Safety of Antimalarials in the FIRst trimEster

Summary

The SAFIRE study aims to find effective treatments with acceptable safety for malaria in early pregnancy, a particularly sensitive time for the adverse consequences of malaria in pregnancy for both mother and baby. Currently, WHO recommends the antimalarial drug artemether-lumefantrine (AL) for the treatment of uncomplicated malaria in the first trimester of pregnancy. Other promising treatments are being rolled out in malaria-endemic countries for use in adults and children and data on current exposures in the first trimester are limited and insufficient to support a recommendation. This is due to the fact that pregnant women are often excluded from clinical trials to protect fetuses, unintentionally depriving them of newer, potentially better treatments. Instead, they often received older, less effective drugs. The International Council for Harmonisation (ICH E21) and stringent regulatory authorities (e.g. EMA, FDA and MHRA) now encourage pregnant women to be included in well-designed studies to ensure they can safely benefit from medical advances.

This study will compare AL with the newer antimalarial drugs that have shown no significant safety concerns in laboratory studies, accidental use during early pregnancy, or trials in later pregnancy stages. The main goal is to see if these new drugs work as well as AL in treating malaria and are safe for the mother, her pregnancy and the developing baby. The newer antimalarials being tested also offer additional benefits to pregnant women, such as preventing new malaria infections for longer after treatment than the current standard treatment (AL). Also, they can be taken just once a day instead of twice daily, like AL. A simpler dosing schedule could improve adherence to the study medication, meaning women are more likely to take the full course of treatment as prescribed. This, in turn, enhances its effectiveness in real-world settings. Future antimalarials to be tested will include those with improved resistance profiles, offering more effective options for combating drug-resistant strains.

SAFIRE uses a special "Bayesian Adaptive Platform Trial" (APT) design. This open-ended approach allows researchers to add new interventions under the same protocol, leveraging the existing trial network with infrastructure. The use of a common protocol with innovative adaptive statistical design allows the trial to stop early if it becomes clear that the new drugs are unsafe.

This multi-centre trial will be conducted in several countries in Africa where malaria is very common. Women will be randomly assigned to receive either AL or one of the new treatments. Participants will be seen daily for 4 days, then weekly for 6 weeks to assess the response to treatment, and then monthly until delivery. Their health and outcomes will be closely monitored during and after pregnancy. Newborns will be followed for 6 months. An independent data safety and monitoring board (DSMB) will regularly monitor safety data as it accumulates. By finding more treatment options, this study could improve care for pregnant women with malaria and lead to better health for mothers and babies in areas where malaria is widespread. The results will help inform global health policies and potentially change how we treat malaria in early pregnancy.

Conditions

• Malaria, Pregnancy
• Malaria, Antepartum
• Malaria (Uncomplicated)

Interventions

DRUG

dihydroartemisinin-piperaquine (DP)

Weight-based dosing of 3 (\<60kg), 4 (6-80kg) or 5 (\>80 kg) 40/320 mg tablets of dihydroartemisinin-piperaquine given once daily for 3 days

DRUG

Pyronaridine-artesunate (PA)

Weight-based dosing of 2 (24-\<45 kg), 3 (45-\<65kg), or 4 (\>=65 kg) 180/60 mg tablets of pyronaridine-artesunate, once daily for 3 days.

DRUG

Artemether-lumefantrine

1 x 80/480 or 4 x 20/120 mg tablets of artemether-lumefantrine, given twice daily, approximately 8 hours apart for 3 days

Sponsors & Collaborators

• Malaria Research and Training Center, Mali International Center of Excellence in Research, University of Sciences, Techniques, and Technologies of Bamako, Mali

  collaborator UNKNOWN

• KEMRI Centre for Global Health Research (CGHR), Kisumu, Kenya

  collaborator UNKNOWN

• Clinical Research Unit of Nanoro (CRUN), Institut de Recherche en Sciences de la Santé

  collaborator UNKNOWN

• Medicines for Malaria Venture (co-sponsor)

  collaborator UNKNOWN

• US Centers for Disease Control and Prevention (CDC), Division of Parasitic Diseases & Malaria

  collaborator UNKNOWN

• Liverpool School of Tropical Medicine

  lead OTHER

Principal Investigators

• Fieko ter Kuile, MD · Liverpool School of Tropical Medicine

• Kassoum Kayentao, MD · Universite des Sciences, des Techniques et des Technologies de Bamako

• Stephanie Dellicour, PhD · Liverpool School of Tropical Medicine

• Hellen Barsosio, MD · KEMRI Centre for Global Health Research (CGHR)

• Innocent Valea, PhD · Institut de Recherche en Sciences de la Santé (IRSS)

• Myriam El Gaaloul, PharmD · Medicines for Malaria Venture

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SEQUENTIAL

Eligibility

Min Age

16 Years

Sex

FEMALE

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-09-30

Primary Completion

2028-08-31

Completion

2029-08-31

Countries

• Burkina Faso
• Kenya
• Mali

Study Locations