Prevention of Malaria in HIV-uninfected Pregnant Women and Infants

Study Overview
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Brief Summary
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This will be a double-blinded randomized controlled phase III trial of 782 HIV uninfected pregnant women and the children born to them. HIV uninfected women at 12-20 weeks gestation will be randomized in equal proportions to one of two intermittent preventive treatment in pregnancy (IPTp) treatment arms: 1) monthly sulfadoxine-pyrimethamine (SP), or 2) monthly dihydroartemisinin-piperaquine (DP). Both interventions arms will have either SP or DP placebo to ensure adequate blinding is achieved in the study. Follow-up for the pregnant women will end approximately 6 weeks after giving birth. All children born to mothers enrolled in the study will be followed from birth until they reach 12 months of age.

Detailed Description
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Pregnant women will be scheduled to be seen in the clinic every 4 weeks during their pregnancy and then 1 and 6 weeks following delivery. In addition, pregnant women will be instructed to come to the study clinic for all their medical care and avoid the use of any outside medications. Children will be scheduled to be seen in the clinic at 1, 4, 6, and 8 weeks of age and then every 4 weeks until they reach 52 weeks of age. Parents/guardians will be instructed to bring their children to the study clinic for all medical care and avoid the use of any outside medications. The study clinic will remain open 7 days a week from 8 a.m. to 5 p.m. Study participants not seen in the clinic for their every 4 week routine visits will be visited at home and requested to come to the study clinic as soon as possible. Pregnant women and children will receive standard of care as designated in the Uganda Ministry of Health guidelines. Routine antenatal care will include screening and treatment for sexually transmitted infections, blood pressure assessment, urine dipstick for proteinuria, prescription of iron, folate, multivitamins and mebendazole. Routine care in children will include immunizations, vitamin A supplementation, and management of anemia using Integrated Management of Childhood Illness (IMCI) guidelines. During routine assessments subjects will be asked about visits to outside health facilities and the use of any medications outside the study protocol. Standardized assessment of adherence will be done for study drugs administered at home and insecticide treated net use. A routine history and physical exam will be performed using a standardized clinical assessment form. Blood will be collected by finger prick for thick smear (in very young children, heel sticks may be substituted for finger pricks), capillary plasma (for routine visits where phlebotomy is not done in pregnant women only) and filter paper samples. If a pregnant woman or parent/guardian of a child reports a fever in the last 24 hours or the patient has a documented temperature > 38.0˚C tympanic, the patient's thick blood smear will be read immediately and if positive the patient will be diagnosed and treated for malaria. If the thick blood smear is negative, the patient will be managed by study physicians for a non-malarial febrile illness. If the patient is afebrile and does not report a recent fever, a thick blood smear will not be obtained, except when following routine testing schedules. In pregnant mothers, thick blood smears other than those done when a mother has fever will not be used for clinical care of study participants. Phlebotomy for routine laboratory tests (CBC and ALT) to monitor for potential adverse events from study medications, storage of plasma and for immunology studies will be performed every 8 weeks in pregnant women. Phlebotomy for routine laboratory tests (CBC) and immunology studies will be performed at 12, 28, and 52 weeks of age in children. For pregnant women, study drugs will be administered at the time of each routine visit. ECGs will be performed to measure the QTc interval in all pregnant women just prior to the 1st dose of study drugs and 2-3 hours after their 3rd dose of study drugs at 20, 28 and 36 weeks of gestation. In addition a finger prick capillary plasma sample will be collected just prior to performing the ECGs after the 3rd dose of study drugs at 20, 28, and 36 weeks of gestation in pregnant women.

Official Title
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Prevention of Malaria in HIV-uninfected Pregnant Women and Infants

Conditions
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Malaria

Intervention / Treatment
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* Drug: Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy
* Drug: Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnancy confirmed by positive urine pregnancy test or intrauterine pregnancy by ultrasound Estimated gestational age between 12-20 weeks Confirmed to be HIV uninfected by rapid test 16 years of age or older Resident of Busia District, Uganda Provision of informed consent by the pregnant woman for herself and her unborn child Agreement to come to the study clinic for any febrile episode or other illness and avoid medications given outside the study protocol Plan 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 SP preventive therapy or any other antimalarial therapy during this pregnancy Early or active labor (documented by cervical change with uterine contractions)

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy<br>Women will be given SP (3 full strength tabs, 500 mg/25 mg) every four weeks times during pregnancy. In addition, 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) 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. | Drug: Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy<br> <br> * Other names: Kamsidar (KPI);|
| Active Comparator: Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy<br>Women will be given DP (3 full strength tabs, 40 mg/320 mg, given once a day for 3 consecutive days) every 4 weeks during pregnancy. In addition, 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) 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. | Drug: Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy<br> <br> * Other names: Duo-Cotexin (Holley-Cotec);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Deliver With a Composite Adverse Birth Outcome | Composite adverse birth outcome defined as any one of the following: 1) Low birth weight (< 2500 gm); 2) Preterm delivery (< 37 weeks gestational age); 3) Small for gestational age (< 10th percentile relative to an external growth reference) | Delivery | 
| Incidence of Malaria in Infants | episodes per person year | Time at risk will begin at birth and end when study participants reaches 12 months of age or early study termination | 
| Mean Gestational Age in Weeks at Birth | Gestational age in weeks determined by ultrasound dating (gold standard) and by the metabolic profiling outcome from biological specimens including placental tissue and placental blood. | At the time of delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of Placental Malaria by Histology | Any evidence of placental infection (parasites or pigment). Number of participants with placental tissue positive for malaria parasites or pigment. | Delivery | 
| Prevalence of Placental Parasitemia | Proportion of placental blood samples positive for parasites by Loop-mediated isothermal amplification (LAMP) or microscopy | Delivery | 
| Prevalence of Maternal Malaria | Maternal blood positive for malaria parasites by microscopy. | Gestational age between 12-20 weeks (at study entry) up to delivery | 
| Number of Participants With Adverse Events | All grade 3 and 4 adverse events | Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery | 
| Prevalence of Anemia in Pregnant Women | hemoglobin < 11 g/dL | Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery | 
| Prevalence of Anemia in Infants | Defined as the proportion with hemoglobin < 10 g/dL measure routinely at 12, 28, and 52 weeks of age. Number of cases per person year (PPY). This is a prevalence measure but are repeated measures during infancy. In other words we measured this outcome up to 3 times for each participant during infancy (at 12, 28 and 52 weeks of age). | Birth up to 12 months of age or early termination | 
| Prevalence of Asymptomatic Parasitemia in Pregnant Women | Proportion of routine monthly samples positive for parasites by microscopy and LAMP | Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery | 
| Prevalence of Asymptomatic Parasitemia in Infants | Proportion of routine monthly samples positive for parasites by microscopy and LAMP | Birth up to 12 months of age or early termination | 
| Incidence of Complicated Malaria in Infants | Complicated malaria defined as an episode of malaria with danger signs (any of the following: less than 3 convulsions over 24 h, inability to sit or stand, vomiting everything, unable to breastfeed or drink) or the meeting standardized criteria for severe malaria. | Birth up to 12 months of age or early termination | 
| Incidence of Hospital Admissions in Infants | Admission to the pediatric ward for any cause | Birth up to 12 months of age or early termination | 
| Infant Mortality Rate | Any deaths occurring after birth | Birth up to 12 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Chemoprevention, Sulfadoxine-Pyrimethamine, Dihydroartemisinin-Piperaquine