- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02163447
Reducing the Burden of Malaria in HIV-uninfected Pregnant Women and Infants (PROMOTE-BC1)
Reducing the Burden of Malaria in HIV-uninfected Pregnant Women and Infants (PROMOTE Birth Cohort 1)
Study Overview
Status
Conditions
Intervention / Treatment
- Drug: 3 dose sulfadoxine-pyrimethamine (SP) for adult women during pregnancy
- Drug: 3-monthly dihydroartemisinin-piperaquine (DP) for infants
- Drug: 3 dose dihydroartemisinin-piperaquine (DP) for adult women during pregnancy
- Drug: Monthly dihydroartemisinin-piperaquine (DP) for infants
- Drug: Monthly dihydroartemisinin-piperaquine (DP) for adult women during pregnancy
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.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Tororo, Uganda
- IDRC Research Clinic -Tororo District Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
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
- Residency within 30km of the study clinic
- 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 more than 30km from the study clinic
- 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
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 |
---|---|
Active Comparator: 3 dose SP pregnancy / 3 monthly DP infancy
Women will be given SP (3 full strength tabs, 500 mg/25 mg) 3 times during pregnancy at 20, 28, and 36 weeks gestational age. In addition, placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two pills on day 1 (SP and placebo, DP and placebo, or two placebos) followed by one pill 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. Infants will be given DP (once a day for 3 consecutive days using weight-based guidelines) every 12 weeks between 8 and 104 weeks of age. Infants randomized to receive DP every 12 weeks will receive placebo mimicking the dosing of DP every 4 weeks when they are not receiving study drug. |
Other Names:
Other Names:
|
Active Comparator: 3 dose DP pregnancy / 3 monthly DP infancy
Women will be given DP (3 full strength tabs, 40 mg/320 mg, given once a day for 3 consecutive days) 3 times during pregnancy at 20, 28, and 36 weeks gestational age. In addition, placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two pills on day 1 (SP and placebo, DP and placebo, or two placebos) followed by one pill 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. Infants will be given DP (once a day for 3 consecutive days using weight-based guidelines) every 12 weeks between 8 and 104 weeks of age. Infants randomized to receive DP every 12 weeks will receive placebo mimicking the dosing of DP every 4 weeks when they are not receiving study drug. |
Other Names:
Other Names:
|
Active Comparator: 3 dose DP pregnancy / monthly DP infancy
Women will be given DP (3 full strength tabs, 40 mg/320 mg, given once a day for 3 consecutive days) 3 times during pregnancy at 20, 28, and 36 weeks gestational age. In addition, placebos will be used to mimic the identical dosing strategy such that every 4 weeks women will receive two pills on day 1 (SP and placebo, DP and placebo, or two placebos) followed by one pill 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. Infants will be given DP (once a day for 3 consecutive days using weight-based guidelines) every 4 weeks between 8 and 104 weeks of age. |
Other Names:
Other Names:
|
Active Comparator: monthly DP pregnancy / 3 monthly DP infancy
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 pills on day 1 (SP and placebo, DP and placebo, or two placebos) followed by one pill 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. Infants will be given DP (once a day for 3 consecutive days) every 12 weeks between 8 and 104 weeks of age. Infants randomized to receive DP every 12 weeks will receive placebo mimicking the dosing of DP every 4 weeks when they are not receiving study drug. |
Other Names:
Other Names:
|
Active Comparator: monthly DP pregnancy / monthly DP infancy
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 pills on day 1 (SP and placebo, DP and placebo, or two placebos) followed by one pill 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. Infants will be given DP (once a day for 3 consecutive days) every 4 weeks between 8 and 104 weeks of age. |
Other Names:
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Prevalence of Placental Malaria
Time Frame: Delivery
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Prevalence of placental malaria based on placental histopathology dichotomized into any evidence of placental infection (parasites or pigment) vs. no evidence and by histopathology as a categorical variable based on Rogerson et al criteria.
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Delivery
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Incidence of Malaria in Pregnant Women
Time Frame: Time at risk will begin after first dose of study drug and will end when study participants deliver or early study termination
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Incidence of malaria, defined as the number of incident episodes per time at risk.
Incident cases will include all treatments for malaria not proceeded by another treatment in the previous 14 days.
|
Time at risk will begin after first dose of study drug and will end when study participants deliver or early study termination
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Incidence of Malaria in Infants
Time Frame: 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)
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Incident cases will include all treatments for malaria not proceeded by another treatment in the previous 14 days.
