Reducing the Burden of Malaria in HIV-Infected Pregnant Women and Their HIV-Exposed Children (PROMOTE-BC2)

Study Overview
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Brief Summary
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This is a double-blinded, randomized controlled trial of 200 HIV-infected pregnant women living in Tororo, Uganda, an area of high malaria transmission. HIV-infected pregnant women between 12 and 28 weeks gestation will be randomized to receive enhanced malaria chemoprevention with monthly dihydroartemisinin-piperaquine (DP) versus monthly DP placebo. Their HIV-exposed children will receive the same prevention regimen from 2 to 24 months of age to which the mothers were randomized. All women will receive daily trimethoprim-sulfamethoxazole (TS) throughout the study per Uganda Ministry of Health guidelines. Children will also receive daily TS from 6 weeks to 24 months of age. TS will be considered a study drug only in infants and children beginning 6 weeks after cessation of breastfeeding and upon exclusion of HIV infection. Women and their children will be followed for 36 months after delivery. In a subset of the study population, the investigators will conduct an intensive pharmacokinetic study that will evaluate pharmacokinetic exposure of DP and EFV. The investigators will also measure HIV-related outcomes among the women enrolled in the study. The investigators will test the hypothesis that for HIV-infected mothers and HIV-exposed infants, that enhanced versus standard malaria chemoprevention in HIV-infected pregnant women and their children will reduce the incidence of malaria among children from 0 to 24 months of age 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 study clinic every 4 weeks during their pregnancy. Women will be seen at 1 week, 6 weeks, and 3 months postpartum and every 3 months thereafter. 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. Women will be provided all routine HIV care at the clinic according to Uganda MOH guidelines. All women will have ARVs and TS dispensed at the study clinic. Counseling on breastfeeding and infant feeding will be provided per Uganda MOH guidelines. HIV care and breastfeeding and infant feeding recommendations may be changed to reflect the most recent standard of care per MOH guidelines. 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. Children will have care for HIV-exposed children according to MOH guidelines, with the exception that TS will be continued until 2 years of life. 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. 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, 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-Infected Pregnant Women and Their HIV-Exposed Children (PROMOTE Birth Cohort 2)

Conditions
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Human Immunodeficiency Virus, Malaria

Intervention / Treatment
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* Drug: Monthly dihydroartemisinin-piperaquine (DP) + daily trimethoprim/sulfamethoxazole (TS)
* Drug: Monthly placebo + daily trimethoprim/sulfamethoxazole (TS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Intrauterine pregnancy confirmed by ultrasound Estimated gestational age between 12-28 weeks Confirmed to be HIV-infected by Uganda country standard rapid HIV test 16 years of age or older Residency within 30 km of the study clinic Provision of informed consent 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 TS or DP Refusal to take cART during pregnancy or as part of routine HIV care Active medical problem requiring inpatient evaluation at the time of screening Intention of moving more than 30 km from the study clinic Active WHO stage 4 condition not stable under treatment Signs or symptoms of early or active labor Currently on ritonavir Currently taking drugs associated with known risk of Torsades de pointes Currently taking CYP3A inhibitor medications which potentially inhibit the metabolism of piperaquine History of cardiac problems or fainting

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: Daily TS + Monthly DP pregnancy<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. During pregancy, TS will be given to women at a dose of 960mg once daily. | Drug: Monthly dihydroartemisinin-piperaquine (DP) + daily trimethoprim/sulfamethoxazole (TS)<br> <br> * Other names: Duo-Cotexin (Holley-Cotec);|
| Placebo Comparator: Daily TS + DP Placebo pregnancy<br>Women will be given DP placebo (3 tabs, given once a day for 3 consecutive days) every 4 weeks during pregnancy. During pregnancy, TS will be given to women at a dose of 960mg once daily. | Drug: Monthly placebo + daily trimethoprim/sulfamethoxazole (TS)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Placental Malaria | The primary outcome will be the prevalence of placental malaria based on placental histopathology and dichotomized into any evidence of placental infection (parasites or pigment) vs. no evidence of placental infection. | at delivery estimated to be within 10 to 30 weeks of study entry | 
| Incidence of Malaria, Pregnant Women | The primary outcome will be the 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 following administration of first dose of study drug to delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal Parasitemia at Delivery by Microscopy and LAMP | Proportion of women with parasitemia detected by microscopy or LAMP at delivery | At delivery | 
| Placental Parasitemia (Number of Women With Placental Blood Samples Positive for Malaria by Microscopy or PCR) | Proportion of placental blood samples positive for malaria by microscopy or PCR | At delivery | 
| Number of Monthly Routine Visits With Positive Blood Samples for Parasites | Proportion of monthly routine blood samples positive by LAMP for parasites | Following administration of first dose of study drug to delivery | 
| Composite Adverse Birth Outcome (Proportion With Low Birth Weight (<2500 gm), Spontaneous Abortion (<28 Weeks), Stillbirth (Fetal Demise ≥28 Weeks), Congenital Anomaly, or Preterm Delivery (<37 Weeks) | Proportion with low birth weight (<2500 gm), spontaneous abortion (<28 weeks), stillbirth (fetal demise ≥28 weeks), congenital anomaly, or preterm delivery (<37 weeks) | At delivery | 
| Number of Routine Visits Measured Every 8 Weeks During Pregnancy for Which the Participants Had Anemia | Anemia (hemoglobin less than 11g/dL) measured every 8 weeks during pregnancy | Following administration of first dose of study drugs to delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chemoprevention, Malaria, Uganda, Dihydroartemisinin-piperaquine, Trimethoprim-sulfamethoxazole, Human Immunodeficiency Virus