Clinical trial NCT05934318: L-ArGinine to pRevent advErse prEgnancy Outcomes (AGREE)
Official title: Oral Antenatal L-citrulline Supplementation to Reduce Adverse Pregnancy Outcomes: a Two-arm, Randomized, Placebo-controlled Multi-site Trial in Kenya
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Pregnancy
Malaria
Nutrition
Placental Development
Preterm Birth
Fetal Growth Restriction
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
Collaborators: name: Kenya Medical Research Institute
name: University of Toronto
name: Telethon Kids Institute
First posted: 2023-07-06
Enrollment: 2960
Sex: FEMALE
Minimum age (years): 16
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: * 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
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Adverse pregnancy outcome
timeFrame: 27 months
Secondary outcomes:
measure: Gestational hypertension
timeFrame: 27 months
measure: Malaria infection during pregnancy
timeFrame: 27 months
measure: Placental malaria
timeFrame: 27 months
measure: Individual components of the placental malaria composite
timeFrame: 27 months
measure: Uncomplicated clinical malaria during pregnancy
timeFrame: 27 months
measure: SARS-CoV-2 infection during pregnancy
timeFrame: 27 months
measure: Maternal anaemia during pregnancy and delivery
timeFrame: 27 months
measure: Individual components of the adverse pregnancy outcome composite, and sub-composites
timeFrame: 27 months
measure: Fetal growth
timeFrame: 27 months
measure: Birthweight-for-gestational age
timeFrame: 27 months
measure: Neonatal length and stunting
timeFrame: 27 months
measure: Congenital anaemia
timeFrame: 27 months
measure: Congenital malaria infection
timeFrame: 27 months
measure: Congenital SARS-CoV-2 infection
timeFrame: 27 months
measure: Neonatal death
timeFrame: 27 months
measure: Perinatal mortality
timeFrame: 27 months
measure: Composite of fetal loss and neonatal mortality
timeFrame: 27 months
measure: Neonatal sepsis
timeFrame: 27 months
measure: Early childhood neurocognitive development
timeFrame: 27 months
measure: Allergic reaction
timeFrame: 27 months
measure: Maternal mortality
timeFrame: 27 months
measure: Congenital abnormalities
timeFrame: 27 months
measure: Vomiting study supplement
timeFrame: 27 months
measure: Gastrointestinal complaints
timeFrame: 27 months
measure: Symptoms of dizziness or syncope or palpitations
timeFrame: 27 months
measure: Markers of L-arginine bioavailability and nitric oxide biogenesis
timeFrame: 27 months
measure: Markers of endothelial function, placental function and inflammation
timeFrame: 27 months
measure: Evidence of malaria or SARS-CoV-2 vertical transmission
timeFrame: 27 months
measure: Evidence of SARS-CoV-2 infection
timeFrame: 27 months
measure: Mediators of host immune function
timeFrame: 27 months
measure: Microbial diversity
timeFrame: 27 months
Other outcomes:
Locations:
Study officials:
affiliation: University of Toronto
name: Kevin Kain, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Toronto
name: Julie Wright, MD
role: STUDY_DIRECTOR
References: