3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and metronidazole placebo administered as directly observed therapy.

3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and 4 tablets each containing 500mg metronidazole administered as directly observed therapy .

3 tablets of 40mg of dihydroartemisinin and 320mg of piperaquine, first dose and will be administered as directly observed therapy with the remaining two doses on the next two consecutive days at home. 4 tablets each containing 500mg metronidazole administered as directly observed therapy.

Pregnancy Malaria

Bacterial Vaginoses

Trichomonas Vaginitis

Metronidazole (MTZ) is indicated for the treatment of BV and TV and is also safe to administer in the second and third trimesters of pregnancy, and its use with SP or DP may result in better birth outcomes than SP alone. Malaria parasites have developed resistance against SP and the treatment is sub-optimal at clearing malaria infection compared to dihydroartemisinin-piperaquine (DP), therapy that has a suitable profile for use in IPTp. This intervention arm can be compared to the intervention arm IPTp-DP plus MTZ to assess whether DP is superior to SP in preventing adverse birth outcomes. This intervention arm will also be compared to the IPTp-SP plus MTZ placebo arm to assess whether the combination of MTZ with IPTp-SP is superior to IPTp-SP alone in reducing adverse pregnancy outcomes.

IPTp-sulphadoxine-pyrimethamine plus metronidazole

Metronidazole (MTZ) is indicated for the treatment of BV and TV and is also safe to administer in the second and third trimesters of pregnancy, and its use with SP or DP may result in better birth outcomes than SP alone. Malaria parasites have developed resistance against SP and the treatment is sub-optimal at clearing malaria infection compared to dihydroartemisinin-piperaquine (DP), therapy that has a suitable profile for use in IPTp. This intervention arm can be compared to the intervention arm IPTp-SP plus MTZ to assess whether DP is superior to SP in in reducing adverse pregnancy outcomes.

IPTp-dihydroartemisinin-piperaquine plus metronidazole

The World Health Organization (WHO) recommends providing intermittent preventive treatment (IPTp) using sulphadoxine-pyrimethamine (SP) to pregnant women during the second and third trimesters of pregnancy to clear placental infection.

IPTp-sulphadoxine-pyrimethamine

Nchelenge District Health Facilites

The ASPIRE Trial - Aiming for Safe Pregnancies by Reducing Malaria and Infections of the Reproductive Tract

Effects of Metronidazole Plus Intermittent Preventive Treatment of Malaria in Pregnancy on Birth Outcomes: a Randomised Controlled Trial in Zambia

Composite endpoint of foetal morbidity, defined as any of the following: foetal loss (spontaneous abortion or stillbirth), singleton live births born small-for-gestational age (SGA), or with low birthweight (LBW), preterm (PT) (SGA-LBW-PT), subsequent neonatal death by day 28. Small for gestational age will be defined using the new INTERGROWTH population reference's 10th percentile.

Prevalence of individual components of primary outcome

Neonatal length and stunting (height-for-age Z-score<-2)

Incidence of clinical malaria during pregnancy

Prevalence and incidence of peripheral maternal (blood) malaria infection during pregnancy by microscopy

Prevalence of placental malaria by microscopy, PCR and placental histology

Prevalence and incidence of maternal anaemia (Hb < 11g/dl) at enrolment, last antenatal visit and delivery

Maternal haemoglobin concentration (g/dL) during pregnancy and delivery

Prevalence of anaemia (Hb < 13g/dL) from newborn cord blood

Prevalence of malaria infection by microscopy or PCR from newborn cord blood

TV clearance from visit 1 to visit 2 among women found retrospectively to have had TV

BV clearance from visit 1 to visit 2 among women found retrospectively to have had BV

Prevalence and incidence of vomiting investigational product (IP) twice at the same IP administration visit

Prevalence of dizziness after a course of IP

Prevalence of gastrointestinal complaints after a course of IP

Prevalence of STIs/RTIs prior to delivery (syphilis, gonorrhoea, chlamydia trichomoniasis, and bacterial vaginosis)

Changes in maternal reproductive tract and gut microbiota from randomisation to last antenatal visit prior to delivery, and neonatal gut microbiota

Changes in intestinal microbiota of mothers will be characterised across treatment groups via analysis of vaginal swabs and stool samples.

Changes in intestinal bacterial loads of mothers will be characterised across treatment groups via analysis of vaginal swabs and stool samples.

Prevalence of markers of inflammation across treatment groups as assessed via analysis of vaginal swabs.

Sensitivity of pathogens to sulphadoxine and other antimicrobial agents will be assessed across treatment groups by sensitivity testing of cultured bacterial isolates from vaginal swabs.

