Reducing the Burden of Malaria in HIV-uninfected Pregnant Women and Infants

Study Overview
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Brief Summary
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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
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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.

Official Title
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Reducing the Burden of Malaria in HIV-uninfected Pregnant Women and Infants (PROMOTE Birth Cohort 1)

Conditions
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Malaria

Intervention / Treatment
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* Drug: Monthly dihydroartemisinin-piperaquine (DP) for adult women during pregnancy
* Drug: 3 dose dihydroartemisinin-piperaquine (DP) for adult women during pregnancy
* Drug: 3 dose sulfadoxine-pyrimethamine (SP) for adult women during pregnancy
* Drug: Monthly dihydroartemisinin-piperaquine (DP) for infants
* Drug: 3-monthly dihydroartemisinin-piperaquine (DP) for infants


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 3 dose SP pregnancy / 3 monthly DP infancy<br>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. | Drug: 3 dose sulfadoxine-pyrimethamine (SP) for adult women during pregnancy<br> <br> * Other names: Kamsidar (KPI);Drug: 3-monthly dihydroartemisinin-piperaquine (DP) for infants<br> <br> * Other names: Duo-Cotexin (Holley-Cotec);|
| Active Comparator: 3 dose DP pregnancy / 3 monthly DP infancy<br>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. | Drug: 3 dose dihydroartemisinin-piperaquine (DP) for adult women during pregnancy<br> <br> * Other names: Duo-Cotexin (Holley-Cotec);Drug: 3-monthly dihydroartemisinin-piperaquine (DP) for infants<br> <br> * Other names: Duo-Cotexin (Holley-Cotec);|
| Active Comparator: 3 dose DP pregnancy / monthly DP infancy<br>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. | Drug: 3 dose dihydroartemisinin-piperaquine (DP) for adult women during pregnancy<br> <br> * Other names: Duo-Cotexin (Holley-Cotec);Drug: Monthly dihydroartemisinin-piperaquine (DP) for infants<br> <br> * Other names: Duo-Cotexin (Holley-Cotec);|
| Active Comparator: monthly DP pregnancy / 3 monthly DP infancy<br>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. | Drug: Monthly dihydroartemisinin-piperaquine (DP) for adult women during pregnancy<br> <br> * Other names: Duo-Cotexin (Holley-Cotec);Drug: 3-monthly dihydroartemisinin-piperaquine (DP) for infants<br> <br> * Other names: Duo-Cotexin (Holley-Cotec);|
| Active Comparator: monthly DP pregnancy / monthly DP infancy<br>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. | Drug: Monthly dihydroartemisinin-piperaquine (DP) for adult women during pregnancy<br> <br> * Other names: Duo-Cotexin (Holley-Cotec);Drug: Monthly dihydroartemisinin-piperaquine (DP) for infants<br> <br> * Other names: Duo-Cotexin (Holley-Cotec);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of Placental Malaria | 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. | Delivery | 
| Incidence of Malaria in Pregnant Women | 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 | 
| Incidence of Malaria in Infants | 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. | 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) | 
| Incidence of Malaria in Infants | 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. | 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 | Prevalence of placental blood samples positive for parasites by microscopy or LAMP | Delivery | 
| Number of Participants With Maternal Blood Samples Positive for Parasites by Microscopy and LAMP at Delivery | Prevalence of maternal parasitemia at delivery by microscopy and LAMP | At delivery | 
| Number of Participants With One or More Birth Outcomes: Congenital Malformations, Spontaneous Abortion, LBW (<2500g), Still Birth, Pre-term Delivery | Congenital malformations, spontaneous abortion, LBW (<2500g), still birth, pre-term delivery | Delivery | 
| Prevalence of Anemia in Pregnant Women | Prevalence of routine hemoglobin measurements < 11 g/dL | After first dose of study drugs up to delivery or early termination | 
| Incidence of Complicated Malaria in Infants | Any treatment for malaria meeting criteria for severe malaria or danger signs | Birth up to 24 months of age or early study termination | 
| Incidence of Hospital Admissions in Infants | Admission to a hospital for pediatric inpatient care for any reason | Birth up to 24 months of age or early study termination | 
| Prevalence of Gametocytemia in Pregnant Women | Proportion of urgent blood smears positive for gametocytes | Gestational age between 12-20 weeks (at study entry) up to delivery | 
| Prevalence of Parasitemia in Infants | Proportion of routine monthly samples positive for parasites by LAMP. Proportion of routine samples (LAMP or blood smears) positive for asexual parasites. | Birth up to 24 months of age or early study termination | 
| Prevalence of Parasitemia at the Time of Monthly Routine Visits During Pregnancy | Detection of malaria parasites by LAMP during pregnancy | After first dose of study drug through delivery or early termination | 
| Prevalence of Gametocytemia in Infants | Proportion of routine blood smears positive for gametocytes | Birth up to 24 months of age or early study termination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sulfadoxine-pyrimethamine, Dihydroartemisinin-piperaquine, Chemoprevention, Malaria, Uganda