Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202303697293140 Date of Approval: 27/03/2023
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title L-citrulline supplementation to reduce adverse pregnancy outcomes
Official scientific title Oral antenatal L-citrulline supplementation to reduce adverse pregnancy outcomes: a two-arm, randomized, placebo-controlled multi-site trial in Kenya (L-ArGinine to pRevent advErse prEgnancy outcomes (AGREE).
Brief summary describing the background and objectives of the trial Malaria infections in pregnancy are more frequent and are associated with worse clinical outcomes than malaria infections in non-pregnant individuals.It has a profound fetal health consequences including increased risk of miscarriage, stillbirth, preterm birth and fetal growth restriction resulting in low birth weight infants and infant deaths . Despite their importance to global health,there is a poor understanding of the mechanisms underlying these adverse pregnancy outcomes and how best to predict and prevent them.Using a preclinical model, we have previously shown that dietary L-arginine supplementation enhances placental vascular development and improves pregnancy outcomes, however, one of the limiting features of oral L-arginine supplementation is the unpalatable bitter taste of the amino acid; thus, this study will use related amino acid, L-citrulline, to increase bioavailable L-arginine inorder to improve adverse pregnancy outcomes. Our primary objective is 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. We will therefore conduct an individually randomized, two-arm, parallel-group, placebo-controlled clinical trial involving 2,960 pregnant women randomly assigned (1:1) to one of two study arms: L-citrulline arm and placebo arm, with the following hypotheses: Antenatal L-citrulline supplementation will reduce adverse pregnancy outcomes compared to women receiving placebo and L-citrulline supplementation will improve L-arginine bioavailability, nitric oxide biogenesis and normalize the angiogenic pathways disrupted by malaria infection in pregnancy.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) AGREE
Disease(s) or condition(s) being studied Pregnancy and Childbirth
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Prevention
Anticipated trial start date 15/05/2023
Actual trial start date
Anticipated date of last follow up 15/05/2028
Actual Last follow-up date
Anticipated target sample size (number of participants) 2960
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
3283984 KEMRI SERU
19109 KEMRISERUCGHR
205127 UHN CAPCR
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Permuted block randomization Sealed opaque envelopes Masking/blinding used Care giver/Provider,Outcome Assessors,Participants
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Placebo Women randomised to this intervention will receive twice daily 6.0 g sachet of placebo + antenatal standard of care with enhanced monitoring. Women randomized to this arm will take the suppliment at enrolment and then twice daily until 6 weeks post delivery Women randomized to this arm will receive 6.0 g per day of dissolvable powder containing 3.0 g maltodextrin and 2.9 g microcrystalline cellulose without additional L-Citrulline, plus antenatal standard of care with enhanced monitoring 1480 Placebo
Experimental Group Lcitrulline powder Women ranndomized to this arm will receive a twice daily 6.0 g L-citrulline sachet, containing 5.0 g of quality-assured L-citrulline powder, 0.54 g maltodextrin and 0.38g microcrystalline cellulose, + antenatal standard of care with enhanced monitoring. Women randomized to this arm be given the intervention at enrolment and each subsequent monthly antenatal visit until 6 weeks post delivery Women randomized to this arm will receive twice daily 6.0 g sachet, each containing 5.0 g of quality-assured L-citrulline powder, 0.54 g maltodextrin and 0.38g microcrystalline cellulose, + antenatal standard of care with enhanced monitoring. 1480
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
Pregnant women aged 16 to 40 years, Gestation should be less than 24 weeks cornfirmed by ultrasound The pregnancy should be viable singleton pregnancy The woman should be a residents of the study area, willing to adhere to scheduled and unscheduledstudy visit procedures, and willing to deliver in a study clinic or hospital. Multiple pregnancies Pre-existing hypertension, women with renal disease and/or diabetes, or severe anaemia (Hb < 5 g/dL) HIV-positive women Malformations or nonviable pregnancy observed on enrolment ultrasound known allergy or contraindication to any of the study supplements unable to give consent Concurrent participation in any other clinical trial Adult: 19 Year-44 Year 16 Year(s) 40 Year(s) Female
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 09/02/2021 KEMRI Scientific and Ethics Review Unit
Ethics Committee Address
Street address City Postal code Country
Nairobi Nairobi 54840 Kenya
