PROMOTE-BC3: Prevention of Malaria in HIV-uninfected Pregnant Women and Infants

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT02793622
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), Bill and Melinda Gates Foundation (Other)
• Enrollment: 782
• Location: 1
• Arms: 2
• Duration (Months): 27.1
• Patients Per Site Per Month: 28.9

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Malaria	Drug: Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy; Drug: Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 782 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Prevention of Malaria in HIV-uninfected Pregnant Women and Infants
• Study Start Date: Sep 1, 2016
• Actual Primary Completion Date: Dec 4, 2018
• Actual Study Completion Date: Dec 4, 2018

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy; Other Names: Kamsidar (KPI)
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.	Drug: Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy; Other Names: Duo-Cotexin (Holley-Cotec)

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Deliver With a Composite Adverse Birth Outcome [Delivery]

   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)

2. Incidence of Malaria in Infants [Time at risk will begin at birth and end when study participants reaches 12 months of age or early study termination]

   episodes per person year

3. Mean Gestational Age in Weeks at Birth [At the time of delivery]

   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.

Secondary Outcome Measures

1. Prevalence of Placental Malaria by Histology [Delivery]

   Any evidence of placental infection (parasites or pigment). Number of participants with placental tissue positive for malaria parasites or pigment.

2. Prevalence of Placental Parasitemia [Delivery]

   Proportion of placental blood samples positive for parasites by Loop-mediated isothermal amplification (LAMP) or microscopy

3. Prevalence of Maternal Malaria [Gestational age between 12-20 weeks (at study entry) up to delivery]

   Maternal blood positive for malaria parasites by microscopy.

4. Number of Participants With Adverse Events [Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery]

   All grade 3 and 4 adverse events

5. Prevalence of Anemia in Pregnant Women [Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery]

   hemoglobin < 11 g/dL

6. Prevalence of Anemia in Infants [Birth up to 12 months of age or early termination]

   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).

7. Prevalence of Asymptomatic Parasitemia in Pregnant Women [Starting at the time of their first study drug administration, approximately gestational age between 12-20 weeks, up to one month post-delivery]

   Proportion of routine monthly samples positive for parasites by microscopy and LAMP

8. Prevalence of Asymptomatic Parasitemia in Infants [Birth up to 12 months of age or early termination]

   Proportion of routine monthly samples positive for parasites by microscopy and LAMP

9. Incidence of Complicated Malaria in Infants [Birth up to 12 months of age or early termination]

   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.

10. Incidence of Hospital Admissions in Infants [Birth up to 12 months of age or early termination]

    Admission to the pediatric ward for any cause

11. Infant Mortality Rate [Birth up to 12 months of age]

    Any deaths occurring after birth

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	IDRC - Tororo Research Clinic	Tororo		Uganda

Sponsors and Collaborators

• University of California, San Francisco
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Bill and Melinda Gates Foundation

Investigators

• Principal Investigator: Grant Dorsey, MD PhD, University of California, San Francisco
• Principal Investigator: Diane V Havlir, MD, University of California, San Francisco
• Principal Investigator: Moses Kamya, MBChB MMed PhD, Makarere Univeritys ; Infectious Disease Research Collaboration

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 27, 2018

More Information

Publications

None provided.

• Responsible Party: Grant Dorsey, M.D, Ph.D., Professor, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02793622
• Other Study ID Numbers: PROMOTE-BC3
• First Posted: Jun 8, 2016
• Last Update Posted: Apr 14, 2021
• Last Verified: Apr 1, 2021

• Keywords provided by Grant Dorsey, M.D, Ph.D., Professor, University of California, San Francisco: Chemoprevention; Malaria; Sulfadoxine-Pyrimethamine; Dihydroartemisinin-Piperaquine
• Additional relevant MeSH terms: Malaria; Pyrimethamine; Piperaquine; Sulfadoxine; Fanasil, pyrimethamine drug combination; Artenimol

Study Results

Participant Flow

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Period Title: Overall Study
STARTED	391	391
COMPLETED	338	349
NOT COMPLETED	53	42

Baseline Characteristics

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy	Total
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy	Total of all reporting groups
Overall Participants	391	391	782
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	23	23	23
Sex: Female, Male (Count of Participants)
Female	391 100%	391 100%	782 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	391 100%	391 100%	782 100%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Uganda	391 100%	391 100%	782 100%
Gestational age category (weeks) (Count of Participants)
12-16 weeks	234 59.8%	242 61.9%	476 60.9%
>16-20 weeks	157 40.2%	149 38.1%	306 39.1%
Detection of malaria parasites by microscopy or qPCR (Count of Participants)
Count of Participants [Participants]	326 83.4%	317 81.1%	643 82.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Deliver With a Composite Adverse Birth Outcome
Description	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)
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

Number of livebirths reported here. SP: 338 women followed through delivery resulting in 348 infants (10 twin sets). 9 mothers/infants excluded (4 spontaneous abortions, 5 stillbirths). DP: 349 women followed through delivery resulting in 352 infants (3 twin sets). 12 mothers and 13 infants excluded (10 spontaneous abortions, 3 stillbirths).

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	329	337
Count of Participants [Participants]	60 15.3%	54 13.8%

2. Primary Outcome

Title	Incidence of Malaria in Infants
Description	episodes per person year
Time Frame	Time at risk will begin at birth and end when study participants reaches 12 months of age or early study termination

Outcome Measure Data

Analysis Population Description

339 live births included in the analyses for both groups.

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	339	339
Number [episodes per person year]	1.98	1.71

3. Primary Outcome

Title	Mean Gestational Age in Weeks at Birth
Description	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.
Time Frame	At the time of delivery

Outcome Measure Data

Analysis Population Description

339 live births included in the analyses for both groups.

