L-ArGinine to pRevent advErse prEgnancy Outcomes (AGREE)
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- The protocol lists: L-citrulline.
- Who it may be relevant to
- Registry conditions: Pregnancy, Malaria, Nutrition, Placental Development. Basic parameters: 16 years — 40 years · Female.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- Kenya
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
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Official title
Oral Antenatal L-citrulline Supplementation to Reduce Adverse Pregnancy Outcomes: a Two-arm, Randomized, Placebo-controlled Multi-site Trial in Kenya
Overview
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.
Interventions
- 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
Primary outcome measures
- Adverse pregnancy outcome [Time frame: 27 months]
Secondary outcome measures (12)
- Gestational hypertension [Time frame: 27 months]
- Malaria infection during pregnancy [Time frame: 27 months]
- Placental malaria [Time frame: 27 months]
- Individual components of the placental malaria composite [Time frame: 27 months]
- Uncomplicated clinical malaria during pregnancy [Time frame: 27 months]
- SARS-CoV-2 infection during pregnancy [Time frame: 27 months]
- Maternal anaemia during pregnancy and delivery [Time frame: 27 months]
- Individual components of the adverse pregnancy outcome composite, and sub-composites [Time frame: 27 months]
- Fetal growth [Time frame: 27 months]
- Birthweight-for-gestational age [Time frame: 27 months]
- Neonatal length and stunting [Time frame: 27 months]
- Congenital anaemia [Time frame: 27 months]
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
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: Yes
Study design
- Allocation
- Randomized
- Model
- Parallel assignment
- Masking
- Quadruple blind
- Primary purpose
- Prevention
Study locations
Kenya · 1 center
- KEMRI Centre for Global Health Research — Kisumu
Identifiers
NCT: NCT05934318 · 19-109 · PACTR202303697293140