Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202505891635396 Date of Registration: 19/05/2025
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title SAFIRE: Safety of Antimalarials in the FIRst Trimester
Official scientific title A multicentre open-label, non-inferiority adaptive platform randomised controlled trial to evaluate the efficacy, safety, and tolerability of antimalarials for the treatment of uncomplicated malaria in the first trimester of pregnancy: Master protocol
Brief summary describing the background and objectives of the trial 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. These include antimalarials that have shown no significant safety concerns in preclinical studies, in women inadvertently treated with these drugs in the first trimester, or in clinical trials during the second and third trimesters of pregnancy. SAFIRE aims to efficiently generate evidence on the safety and efficacy of alternative antimalarials for treating uncomplicated malaria in the first trimester. Only antimalarials that have shown promising safety profiles in preclinical studies and observational pregnancy exposure registries will be considered. 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 for other potentially effective and safe antimalarials. Furthermore, stringent regulatory authorities now encourage more research involving pregnant women. Objectives: The primary objective in the initial phase is to confirm the efficacy of these alternative antimalarials in pregnant women in the first trimester with uncomplicated malaria by demonstrating non-inferiority to the current
Type of trial RCT
Acronym (If the trial has an acronym then please provide) SAFIRE
Disease(s) or condition(s) being studied
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Treatment: Drugs
Anticipated trial start date 16/05/2025
Actual trial start date 01/09/2025
Anticipated date of last follow up 01/01/2029
Actual Last follow-up date
Anticipated target sample size (number of participants) 1510
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
24036 LSTM-REC
MMVSAFIRE2401 MMV
5355146 KEMRI-SERU
202501003 Burkina Faso CERS
2024312CEUSTTB Mali CEUSTTB2
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Dynamic (adaptive) random allocation such as minimization Allocation Sequence/Code was not concealed Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Dihydroartemisinin piperaquine Weight-based dosing of 3 (<60kg), 4 (6-80kg) or 5 (>80 kg) 40/320 mg tablets of dihydroartemisinin-piperaquine. Once daily for 3 days In the initial phase of the platform trial, pregnant women with uncomplicated malaria in their first trimester will be randomised to receive a 3-day dihydroartemisinin-piperaquine (DP). 604
Experimental Group Pyronaridine artesunate 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. In the initial phase of the platform trial, pregnant women with uncomplicated malaria in their first trimester will be randomised to receive a 3-day treatment course of AL (artemether-lumefantrine), dihydroartemisinin-piperaquine (DP) or pyronaridine-artesunate (PA) 604
Control Group 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 twice daily, approximately 8 hours apart for 3 days In the initial phase of the platform trial, pregnant women with uncomplicated malaria in their first trimester will be randomised to receive a 3-day treatment course of AL (artemether-lumefantrine), dihydroartemisinin-piperaquine (DP) or pyronaridine-artesunate (PA) 302 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
• ≥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 • Ability to provide written informed consent • 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 80 and over: 80+ Year,Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Middle Aged: 45 Year(s)-64 Year(s) 16 Year(s) 100 Year(s) Female
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 16/04/2025 KEMRI scientific and ethical committee
Ethics Committee Address
Street address City Postal code Country
Mbagadhi Nairobi 00200 Kenya
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 01/01/2025 Ministry of Higher education research and innovation
Ethics Committee Address
Street address City Postal code Country
Burkinafaso Burkinafaso 03BP7009 Burkina Faso
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 31/12/2024 University of sciences techniques and technologies of Bamako
Ethics Committee Address
Street address City Postal code Country
Bamako Bamako BP1805 Mali
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Primary efficacy endpoint • PCR-adjusted adequate clinical and parasitological response (ACPR) by Day 42 day 42
Primary Outcome Key safety endpoint • A composite endpoint of miscarriage, stillbirth, or major congenital anomalies. Delivery
Secondary Outcome Adverse events and serious adverse events (SAEs) incidence and severity, including significant changes in relevant laboratory values Throughout the study
Secondary Outcome Drug discontinuation due to adverse drug reactions at any time during pregnancy. Any time during the study
Secondary Outcome Gestational age at delivery, birthweight, Z-scores for birthweight for gestational age, and their binary versions (preterm birth [PTD], low birth weight [LBW], and small-for-gestational age [SGA]) and neonatal death Delivery
Secondary Outcome Vulnerable newborn: the composite of LBW, PTD or SGA among live births. Delivery
Secondary Outcome Adverse pregnancy outcome: a composite of miscarriage, stillbirth, major congenital anomalies, vulnerable newborn (PTB/LBW/SGA) or neonatal deaths Delivery
Secondary Outcome PCR-adjusted ACPR by Day 28 Day 28
Secondary Outcome PCR-unadjusted ACPR rate by Day 28 and 42 (i.e, no treatment failure or new infection) Day 28 and 42
Secondary Outcome Survival analysis over 42 days for recurrent, recrudescent and new infections Day 42
Secondary Outcome Fever clearance by Day 3 Day 3
Secondary Outcome Parasite clearance by Day 3, including sub-microscopic malaria infection Day 3
Secondary Outcome Gametocyte carriage and clearance Day 42
Secondary Outcome Proportion anaemic and mean haemoglobin on Days 14, 28 and 42 and at delivery Days 14, 28 and 42 and at delivery
Secondary Outcome Prevalence of placenta malaria at delivery (active infection). Delivery
Secondary Outcome PK parameters such as Cmax, AUC, and T1/2 wherever possible Pk time points
Secondary Outcome Neurodevelopment score from infants at 3 and 6 months using Bayley Scales of Infant and Toddler Development 3 and 6 months
Secondary Outcome Incidence of developmental delays or abnormalities detected during routine paediatric exams in the first 6 months of life. 6 months
Secondary Outcome Attainment of key developmental milestones, assessed at 3 and 6 months 3 and 6 months
Secondary Outcome Parent questionnaires on infant temperament, sleep patterns, and behavioural development at 3 and 6 months 3 and 6 months
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Burkina Faso Clinical Research Unit of Nanoro Nanoro Burkina Faso Burkina Faso
Mali Malaria Research and Training Center Bamako. Bamako. Mali
Kenya medical research institute Centre for Global Health Research Kisumu kisian Kisumu 40100 Kenya
FUNDING SOURCES
Name of source Street address City Postal code Country
Global Health European and Developing Countries Clinical Trials Partnership 3 Joint Undertaking Avenue de la Toison dOr Brussels Belgium
the European Union UK Research and Innovation Rue du Trone 4 Brussels Belgium
the State Secretariat for Education Research and Innovation of the Swiss Confederation Einsteinstrasse 2 Switzerland Switzerland
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Liverpool School of Tropical Medicine Pembroke Place Liverpool United Kingdom University
Primary Sponsor Medicines for Malaria Venture Route de Pre Bois 20 Geneva 15 Switzerland Other Collaborative Groups
COLLABORATORS
Name Street address City Postal code Country
Abel Kakuru Makerere University College Kampala Uganda
Hypolite Muhindo Mavoko Congo Congo Congo
Wiweka Kaszubska Route de Pre Bois 20 Geneva Switzerland
Maud Majeres Lugand Route de PreBois 20 Geneva Switzerland
Kyle Wathen Cytel Route de Pre Bois 20 Geneva Switzerland
Natalia Natasha Muhlemann Route de Pre Bois 20 Geneva Switzerland
Henk DFH Schallig Meibergdreef 9 Amsterdam Netherlands
Julie Gutman 1600 Clifton Rd Atlanta United States of America
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Stephanie Dellicour stephanie.dellicour@lstmed.ac.uk +441517029588 Pembroke Place
City Postal code Country Position/Affiliation
Liverpool United Kingdom principal investigator
Role Name Email Phone Street address
Public Enquiries Dr Hellen Barsosio hellen.barsosio@lstmed.ac.uk +254719436833 Kisumu Kisian
City Postal code Country Position/Affiliation
Kisumu 40100 Kenya principal investigators
Role Name Email Phone Street address
Scientific Enquiries Innocent Prof Feiko ter Kuile feiko.terkuile@lstmed.ac.uk +254708739228 Kisumu kisian
City Postal code Country Position/Affiliation
Kisumu 40100 Kenya Chief Investigator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Biological samples and data will be shared using material and data transfer agreements with the collaborating institutions to minimise the risk of unauthorised analysis beyond the scope of the agreed parameters. The full protocol will be available upon request to any interested professional and may be published in a peer-reviewed journal or deposited in an online repository. Individual, de-identified participant data will be made available for meta-analyses as soon as the data analysis is completed, with the understanding that the results of the meta-analysis will not be published before the results of the individual trial without the prior agreement of the investigators. Aggregated or de-identified participant data will be shared with the WHO/TDR pregnancy exposure registry ("Central registry for epidemiological surveillance of drug safety in pregnancy") and local regulators for inclusion in their pregnancy exposure registry. If requested, the data may also be shared with the manufacturers of the investigational products for inclusion in their pregnancy exposure registry to aid the update of their Summary of Product Characteristic ( SmPC) and Patient Information Leaflets (PILs). No later than one year after the publication of the trial results, a fully de-identified dataset of the complete patient-level data will be available for sharing purposes, such as via the WWARN repository platform (http://www.wwarn.org/working-together/sharing-data/accessing-data). All requests for data for secondary analysis will be considered by the publication and data access committee to ensure that the use of data is within the terms of consent and ethics approval. Informed Consent Form,Study Protocol No later than one year after the publication of the trial results peer-reviewed journal or deposited in an online repository
URL Results Available Results Summary Result Posting Date First Journal Publication Date
http://www.wwarn.org/working-together/sharing-data/accessing-data No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information
Section Name Field Name Date Reason Old Value Updated Value
Eligibility Age group 19/05/2025 PACTR Admin Adolescent: 13 Year-18 Year, Adult: 19 Year-44 Year, Middle Aged: 45 Year(s)-64 Year(s) Adolescent: 13 Year-18 Year, Adult: 19 Year-44 Year, Middle Aged: 45 Year(s)-64 Year(s), Aged: 65+ Year(s), 80 and over: 80+ Year