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

NCT ID: NCT05426434

Last Updated: 2025-06-06

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 1172 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-08-31
• Study Completion Date: 2025-12-31

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.

Conditions

Malaria; Malaria in Pregnancy; Pregnancy Related

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

SP + DP placebo every 4 weeks

Control arm

Group Type: ACTIVE_COMPARATOR

Sulfadoxine pyrimethamine (SP)

Intervention Type: DRUG

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

SP + DP given every 4 weeks

Intervention arm

Group Type: EXPERIMENTAL

Dihydroartemisinin-Piperaquine (DP)

Intervention Type: DRUG

DP (D-Artepp) will be supplied by Fosun Pharma, China. DP will consist of three 40mg/320mg) tablets given once a day for three consecutive days

Sulfadoxine pyrimethamine (SP)

Intervention Type: DRUG

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

Interventions

Dihydroartemisinin-Piperaquine (DP)

DP (D-Artepp) will be supplied by Fosun Pharma, China. DP will consist of three 40mg/320mg) tablets given once a day for three consecutive days

Intervention Type: DRUG

Sulfadoxine pyrimethamine (SP)

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

Intervention Type: DRUG

Other Intervention Names

D-Artepp; 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

• Minimum Eligible Age: 16 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Papua New Guinea Institute of Medical Research

OTHER_GOV

Sponsor Role: collaborator

University of Melbourne

OTHER

Sponsor Role: collaborator

Curtin University

OTHER

Sponsor Role: collaborator

Liverpool School of Tropical Medicine

OTHER

Sponsor Role: collaborator

Menzies School of Health Research

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Holger Unger, PhD MBChB

Role: PRINCIPAL_INVESTIGATOR

Menzies School of Health Research, Darwin, Australia

Locations

Papua New Guinea Institute of Medical Research

Madang, Madang Province, Papua New Guinea

Countries

Papua New Guinea

Other Identifiers

2021-4107

Identifier Type: -

Identifier Source: org_study_id