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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Malaria, Malaria in Pregnancy, Pregnancy Related

Intervention / Treatment
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* Drug: Dihydroartemisinin-Piperaquine (DP)
* Drug: Sulfadoxine pyrimethamine (SP)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double blinded randomized controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SP + DP placebo every 4 weeks<br>Control arm | Drug: Sulfadoxine pyrimethamine (SP)<br>* SP (G-COSPE) will be supplied by Fosun Pharma, China. SP will be given as a single dose consisting of three 500mg/25mg tablets.<br>* Other names: G-COSPE;|
| Experimental: SP + DP given every 4 weeks<br>Intervention arm | Drug: Dihydroartemisinin-Piperaquine (DP)<br>* 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<br>* Other names: D-Artepp;Drug: Sulfadoxine pyrimethamine (SP)<br>* SP (G-COSPE) will be supplied by Fosun Pharma, China. SP will be given as a single dose consisting of three 500mg/25mg tablets.<br>* Other names: G-COSPE;|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| Other SAEs and AEs | Incidence of AEs and SAEs | 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 | 
| 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 |