverse birth outcome | 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 | Time of delivery up to 28 days postpartum | 
| Incidence of individual grade 3-4 AE or SAE per time at risk | Grade 3-4 AEs as 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 | 
| Incidence of grade 3-4 AEs related to study drugs | 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 | 
| Vomiting following administration of study drugs | 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. | Total time receiving study drugs, an average of 20 weeks | 
| Measure of non-adherence with study drugs | 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. | Total time receiving study drugs, an average of 20 weeks | 
| Risk of placental malaria | Detection of malaria parasites or pigment by histopathology | At the time of delivery | 
| Incidence of malaria during pregnancy | New episodes of fever plus positive blood smear per person time | Day study drugs are first given until delivery | 
| Prevalence of parasitemia during pregnancy | Proportion of routine samples with asexual parasites detected by microscopy or qPCR | Day study drugs are first given until delivery | 
| Prevalence of anemia during pregnancy | Proportion of routine hemoglobin measurements < 11 g/dL | Day study drugs are first given until delivery | 
| Prevalence of markers of DP resistance | Proportion of parasite positive samples with molecular markers of DP resistance | Day study drugs are first given until delivery | 
| Prevalence of Reproductive tract infections (RTIs) at delivery | Proportion of vaginal samples collected as the time of delivery positive for RTIs | At time of delivery | 
| Relative changes in vaginal microbiota | Measures of relative abundance of microorganisms | Day of study enrollment until 32 weeks gestational age | 
| Absolute changes vaginal microbiota | Measures of absolute abundance of microorganisms | Day of study enrollment until 32 weeks gestational age | 
| Relative changes intestinal microbiota | Measures of relative abundance of microorganisms | Day of study enrollment until 32 weeks gestational age | 
| Absolute changes intestinal microbiota | Measures of absolute abundance of microorganisms | Day of study enrollment until 32 weeks gestational age | 
| Prevalence of markers of SP resistance | Proportion of parasite positive samples with molecular markers of SP resistance | Day study drugs are first given until delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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microbiome, dihydroartemisinin-piperaquine, sulfadoxine-pyrimethamine, IPTp, reproductive tract infection, drug resistance