Chronic Hypertension and l-citrulline study

ISRCTN	ISRCTN12695929
DOI	https://doi.org/10.1186/ISRCTN12695929
Clinical Trials Information System (CTIS)	2015-005792-25
Protocol serial number	35351
Sponsor	Central Manchester University Hospitals NHS Foundation Trust
Funders	National Institute for Health Research, Wellcome Trust

Submission date: 18/09/2017
Registration date: 20/09/2017
Last edited: 04/10/2023

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Pregnancy and Childbirth

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Chronic hypertension (high blood pressure) affects 2% of pregnancies and is associated with significant risks for both mother and baby. There is a 1 in 4 chance that complications will arise in pregnancy (pre-eclampsia (diabetes during pregnancy) and/or fetal growth restriction) requiring a preterm delivery. Oral L-citrulline is an amino acid supplement which has been associated with an improvement in blood pressure and blood vessel function. In a phase I study of 24 obese pregnant women, three weeks treatment of L-Citrulline (3g/day) was associated with a significant reduction in blood pressure, which persisted after the treatment had ceased until the end of pregnancy. There was also a marked change in factors involved in blood vessel function, which are altered in pregnancies complicated by placental dysfunction, at several time points over pregnancy. This suggests a potential beneficial effect of oral L-citrulline on placental and/or vessel function. The potential use of an amino acid supplement, which is safe, readily available and of relatively low-cost, represents an appealing intervention for the long-term management of chronic hypertensive diseases, especially in pregnancy where the number of treatment options might be more limited, and non-pharmacological interventions are more acceptable. At present, there is no information regarding either the efficacy or acceptability of L-citrulline supplementation to modulate cardiovascular function in women with chronic hypertension in early pregnancy. The aim of this study is to assess the acceptability and feasibility of using L-citrulline supplements for women with chronic hypertension to then plan a larger study, which to determine whether oral L-citrulline treatment is cost-effective for the treatment of chronic hypertension.

Who can participate?
Women aged 18 and older who are 12-16 weeks pregnant who have high blood pressure.

What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive a supplement with amino acid L-citrulline twice per day for a maximum of 10 weeks around 14-22 weeks of pregnancy. Those in the second group receive a placebo (dummy) supplement for 10 weeks around 14-22 weeks of pregnancy. Participants are follow up until 12 weeks post giving birth to measure their blood pressure.

What are the possible benefits and risks of participating?
Participation in this study could help lower blood pressure in hypertensive pregnant women. There are no risks associated with participation.

Where is the study run from?
1. St Mary’s Hospital Manchester (UK)
2. St Thomas’s Hospital London (UK)

When is the study starting and how long is it expected to run for?
September 2012 to January 2019

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Miss Sophie Hennessy
cherry.trial@liverpool.ac.uk

Contact information

Miss Sophie Hennessy
Public

Clinical Trials Research Centre
University of Liverpool
Institute of Child Health
Alder Hey Children's NHS Foundation Trust
Liverpool
L12 2AP
United Kingdom

