Clinical trial NCT02163447: Reducing the Burden of Malaria in HIV-uninfected Pregnant Women and Infants
Official title: Reducing the Burden of Malaria in HIV-uninfected Pregnant Women and Infants (PROMOTE Birth Cohort 1)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Keywords: Chemoprevention
Malaria
Uganda
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)
First posted: 2014-06-13
Enrollment: 300
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 300 HIV uninfected pregnant women and the children born to them. The study interventions will be divided into two phases. In the first phase, HIV uninfected women at 12-20 weeks gestation will be randomized in equal proportions to one of three intermittent preventive therapy in pregnancy (IPTp) treatment arms: 1) 3 doses of sulfadoxine-pyrimethamine (SP), 2) 3 doses of dihydroartemisinin-piperaquine (DP), or 3) monthly DP. All three interventions arms will have either SP or DP placebo to ensure adequate blinding is achieved. Follow-up for the pregnant women will end approximately 6 weeks after giving birth. In the second phase of the study, all children born to mothers enrolled in the study will be followed from birth until they reach 36 months of age. Children born to mothers randomized to receive 3 doses of SP during pregnancy will receive DP every 3 months between 2-24 months of age. Children born to mothers randomized to receive 3 doses of DP or monthly DP during pregnancy will receive either DP every 3 months or monthly DP between 2-24 months of age. To ensure adequate blinding, children who will receive DP every 3 months will be given DP placebo during the months they will not be taking DP. Children will then be followed an additional year between 24-36 months of age following the interventions. We will test the hypothesis that IPT with DP will significantly reduce the burden of malaria in pregnancy and infancy and improve the development of naturally acquired antimalarial immunity.

Detailed description: Pregnant women will be scheduled to be seen in the clinic every 4 weeks during their pregnancy 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 every 4 weeks and parents /guardians of children will be instructed to bring their child 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.

Each time a study participant is seen in the clinic a standardized history and physical exam will be performed. Patients who are febrile (tympanic temperature \> 3 8.0˚C) or report history of fever in the past 24 hours will have blood obtained by finger prick for a thick blood smear. If the thick blood smear is positive, the patient will be diagnosed with 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.

Routine assessments will be done in the clinic every 4 weeks for both pregnant women and children. Pregnant women and children will receive standards of care as designated in the Uganda MOH guidelines. Routine care in children will use 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 also 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, collection of plasma for PK studies, and filter paper samples. Phlebotomy for routine laboratory tests (CBC and ALT) to monitor for potential adverse events from study medications and for immunology studies will be performed every 8 weeks in pregnant women and every 16 weeks in children. Non malaria screening will also include stool ova and parasite examination, circulating filarial antigens (by ICT card for Wucheria), and blood smear for microfilaremia (including Mansonella perstans) using Knott's technique. For pregnant women and children 2-24 months of age, study drugs will be administered at the time of each routine visit.

Eligibility criteria: Inclusion Criteria:

1. Pregnancy confirmed by positive urine pregnancy test or intrauterine pregnancy by ultrasound
2. Estimated gestational age between 12-20 weeks
3. Confirmed to be HIV uninfected by rapid test
4. 16 years of age or older
5. Residency within 30km of the study clinic
6. Provision of informed consent by the pregnant woman for herself and her unborn child
7. Agreement to come to the study clinic for any febrile episode or other illness and avoid medications given outside the study protocol
8. Plan to deliver in the hospital

Exclusion Criteria:

1. History of serious adverse event to SP or DP
2. Active medical problem requiring inpatient evaluation at the time of screening
3. Intention of moving more than 30km from the study clinic
4. Chronic medical condition requiring frequent medical attention
5. Prior SP preventive therapy or any other antimalarial therapy during this pregnancy
6. Early or active labor (documented by cervical change with uterine contractions)

Primary outcomes:
measure: Prevalence of Placental Malaria
timeFrame: Delivery
measure: Incidence of Malaria in Pregnant Women
timeFrame: Time at risk will begin after first dose of study drug and will end when study participants deliver or early study termination
measure: Incidence of Malaria in Infants
timeFrame: Time at risk will begin at birth and will end when study participants reaches 24 months of age or early study termination (if prior to 24 months of age)
measure: Incidence of Malaria in Infants
timeFrame: Time at risk will begin at 24 months of age and will end when study participants reaches 36 months of age or termination
Secondary outcomes:
measure: Number of Participants With Blood Samples Positive for Parasites by Microscopy or LAMP
timeFrame: Delivery
measure: Number of Participants With Maternal Blood Samples Positive for Parasites by Microscopy and LAMP at Delivery
timeFrame: At delivery
measure: Number of Participants With One or More Birth Outcomes: Congenital Malformations, Spontaneous Abortion, LBW (<2500g), Still Birth, Pre-term Delivery
timeFrame: Delivery
measure: Prevalence of Anemia in Pregnant Women
timeFrame: After first dose of study drugs up to delivery or early termination
measure: Incidence of Complicated Malaria in Infants
timeFrame: Birth up to 24 months of age or early study termination
measure: Incidence of Hospital Admissions in Infants
timeFrame: Birth up to 24 months of age or early study termination
measure: Prevalence of Gametocytemia in Pregnant Women
timeFrame: Gestational age between 12-20 weeks (at study entry) up to delivery
measure: Prevalence of Parasitemia in Infants
timeFrame: Birth up to 24 months of age or early study termination
measure: Prevalence of Parasitemia at the Time of Monthly Routine Visits During Pregnancy
timeFrame: After first dose of study drug through delivery or early termination
measure: Prevalence of Gametocytemia in Infants
timeFrame: Birth up to 24 months of age or early study termination
Other outcomes:
Locations:
city: Tororo
country: Uganda
facility: IDRC Research Clinic -Tororo District Hospital
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: Makerere University; Infectious Diseases Research Collaboration
name: Moses Kamya, MBChB, MMed, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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