Intermittent Preventive Treatment with DHA-piperaquine for malaria in pregnancy in areas with high sulphadoxine-pyrimethamine resistance in Africa

Context of the research
Each year over 30 million pregnancies occur in malaria endemic areas of sub-Saharan Africa. Malaria in pregnancy (MiP) has devastating consequences for the mother and unborn child. The control of malaria in pregnancy in parts of East and southern Africa is under threat. Pregnant women are often infected with malaria without showing any outward signs or symptoms which, if left undetected and untreated, can cause anaemia and interfere with the development of the foetus leading to loss of the pregnancy, or premature birth and low birth weight, which in turn increases the risk of early infant death. The World Health Organisation (WHO) therefore recommends a preventive strategy called 'intermittent preventive treatment in pregnancy' (IPTp) in which mothers receive a single dose of 3 tablets of medication called sulphadoxine-pyrimethamine (SP) at each scheduled antenatal visit starting in the 2nd and 3rd trimester. However, the effectiveness of this strategy is being compromised due to high levels of resistance to SP in the malaria parasite population.

The recent search for safe, effective and well-tolerated alternatives drugs has proven elusive because most of the new candidates tested were not tolerated well enough to be used for preventive purposes. Other trials evaluating test and treat strategies have also proven disappointing. All hopes are now pinned on an antimalarial called dihydroartemisinin-piperaquine (DP), which is known to be safe in the 2nd and 3rd trimester of pregnancy and highly effective for treatment of clinical malaria. The high profile journals Lancet and the New England Journal of Medicine recently published the results of two exploratory trials, completed in 2015 (including one by this research team in Kenya). These showed that DP, when taken as IPT by pregnant women, was well tolerated and much more effective than SP in preventing malaria. However these two trials were not big enough to be able to evaluate the impact on the pregnancy outcome and the health of the newborn. WHO reviewed the evidence in July 2015 and concluded that DP is indeed a promising alternative to SP and recommended that a larger, confirmatory, trial is needed, before it can consider whether to recommend this drug as an alternative to SP in areas of high resistance.

Study aims and objectives
This multi-centre trial will enrol about 3,000 pregnant women in six hospitals in Kenya and Malawi and compare the safety, tolerance and beneficial effects of IPTp with DP to the current strategy with sulphadoxine-pyrimethamine in reducing pregnancy loss, low birthweight, preterm birth and small-for-gestational-age babies, and early infant deaths. The trial will include sub-studies on health economics to determine the cost of the strategy in relation to its benefits, the acceptability of the intervention among pregnant women and health providers, paying particular attention to adherence to the 3-day regimen, and the operational feasibility of implementing the intervention in the routine health system.

Potential applications and benefits
After a decade of intensive multi-centre trials to find new prevention strategies for malaria in pregnancy, DP has been shortlisted as the only potential alternative to SP for IPTp, but evidence of its benefits on infant outcomes is needed. As an experienced network, specialised in malaria prevention trials in pregnancy, we are in a unique position to address these gaps in an expedited manner. The findings of this new trial will provide the definitive evidence for whether or not this drug should be recommended to replace SP in areas with high levels of resistance by the parasite to SP. A positive result may lead to a direct policy change by the WHO in countries experiencing these levels of parasite resistance, including most countries in East and southern Africa, benefiting women at risk of malaria in these regions resulting in healthier pregnancies and healthier newborns.

Malaria in pregnancy (MiP) has devastating consequences for the mother and unborn child. The intermittent preventive therapy with sulphadoxine-pyrimethamine (IPTp-SP) strategy recommended by WHO is threatened by high levels of parasite resistance. The search for safe, effective and well-tolerated alternatives drugs or strategies for IPTp-SP has proven elusive. However, two recent exploratory trials showed IPTp with dihydroartemisinin-piperaquine (DP) to be well tolerated and associated with marked reductions in malaria infection, but they were not powered to evaluate the impact on adverse pregnancy outcome. WHO reviewed the evidence in July 2015 and concluded that DP is a promising alternative to SP but that a larger confirmatory trial is needed before implementation of IPTp-DP could be recommended. We will determine the efficacy, safety and cost-effectiveness of IPTp-DP in a definitive trial to inform WHO policy decision makers whether or not this is a suitable alternative strategy in endemic areas with high SP resistance.

