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Clinical Trial Results:
Feasibility study on the effects of L-citrulline on uteroplacental and cardiovascular function in hypertensive pregnant women.

Summary
EudraCT number	2015-005792-25
Trial protocol	GB
Global end of trial date	06 Mar 2019

Results information
Results version number	v1(current)
This version publication date	18 Mar 2020
First version publication date	18 Mar 2020
Other versions
Summary report(s)	Cherry results

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

R04341

ISRCTN number

ISRCTN12695929

US NCT number

WHO universal trial number (UTN)

Other trial identifiers

REC number: 16/NW/0557

Sponsor organisation name

Manchester University NHS Foundation Trust

Sponsor organisation address

Oxford Road, Manchester, United Kingdom, M13 9WL

Public contact

Dr Lynne Webster, Manchester University NHS Foundation Trust, research.sponsor@mft.nhs.uk

Scientific contact

Dr Lynne Webster, Manchester University NHS Foundation Trust, research.sponsor@mft.nhs.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

07 Sep 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

07 Sep 2018

Global end of trial reached?

Yes

Global end of trial date

06 Mar 2019

Was the trial ended prematurely?

Main objective of the trial

Process outcome: Recruitment rate (number of women eligible, recruited and completing study per month per centre) Clinical outcome: Reduction in diastolic blood pressure following L-citrulline supplementation compared with placebo (baseline compared 8 weeks post treatment)

Protection of trial subjects

Trial monitoring was carried out to ensure that the rights and well-being of human participants were protected during the course of a clinical trial. A detailed risk assessment was performed for CHERRY to determine the level and type of monitoring required for specific hazards. Monitoring activities were carried out via central monitoring, this included safety and consent monitoring and site visits were conducted when required. A trial steering committee and Idependent data safety & monitoring committee were convened and met regulalry throughout the trial to provide idependent oversight of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Jul 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 36

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Randomisation start (first recruting site opened): 04/07/2017. Randomisation end (last recruting site closed): 31/01/2018. Recruitment planned at 2 sites in UK. Only 1 site opened.

Screening details

42 patients screened, 41 eligible, 36 consented, 36 randomised.

Number of subjects started

42 ^[1]

Intermediate milestone: Number of subjects

Screened: 42

Intermediate milestone: Number of subjects

Eligible: 41

Intermediate milestone: Number of subjects

Consented: 36

Intermediate milestone: Number of subjects

Randomised: 36

Number of subjects completed

Reason: Number of subjects

Did not provide consent: 5

Reason: Number of subjects

Ineligible: 1

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The number of patients who started the pre-assignment period (screened = 42) is larger than the number who enrolled in the trial (randomised = 36).

Period 1 title

Baseline & Analysis (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst

Are arms mutually exclusive

Yes

Arm A

Arm description

L-citrulline

Arm type

Experimental

Investigational medicinal product name

L-citrulline

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Dietary supplements of L-Citrulline (3g)/ placebo were taken twice daily from randomisation, 14 +/-2 weeks gestational age unitl 22+/-2 weeks gestational age (maximum 10 weeks). Each 30ml of L Citrulline solution contains: L Citrulline 3g Orange syrup 4.5mL Sodium methylhydroxybenzoate 24mg Sodium propylhydroxybenzoate 6mg Dilute hydrochloric acid 10% 0.069mL Purified water to 30ml

Arm B

Arm description

Placebo

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Dietary supplements of L-Citrulline (3g)/ placebo were taken twice daily from randomisation, 14 +/-2 weeks gestational age unitl 22+/-2 weeks gestational age (maximum 10 weeks). Each 30ml of placebo solution contains: Orange syrup 4.5mL Sodium methylhydroxybenzoate 24mg Sodium propylhydroxybenzoate 6mg Dilute hydrochloric acid 10% 0.069mL Purified water to 30ml

