- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02793622
Prevention of Malaria in HIV-uninfected Pregnant Women and Infants (PROMOTE-BC3)
April 12, 2021 updated by: Grant Dorsey, M.D, Ph.D., University of California, San Francisco
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.
Study Overview
Status
Completed
Conditions
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.
Study Type
Interventional
Enrollment (Actual)
782
Phase
- Phase 3
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Tororo, Uganda
- IDRC - Tororo Research Clinic
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
16 years and older (Child, Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
Female
Description
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)
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Active Comparator: 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.
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Other Names:
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Active Comparator: 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.
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Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants Who Deliver With a Composite Adverse Birth Outcome
Time Frame: Delivery
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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)
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Delivery
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Incidence of Malaria in Infants
Time Frame: Time at risk will begin at birth and end when study participants reaches 12 months of age or early study termination
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episodes per person year
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Time at risk will begin at birth and end when study participants reaches 12 months of age or early study termination
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Mean Gestational Age in Weeks at Birth
Time Frame: At the time of delivery
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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.
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At the time of delivery
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Prevalence of Placental Malaria by Histology
Time Frame: Delivery
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Any evidence of placental infection (parasites or pigment).
Number of participants with placental tissue positive for malaria parasites or pigment.
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Delivery
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Prevalence of Placental Parasitemia
Time Frame: Delivery
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Proportion of placental blood samples positive for parasites by Loop-mediated isothermal amplification (LAMP) or microscopy
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Delivery
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Prevalence of Maternal Malaria
Time Frame: Gestational age between 12-20 weeks (at study entry) up to delivery
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Maternal blood positive for malaria parasites by microscopy.
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Gestational age between 12-20 weeks (at study entry) up to delivery
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Number of Participants With Adverse Events
Time Frame: Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery
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All grade 3 and 4 adverse events
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Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery
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Prevalence of Anemia in Pregnant Women
Time Frame: Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery
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hemoglobin < 11 g/dL
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Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery
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Prevalence of Anemia in Infants
Time Frame: Birth up to 12 months of age or early termination
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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
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Prevalence of Asymptomatic Parasitemia in Pregnant Women
Time Frame: Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery
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Proportion of routine monthly samples positive for parasites by microscopy and LAMP
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Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery
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Prevalence of Asymptomatic Parasitemia in Infants
Time Frame: Birth up to 12 months of age or early termination
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Proportion of routine monthly samples positive for parasites by microscopy and LAMP
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Birth up to 12 months of age or early termination
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Incidence of Complicated Malaria in Infants
Time Frame: Birth up to 12 months of age or early termination
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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.
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Birth up to 12 months of age or early termination
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Incidence of Hospital Admissions in Infants
Time Frame: Birth up to 12 months of age or early termination
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Admission to the pediatric ward for any cause
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Birth up to 12 months of age or early termination
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Infant Mortality Rate
Time Frame: Birth up to 12 months of age
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Any deaths occurring after birth
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Birth up to 12 months of age
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Collaborators
Investigators
- Principal Investigator: Grant Dorsey, MD PhD, University of California, San Francisco
- Principal Investigator: Moses Kamya, MBChB MMed PhD, Makarere Univeritys ; Infectious Disease Research Collaboration
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Kajubi R, Ochieng T, Kakuru A, Jagannathan P, Nakalembe M, Ruel T, Opira B, Ochokoru H, Ategeka J, Nayebare P, Clark TD, Havlir DV, Kamya MR, Dorsey G. Monthly sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnancy: a double-blind, randomised, controlled, superiority trial. Lancet. 2019 Apr 6;393(10179):1428-1439. doi: 10.1016/S0140-6736(18)32224-4. Epub 2019 Mar 22.
- 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.
- Briggs J, Ategeka J, Kajubi R, Ochieng T, Kakuru A, Ssemanda C, Wasswa R, Jagannathan P, Greenhouse B, Rodriguez-Barraquer I, Kamya M, Dorsey G. Impact of Microscopic and Submicroscopic Parasitemia During Pregnancy on Placental Malaria in a High-Transmission Setting in Uganda. J Infect Dis. 2019 Jul 2;220(3):457-466. doi: 10.1093/infdis/jiz130.
