Oral Antenatal L-citrulline Supplementation to Reduce Adverse Pregnancy Outcomes: a Two-arm, Randomized, Placebo-controlled Multi-site Trial in Kenya
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 2,960
- 试验地点
- 1
- 主要终点
- Adverse pregnancy outcome
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 16 Years 至 40 Years（Child, Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
结局指标
主要结局
Adverse pregnancy outcome
时间窗: 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.
次要结局
- Allergic reaction(27 months)
- Individual components of the placental malaria composite(27 months)
- Gestational hypertension(27 months)
- Malaria infection during pregnancy(27 months)
- Placental malaria(27 months)
- Congenital abnormalities(27 months)
- Birthweight-for-gestational age(27 months)
- Neonatal length and stunting(27 months)
- Neonatal death(27 months)
- Uncomplicated clinical malaria during pregnancy(27 months)
- Maternal anaemia during pregnancy and delivery(27 months)
- Congenital anaemia(27 months)
- Congenital SARS-CoV-2 infection(27 months)
- Composite of fetal loss and neonatal mortality(27 months)
- Neonatal sepsis(27 months)
- Early childhood neurocognitive development(27 months)
- Markers of L-arginine bioavailability and nitric oxide biogenesis(27 months)
- Mediators of host immune function(27 months)
- SARS-CoV-2 infection during pregnancy(27 months)
- Individual components of the adverse pregnancy outcome composite, and sub-composites(27 months)
- Fetal growth(27 months)
- Perinatal mortality(27 months)
- Evidence of malaria or SARS-CoV-2 vertical transmission(27 months)
- Microbial diversity(27 months)
- Markers of endothelial function, placental function and inflammation(27 months)
- Congenital malaria infection(27 months)
- Gastrointestinal complaints(27 months)
- Symptoms of dizziness or syncope or palpitations(27 months)
- Evidence of SARS-CoV-2 infection(27 months)
- Maternal mortality(27 months)
- Vomiting study supplement(27 months)