In world first, consortium aims to test antimalarials in early pregnancy

A group of research experts have joined together to conduct a phase 3 clinical trial testing the safety and efficacy of antimalarial treatments for women in their first trimester of pregnancy — an effort that they said has not been done before. The Safety of Antimalarials in the FIrst TRimEster of pregnancy, or SAFIRE, consortium plans to test multiple antimalarial treatments. They plan to start by comparing the safety, tolerability, and efficacy of artemether-lumefantrine to pyronaridine-artesunate. Artemether-lumefantrine is the only artemisinin-based combination therapy, or ACT, recommended by the World Health Organization for women in their first trimester of pregnancy, while pyronaridine-artesunate is an ACT recommended by WHO to treat malaria in the general population, but currently not recommended for pregnant women in their first trimester due to limited data. According to a news release, preclinical data and clinical data on pyronaridine-artesunate from pregnancy registries — studies set up to collect information on the effect of antimalarial medicines on mothers and their unborn children during pregnancy — are “reassuring for both mothers and their newborns.” Researchers plan to submit data from these studies to ethics and regulatory bodies to obtain approval for the trial. If all goes well, they plan to enroll women in the trial in early 2025. They hope that data generated from the trial will be able to support the design of future trials focused on other infectious diseases affecting pregnant women in low- and middle-income countries. The goal Malaria infection poses several risks for pregnant women and their unborn children. It can cause maternal anemia, miscarriage, and stillbirth. However, pregnant women are often excluded in clinical trials due to safety concerns. At present, WHO recommends only one ACT — artemether-lumefantrine — to treat uncomplicated malaria for women in their first trimester of pregnancy. The combination drug has been used for more than two decades to treat uncomplicated malaria, which is when someone shows symptoms of infection but their organs are unaffected, but WHO only recommended its use in pregnant women in their first trimester in 2022. Other ACTs such as artesunate-amodiaquine, artesunate-mefloquine, and dihydroartemisinin-piperaquine are not recommended by WHO for routine use. However, they can be considered in instances where there is reported resistance to artemether, or where artemether-lumefantrine is not available, Dr. Stephan Duparc, chief medical officer for the Medicines for Malaria Venture, wrote to Devex. But pyronaridine-artesunate is not recommended even if artemether-lumefantrine is not available because there are currently no documented records of its use during the first trimester of pregnancy, he added. This leaves pregnant women in their first trimester with few options for treatment. “This study will allow us to generate such data needed by the WHO to revise their malaria treatment guidelines,” Duparc wrote. Potential challenges Recruiting for the trial is a challenge in itself. Women may not know they are pregnant until their second trimester, or not disclose their pregnancy for sociocultural reasons, such as being pregnant out of wedlock. The researchers also need to effectively time the recruitment during the seasonal malaria period in Mali and Burkina Faso, which typically lasts for four to five months in a year. Failing to do so could delay the trial. Another challenge is ensuring trial participants stay for the duration of the study. The trial has a long period, with researchers aiming to follow up with women and their children up to six months post delivery. In other trials, high drop out rates were observed among adolescent girls and young women who relocate, accept work elsewhere, or even get remarried, according to Dr. Hellen Barsosio, research scientist of maternal and newborn health at the Kenya Medical Research Institute. She said to mitigate dropping out, they will recruit women from the study area and “ask about their plans to continue follow-up post-delivery.” The consortium also needs to address regulatory and ethical concerns. While data they have on pregnant women exposed to pyronaridine-artesunate “has been reassuring so far,” Barsosio said they are working with an independent global safety board that will be meeting in October 2024 to review all safety data before the trial starts and recommend whether they can proceed. In-country ethics and regulatory bodies will also review the trial protocol and safety data prior to the start of the trial. During the trial, an independent data safety and monitoring group will review the progress of the trial, and look for any safety concerns, and stop it if they find one. The researchers will also engage the women and their families in joining the trial, and communicate that they can drop out of the trial at any time. All this is to ensure the safety of participating women and their unborn children, which Barsosio said is “at the heart of this trial.”