- Okiring J, Olwoch P, Kakuru A, Okou J, Ochokoru H, Ochieng TA, Kajubi R, Kamya MR, Dorsey G, Tusting LS. Household and maternal risk factors for malaria in pregnancy in a highly endemic area of Uganda: a prospective cohort study. Malar J. 2019 Apr 23;18(1):144. doi: 10.1186/s12936-019-2779-x.
- Kakuru A, Jagannathan P, Kajubi R, Ochieng T, Ochokoru H, Nakalembe M, Clark TD, Ruel T, Staedke SG, Chandramohan D, Havlir DV, Kamya MR, Dorsey G. Impact of intermittent preventive treatment of malaria in pregnancy with dihydroartemisinin-piperaquine versus sulfadoxine-pyrimethamine on the incidence of malaria in infancy: a randomized controlled trial. BMC Med. 2020 Aug 10;18(1):207. doi: 10.1186/s12916-020-01675-x.
- Savic RM, Jagannathan P, Kajubi R, Huang L, Zhang N, Were M, Kakuru A, Muhindo MK, Mwebaza N, Wallender E, Clark TD, Opira B, Kamya M, Havlir DV, Rosenthal PJ, Dorsey G, Aweeka FT. Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine. Clin Infect Dis. 2018 Sep 14;67(7):1079-1088. doi: 10.1093/cid/ciy218.
- Ategeka J, Kakuru A, Kajubi R, Wasswa R, Ochokoru H, Arinaitwe E, Yeka A, Jagannathan P, Kamya MR, Muehlenbachs A, Chico RM, Dorsey G. Relationships Between Measures of Malaria at Delivery and Adverse Birth Outcomes in a High-Transmission Area of Uganda. J Infect Dis. 2020 Aug 4;222(5):863-870. doi: 10.1093/infdis/jiaa156.
- Roh ME, Kuile FOT, Rerolle F, Glymour MM, Shiboski S, Gosling R, Gutman J, Kakuru A, Desai M, Kajubi R, L'Ianziva A, Kamya MR, Dorsey G, Chico RM. Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis. Lancet Glob Health. 2020 Jul;8(7):e942-e953. doi: 10.1016/S2214-109X(20)30119-4.
- 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.
- Hughes E, Wallender E, Kajubi R, Jagannathan P, Ochieng T, Kakuru A, Kamya MR, Clark TD, Rosenthal PJ, Dorsey G, Aweeka F, Savic RM. Piperaquine-Induced QTc Prolongation Decreases With Repeated Monthly Dihydroartemisinin-Piperaquine Dosing in Pregnant Ugandan Women. Clin Infect Dis. 2022 Aug 31;75(3):406-415. doi: 10.1093/cid/ciab965.
- Zehner N, Adrama H, Kakuru A, Andra T, Kajubi R, Conrad M, Nankya F, Clark TD, Kamya M, Rodriguez-Barraquer I, Dorsey G, Jagannathan P. Age-Related Changes in Malaria Clinical Phenotypes During Infancy Are Modified by Sickle Cell Trait. Clin Infect Dis. 2021 Nov 16;73(10):1887-1895. doi: 10.1093/cid/ciab245.
- 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.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
September 1, 2016
Primary Completion (Actual)
December 4, 2018
Study Completion (Actual)
December 4, 2018
Study Registration Dates
First Submitted
May 20, 2016
First Submitted That Met QC Criteria
June 3, 2016
First Posted (Estimate)
June 8, 2016
Study Record Updates
Last Update Posted (Actual)
April 14, 2021
Last Update Submitted That Met QC Criteria
April 12, 2021
Last Verified
April 1, 2021
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Infections
- Vector Borne Diseases
- Parasitic Diseases
- Protozoan Infections
- Malaria
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Antiprotozoal Agents
- Antiparasitic Agents
- Antimalarials
- Folic Acid Antagonists
- Anti-Infective Agents, Urinary
- Renal Agents
- Pyrimethamine
- Piperaquine
- Sulfadoxine
- Fanasil, pyrimethamine drug combination
- Artenimol
Other Study ID Numbers
- PROMOTE-BC3
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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