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary 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. After enrolment
Secondary Outcome EFFICACY OUTCOME Peripheral arterial resistance and Systolic and diastolic blood pressure; gestational hypertension Malaria infection during pregnancy detected by microscopy and PCR Placental malaria detected by microscopy, by molecular methods, or by histology (past and active infection) Individual components of the placental malaria composite Uncomplicated clinical malaria during pregnancy Severity of maternal malaria infection SARS-CoV-2 infection severity during pregnancy Maternal anaemia and haemoglobin concentration during pregnancy and delivery Individual components of the adverse pregnancy outcome composite, and sub-composites including fetal loss (spontaneous abortions and stillbirth) and adverse livebirth (SGA-LBW-PTB composite) Fetal growth (estimated by validated ultrasound and maternal biomarkers2) Birthweight, gestational age, birthweight-for-gestational age Newborn anthropometric measures: head circumference, length, umbilical abdominal circumference, and mid-upper arm circumference Congenital anaemia Congenital malaria infection Congenital SARS-CoV-2 infection Neonatal death Composite of fetal loss and neonatal mortality Neonatal sepsis Early childhood neurocognitive development After enrolment
Secondary Outcome SAFETY OUTCOMES Allergic reaction,anaphylaxis, hives/rash Maternal mortality Other SAEs and AEs Congenital abnormalities After enrolment
Secondary Outcome TOLERANCE OUTCOMES Vomiting study supplement Gastrointestinal complaints including nausea, dyspepsia, diarrhoea Other symptoms including dizziness, syncope, palpitations After adminstration of study intervention
Secondary Outcome LABORATORY OUTCOMES concentration, asymmetric dimethylarginine (ADMA) concentration, L-arginine/ADMA ratio, and symmetric dimethylarginine (SDMA concentration) and Markers of L-arginine bioavailability and nitric oxide biogenesis including: plasma L-arginine Markers of endothelial function, placental function and inflammation including plasma concentrations of Angiopoietin (Ang)-1, Ang-2, soluble Tyrosine kinase with immunoglobulin-likLaboratoryand EGF-like domains (sTIE)1, sTIE2, Vascular Endothelial Growth Factor (VEGF), soluble VEGFreceptor1, 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 After enrolment
Secondary Outcome LABORATORY OUTCOME Evidence of SARS-CoV-2 infection (antigen, PCR, and/or serology) and malaria or SARS-CoV-2 vertical transmission Nutritional and microbial composition of breast milk After enrolment
Secondary Outcome LABORATORY OUTCOME Concentrations of circulating mediators of host immune function, response, endothelial function, and nutrition in the newborn at birth and six weeks of life at birth and six weeks
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Ahero Sub County Hospital Kisumu Kisumu 1578 Kenya
Rabuor Sub county Hospital Kisumu Kisumu 1578 Kenya
Akala Sub County Hospital Siaya Siaya 1578 Kenya
Alupe subcounty hospital Busia Busia 1578 Kenya
FUNDING SOURCES
Name of source Street address City Postal code Country
The Open Philanthropy Project 182 Howard Street San Francisco United States of America
The Canadian Institutes of Health Research 160 Elgin Street Ottawa Canada
The W.Garfield Weston Foundation 10 Grosvenor Street London United Kingdom
The Telethon Kids Institute 15 Hospital Ave Australia Australia
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor The Liverpool School of Tropical Medicine Pembroke Place London 111111 United Kingdom Other Collaborative Groups
COLLABORATORS
Name Street address City Postal code Country
Dr Bryan Coburn Advanced Diagnostics, Toronto General Research Institute Toronto Canada
Dr Andrea Weckman University of Toronto 27 Kings College Toronto Canada
Dr Tobias Kollmann Telethon Kids Network 15 Hospital Avenue Australia Australia
CONTACT PEOPLE
Role Name Email Phone Street address
Scientific Enquiries Feiko TerKuile Feiko.TerKuile@lstmed.ac.uk +254724464507 Kisumu
City Postal code Country Position/Affiliation
Kisumu 40100 Kenya Chief Investigator
Role Name Email Phone Street address
Public Enquiries Feiko TerKuile Feiko.TerKuile@lstmed.ac.uk +254724464507 Kisumu
City Postal code Country Position/Affiliation
Kisumu 40100 Kenya Chief Investigator
Role Name Email Phone Street address
Principal Investigator Hellen Barsosio hellen.barsosio@lstmed.ac.uk +254724464507 Kisumu
City Postal code Country Position/Affiliation
Kisumu 40100 Kenya Senior Research scientist
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes 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 inpeer-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. Study Protocol A fully de-identified data set of the complete patient-level data will be available for sharing purposes not later than five years after the publication of the trial. 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 approval
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information