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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Pregnancy Related; Malaria; Malaria in Pregnancy
• Intervention / Treatment: Drug: Sulfadoxine pyrimethamine (SP); Drug: Dihydroartemisinin-Piperaquine (DP)

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.

• Study Type: Interventional
• Enrollment (Estimated): 1172
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Holger Unger, PhD MBChB; Phone Number: +61889468411; Email: holger.unger@menzies.edu.au
• Study Contact Backup: Name: Hellen Mnjala; Phone Number: +254722710920; Email: hellen.mnjala@menzies.edu.au

Study Locations

• Papua New Guinea
  • Madang Province
    • Madang, Madang Province, Papua New Guinea, 511
      • Recruiting
      • Papua New Guinea Institute of Medical Research
      • Contact: Moses Laman, MBBS; Email: drmlaman@yahoo.com
      • Contact: Alice Mengi, MBBS; Email: alicemengi9@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: SP + DP placebo every 4 weeks; Control arm	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.; Other Names: G-COSPE
Experimental: SP + DP given every 4 weeks; Intervention arm	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.; Other Names: G-COSPE; Drug: 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; Other Names: D-Artepp

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Malaria infection in pregnancy	'Malaria infection in pregnancy' is a composite outcome, defined as one or more episode of P. falciparum and/or P. vivax infection, detected by microscopy and/or qPCR in peripheral blood or placental blood, or P. falciparum and/or P. vivax infection, detected as active infection on placental histology. The surveillance period will run from two weeks after the first dose of the first monthly treatment up until and including delivery (numerator) in women who attend at least one scheduled or unscheduled visit during the surveillance period (denominator). Proportion of women with 'malaria infection in pregnancy'	Starting two weeks after initial dose until and including delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other SAEs and AEs	Incidence of AEs and SAEs	8 months from randomisation
Dizziness	Prevalence of dizziness after a course of IP	6 months from randomisation
Gastrointestinal complaints	Prevalence of gastrointestinal complaints after a course of IP	6 months from randomisation
Adverse pregnancy outcome	Composite adverse birth outcome is defined as the occurrence of any of the following: Spontaneous miscarriage: Fetal loss <28 weeks of gestational age; Stillbirth: Infant born deceased at ≥28 weeks of gestational age; Low birth weight (LBW): Live birth with birth weight <2,500 grams; Preterm birth (PTB): Live birth <37 weeks gestational age; Small-for-gestational age (SGA): Live birth with birth weight-for-gestational-age <10th percentile of the INTERGROWTH-21st reference; Neonatal death: Live birth with neonatal death within the first 28 days of life Prevalence of adverse pregnancy outcome	Time of delivery up to 28 days postpartum
Clinical malaria during pregnancy	Incidence of new episodes of fever or history of fever plus positive RDT confirmed by microscopy and/or qPCR during pregnancy	Starting two weeks after initial dose until and including delivery
Parasitemia during pregnancy	Proportion of samples with parasites detected in maternal peripheral blood samples by microscopy or qPCR	Starting two weeks after initial dose until and including delivery
Composite placental malaria detected by microscopy, qPCR or by histology	Prevalence of placental parasites by microscopy, qPCR, or placental histology	At time of delivery
Placental malaria detected by microscopy	Prevalence of parasites in placental blood by microscopy	At time of delivery
Placental malaria detected by qPCR	Prevalence of parasites in placental blood by qPCR	At time of delivery
Active placental malaria detected by histology	Prevalence of active infection (presence of parasites) on histology	At time of delivery
Past placental malaria detected by histology	Prevalence of past infection (pigment only) on histology	At time of delivery
Placental malaria detected by histology	Prevalence of placental infection (active or past) on histology	At time of delivery
Composite fetal loss and neonatal death	Prevalence of fetal loss (spontaneous miscarriage or stillbirth) and neonatal death	Time of delivery up to 28 days postpartum
Composite of SGA-LBW-PTB	Prevalence of small for gestational age, low birth weight, and preterm birth	At time of delivery
SGA	Prevalence of small for gestational age using the new Intergrowth-21st population reference's 10th centile	At time of delivery
LBW	Prevalence of low birth weight	At time of delivery
PTB	Prevalence of preterm birth	At time of delivery
Birth weight	Mean birthweight	At time of delivery
Neonatal length	Neonatal length	At time of delivery
Maternal nutritional status	Changes in maternal body mass index (BMI)	8 months from randomisation
Maternal nutritional status	Changes in maternal mid-upper arm circumference (MUAC)	6 months from randomisation
Maternal anemia during pregnancy and at delivery	Proportion of routine haemoglobin measurements <100 g/L	6 months from randomisation
Maternal hemoglobin levels during pregnancy and at delivery	Mean hemoglobin (g/L) at the third trimester antenatal visit and at delivery	6 months from randomisation
Congenital anemia	Prevalence of anaemia (Hb <130 g/L) from newborn cord blood	At delivery
Maternal gametocyte carriage during pregnancy and at delivery	Proportion of P. falciparum positive samples with gametocytes at the third trimester antenatal visit and at delivery, by light microscopy and RT-qPCR	6 months from randomisation
Molecular markers of DP resistance	Proportion of parasite positive samples with molecular markers of DP resistance	6 months from randomisation
Molecular markers of SP drug resistance	Proportion of parasite positive samples with molecular markers of SP resistance	6 months from randomisation
Maternal mortality	he death of a woman while pregnant or within 42 days of the end of pregnancy, irrespective of the duration and site of the pregnancy, but not from accidental or incidental causes	8 months from randomisation
Congenital malformations	Any visible external congenital abnormality on surface examination	8 months from randomisation
(History) of vomiting study drug	Prevalence of vomiting investigational product (IP) twice at the same IP administration visit	6 months from randomisation

Collaborators and Investigators

• Sponsor: Menzies School of Health Research
• Collaborators: Liverpool School of Tropical Medicine; University of Melbourne; Curtin University; Papua New Guinea Institute of Medical Research
• Investigators: Principal Investigator: Holger Unger, PhD MBChB, Menzies School of Health Research, Darwin, Australia

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2022
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: June 14, 2022
• First Submitted That Met QC Criteria: June 16, 2022
• First Posted (Actual): June 22, 2022

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 19, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Anti-Infective Agents, Urinary; Pyrimethamine; Piperaquine; Sulfadoxine; Fanasil, pyrimethamine drug combination; Artenimol
• Other Study ID Numbers: 2021-4107

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No