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	339	339
Mean (Standard Deviation) [weeks]	39.4 (1.9)	39.6 (1.6)

4. Secondary Outcome

Title	Prevalence of Placental Malaria by Histology
Description	Any evidence of placental infection (parasites or pigment). Number of participants with placental tissue positive for malaria parasites or pigment.
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

analysis population is women who delivered and had histopathology results (i.e. some women who delivered did not have histopathology results)

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	322	331
Count of Participants [Participants]	197 50.4%	94 24%

5. Secondary Outcome

Title	Prevalence of Placental Parasitemia
Description	Proportion of placental blood samples positive for parasites by Loop-mediated isothermal amplification (LAMP) or microscopy
Time Frame	Delivery

Outcome Measure Data

Analysis Population Description

LAMP and microscopy performed for the number of participants reported in each group.

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	339	339
LAMP	71 18.2%	7 1.8%
Microscopy	29 7.4%	1 0.3%

6. Secondary Outcome

Title	Prevalence of Maternal Malaria
Description	Maternal blood positive for malaria parasites by microscopy.
Time Frame	Gestational age between 12-20 weeks (at study entry) up to delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	336	342
Count of Participants [Participants]	28 7.2%	1 0.3%

7. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	All grade 3 and 4 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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	375	373
Count of Participants [Participants]	54 13.8%	43 11%

8. Secondary Outcome

Title	Prevalence of Anemia in Pregnant Women
Description	hemoglobin < 11 g/dL
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

Outcome Measure Data

Analysis Population Description

Number of women initiated on study drugs reported here.

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	375	373
Count of Participants [Participants]	28 7.2%	8 2%

9. Secondary Outcome

Title	Prevalence of Anemia in Infants
Description	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).
Time Frame	Birth up to 12 months of age or early termination

Outcome Measure Data

Analysis Population Description

339 live births included in the analyses for both groups.

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	339	339
Measure routine hemoglobin measurement	878	892
Count of Units [routine hemoglobin measurement]	222	216

10. Secondary Outcome

Title	Prevalence of Asymptomatic Parasitemia in Pregnant Women
Description	Proportion of routine monthly samples positive for parasites by microscopy and LAMP
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	391	391
Measure blood smears	1687	1757
Count of Units [blood smears]	519	9

11. Secondary Outcome

Title	Prevalence of Asymptomatic Parasitemia in Infants
Description	Proportion of routine monthly samples positive for parasites by microscopy and LAMP
Time Frame	Birth up to 12 months of age or early termination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	339	339
Measure blood smears	3879	3933
Count of Units [blood smears]	344	357

12. Secondary Outcome

Title	Incidence of Complicated Malaria in Infants
Description	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.
Time Frame	Birth up to 12 months of age or early termination

Outcome Measure Data

Analysis Population Description

339 live births included in the analyses for both groups.

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	339	339
Count of Participants [Participants]	44 11.3%	24 6.1%

13. Secondary Outcome

Title	Incidence of Hospital Admissions in Infants
Description	Admission to the pediatric ward for any cause
Time Frame	Birth up to 12 months of age or early termination

Outcome Measure Data

Analysis Population Description

339 live births included in the analyses for both groups.

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	339	339
Count of Participants [Participants]	19 4.9%	8 2%

14. Secondary Outcome

Title	Infant Mortality Rate
Description	Any deaths occurring after birth
Time Frame	Birth up to 12 months of age

Outcome Measure Data

Analysis Population Description

339 live births included in the analyses for both groups.

Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy	Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Measure Participants	339	339
Count of Participants [Participants]	9 2.3%	7 1.8%

Adverse Events

Time Frame	Adverse event data were collected following the initiation of study drugs through to 6 weeks postpartum.
Adverse Event Reporting Description	Adverse events were assessed and graded according to standardized criteria (National Institutes of Health, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0) at every visit to the study clinic. The number of participants at risk are all women that were enrolled, randomized, AND received at least 1 dose of study drugs.
Arm/Group Title	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy		Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
Arm/Group Description	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. Monthly Sulfadoxine-Pyrimethamine (SP) 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. Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
All Cause Mortality
	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy		Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/375 (0.3%)		3/373 (0.8%)
Serious Adverse Events
	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy		Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/375 (2.9%)		19/373 (5.1%)
Blood and lymphatic system disorders
Anemia	4/375 (1.1%)	4	2/373 (0.5%)	2
Thrombocytopenia	5/375 (1.3%)	5	2/373 (0.5%)	2
Elevated Alanine Aminotransferase	0/375 (0%)	0	1/373 (0.3%)	1
Congenital, familial and genetic disorders
Congenital anomaly	2/375 (0.5%)	2	10/373 (2.7%)	10
Pregnancy, puerperium and perinatal conditions
Haemorrhage	0/375 (0%)	0	2/373 (0.5%)	2
Psychiatric disorders
Altered mental status	0/375 (0%)	0	1/373 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/375 (0.3%)	1	1/373 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy		Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	341/375 (90.9%)		341/373 (91.4%)
Gastrointestinal disorders
Diarrhea	50/375 (13.3%)	62	49/373 (13.1%)	66
Vomitting	34/375 (9.1%)	44	35/373 (9.4%)	45
General disorders
Abdominal pain	273/375 (72.8%)	822	282/373 (75.6%)	800
Cough	254/375 (67.7%)	603	268/373 (71.8%)	681
Headache	256/375 (68.3%)	586	237/373 (63.5%)	604
Malaise	48/375 (12.8%)	54	44/373 (11.8%)	52
Chills	26/375 (6.9%)	27	24/373 (6.4%)	26
Renal and urinary disorders
Pyuria	51/375 (13.6%)	63	59/373 (15.8%)	69

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.