The study investigators will test the hypotheses that A) infants born to mothers randomized to receive IPTp with 3 dose DP or monthly DP will have a lower incidence of malaria during the first 24 months of life compared to infants born to mothers who were randomized to receive IPTp with 3 doses of SP, and, B) infants randomized to receive monthly DP between 2-24 months of age will have a lower incidence of malaria between 24-36 months of age after the intervention is stopped compared to infants randomized q 3 monthly DP between 2-24 months of age.
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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)
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Incidence of Malaria in Infants
Time Frame: Time at risk will begin at 24 months of age and will end when study participants reaches 36 months of age or termination
|
Incident cases will include all treatments for malaria not proceeded by another treatment in the previous 14 days.
The study investigators will test the hypotheses that A) infants born to mothers randomized to receive IPTp with 3 dose DP or monthly DP will have a lower incidence of malaria during the first 24 months of life compared to infants born to mothers who were randomized to receive IPTp with 3 doses of SP, and, B) infants randomized to receive monthly DP between 2-24 months of age will have a lower incidence of malaria between 24-36 months of age after the intervention is stopped compared to infants randomized q 3 monthly DP between 2-24 months of age.
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Time at risk will begin at 24 months of age and will end when study participants reaches 36 months of age or termination
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Blood Samples Positive for Parasites by Microscopy or LAMP
Time Frame: Delivery
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Prevalence of placental blood samples positive for parasites by microscopy or LAMP
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Delivery
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Number of Participants With Maternal Blood Samples Positive for Parasites by Microscopy and LAMP at Delivery
Time Frame: At delivery
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Prevalence of maternal parasitemia at delivery by microscopy and LAMP
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At delivery
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Number of Participants With One or More Birth Outcomes: Congenital Malformations, Spontaneous Abortion, LBW (<2500g), Still Birth, Pre-term Delivery
Time Frame: Delivery
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Congenital malformations, spontaneous abortion, LBW (<2500g), still birth, pre-term delivery
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Delivery
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Prevalence of Anemia in Pregnant Women
Time Frame: After first dose of study drugs up to delivery or early termination
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Prevalence of routine hemoglobin measurements < 11 g/dL
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After first dose of study drugs up to delivery or early termination
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Incidence of Complicated Malaria in Infants
Time Frame: Birth up to 24 months of age or early study termination
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Any treatment for malaria meeting criteria for severe malaria or danger signs
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Birth up to 24 months of age or early study termination
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Incidence of Hospital Admissions in Infants
Time Frame: Birth up to 24 months of age or early study termination
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Admission to a hospital for pediatric inpatient care for any reason
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Birth up to 24 months of age or early study termination
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Prevalence of Gametocytemia in Pregnant Women
Time Frame: Gestational age between 12-20 weeks (at study entry) up to delivery
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Proportion of urgent blood smears positive for gametocytes
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Gestational age between 12-20 weeks (at study entry) up to delivery
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Prevalence of Parasitemia in Infants
Time Frame: Birth up to 24 months of age or early study termination
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Proportion of routine monthly samples positive for parasites by LAMP.
Proportion of routine samples (LAMP or blood smears) positive for asexual parasites.
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Birth up to 24 months of age or early study termination
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Prevalence of Parasitemia at the Time of Monthly Routine Visits During Pregnancy
Time Frame: After first dose of study drug through delivery or early termination
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Detection of malaria parasites by LAMP during pregnancy
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After first dose of study drug through delivery or early termination
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Prevalence of Gametocytemia in Infants
Time Frame: Birth up to 24 months of age or early study termination
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Proportion of routine blood smears positive for gametocytes
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Birth up to 24 months of age or early study termination
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Grant Dorsey, MD, PhD, University of California, San Francisco
- Principal Investigator: Moses Kamya, MBChB, MMed, PhD, Makerere University; Infectious Diseases Research Collaboration
Publications and helpful links
General Publications
- Kakuru A, Jagannathan P, Muhindo MK, Natureeba P, Awori P, Nakalembe M, Opira B, Olwoch P, Ategeka J, Nayebare P, Clark TD, Feeney ME, Charlebois ED, Rizzuto G, Muehlenbachs A, Havlir DV, Kamya MR, Dorsey G. Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. N Engl J Med. 2016 Mar 10;374(10):928-39. doi: 10.1056/NEJMoa1509150.
- Muhindo MK, Kakuru A, Natureeba P, Awori P, Olwoch P, Ategeka J, Nayebare P, Clark TD, Muehlenbachs A, Roh M, Mpeka B, Greenhouse B, Havlir DV, Kamya MR, Dorsey G, Jagannathan P. Reductions in malaria in pregnancy and adverse birth outcomes following indoor residual spraying of insecticide in Uganda. Malar J. 2016 Aug 26;15(1):437. doi: 10.1186/s12936-016-1489-x.
