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

Phase 3

Completed

Conditions: Malaria
Human Immunodeficiency Virus

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

Registration Number: NCT02282293

Lead Sponsor: University of California, San Francisco

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 200

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Daily TS + Monthly DP pregnancy	Monthly dihydroartemisinin-piperaquine (DP) + daily trimethoprim/sulfamethoxazole (TS)	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.
Daily TS + DP Placebo pregnancy	Monthly placebo + daily trimethoprim/sulfamethoxazole (TS)	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Placental Malaria	at delivery estimated to be within 10 to 30 weeks of study entry	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.
Incidence of Malaria, Pregnant Women	Time at risk will begin following administration of first dose of study drug to delivery	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.

Secondary Outcome Measures

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