Aim:

To provide the Papua New Guinea National Malaria Control Program (NMCP) and WHO with evidence to determine whether monthly intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) plus dihydroartemsinin-piperaquine (DP) is a safe and efficacious alternative to the current strategy of IPTp with SP to control malaria infection in pregnant women and improve birth outcomes.

Key objectives:

A double-blinded randomised controlled clinical trial will a) compare the risk of malaria infection among pregnant women randomized to receive monthly IPTp with SP vs. SP plus DP; b) compare the risk of adverse pregnancy outcomes among pregnant women randomized to receive monthly IPTp with SP vs. SP plus DP; and c) compare safety and tolerability of monthly IPTp with SP vs SP plus DP. 

Rationale:

Plasmodium falciparum and P. vivax infections cause malaria, maternal anaemia 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 [1]. 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 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 [2]. However, the emergence and spread of high-grade parasite resistance to SP threatens to compromise this strategy [3, 4]. 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[5]. 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[5-7]. IPTp with DP also reduced the risk of P. vivax parasitaemia in Papua Indonesia when compared to a single screen and treat approach[8]. 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[9]. 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[10].

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 is likely to 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 or similar settings 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.

Implications for policy and practice:

Novel strategies to adequately protect pregnant women from the deleterious impacts of malaria and reduce adverse pregnancy outcomes are required. 

Results from the trial will inform national and WHO recommendations for malaria-endemic countries experiencing increasing levels of drug resistance, and high burdens of malaria and non-malaria related adverse pregnancy outcomes. 

Enhanced antimalarial protection not only benefit women at risk but may also assist wider elimination efforts by reducing transmission of infection from pregnant women.

The findings of this trial may have important policy implications, and the evidence generated will inform practice for PNG and sub-Saharan Africa.

The research is designed and steered in partnership with key stakeholders and the PNG National Malaria Control Program, paving the way for translation and implementation. Findings of the SAPOT trial have great potential to contribute significantly to achieving the targets of eliminating malaria and markedly reducing adverse maternal and infant health outcomes by 2030. 

For more information about this trial, please visit the SAPOT Clinical Trial page. 

Enrolments for the trial start 1 August 2022.

Chief Investigator:
Project Manager:
  • Catherine Martel
Contact information:
Project dates:
  • 2022-2025 (4 years)
  • Participant enrolment starting 1 August 2022.

Image caption: The 2022 SAPOT Team, photo taken by Barry Peter. 

Funders:
  • NHMRC 
Collaborators:

PNGIMR (Papua New Guinea Institute for Medical Research)

  • Dr Moses Laman 
  • Dr John Bolnga

Menzies School of Health Research

  • Prof Ric Price 
  • Assoc Prof Kamala Thriemer 

University of Melbourne

  • Prof Stephen Rogerson  

Liverpool School of Tropical Medicine:

  • Prof Feiko ter Kuile 

Curtin University:

  • Dr Brioni Moore 

Photo credits:

  • Pearl Gan in association with OUCRU, Vietnam and EOCRU, Indonesia.

The following references support the rationale for this clinical trial:

1.    Rogerson SJ, Desai M, Mayor A, Sicuri E, Taylor SM, van Eijk AM: Burden, pathology, and costs of malaria in pregnancy: new developments for an old problem. Lancet Infect Dis 2018, 18(4):e107-e118.
2.    WHO: WHO Guidelines for malaria, 3 June 2022. In. Geneva: World Health Organization (WHO); 2022.
3.    Desai M, Gutman J, Taylor SM, Wiegand RE, Khairallah C, Kayentao K, Ouma P, Coulibaly SO, Kalilani L, Mace KE et al: Impact of Sulfadoxine-Pyrimethamine Resistance on Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy at Clearing Infections and Preventing Low Birth Weight. Clin Infect Dis 2016, 62(3):323-333.
4.    Koleala T, Karl S, Laman M, Moore BR, Benjamin J, Barnadas C, Robinson LJ, Kattenberg JH, Javati S, Wong RP et al: Temporal changes in Plasmodium falciparum anti-malarial drug sensitivity in vitro and resistance-associated genetic mutations in isolates from Papua New Guinea. Malar J 2015, 14:37.
5.    Kajubi R, Ochieng T, Kakuru A, Jagannathan P, Nakalembe M, Ruel T, Opira B, Ochokoru H, Ategeka J, Nayebare P et al: Monthly sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnancy: a double-blind, randomised, controlled, superiority trial. Lancet 2019, 393(10179):1428-1439.
6.    Desai M, Gutman J, L'Lanziva A, Otieno K, Juma E, Kariuki S, Ouma P, Were V, Laserson K, Katana A et al: Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin-piperaquine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial. Lancet 2015, 386(10012):2507-2519.
7.    Kakuru A, Jagannathan P, Muhindo MK, Natureeba P, Awori P, Nakalembe M, Opira B, Olwoch P, Ategeka J, Nayebare P et al: Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. N Engl J Med 2016, 374(10):928-939.
8.    Ahmed R, Poespoprodjo JR, Syafruddin D, Khairallah C, Pace C, Lukito T, Maratina SS, Asih PBS, Santana-Morales MA, Adams ER et al: Efficacy and safety of intermittent preventive treatment and intermittent screening and treatment versus single screening and treatment with dihydroartemisinin-piperaquine for the control of malaria in pregnancy in Indonesia: a cluster-randomised, open-label, superiority trial. Lancet Infect Dis 2019, 19(9):973-987.
9.    Roh ME, Kuile FOT, Rerolle F, Glymour MM, Shiboski S, Gosling R, Gutman J, Kakuru A, Desai M, Kajubi R et al: Overall, anti-malarial, and non-malarial effect of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine on birthweight: a mediation analysis. The Lancet Global health 2020, 8(7):e942-e953.
10.    Waltmann A, McQuade ETR, Chinkhumba J, Operario DJ, Mzembe E, Itoh M, Kayange M, Puerto-Meredith SM, Mathanga DP, Juliano JJ et al: The positive effect of malaria IPTp-SP on birthweight is mediated by gestational weight gain but modifiable by maternal carriage of enteric pathogens. EBioMedicine 2022, 77:103871.

None from this trial yet.