- Conrad MD, Mota D, Foster M, Tukwasibwe S, Legac J, Tumwebaze P, Whalen M, Kakuru A, Nayebare P, Wallender E, Havlir DV, Jagannathan P, Huang L, Aweeka F, Kamya MR, Dorsey G, Rosenthal PJ. Impact of Intermittent Preventive Treatment During Pregnancy on Plasmodium falciparum Drug Resistance-Mediating Polymorphisms in Uganda. J Infect Dis. 2017 Nov 15;216(8):1008-1017. doi: 10.1093/infdis/jix421.
- Kapisi J, Kakuru A, Jagannathan P, Muhindo MK, Natureeba P, Awori P, Nakalembe M, Ssekitoleko R, Olwoch P, Ategeka J, Nayebare P, Clark TD, Rizzuto G, Muehlenbachs A, Havlir DV, Kamya MR, Dorsey G, Gaw SL. Relationships between infection with Plasmodium falciparum during pregnancy, measures of placental malaria, and adverse birth outcomes. Malar J. 2017 Oct 5;16(1):400. doi: 10.1186/s12936-017-2040-4.
- Jagannathan P, Kakuru A, Okiring J, Muhindo MK, Natureeba P, Nakalembe M, Opira B, Olwoch P, Nankya F, Ssewanyana I, Tetteh K, Drakeley C, Beeson J, Reiling L, Clark TD, Rodriguez-Barraquer I, Greenhouse B, Wallender E, Aweeka F, Prahl M, Charlebois ED, Feeney ME, Havlir DV, Kamya MR, Dorsey G. Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy and risk of malaria in early childhood: A randomized controlled trial. PLoS Med. 2018 Jul 17;15(7):e1002606. doi: 10.1371/journal.pmed.1002606. eCollection 2018 Jul.
- Muhindo MK, Jagannathan P, Kakuru A, Opira B, Olwoch P, Okiring J, Nalugo N, Clark TD, Ruel T, Charlebois E, Feeney ME, Havlir DV, Dorsey G, Kamya MR. Intermittent preventive treatment with dihydroartemisinin-piperaquine and risk of malaria following cessation in young Ugandan children: a double-blind, randomised, controlled trial. Lancet Infect Dis. 2019 Sep;19(9):962-972. doi: 10.1016/S1473-3099(19)30299-3. Epub 2019 Jul 12.
- Conroy AL, Bangirana P, Muhindo MK, Kakuru A, Jagannathan P, Opoka RO, Liechty EA, Nakalembe M, Kamya MR, Dorsey G, John CC. Case Report: Birth Outcome and Neurodevelopment in Placental Malaria Discordant Twins. Am J Trop Med Hyg. 2019 Mar;100(3):552-555. doi: 10.4269/ajtmh.18-0659.
- Wallender E, Ali AM, Hughes E, Kakuru A, Jagannathan P, Muhindo MK, Opira B, Whalen M, Huang L, Duvalsaint M, Legac J, Kamya MR, Dorsey G, Aweeka F, Rosenthal PJ, Savic RM. Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children. Nat Commun. 2021 Nov 18;12(1):6714. doi: 10.1038/s41467-021-27051-8.
- Hughes E, Imperial M, Wallender E, Kajubi R, Huang L, Jagannathan P, Zhang N, Kakuru A, Natureeba P, Mwima MW, Muhindo M, Mwebaza N, Clark TD, Opira B, Nakalembe M, Havlir D, Kamya M, Rosenthal PJ, Dorsey G, Aweeka F, Savic RM. Piperaquine Exposure Is Altered by Pregnancy, HIV, and Nutritional Status in Ugandan Women. Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01013-20. doi: 10.1128/AAC.01013-20. Print 2020 Nov 17.
- Whalen ME, Kajubi R, Chamankhah N, Huang L, Orukan F, Wallender E, Kamya MR, Dorsey G, Jagannathan P, Rosenthal PJ, Mwebaza N, Aweeka FT. Reduced Exposure to Piperaquine, Compared to Adults, in Young Children Receiving Dihydroartemisinin-Piperaquine as Malaria Chemoprevention. Clin Pharmacol Ther. 2019 Dec;106(6):1310-1318. doi: 10.1002/cpt.1534. Epub 2019 Jul 22.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
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
- Artemisinins
Other Study ID Numbers
- PROMOTE-BC1
- P01HD059454 (U.S. NIH Grant/Contract)
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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