Number of subjects in period 1	Arm A	Arm B
Started	24	12
Completed	24	12

Baseline characteristics

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Reporting group title

Arm A

Reporting group description

L-citrulline

Reporting group title

Arm B

Reporting group description

Placebo

Reporting group values	Arm A	Arm B	Total
Number of subjects	24	12	36
Age categorical
Age
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	24	12	36
From 65-84 years	0	0	0
85 years and over	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	33.73 ± 4.09	34.26 ± 4.42	-
Gender categorical
Units: Subjects
Female	24	12	36
Male	0	0	0
Antihypertensive medication
Any antihypertensive medication taken if last 12 months
Units: Subjects
Yes	15	6	21
No	9	6	15
Cardiac disease
Units: Subjects
Yes	0	0	0
No	23	12	35
Data unobtainable	1	0	1
Diagnosis
Units: Subjects
Primary	19	11	30
Secondary	4	1	5
Data unobtainable	1	0	1
Ethnicity
Units: Subjects
Black African	6	2	8
Black Caribbean	1	2	3
East/ Central Asian	2	0	2
South Asian	2	0	2
White	12	8	20
Other	1	0	1
Viable pregnancies
Number of past viable pregnancies
Units: Subjects
Zero	6	0	6
One	8	8	16
Two	3	1	4
Three	6	1	7
Four	0	0	0
Five	1	1	2
Six	0	0	0
Seven	0	1	1
Presence of Proteinuria
Units: Subjects
Yes	2	0	2
No	22	12	34
BMI
Units: Kg/ m^2
arithmetic mean (standard deviation)	31.13 ± 7.59	33.36 ± 10.16	-
Diastolic Blood pressure
Units: mmHg
arithmetic mean (standard deviation)	86.96 ± 8.08	93.47 ± 10.21	-
Gestational age
Units: days
arithmetic mean (standard deviation)	94.08 ± 8.14	95.42 ± 5.25	-
Systolic blood pressure
Units: mmHg
arithmetic mean (standard deviation)	131.4 ± 11.65	138.08 ± 15.47	-
Time since diagnosis
Units: Years
median (inter-quartile range (Q1-Q3))	3.35 (0.98 to 10.23)	4.71 (1.46 to 9.71)	-

End points

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Reporting group title

Arm A

Reporting group description

L-citrulline

Reporting group title

Arm B

Reporting group description

Placebo

Primary: Diastolic blood pressure

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End point title

Diastolic blood pressure

End point description

Change in diastolic BP (average of 3 readings) between randomisation (visit 1) and the 8 week clinic visit (visit 3). Within-patient change in diastolic BP from randomisation will be calculated by subtracting each patient’s average diastolic BP measurement at randomisation (visit 1) from their average diastolic BP measurement at 8 weeks (visit 3). Standardised within-patient change in diastolic BP will be calculated by dividing each patient’s change in diastolic BP from baseline by the number of days between visit 3 and visit 1. Within-patient change and standardised within-patient change from visit 1 to visit 3 of dBP was presented using mean and 95% confidence interval for each treatment group separately. (See supplementary material for confidence intervals).

End point type

Primary

End point timeframe

Change in diastolic BP between randomisation (visit 1) and the 8 week clinic visit (visit 3).

End point values	Arm A	Arm B
Number of subjects analysed	24	12
Units: mmHg
arithmetic mean (standard deviation)
dBP differences	-1.82 ± 9.56	-5 ± 12.21
dBP standardised differences	-0.03 ± 0.16	-0.08 ± 0.2

Exploratory regression dBP

Statistical analysis description

Exploratory regression analyses was conducted using ANCOVA for each continous outcomes to directly account for the duration in days between visit 1 and visit 3 when assessing the change in outcome from visit 1 to visit 3. In particular, the visit 3 outcome was regressed against visit 1 outcome, treatment group and duration (in days) between visit 1 and visit 3.

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.857

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.64

Confidence interval

level

95%

sides

2-sided

lower limit

-7.77

upper limit

6.5

Variability estimate

Standard error of the mean

Dispersion value

3.5

Notes
[1] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size

Primary: Recrutiment rates

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End point title

Recrutiment rates ^[2]

End point description

The primary process outcomes is overall recruitment rate, based on the screening logs. Recruitment rate = total number recruited / total eligible women entered on screening log. Recruitment rate (averaged over the entire recruitment period) was presented with 95% CI, along with the number of women eligible and recruited (see supplementary material for confidence interval).

End point type

Primary

End point timeframe

Screening occured prior to randomisation.

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No between group comparisons were conducted for this outcome.

End point values	Arm A	Arm B
Number of subjects analysed	24 ^[3]	12 ^[4]
Units: persons
Eligible	41	41
Randomised	24	12

Notes
[3] - The number eligible (above) can only be provided overall for both arms (41).
[4] - The number eligible (above) can only be provided overall for both arms (41).

