L-ArGinine to pRevent advErse prEgnancy Outcomes (AGREE) (AGREE)

June 24, 2025 updated by: Liverpool School of Tropical Medicine

Oral Antenatal L-citrulline Supplementation to Reduce Adverse Pregnancy Outcomes: a Two-arm, Randomized, Placebo-controlled Multi-site Trial in Kenya

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
2960

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Child
  • Adult

Accepts Healthy Volunteers

Yes

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: 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.
Dietary supplement: 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
Other Names:
  • L-arginine
No Intervention: 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.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Adverse pregnancy outcome
Time Frame: 27 months
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 Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Gestational hypertension
Time Frame: 27 months
Assessed with systolic and diastolic blood pressure
27 months
Malaria infection during pregnancy
Time Frame: 27 months
detected by microscopy and PCR (not for point of care) on peripheral blood
27 months
Placental malaria
Time Frame: 27 months
detected by microscopy, by molecular methods, or by histology (past and active infection) on placental samples
27 months
Individual components of the placental malaria composite
Time Frame: 27 months
detected by microscopy, by molecular methods, or by histology (past and active infection) on placental samples
27 months
Uncomplicated clinical malaria during pregnancy
Time Frame: 27 months
RDTs will be used at the point of care for any patient presenting with fever, history of fever within 48h, or any other symptoms of clinical malaria infection. RDT-positivity is defined as either pLDH or HRP2 antigen positivity.
27 months
SARS-CoV-2 infection during pregnancy
Time Frame: 27 months
Plasma samples will also be assayed for SARS-CoV-2 antibodies using validated techniques available at the time of analysis. If women are symptomatic a rapid SARS-COV-2 antigen test will also be conducted. If the rapid SARS-COV-2 antigen test is negative a confirmatory PCR will be conducted.
27 months
Maternal anaemia during pregnancy and delivery
Time Frame: 27 months
Maternal anaemia is defined as haemoglobin concentration (Hb)<11g/dL; moderate maternal anaemia: Hb<9g/dL); severe anaemia: Hb<7g/dL); congenital anaemia: newborn Hb<12.5 g/dL.
27 months
Individual components of the adverse pregnancy outcome composite, and sub-composites
Time Frame: 27 months
Including fetal loss (spontaneous abortions and stillbirth) and adverse livebirth (SGA-LBW-PTB composite). Gestational age will be assessed using ultrasound dating at enrolment. Preterm birth is defined as <37 weeks' gestation. Newborns will be weighed within 24 hours of delivery using digital scales (± 10 g) with LBW defined as <2,500g. Small for gestational age (SGA) will be defined as birth weight below the tenth percentile for a given gestational age and sex using the new INTERGROWTH reference population. Neonatal length and stunting will be assessed within 24 hours of delivery. Infants will be defined as stunted if their height-for-age is more than two standard deviations below the WHO Child Growth Standards median.
27 months
Fetal growth
Time Frame: 27 months
estimated by validated ultrasound and maternal biomarkers
27 months
Birthweight-for-gestational age
Time Frame: 27 months
Gestational age will be assessed using ultrasound dating at enrolment. Small for gestational age (SGA) will be defined as birth weight below the tenth percentile for a given gestational age and sex using the new INTERGROWTH reference population.
27 months
Neonatal length and stunting
Time Frame: 27 months
Newborns will be measured for length within 24 hours of delivery. Infants will be defined as stunted if their height-for-age is more than two standard deviations below the WHO Child Growth Standards median.
27 months
Congenital anaemia
Time Frame: 27 months
congenital anaemia: newborn Hb<12.5 g/dL.
27 months
Congenital malaria infection
Time Frame: 27 months
detected by microscopy and PCR (not for point of care) on cord blood samples
27 months
Congenital SARS-CoV-2 infection
Time Frame: 27 months
SARS-CoV-2 antibodies detected on cord blood samples
27 months
Neonatal death
Time Frame: 27 months
vital status on discharge (alive/dead), vital status at 7 days (alive/dead) and 28 days (alive /dead) post admission will be documented.
27 months
Perinatal mortality
Time Frame: 27 months
vital status on discharge (alive/dead), vital status at 7 days (alive/dead)
27 months
Composite of fetal loss and neonatal mortality
Time Frame: 27 months
miscarriage, still births or vital status on discharge (alive/dead), vital status at 7 days (alive/dead) and 28 days (alive /dead) post admission will be documented.
27 months
Neonatal sepsis
Time Frame: 27 months
WHO Integrated Management of Childhood Illness criteria128, specifically any one of the following signs (i) not able to feed at all or not feeding well, (ii) convulsions, (iii) severe chest indrawing, (iv) high body temperature (380C or above), (iv) low body temperature (less than 35.50C), (v) movement only when stimulated or no movement at all (vi) in infants less than 7 days old, fast breathing (60 breaths per minute or more).
27 months
Early childhood neurocognitive development
Time Frame: 27 months