A full economic evaluation of the cost of providing trials interventions and alternatives, and economic outcomes related to the primary endpoint

Qualitative metrics of mothers' and health care providers' preferences for treatment-arm attributes and masking flavours at dosing to increase acceptability, assessed by a piloted questionnaire.

Data will be shared upon receiving formal request and subject to sharing agreement.

London School of Hygiene and Tropical Medicine

In this group in the PROMOTE-II study, mothers receive 3 doses of sulfadoxine-pyrimethamine (SP), and children receive every 3 month dihydroartemisinin-piperaquine (DP). No intervention is given in the observational PROTECT study.

In this group in the PROMOTE-II study, mothers receive 3 doses of DP, and children receive every 3 month DP.No intervention is given in the observational PROTECT study.

In this group in the PROMOTE-II study, mothers receive 3 doses of DP, and children receive monthly DP. No intervention is given in the observational PROTECT study.

In this group in the PROMOTE-II study, mothers receive monthly DP, and children receive every 3 month DP. No intervention is given in the observational PROTECT study.

In this group in the PROMOTE-II study, mothers receive monthly DP, and children receive every monthly DP. No intervention is given in the observational PROTECT study.

Neurobehavioral Manifestations

No intervention in PROTECT

Tororo District Hospital

Prophylaxis Against Malaria to Enhance Child Development (PROTECT Study)

Prophylaxis Against Malaria to Enhance Child Development

Chandy John

Professor of Pediatrics

Indiana University

Makerere University

Daily point-of-care fortification of (complementary) foods with 3 mg iron as NaFeEDTA.

Daily point-of-care fortification of (complementary) foods with 12.5 mg iron as encapsulated ferrous fumarate.

Daily point-of-care fortification of (complementary) foods with placebo.

Anaemia

Daily home fortification for 30 days with 3 mg iron as NaFeEDTA, vitamin A (300 RE μg as retinyl palmitate) and 5 mg zinc (as gluconate)

Low-dose iron as NaFeEDTA

Daily home fortification for 30 days with 12.5 mg iron as encapsulated ferrous fumarate, vitamin A (300 RE μg as retinyl palmitate) and 5 mg zinc (as gluconate)

Conventional dose iron as ferrous salt

Daily home fortification for 30 days with vitamin A (300 RE μg as retinyl palmitate) and 5 mg zinc (as gluconate)

Placebo

Maseno University

Safe and Efficacious Iron for Children in Kenya

Comparison of Home Fortification With Two Iron Formulations in Kenyan Children Protected Against Malaria by Artemisinin-based Combination Therapy: a Placebo-controlled Non-inferiority Trial

Iron status will be assessed by plasma concentrations of ferritin and soluble transferrin receptor

Faecal calprotectin concentration is used as an indicator of intestinal inflammation

P. falciparum infection will be defined as the presence of either asexual parasites in blood smears or parasite antigens (either histidine-rich protein-2, or Plasmodium lactate dehydrogenase) in whole blood

Adherence will be defined for each individual as the number of days that the dispensing bottle has been opened during the 30-day intervention period

At various time points in the post-intervention period, we will sample children without replacement to measure their haemoglobin concentration. Taking into account our wish to restrict phlebotomies during the post-intervention period to a single occasion per child, we will withdraw the child from further study. These measurements should allow us to estimate the time point when ≥10% of children has developed severe anaemia (haemoglobin concentration <70 g/L).

Maseno University, Maseno, Kenya

Malaria

Rapid non-invasive malaria diagnostic test

Urine Malaria Test

College of Medicine of the University of Lagos

Clinical Performance Evaluation of Fyodor Urine Malaria Test (UMT)

Clinical Validation of Fyodor Urine Malaria Test (UMT)

• Establish sensitivity and specificity of the UMT for malaria diagnosis in febrile patients.

Determine how quickly the cognate malaria antigens are cleared from patient urine after the prescribed three-day course of artemisinin-combination therapy (ACT);
Negative UMT results (as confirmed by microscopy during the study) will establish the effectiveness of malaria treatment and provide a means to rapidly monitor effective treatment;
Establish broader UMT utility for epidemiological monitoring in asymptomatic (afebrile) individuals.

dihydroartemisinin/inflamación

The ASPIRE Trial - Aiming for Safe Pregnancies by Reducing Malaria and Infections of the Reproductive Tract

Prophylaxis Against Malaria to Enhance Child Development (PROTECT Study)

Safe and Efficacious Iron for Children in Kenya

Clinical Performance Evaluation of Fyodor Urine Malaria Test (UMT)

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