No statistical analyses for this end point

Primary: Acceptability of intervention

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End point title

Acceptability of intervention ^[5]

End point description

Acceptability of the intervention was assessed based on feedback from questions 1-3 of a patient questionnaire: Q1: The number (and percentage) of women who selected each response (i.e. who found taking the treatment easy, neither difficult/easy or difficult) will be summarised for each treatment group separately. Q2: The number (and percentage) of women who described the taste of the treatment as delicious/pleasant (as opposed to neither unpleasant/awful) will be summarised for each treatment group separately. Q3: The number (and percentage) of women who selected each response (i.e. missed doses every day, 1-2 times per week, 1-2 per month or hardly ever) will be summarised for each treatment group separately.

End point type

Primary

End point timeframe

After completion of intervention.

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No between group comparisons were conducted for this outcome.

End point values	Arm A	Arm B
Number of subjects analysed	22 ^[6]	10 ^[7]
Units: persons
Q1: Easy	18	8
Q1: Neither difficult or easy	2	2
Q1: Difficult	2	0
Q2: Delicious	1	0
Q2: Pleasent	12	4
Q2: Unpleasant	8	6
Q2: Awful	1	0
Q3: Every day	0	1
Q3: Once/ twice per week	8	2
Q3: Once/ twice per month	4	2
Q3: Hardly ever	10	5

Notes
[6] - n missing = 2
[7] - n missing = 2

No statistical analyses for this end point

Secondary: Ambulatory BP monitor

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End point title

Ambulatory BP monitor

End point description

Within-patient change in average day and night time systolic and diastolic ABPM measurements from randomisation will be calculated by subtracting each patient’s average visit 1 systolic ABPM measurement from their average visit 3 systolic ABPM measurement, for day and night time averages separately. Standardised within-patient change in average day and night time systolic and diastolic ABPM from baseline will be calculated by dividing each patient’s change in average day and night time systolic ABPM by the number of days between visit 3 and visit 1, for day and night time averages separately. Within-patient change and standardised within-patient change from visit 1 to visit 3 of ABPM measurements was presented using mean and 95% confidence interval for each treatment group separately. (See supplementary material for confidence intervals).

End point type

Secondary

End point timeframe

Change in average day and night time ambulatory BP monitor (ABPM) measurements (systolic and diastolic) between randomisation (visit 1) and the 8 week clinic visit (visit 3).

End point values	Arm A	Arm B
Number of subjects analysed	20 ^[8]	9 ^[9]
Units: mmHg
arithmetic mean (standard deviation)
day time sBP differences	-0.35 ± 7.18	-2.78 ± 6.82
day time sBP standardised differences	-0.003 ± 0.12	-0.04 ± 0.12
night time sBP differences	0.18 ± 8.92	3.29 ± 8.6
night time sBP standardised differences	0.01 ± 0.16	0.06 ± 0.15
day time dBP differences	-2.05 ± 7.25	-3.11 ± 5.97
day time dBP standardised differences	-0.03 ± 0.13	-0.05 ± 0.1
night time dBP differences	0.41 ± 7.67	2 ± 5.63
night time dBP standardised differences	0.01 ± 0.13	0.04 ± 0.09

Notes
[8] - Day time: n=20, n missing= 4. Night time: n=17, n missing=7
[9] - Day time: n=9, n missing= 3. Night time: n=7, n missing=5

Exploratory regression day time sBP (ABPM)

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[10]

P-value

= 0.354

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

2.71

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2

upper limit

8.63

Variability estimate

Standard error of the mean

Dispersion value

2.87

Notes
[10] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size.

Exploratory regression night time sBP (ABPM)

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

= 0.4128

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-3.33

Confidence interval

level

95%

sides

2-sided

lower limit

-11.62

upper limit

4.97

Variability estimate

Standard error of the mean

Dispersion value

3.98

Notes
[11] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size. Note: for ABPM night time exploratory regression analysis the group numbers are n=17 for L-citrulline and n=7 for placebo (overall n=24).

Exploratory regression day time dBP (ABPM)

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

= 0.9779

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-6.04

upper limit

5.88

Variability estimate

Standard error of the mean

Dispersion value

2.89

Notes
[12] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size.

