Sulfadoxine-pyrimethamine Plus Dihydroartemisinin-piperaquine for Intermittent Preventive Treatment in Pregnancy

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

Sponsors

Lead Sponsor: Menzies School of Health Research

Collaborator: Papua New Guinea Institute of Medical Research
University of Melbourne
Curtin University
Liverpool School of Tropical Medicine

Source Menzies School of Health Research
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.

Overall Status Not yet recruiting
Start Date 2022-08-01
Completion Date 2025-12-01
Primary Completion Date 2025-02-01
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Malaria infection in pregnancy Starting two weeks after initial dose until and including delivery
Secondary Outcome
Measure Time Frame
Adverse pregnancy outcome Time of delivery up to 28 days postpartum
Clinical malaria during pregnancy Starting two weeks after initial dose until and including delivery
Parasitemia during pregnancy Starting two weeks after initial dose until and including delivery
Composite placental malaria detected by microscopy, qPCR or by histology At time of delivery
Placental malaria detected by microscopy At time of delivery
Placental malaria detected by qPCR At time of delivery
Active placental malaria detected by histology At time of delivery
Past placental malaria detected by histology At time of delivery
Placental malaria detected by histology At time of delivery
Composite fetal loss and neonatal death Time of delivery up to 28 days postpartum
Composite of SGA-LBW-PTB At time of delivery
SGA At time of delivery
LBW At time of delivery
PTB At time of delivery
Birth weight At time of delivery
Neonatal length At time of delivery
Maternal nutritional status 8 months from randomisation
Maternal nutritional status 6 months from randomisation
Maternal anemia during pregnancy and at delivery 6 months from randomisation
Maternal hemoglobin levels during pregnancy and at delivery 6 months from randomisation
Congenital anemia At delivery
Maternal gametocyte carriage during pregnancy and at delivery 6 months from randomisation
Molecular markers of DP resistance 6 months from randomisation
Molecular markers of SP drug resistance 6 months from randomisation
Maternal mortality 8 months from randomisation
Congenital malformations 8 months from randomisation
Other SAEs and AEs 8 months from randomisation
(History) of vomiting study drug 6 months from randomisation
Dizziness 6 months from randomisation
Gastrointestinal complaints 6 months from randomisation
Enrollment 1172
Condition
Intervention

Intervention Type: Drug

Intervention Name: Dihydroartemisinin-Piperaquine (DP)

Description: DP (D-Artepp) will be supplied by Fosun Pharma, China. DP will consist of three 40mg/420mg) tablets given once a day for three consecutive days

Arm Group Label: SP + DP given every 4 weeks

Other Name: D-Artepp

Intervention Type: Drug

Intervention Name: Sulfadoxine pyrimethamine (SP)

Description: SP (G-COSPE) will be supplied by Fosun Pharma, China. SP will be given as a single dose consisting of three 500mg/25mg tablets.

Other Name: G-COSPE

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

Gender:

Female

Minimum Age:

16 Years

Maximum Age:

N/A

Healthy Volunteers:

Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
Holger Unger, PhD MBChB Principal Investigator Menzies School of Health Research, Darwin, Australia
Overall Contact Contact information is only displayed when the study is recruiting subjects.
Verification Date

2022-06-01

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: SP + DP placebo every 4 weeks

Type: Active Comparator

Description: Control arm

Label: SP + DP given every 4 weeks

Type: Experimental

Description: Intervention arm

Acronym SAPOT
Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Intervention Model Description: Double blinded randomized controlled trial

Primary Purpose: Prevention

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description: 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 SP and DP) followed by one drug on days 2 and 3 (placebo or DP). One placebo that mimics the appearance of DP will be used. A randomization list will be computer generated by a member of the project who will not be directly involved in the conduct of the study. The randomization list will include consecutive treatment numbers with corresponding random treatment assignments. Randomized codes will correspond to the 2 treatment arms using permuted variable sized blocks.

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