We will conduct a 24-month, multi-centre, 2-arm, double blind, placebo-controlled, individually randomised trial involving 2,942 women in 6 sites to determine if IPTp-DP (Eurartesim) is superior to the existing IPTp-SP strategy in areas in western Kenya (KEMRI) and Malawi (College of Medicine) with high SP resistance. The study has 80% power to detect a 20% reduction (RR=0.8) from 23% to 18.4% (a=0.05) in the primary outcome: 'adverse pregnancy outcome', a composite of foetal loss, live births born either small-for-gestational age, with low birthweight, or preterm, or neonatal death. It also provides 85% power to a prospective meta-analysis combining the evidence from this and previous trials to detect a 17% reduction in this outcome (a=0.05).

It also includes sub-studies on the antimicrobial activity of SP, including on the gut and vaginal microbiota, cardiac safety studies of monthly DP, and an operational feasibility component.

Community: The ultimate beneficiaries will be mothers and their infants, especially those in east and southern Africa experiencing high levels of SP resistance. Malaria in pregnancy (MiP) has devastating consequences for the mother and unborn child. Without pregnancy-specific protection, it is estimated 12.4 million pregnant women (44.9% of all livebirths) would have been exposed to malaria infection each year in Africa, responsible for an estimated 900,000 low birthweight deliveries, and a quarter of these pregnancies occur in high SP resistant areas.

WHO and RBM: WHO, with its mandate to set global health policy, is a primary beneficiary of this research. Because the results of several recent trials with other antimalarials (mefloquine, amodiaquine and chloroquine-azithromycin) other strategies (intermittent screening and treatment) were disappointing, IPTp-DP now appears the only viable alternative that is being considered by WHO to replace SP in the near future. The results of this trial are therefore eagerly anticipated. All the senior investigators provide regular support to WHO's Evidence Review Group (ERG) for MIP (see 'Pathways to Impact'). Without guidance from WHO, national malaria control programs are hesitant to make changes to drug based policies in pregnancy because of concerns of the unknown safety profiles of new drugs. Thus, the role of WHO Geneva is critical to ensure germane research finding are translated into national policies, especially for malaria in pregnancy.

We are also active members of the Roll Back Malaria (RBM) MiP Working Group, responsible for generating consensus among RBM Partners on key strategic issues and best practices for ensuring effective delivery and scaling-up of interventions for the prevention and control of MiP.

National policy makers and stakeholders: MOH in Kenya and Malawi are key collaborators and have been involved in our previous trials in both countries. Both countries experience high levels of SP resistance and the MOH is under pressure to provide guidance on alternative preventive strategies for malaria in pregnancy. This trial will therefore provide essential evidence for the most promising alternative to the current strategy. The results will be disseminated at a stakeholders' meeting held at 36 months with key national policy makers and policy implementers in Kenya and Malawi, and representatives of local Health Offices and local communities. It is anticipated that policy impact occurs within 12 months of study completion, following recommendations by WHO.

Regional Level: WHO AFRO: The regional office of WHO is regularly called upon by African member states to provide guidance on malaria control in an ever changing context of drug resistance and transmission reduction. WHO-AFRO will be responsible for rolling out any policy formulated by WHO-HQ to other countries in the Africa region.

UK government: The UK Government has made tackling malaria a major priority, as described in the Malaria Framework for Results, which outlines DFID's strategic plans for malaria control until 2015. This research will contribute directly to UK policy and the UK's achievements will contribute directly to reaching international targets set out in the Global Malaria Action Plan 2016-2030 and the Sustainable Development Goals.

Impact on researcher and health worker capacity: Research capacity and leadership in the partner institutes in Kenya and Malawi will be enhanced by providing short- and long-term training and mentorship for research staff and students. Health worker capacity will also be strengthened through training on the administration of IPTp with DP, improving skills in drug administration, focused antenatal care, and routine recording and reporting.

Commercial private sector: Sigma Tau, Italy, and other manufacturers of DP, will also benefit from the results of the trial in terms of increased evidence for its safety, efficacy and application in pregnancy.