Early childhood neurocognitive development will be assessed longitudinally over the first two years of life using a combination of questionnaires, direct assessments, and objective measures appropriate to the developmental periods within this time frame. The Home Observation for Measurement of the Environment (HOME) is a 58-question assessment. The WHO Motor Development Milestones checklist is a simple, WHO-validated assessment of six gross motor milestones in early childhood development. The Mullen Scales of Early Learning (MSEL) is a comprehensive evaluation assessing early childhood development in five domains. The MacArthur Bates Communication Developmental Inventory (MCAB-CDI)132 is an interview-style questionnaire that consists of 100 vocabulary items, 6 gesture items, and 5 grammatical items to assess communication/language development.
27 months
Allergic reaction
Time Frame: 27 months
defined as anaphylaxis, hives/rash after taking the supplement.
27 months
Maternal mortality
Time Frame: 27 months
Maternal mortality will be defined as the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes. A verbal autopsy questionnaire will attempt to determine the cause of death.
27 months
Congenital abnormalities
Time Frame: 27 months
any abnormality detected in surface and clinical examination at birth and week 1 and 6-8
27 months
Vomiting study supplement
Time Frame: 27 months
vomiting within 30 minutes of taking the supplement
27 months
Gastrointestinal complaints
Time Frame: 27 months
including nausea, dyspepsia, diarrhea reported at scheduled and unscheduled visits and and through follow-up phone calls and home visits
27 months
Symptoms of dizziness or syncope or palpitations
Time Frame: 27 months
Study staff will administer a questionnaire to assess for the occurrence of tolerability adverse events (including nausea, dyspepsia, diarrhoea, dizziness, palpitations) at scheduled and unscheduled visits, and and through follow-up phone calls and home visits
27 months
Markers of L-arginine bioavailability and nitric oxide biogenesis
Time Frame: 27 months
L-arginine bioavailability will be assessed by plasma concentrations of L-arginine, ADMA and the L-arginine/ADMA ratio. Plasma SDMA will also be quantified.
27 months
Markers of endothelial function, placental function and inflammation
Time Frame: 27 months
including plasma concentrations of Angiopoietin (Ang)-1, Ang-2, soluble Tyrosine kinase with immunoglobulin-like and EGF-like domains (sTIE)1, sTIE2, Vascular Endothelial Growth Factor (VEGF), soluble VEGF-receptor1, soluble Endoglin (sEng), Placental Growth Factor (PLGF), soluble Intercellular Adhesion Molecule (sICAM), soluble Tumour Necrosis Factor (sTNF) receptor 2 (sTNFR2), C5a, Chitinase-3-like protein 1 (CHI3L1), C-reactive protein (CRP), Interleukin (IL)-18 binding protein (IL-18BP), IL-6, Pregnancy-associated Protein A (PAPP-A), beta-human chorionic gonadotropin (β-hCG); and urine concentrations of protein and complement
27 months
Evidence of malaria or SARS-CoV-2 vertical transmission
Time Frame: 27 months
Laboratory and nutritional outcomes
27 months
Evidence of SARS-CoV-2 infection
Time Frame: 27 months
Laboratory and nutritional outcomes: (antigen, PCR, and/or serology)
27 months
Mediators of host immune function
Time Frame: 27 months
Concentrations of circulating mediators of host immune function, response, endothelial function, and nutrition in the newborn at birth and six weeks of life
27 months
Microbial diversity
Time Frame: 27 months
(N=132 maternal and N=132 newborn participants). Shannon diversity and other measures of microbial diversity richness and abundance in maternal intestinal and vaginal microbiota at enrolment and the first post-treatment timepoint, across gestation and at six weeks post-partum, and in newborn intestinal microbiota at six weeks of life. Nutritional and microbial composition of breast milk
27 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Liverpool School of Tropical Medicine

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
University of Toronto
Kenya Medical Research Institute
Telethon Kids Institute

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Kevin Kain, PhD, University of Toronto
  • Study Director: Julie Wright, MD, University of Toronto

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 29, 2023

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 30, 2026

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 30, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 5, 2023

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 28, 2023

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 6, 2023

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 27, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 24, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 19-109
  • PACTR202303697293140 (Registry Identifier: The Pan African Clinical Trials Registry (PACTR))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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 on request to any interested professional and may be published in peer-reviewed journals 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 results of the meta-analysis will not be published prior to the results of the individual trial without the prior agreement of the investigators. A fully de-identified data set of the complete patient-level data will be available for sharing purposes, such as via WWARN repository platform http://www.wwarn.org/working-together/sharing-data/accessing-data).

IPD Sharing Time Frame

No later than five years after the publication of the trial.

IPD Sharing 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.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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