Prevention of Malaria in HIV-uninfected Pregnant Women and Infants

NCT ID: NCT02793622

Last Updated: 2021-04-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 782 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-09-30
• Study Completion Date: 2018-12-04

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.

Conditions

Malaria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy

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.

Group Type: ACTIVE_COMPARATOR

Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy

Intervention Type: DRUG

Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy

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.

Group Type: ACTIVE_COMPARATOR

Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy

Intervention Type: DRUG

Interventions

Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy

Intervention Type: DRUG

Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy

Intervention Type: DRUG

Other Intervention Names

Kamsidar (KPI); Duo-Cotexin (Holley-Cotec)

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)

• Minimum Eligible Age: 16 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

Bill and Melinda Gates Foundation

OTHER

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Grant Dorsey, M.D, Ph.D.

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Grant Dorsey, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Diane V Havlir, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Moses Kamya, MBChB MMed PhD

Role: PRINCIPAL_INVESTIGATOR

Makarere Univeritys ; Infectious Disease Research Collaboration

Locations

IDRC - Tororo Research Clinic

Tororo, , Uganda

Countries

Uganda

References

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Reference Type: RESULT

PMID: 30910321 (View on PubMed)

Harrington WE, Kakuru A, Jagannathan P. Malaria in pregnancy shapes the development of foetal and infant immunity. Parasite Immunol. 2019 Mar;41(3):e12573. doi: 10.1111/pim.12573. Epub 2018 Aug 28.

Reference Type: RESULT

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Reference Type: RESULT

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Reference Type: RESULT

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Reference Type: RESULT

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Reference Type: DERIVED

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Reference Type: DERIVED

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Kakuru A, Roh ME, Kajubi R, Ochieng T, Ategeka J, Ochokoru H, Nakalembe M, Clark TD, Ruel T, Staedke SG, Chandramohan D, Havlir DV, Kamya MR, Dorsey G, Jagannathan P. Infant sex modifies associations between placental malaria and risk of malaria in infancy. Malar J. 2020 Dec 3;19(1):449. doi: 10.1186/s12936-020-03522-z.

Reference Type: DERIVED

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Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

PROMOTE-BC3

Identifier Type: -

Identifier Source: org_study_id