Clinical trial NCT02793622: Prevention of Malaria in HIV-uninfected Pregnant Women and Infants
Official title: Prevention of Malaria in HIV-uninfected Pregnant Women and Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Keywords: Chemoprevention
Malaria
Sulfadoxine-Pyrimethamine
Dihydroartemisinin-Piperaquine
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Bill and Melinda Gates Foundation
First posted: 2016-06-08
Enrollment: 782
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Number of Participants Who Deliver With a Composite Adverse Birth Outcome
timeFrame: Delivery
measure: Incidence of Malaria in Infants
timeFrame: Time at risk will begin at birth and end when study participants reaches 12 months of age or early study termination
measure: Mean Gestational Age in Weeks at Birth
timeFrame: At the time of delivery
Secondary outcomes:
measure: Prevalence of Placental Malaria by Histology
timeFrame: Delivery
measure: Prevalence of Placental Parasitemia
timeFrame: Delivery
measure: Prevalence of Maternal Malaria
timeFrame: Gestational age between 12-20 weeks (at study entry) up to delivery
measure: Number of Participants With Adverse Events
timeFrame: Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery
measure: Prevalence of Anemia in Pregnant Women
timeFrame: Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery
measure: Prevalence of Anemia in Infants
timeFrame: Birth up to 12 months of age or early termination
measure: Prevalence of Asymptomatic Parasitemia in Pregnant Women
timeFrame: Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery
measure: Prevalence of Asymptomatic Parasitemia in Infants
timeFrame: Birth up to 12 months of age or early termination
measure: Incidence of Complicated Malaria in Infants
timeFrame: Birth up to 12 months of age or early termination
measure: Incidence of Hospital Admissions in Infants
timeFrame: Birth up to 12 months of age or early termination
measure: Infant Mortality Rate
timeFrame: Birth up to 12 months of age
Other outcomes:
Locations:
city: Tororo
country: Uganda
facility: IDRC - Tororo Research Clinic
Study officials:
affiliation: University of California, San Francisco
name: Grant Dorsey, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Diane V Havlir, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Makarere Univeritys ; Infectious Disease Research Collaboration
name: Moses Kamya, MBChB MMed PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Vaaben AV, Levan J, Nguyen CBT, Callaway PC, Prahl M, Warrier L, Nankya F, Musinguzi K, Kakuru A, Muhindo MK, Dorsey G, Kamya MR, Feeney ME. In Utero Activation of Natural Killer Cells in Congenital Cytomegalovirus Infection. J Infect Dis. 2022 Sep 4;226(4):566-575. doi: 10.1093/infdis/jiac307.
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