Safety of Antimalarials in the FIRst trimEster

NCT06962319 | Recruiting Phase 3 DMC

• 2 other identifiers: 24-036MMV_SAFIRE_24_01
• Study Type: interventional
• Target: 1,510
• Locations: 3 countries
• Sites: 3

Brief 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)

Keywords

Malaria; Pregnancy; First trimester; antimalaria; artemether-lumefantrine; Adaptive Platform Trial

Outcome Measures

Primary Outcomes (1)

• ACPR

  PCR-adjusted adequate clinical and parasitological response (ACPR) by Day 42

  Day 42

Secondary Outcomes (1)

• Efficacy - ACPR Day 28

  Day 28

Other Outcomes (1)

• Primary safety endpoint - delivery

  Delivery

Study Arms (3)

Pyronaridine-artesunate (PA)

EXPERIMENTAL

PA is the latest registered ACT and is currently the only commonly used ACT singled out by WHO not to be used in the first trimester because of the lack of any safety data when the guidelines were reviewed. PA is currently seeing a rapid expansion of its use in Africa. Thus, PA is likely to be widely used in women of childbearing age in the coming years.

Drug: Pyronaridine-artesunate (PA)

Dihydroartemisinin-piperaquine (DP)

EXPERIMENTAL

DP is an ACT widely used for the treatment of malaria and is registered in at least 30 malariaendemic countries, including Kenya, Mali and Burkina Faso. DP is also widely used in areas with multidrug-resistant P. falciparum and P. vivax in Southeast Asia. In Papua, Indonesia, DP was introduced as first-line treatment in 2006 in the general population, including in the 2nd and 3rd trimesters of pregnancy. DP is effective in reducing recurrent malaria and improving pregnancy outcomes in the second and third trimesters, offering significant benefits over quinine-based regimens. WHO includes DP as a recommended ACT for treating malaria in the second and third trimesters but emphasises the need for more safety data in the first trimester. The slower elimination of piperaquine that contributes to the longer duration of post-treatment prophylaxis relative to AL and the simplicity of the three-day treatment regimen (once daily as opposed to twice daily with AL).

Drug: dihydroartemisinin-piperaquine (DP)

Artemether-lumefantrine

ACTIVE COMPARATOR

Artemether-lumefantrine (AL) will serve as the first standard of care control arm in this platform trial comparing newer antimalarials. AL is the only drug recommended as first-line treatment for uncomplicated malaria in the first trimester of pregnancy, as per the World Health Organisation's 2022 updated guidelines. Other artemisinin-based combination therapies (ACTs) are only recommended if AL is unavailable.

Drug: Artemether-lumefantrine

Interventions

dihydroartemisinin-piperaquine (DP) DRUG

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

Dihydroartemisinin-piperaquine (DP)

Pyronaridine-artesunate (PA) DRUG

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.

Pyronaridine-artesunate (PA)

Artemether-lumefantrine DRUG

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

Artemether-lumefantrine

Eligibility Criteria

• Age: 16 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥2 weeks and \<14 weeks (13-6/7 weeks inclusive) gestation from the last menstrual period (LMP) as assessed by echography
• Microscopy confirmed P. falciparum mono or mixed infections, regardless of symptoms.
• Emancipated minor and aged ≥16 years
• Haemoglobin ≥ 7 g/dL
• Residence within the health facility catchment area
• Willingness to adhere to study requirements and to deliver the baby at the local health facility
• Willingness to adhere to study requirements and to deliver the baby at the local health facility

You may not qualify if:

