L-ArGinine to pRevent advErse prEgnancy Outcomes (AGREE)

NCT05934318 | Recruiting DMC

• 2 other identifiers: 19-109PACTR202303697293140
• Study Type: interventional
• Target: 2,960
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Adverse pregnancy outcome

  The primary outcome is 'adverse pregnancy outcome' defined as a composite of fetal loss (spontaneous abortion or stillbirth), singleton live births born SGA or with LBW, or preterm birth (PTB). 'Small for gestational age' will be defined using the INTERGROWTH population reference's 10th percentile. Fetal loss will be assessed monthly at scheduled ANC visits.

  27 months

Secondary Outcomes (31)

• Gestational hypertension

  27 months

• Malaria infection during pregnancy

  27 months

• Placental malaria

  27 months

• Individual components of the placental malaria composite

  27 months

• Uncomplicated clinical malaria during pregnancy

  27 months

Study Arms (2)

L-citrulline arm

EXPERIMENTAL

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.

Dietary Supplement: L-citrulline

Placebo arm

NO INTERVENTION

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.

Interventions

L-citrulline 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

Also known as: L-arginine

L-citrulline arm

Eligibility Criteria

• Age: 16 Years - 40 Years
• Gender Eligibility Details: Pregnant women
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Liverpool School of Tropical Medicine: lead
• Kenya Medical Research Institute: collaborator
• University of Toronto: collaborator
• Telethon Kids Institute: collaborator

Study Sites (1)

KEMRI Centre for Global Health Research

Kisumu, Kenya

RECRUITING

MeSH Terms

Conditions

Malaria; Premature Birth; Fetal Growth Retardation

Interventions

Citrulline; Arginine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Fetal Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Growth Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Amino Acids, Diamino; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Basic; Amino Acids, Essential

Study Officials

• Kevin Kain, PhD

  University of Toronto

  PRINCIPAL INVESTIGATOR

• Julie Wright, MD

  University of Toronto

  STUDY DIRECTOR

Central Study Contacts

Feiko O. ter Kuile, PhD

CONTACT

+441517053287; feiko.terkuile@lstmed.ac.uk

Hellen C. Barsosio, MD

CONTACT

+254724464507; hbarsosio@kemri.go.ke

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study will be placebo-controlled involving a maltodextrin/lactose anhydrous/citric acid/lemon flavour powder for the L-citrulline powder intervention. The placebo powder will be indistinguishable in size, quantity, taste and colour from the L-citrulline product to ensure blinding of all investigators and study staff during allocation and for the duration of the trial. All participants and the clinical and research staff will be masked to the treatment assignment of these individual women. The trial statistician will also be blinded regarding the treatment code when s/he develops the statistical analysis plan and writes the statistical programmes, which will be validated and completed using dummy randomisation codes.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: * Allocation: randomised; Intervention model: parallel assignment * Design: Superiority trial * Arms: two * Allocation ratio: 1:1; stratified by site (hospital) and gravidity (pauci,- and multigravidae) Masking: placebo-controlled

Study Record Dates

• First Submitted: April 5, 2023
• First Posted: July 6, 2023
• Study Start: December 29, 2023
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2026
• Last Updated: June 27, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: No later than five years after the publication of the trial.
• Access Criteria: Collaborating institutions. All requests for data for secondary analysis will be considered by the Data Access Committee to ensure that the use of data is within the terms of consent and ethics approved.

Locations

KE (1)