Clinical trial NCT05426434: Sulfadoxine-pyrimethamine Plus Dihydroartemisinin-piperaquine for Intermittent Preventive Treatment in Pregnancy
Official title: Intermittent Preventive Treatment in Pregnancy With Sulfadoxine-pyrimethamine Plus Dihydroartemisinin-piperaquine to Prevent Malaria Infection and Reduce Adverse Pregnancy Outcomes in Papua New Guinea - a Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Malaria
Malaria in Pregnancy
Pregnancy Related
Lead sponsor: Menzies School of Health Research
Sponsor class: OTHER
Collaborators: name: Papua New Guinea Institute of Medical Research
name: University of Melbourne
name: Curtin University
name: Liverpool School of Tropical Medicine
First posted: 2022-06-22
Enrollment: 1172
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double blinded randomized controlled trial
Primary purpose: PREVENTION

Brief summary: This trial tests the hypothesis that intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) plus dihydroartemisinin-piperaquine (DP) significantly reduces the risk of malaria infection (primary outcome) and adverse birth outcomes (key secondary outcome) in an endemic area of Papua New Guinea (PNG), compared to IPTp with SP alone (the current standard of care).

To test this hypothesis a double-blinded, placebo-controlled, phase-III, superiority trial will individually randomize 1,172 HIV-uninfected pregnant women enrolled from 12-26 gestational weeks in equal proportions to one of two IPTp arms: 1) SP given every for weeks, or 2) SP+DP given every 4 weeks. DP placebos will be used to ensure adequate blinding is achieved in the study and follow-up will end 28 days after giving birth.

Detailed description: Plasmodium falciparum and P. vivax infections cause malaria, maternal anemia and interfere with the development of the fetus, thereby increasing the risks of adverse pregnancy outcomes such as miscarriage, stillbirth, premature birth, fetal growth restriction, low birth weight, and infant death. Infected pregnant women are frequently asymptomatic, and current point-of-care tests miss placental and low-density infections. Monthly intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is designed to clear asymptomatic infections and provide post-treatment prophylaxis. The World Health Organization recommends IPTp with SP and long-lasting insecticidal bed nets for the prevention of malaria in pregnancy in endemic areas of sub-Saharan Africa. However, the emergence and spread of high-grade parasite resistance to SP threatens to compromise this strategy. Dihydroartemisinin-piperaquine (DP) is a safe fixed-dose artemisinin-based combination therapy used for the management of uncomplicated P. falciparum and P. vivax malaria in pregnancy and has emerged as a potential candidate to replace SP for IPTp. In comparative trials conducted in high-transmission settings in sub-Saharan Africa IPTp with DP was safe and significantly reduced the risk of P. falciparum infection compared to IPTp with SP. IPTp with DP also reduced the risk of P. vivax parasitemia in Papua Indonesia when compared to a single screen and treat approach. However, DP's superior antimalarial efficacy in African studies did not translate to large reductions in adverse pregnancy outcomes in these trials. This suggests that SP, whilst failing as an antimalarial, may prevent adverse pregnancy events via potent non-malarial effects that are not inherent to DP. For example, SP may provide protection from pathogens other than malaria parasites that are directly or indirectly involved in the causation of adverse pregnancy outcomes.

Papua New Guinea (PNG) is characterized by moderate intensity co-transmission of P. falciparum and P. vivax and a high burden of adverse pregnancy outcomes. PNG is the only country outside of Africa that has a policy of IPTp with SP. However, P. vivax resistance to SP is now common, high-grade P. falciparum resistance to SP may be emerging, and DP could provide enhanced antimalarial protection. However, given the high burden of adverse pregnancy outcomes from malaria- and non-malaria related causes, simply replacing SP with DP for IPTp in PNG may not lead to a reduction in adverse birth outcomes. Instead, combining DP with SP for IPTp has the potential to substantially improve health outcomes by reducing the risk of malaria infection whilst harnessing the non-malaria-related benefits of SP.