• Known allergy to any of the study drugs
• History of known pregnancy complications or poor obstetric history, such as repeated miscarriages, stillbirths, or eclampsia
• History or presence of major illnesses likely to influence pregnancy outcome
• Known HIV positive
• Any significant illness at the time of screening requiring hospitalisation, including severe malaria
• Intent to move out of the study catchment area before delivery or planned delivery out of the catchment area
• Recent (2 weeks) treatment with antimalarials or antimicrobials with antimalarial activity (chloroquine, AL, DP, PA, SPAQ, ASAQ, MQAS, azithromycin, clindamycin, tetracycline, quinolones, cotrimoxazole and SP)
• Twin/multiple pregnancy detected
• Non-viable pregnancy confirmed by ultrasound or doppler
• Known history or evidence of clinically significant cardiovascular disorders or family history of sudden death or congenital long QT syndrome or current co administration of other drugs that might contribute to a prolonged QTc interval or cause "Torsades de Point"
• Chronic medical condition requiring frequent medications (e.g., TB, suspected hepatic lesions, liver disease, sickle cell disease, diabetes, epilepsy, asthma and hypertension)
• Prior randomisation in this study during the current pregnancy

Sponsors & Collaborators

• Liverpool School of Tropical Medicine: lead
• Malaria Research and Training Center, Mali International Center of Excellence in Research, University of Sciences, Techniques, and Technologies of Bamako, Mali: collaborator
• KEMRI Centre for Global Health Research (CGHR), Kisumu, Kenya: collaborator
• Clinical Research Unit of Nanoro (CRUN), Institut de Recherche en Sciences de la Santé: collaborator
• Medicines for Malaria Venture (co-sponsor): collaborator
• US Centers for Disease Control and Prevention (CDC), Division of Parasitic Diseases & Malaria: collaborator

Study Sites (3)

Clinical Research Unit of Nanoro (CRUN), Institut de Recherche en Sciences de la Santé, Direction Régionale de l'Ouest (IRSS-DRO)

Nanoro, Burkina Faso

NOT YET RECRUITING

KEMRI Centre for Global Health Research (CGHR)

Kisumu, 40100, Kenya

NOT YET RECRUITING

Malaria Research and Training Center, University of Sciences, Techniques, and Technologies of Bamako (USTTB),

Bamako, 1805, Mali

RECRUITING

Related Links

• Project website

MeSH Terms

Conditions

Malaria

Interventions

pyronaridine tetraphosphate, artesunate drug combination; Artemether, Lumefantrine Drug Combination

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Fieko ter Kuile, MD

  Liverpool School of Tropical Medicine

  PRINCIPAL INVESTIGATOR

• Kassoum Kayentao, MD

  Universite des Sciences, des Techniques et des Technologies de Bamako

  PRINCIPAL INVESTIGATOR

• Stephanie Dellicour, PhD

  Liverpool School of Tropical Medicine

  PRINCIPAL INVESTIGATOR

• Hellen Barsosio, MD

  KEMRI Centre for Global Health Research (CGHR)

  PRINCIPAL INVESTIGATOR

• Innocent Valea, PhD

  Institut de Recherche en Sciences de la Santé (IRSS)

  PRINCIPAL INVESTIGATOR

• Myriam El Gaaloul, PharmD

  Medicines for Malaria Venture

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Amy Smith

CONTACT

+44 151 702 9575; Amy.Smith@lstmed.ac.uk

Ravi Lad

CONTACT

+447856407365; ravi.lad@lstmed.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a Phase IIIb, multicentre, open-label, randomised, non-inferiority, Bayesian sequential adaptive platform clinical trial to investigate the efficacy, safety and tolerability of multipleantimalarial treatment arms simultaneously or sequentially in pregnant women in the first trimester of pregnancy with uncomplicated P. falciparum malaria. The study will be conducted in several phases, starting with an 'Initial' Phase consisting of a 3-arm trial, followed potentially by additional phases when new intervention arms are added. Any additional study arms added in the future will be described in the accompanying Intervention Specific Appendix (ISA\[s\]) and submitted for ethical and regulatory approvals. This open-ended trial continuously evaluates new antimalarials without a set end date, adapting to emerging treatments and research priorities in malaria during pregnancy.

Study Record Dates

• First Submitted: April 29, 2025
• First Posted: May 8, 2025
• Study Start: September 30, 2025
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2029
• Last Updated: November 19, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Time Frame: No later than one year after the publication of the trial results - no end date decided
• Access Criteria: Through a data sharing repository platform such as WWARN.

Locations

MA (1); BU (1); KE (1)