Phone	+44 1517949765
Email	cherry.trial@liverpool.ac.uk

Study information

Primary study design	Interventional
Study design	Randomised; Interventional; Design type: Treatment, Prevention, Dietary
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	CHronic HypERtension and L-citRulline studY: Feasibility study on the effects of L-citrulline on uteroplacental and cardiovascular function in hypertensive pregnant women
Study acronym	CHERRY
Study objectives	Study aims: The aims of the present study are 1. Determine the effect of L-citrulline supplementation on maternal blood pressure in women with chronic hypertension 2. Determine whether L-citrulline supplementation can improve uterine blood flow and other markers associated with adverse pregnancy outcomes Hypothesis: The hypothesis that tight blood pressure control in early pregnancy has a favourable impact on placental development such that the risk of subsequent placental dysfunction is lower. In addition, the beneficial effects on the vascular endothelium of L-Citrulline may impact on the interaction between the placental trophoblast cells and the maternal spiral arteries improving invasion and ultimately placentation.
Ethics approval(s)	North West Haydock REC, 14/09/2016, ref: 16/NW/0557
Health condition(s) or problem(s) studied	Specialty: Reproductive health and childbirth, Primary sub-specialty: Reproductive and Sexual Medicine; UKCRC code/ Disease: Reproductive Health and Childbirth/ Respiratory and cardiovascular disorders specific to the perinatal period
Intervention	Treatment across arms are double blinded with only the trial pharmacist at site and randomising statistician being unblinded. Randomisation is done via a secure web based system and is performed by a member of the research team at site. Once randomisation has occurred an automated blinded email is sent to all relevant members of the research team and an unblinded email is sent to the pharmacist. Group 1: Participants receive supplementation with the amino acid L-citrulline (3g twice per day) from 14±/-2 to 22±/-2 weeks’ gestation (maximum of 10 weeks treatment duration). Group 2: Participants receive supplementation with the placebo from 14±/-2 to 22±/-2 weeks’ gestation (maximum of 10 weeks treatment duration). The women are followed up until 12 weeks post-delivery to measure blood pressure.
Intervention type	Other
Primary outcome measure(s)	1. Recruitment rate is measured by number of women recruited and completing study per month 2. Change in diastolic blood pressure (from baseline to 8 weeks post randomisation following L- citrulline supplementation, compared with placebo – Change in clinic diastolic BP (average of 3 readings) will be calculated at baseline and week 8
Key secondary outcome measure(s)	1. Acceptability of intervention in pregnant women with chronic hypertension is measured by number of women completing treatment and completion of participant questionnaire at end of the treatment period 2. The following results are compared within treatment groups only (paired analysis) as the study is not sufficiently powered to identify a difference between randomised groups: 2.1. Average day and night time Ambulatory Blood Pressure Measurements (ABPM.) ABPM measurements will be downloaded from the software (SpaceLabs) and the day and night time averages calculated by the software. 2.2. Pulse wave velocity measurements will be exported from the Tensioclinic software. Vascular compliance measurements including central BP, pulse wave velocity, augmentation index will be compared within groups. 2.3. Peripheral vascular resistance measurements obtained from the NICOM. Measurements of cardiac output, cardiac index, SVI and TPRI will be compared within groups. 2.4. Uteroplacental blood flow measurements: uterine artery resistance index (RI) and pulsatility index (PI), presence/absence of notching 2.5. Plasma ADMA/arginine concentrations 2.6. Change in antihypertensive therapy
Completion date	04/01/2019

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Female
Target sample size at registration	42
Total final enrolment	36
Key inclusion criteria	1. Viable singleton pregnancy 2. Gestation: 12+0 to 16+0 weeks 3. Aged 18 years or over 4. Able to provide informed consent 5. Diastolic BP of ≥90 mmHg (average of two clinic readings) OR ≥80 mmHg if taking antihypertensive medication OR PWV ≥9m/s before 16 weeks’ gestation 6. Serum creatinine <120 mmol/l at booking
Key exclusion criteria	There is no exclusion criteria.
Date of first enrolment	04/07/2017
Date of final enrolment	01/03/2018

Locations

Countries of recruitment

United Kingdom
England

Study participating centres

St Mary’s Hospital Manchester

Oxford Road
Manchester
M13 9WL
United Kingdom

St Thomas’s Hospital London

Westminster Bridge Road
Lambeth
London
SE1 7E
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
IPD sharing plan	The data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		03/10/2023	04/10/2023	Yes	No
Basic results			17/06/2020	No	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

04/10/2023: Publication reference added.
17/06/2020: The following changes were made to the trial record:
1. Added clinicaltrialsregister.eu link to basic results (scientific).
2. The total final enrollment was added.
25/01/2018: The recruitment end date has been updated from 31/12/2017 to 01/03/2018.