Safety of Antimalarials in the FIRst trimEster

Background: Malaria in pregnancy remains a substantial public health concern in endemic regions, with first-trimester infections being particularly harmful. The World Health Organization (WHO) now recommends artemether-lumefantrine (AL), an artemisinin-based combination therapy (ACT), as the first-line treatment for uncomplicated malaria in the first trimester of pregnancy, replacing quinine. This recommendation followed a comprehensive review of observational data on inadvertent first-trimester exposures from pregnancy exposure registries, which showed that initial concerns about the teratogenicity of artemisinin derivatives raised by preclinical studies and animal models did not apply to human pregnancies.

Several other highly effective ACTs are used in sub-Saharan Africa, a trend likely to increase rapidly as part of WHO's multiple first-line strategies. Moreover, novel treatments that show promise against resistant strains and may potentially impede their emergence or spread could become available. SAFIRE aims to efficiently generate evidence on the safety and efficacy of antimalarials for treating uncomplicated malaria in the first trimester. Each of the antimalarials to be evaluated in this SAFIRE trial should meet the following criteria:

• Registered antimalarial product for the treatment of uncomplicated malaria or at minimum, confirmation of a favourable benefit/risk ratio for the treatment of uncomplicated malaria in a confirmatory Phase III program in children or adults with P. falciparum infection
• No teratogenic concerns in preclinical studies

In the case of antimalarials with a teratogenic signal in preclinical studies:

• No significant safety concerns in women inadvertently treated with these drugs in the first trimester (from observational studies and/or pregnancy exposure registries),

Ideally, no significant safety, tolerability and efficacy concerns in clinical trials during the second and third trimesters of pregnancy would be preferred.

Justification: It took over two decades to accumulate sufficient evidence for WHO to recommend AL for use in the first trimester. There is an urgent need to expedite this process and provide informed guidance to health care providers and mothers on other potentially effective and safe antimalarials, especially in the context of the increased threat of resistance against AL. Furthermore, stringent regulatory authorities now encourage more research involving pregnant women.

Objectives: The primary efficacy objective in the initial phase of this adaptive platform trial is to confirm the efficacy of alternative antimalarials in pregnant women in the first trimester with uncomplicated malaria by demonstrating non-inferiority to the current standard of care with AL. The key safety objective is to assess their non-inferiority compared with AL in terms of safety regarding pregnancy outcomes.

Study design: SAFIRE is a multicentre, open-label, randomised, non-inferiority, adaptive platform trial (APT). The rationale for a non-inferiority approach is that if these newer drugs prove to be non-inferior to AL in terms of efficacy and safety, they offer secondary advantages such as longer post-treatment prophylaxis or simpler dosing regimens (once instead of twice daily for 3 days). These benefits could improve treatment adherence and effectiveness in real-world settings.

The study employs a Bayesian adaptive design, allowing for interim analyses and potential early stopping for safety. The rule for making decisions during interim analysis is to stop enrolment to a new intervention arm if there is more than an 85% chance that the hazard ratio for the safety endpoint exceeds 1.1 (the non-inferiority margin) relative to the standard of care. These frequent interim analyses for safety will allow for the early stopping of the trial arm if safety concerns arise and enable more efficient use of resources and timely decision-making based on accumulating evidence.

The adaptive platform trial design evaluates multiple interventions and uses a shared control group, reducing administrative burden and allowing efficient participant allocation. It provides a flexible framework for introducing new treatment arms, which is ideal for assessing multiple promising antimalarials for first-trimester use.

SAFIRE is an open-ended trial that continuously evaluates new antimalarials without a set end date, adapting to emerging treatments and research priorities in malaria during pregnancy.

The protocol uses a modular design with a master protocol outlining the overall framework and intervention-specific appendices (ISAs) for each antimalarial. This approach enables efficient addition or removal of treatment arms without full master protocol revision, enhancing flexibility and responsiveness.

Methods: Pregnant women in their first trimester (≤13 weeks' gestation) with confirmed uncomplicated Plasmodium falciparum malaria will be randomly assigned to receive either the standard of care with artemether-lumefantrine (AL) or a newer antimalarial. The details of the newer antimalarials, corresponding sample sizes, and allocation ratio are described in ISAs. The primary efficacy endpoint is PCR-adjusted adequate clinical and parasitological response (ACPR) by day 42. The key safety endpoint is a composite of fetal loss or major congenital anomalies. Secondary efficacy endpoints include PCR-unadjusted cure rates (i.e, the cumulative rate of women without recurrent malaria infection due to treatment failure or reinfection), serving as a proxy for the duration of post-treatment prophylaxis.

Collaboration and funding: The initial phase of the study is co-sponsored by the Liverpool School of Tropical Medicine (LSTM) and the Medicines for Malaria Venture (MMV) and is funded by Global Health EDCTP3, the EU, UKRI, and SERI of the Swiss Confederation. As this is an open-ended platform trial, additional sponsors and funders may be added in the future as new treatment arms are incorporated.

Ethical considerations and governance: The trial adheres to stringent ethical standards, including obtaining informed consent from all participants and providing close monitoring for adverse events. An independent Data Safety Monitoring Board will monitor the safety data as they accumulate with predefined stopping rules.

Significance: SAFIRE is designed to inform WHO policy. By expanding the range of safe and effective treatment options, SAFIRE has the potential to improve the management of malaria in early pregnancy, an important period for the developing placenta and fetus, and contribute to better maternal and child health outcomes in endemic areas.