A double-blinded randomized controlled clinical trial will (1) compare the risk of malaria infection among pregnant women randomized to receive monthly IPTp with SP vs. SP+DP; (2) compare the risk of adverse pregnancy outcomes among pregnant women randomized to receive monthly IPTp with SP vs. SP+DP; and (3) compare safety and tolerability of monthly IPTp with SP vs SP+DP. The findings of this trial may have important policy implications, and the evidence generated will inform practice for PNG and sub-Saharan Africa.

Eligibility criteria: Inclusion Criteria:

* Pregnant women between 12-26 weeks' gestation
* 16 years of age or older
* Viable singleton intrauterine pregnancy
* Permanent resident of the study area
* Willing to adhere to scheduled and unscheduled study visit procedures
* Willing to birth in a study clinic or hospital
* Able to provide written informed consent

Exclusion Criteria:

* Multiple pregnancy (i.e. twins/triplets)
* Known heart ailment or other chronic medical condition requiring frequent hospital care
* Active medical problem requiring inpatient evaluation at the time of screening
* Severe malformations or non-viable pregnancy if observed by ultrasound
* Antimalarial therapy in the prior two weeks
* Unable to provide written informed consent
* Known allergy or contraindication to any of the study drugs
* Early or active labour
* Known HIV-positive status

Primary outcomes:
measure: Malaria infection in pregnancy
timeFrame: Starting two weeks after initial dose until and including delivery
Secondary outcomes:
measure: Adverse pregnancy outcome
timeFrame: Time of delivery up to 28 days postpartum
measure: Clinical malaria during pregnancy
timeFrame: Starting two weeks after initial dose until and including delivery
measure: Parasitemia during pregnancy
timeFrame: Starting two weeks after initial dose until and including delivery
measure: Composite placental malaria detected by microscopy, qPCR or by histology
timeFrame: At time of delivery
measure: Placental malaria detected by microscopy
timeFrame: At time of delivery
measure: Placental malaria detected by qPCR
timeFrame: At time of delivery
measure: Active placental malaria detected by histology
timeFrame: At time of delivery
measure: Past placental malaria detected by histology
timeFrame: At time of delivery
measure: Placental malaria detected by histology
timeFrame: At time of delivery
measure: Composite fetal loss and neonatal death
timeFrame: Time of delivery up to 28 days postpartum
measure: Composite of SGA-LBW-PTB
timeFrame: At time of delivery
measure: SGA
timeFrame: At time of delivery
measure: LBW
timeFrame: At time of delivery
measure: PTB
timeFrame: At time of delivery
measure: Birth weight
timeFrame: At time of delivery
measure: Neonatal length
timeFrame: At time of delivery
measure: Maternal nutritional status
timeFrame: 8 months from randomisation
measure: Maternal nutritional status
timeFrame: 6 months from randomisation
measure: Maternal anemia during pregnancy and at delivery
timeFrame: 6 months from randomisation
measure: Maternal hemoglobin levels during pregnancy and at delivery
timeFrame: 6 months from randomisation
measure: Congenital anemia
timeFrame: At delivery
measure: Maternal gametocyte carriage during pregnancy and at delivery
timeFrame: 6 months from randomisation
measure: Molecular markers of DP resistance
timeFrame: 6 months from randomisation
measure: Molecular markers of SP drug resistance
timeFrame: 6 months from randomisation
measure: Maternal mortality
timeFrame: 8 months from randomisation
measure: Congenital malformations
timeFrame: 8 months from randomisation
measure: Other SAEs and AEs
timeFrame: 8 months from randomisation
measure: (History) of vomiting study drug
timeFrame: 6 months from randomisation
measure: Dizziness
timeFrame: 6 months from randomisation
measure: Gastrointestinal complaints
timeFrame: 6 months from randomisation
Other outcomes:
Locations:
city: Madang
country: Papua New Guinea
facility: Papua New Guinea Institute of Medical Research
state: Madang Province
Study officials:
affiliation: Menzies School of Health Research, Darwin, Australia
name: Holger Unger, PhD MBChB
role: PRINCIPAL_INVESTIGATOR
References: