L-ArGinine to pRevent advErse prEgnancy Outcomes (AGREE)

NCT ID: NCT05934318

Last Updated: 2025-06-27

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 2960 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-12-29
• Study Completion Date: 2026-12-30

Brief Summary

There are few safe, effective, and affordable interventions to improve pregnancy outcomes in low resource settings where the highest rates of poor birth outcomes occur. L-citrulline is naturally found in many foods and is changed into another important amino acid, L-arginine, in the body. L-arginine is important for the growth of a healthy placenta and healthy baby. Adding L-citrulline to the diets of pregnant women may be an effective and affordable way to improve the health of their babies.The goal of the AGREE trial is to test whether a dietary supplement containing a common food component, an amino acid called L-citrulline, can help pregnant Kenyan women at risk of malaria have healthier pregnancies and healthier babies. 2,960 pregnant Kenyan women will be enrolled and randomly assigned to take either a twice daily dietary supplement containing L-citrulline or a placebo supplement without additional L-citrulline. Maternal participants will be seen every month until delivery and at weeks 1 and 6 after birth. Infants will also be followed up at ages 6, 12, 18, and 24 months. The primary outcome of the study is 'adverse pregnancy outcome', a composite of foetal loss (miscarriage or still birth), preterm birth, low birth weight, small for gestational age or neonatal mortality. The results of the AGREE trial could help to guide obstetric and public health policy and provide a sustainable solution that could be implemented at the community level.

Detailed Description

L-arginine is an essential amino acid in pregnancy and a key mediator of placental development and function. In many low-resource settings, widespread protein undernutrition contributes to L-arginine deficiency in pregnancy which is associated with an increased risk of adverse pregnancy outcomes. Using a preclinical model, we have previously shown that dietary L-arginine supplementation enhances placental vascular development and improves pregnancy outcomes. L-citrulline is an amino acid that is efficiently converted to L-arginine in the body and has a more palatable flavour profile. The primary objective is to to determine if daily antenatal oral supplementation with L-citrulline can reduce adverse pregnancy outcomes (defined as a composite of fetal loss, infants born preterm, small for gestational age or with low birthweight) among pregnant women at high risk of malaria and protein undernutrition in Kenya.This is an individually randomized, two-arm, parallel-group, placebo-controlled clinical trial involving 2,960 pregnant women randomly assigned to one of two study arms. The intervention arm will contain L-citrulline arm -twice daily 6.0 g sachet, each containing 5.00 g of quality-assured L-citrulline powder, 0.66 g maltodextrin and 0.30 g lactose anhydrous, 0.03 g citric acid, 0.01 g lemon flavour + antenatal standard of care with enhanced monitoring (n=1,480); or placebo arm containing 6.0 g sachet of quality-assured placebo, each consisting of 3.6 g maltodextrin and 2.4 g lactose monohydrate, 0.03 g citric acid, 0.01 g lemon flavour + antenatal standard of care with enhanced monitoring (n=1,480). All participants will continue to take the assigned product for 6 weeks after delivery and will receive an enhanced antenatal standard of care. The primary outcome is the clinical composite 'adverse pregnancy outcome'. Secondary outcomes include longitudinal assessments of physiological and molecular markers of endothelial function, angiogenesis, inflammation, placental function, L-arginine metabolism, neonatal sepsis, mortality, and early childhood neurocognitive development to age 24 months. The effect of L-citrulline supplementation on the composition of the participants' vaginal microbiota and the intestinal microbiota of both the participants and their newborns will be analysed in a subset of 132 mother/infant dyads. All maternal participants of the AGREE trial will be followed for 6 weeks post-partum and the children will be followed until age 2 years. Written informed consent will be obtained.

Conditions

Pregnancy; Malaria; Nutrition; Placental Development; Preterm Birth; Fetal Growth Restriction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

L-citrulline arm

L-citrulline arm is the intervention arm consisting of a twice daily 6.0 g sachet, each containing 5.000 g of quality-assured L-citrulline powder, 0.672 g maltodextrin and 0.286 g lactose anhydrous, 0.03 g citric acid, 0.012 g lemon flavour + antenatal standard of care with enhanced monitoring. The sachets will be provided at enrolment and each subsequent monthly ANC visit.

Group Type: EXPERIMENTAL

L-citrulline

Intervention Type: DIETARY_SUPPLEMENT

Twice daily 6.0 g sachet, each containing 5.00 g of quality-assured L-citrulline powder, 0.66 g maltodextrin and 0.30 g lactose anhydrous, 0.03 g citric acid, 0.01 g lemon flavour + antenatal standard of care with enhanced monitoring

Placebo arm

Placebo arm is the control arm consisting of a twice daily 6.0 g sachet of quality-assured placebo, each consisting of 3.6 g maltodextrin and 2.358 g lactose monohydrate, 0.03 g citric acid, 0.012 g lemon flavour + antenatal standard of care with enhanced monitoring. The sachets will be provided at enrolment and each subsequent monthly ANC visit.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

L-citrulline

Twice daily 6.0 g sachet, each containing 5.00 g of quality-assured L-citrulline powder, 0.66 g maltodextrin and 0.30 g lactose anhydrous, 0.03 g citric acid, 0.01 g lemon flavour + antenatal standard of care with enhanced monitoring

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

L-arginine

Eligibility Criteria

Inclusion Criteria

• Pregnant women aged 16-40 years,
• inclusive to 24 weeks gestational age as confirmed by ultrasound,
• who have a viable singleton pregnancy,
• are residents of the study area,
• willing to adhere to scheduled and unscheduled study visit procedures,
• willing to deliver in a study clinic or hospital

Exclusion Criteria

• multiple pregnancies (i.e. twin/triplets);
• pre-existing hypertension, renal disease and/or diabetes, or severe anaemia (Hb < 5 g/dL);
• HIV-positive or HIV status unknown;
• malformations or nonviable pregnancy observed on enrolment ultrasound;
• known allergy or contraindication to any of the study supplements including lactose intolerance or observing a lactose-free diet;
• unable to give consent; or concurrent participation in any other clinical trial

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Kenya Medical Research Institute

OTHER

Sponsor Role: collaborator

University of Toronto

OTHER

Sponsor Role: collaborator

Telethon Kids Institute

OTHER

Sponsor Role: collaborator

Liverpool School of Tropical Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kevin Kain, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Toronto

Julie Wright, MD

Role: STUDY_DIRECTOR

University of Toronto

Locations

KEMRI Centre for Global Health Research

Kisumu, , Kenya

Site Status: RECRUITING

Countries

Kenya

Central Contacts

Feiko O. ter Kuile, PhD

Role: CONTACT

feiko.terkuile@lstmed.ac.uk

+441517053287

Hellen C. Barsosio, MD

Role: CONTACT

hbarsosio@kemri.go.ke

+254724464507

Facility Contacts

Hellen C Barsosio, MD

Role: primary

hellen.barsosio@lstmed.ac.uk

+254724464507

Everlyne D Ondieki, MPH

Role: backup

evelyne.delylah@lstmed.ac.uk

Other Identifiers

PACTR202303697293140

Identifier Type: REGISTRY

Identifier Source: secondary_id

19-109

Identifier Type: -

Identifier Source: org_study_id