Exploratory regression night time dBP (ABPM)

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[13]

P-value

= 0.4103

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-2.52

Confidence interval

level

95%

sides

2-sided

lower limit

-8.78

upper limit

3.74

Variability estimate

Standard error of the mean

Dispersion value

Notes
[13] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size. Note: for ABPM night time exploratory regression analysis the group numbers are n=17 for L-citrulline and n=7 for placebo (overall n=24).

Secondary: Cardiovascular compliance

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End point title

Cardiovascular compliance

End point description

Within-patient change in central BP, PWV and normalised augmentation index was calculated by subtracting each patient’s randomisation measurements from their 8 week measurements. Standardised within-patient change in measurement from baseline was calculated by dividing each patient’s change in measurement from randomisation by the number of days between visit 3 and visit 1. Normalised augmentation index aortic values are calculated as follows: Augmentation Index Aortic – 0.431*(75-Heart rate) Standardised within-patient change from visit 1 to visit 3 of each vascular compliance measurement was presented using mean and 95% confidence interval for each treatment group separately. (See supplementary material for confidence intervals).

End point type

Secondary

End point timeframe

Change in vascular compliance measurements (central BP, pulse wave velocity (PWV) and normalised augmentation index) measured at randomisation (visit 1) and the 8 week clinic visit (visit 3).

End point values	Arm A	Arm B
Number of subjects analysed	14 ^[14]	8 ^[15]
Units: (see below)
arithmetic mean (standard deviation)
central BP differences (mmHg)	-4.86 ± 19.42	-6.28 ± 29.03
central BP standardised differences (mmHg)	-0.08 ± 0.32	-0.1 ± 0.5
PWV differences (m/s)	-0.36 ± 0.94	0.04 ± 1.51
PWV standardised differences (m/s)	-0.01 ± 0.02	0.0006 ± 0.03
Augmentation index differences (%)	-4.95 ± 10.14	-1.73 ± 41.82
Augmentation index standardised differences (%)	-0.08 ± 0.17	-0.01 ± 0.74

Notes
[14] - n missing = 10
[15] - n missing = 4

Exploratory regression central BP

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[16]

P-value

= 0.8498

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

1.69

Confidence interval

level

95%

sides

2-sided

lower limit

-16.82

upper limit

20.21

Variability estimate

Standard error of the mean

Dispersion value

8.81

Notes
[16] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size.

Exploratory regression PWV

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[17]

P-value

= 0.4429

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.42

Confidence interval

level

95%

sides

2-sided

lower limit

-1.56

upper limit

0.71

Variability estimate

Standard error of the mean

Dispersion value

0.54

Notes
[17] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size

Exploratory regression normalised AIO

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

= 0.8788

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.88

Confidence interval

level

95%

sides

2-sided

lower limit

-27.46

upper limit

23.7

Variability estimate

Standard error of the mean

Dispersion value

12.18

Notes
[18] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size.

Secondary: Vascular compliance

Top of page

End point title

Vascular compliance

End point description

Within-patient change in vascular compliance measure was calculated by subtracting each patient’s visit 1 vascular compliance measurement from their visit 3 vascular compliance measurement. Standardised within-patient change in vascular compliance measurements was calculated by dividing each patient’s change in vascular compliance measurement by the number of days between visit 3 and visit 1. Within-patient change and standardised within-patient change from visit 1 to visit 3 of ADMA concentration and Arginine concentrations was presented using mean and 95% confidence interval for each treatment group separately. (See supplementary material for confidence intervals).

End point type

Secondary

End point timeframe

Change in vascular compliance measurements (cardiac output (CO), cardiac index (CI), stroke volume index (SVI) and total peripheral resistance index (TPRI) between randomisation (visit 1) and the 8 week clinic visit (visit 3).

End point values	Arm A	Arm B
Number of subjects analysed	23 ^[19]	12 ^[20]
Units: (see below)
arithmetic mean (standard deviation)
CO (L/minute) differences	-0.54 ± 1.75	-1.18 ± 1.22
CO (L/minute) standardised differences	-0.01 ± 0.03	-0.02 ± 0.02
CI (L/min/m^2) differences	-0.28 ± 0.88	-0.57 ± 0.63
CI (L/min/m^2) standardised differences	-0.01 ± 0.01	-0.01 ± 0.01
SVI (ml/m^2) differences	-4.43 ± 10.69	-7.82 ± 8.3
SVI (ml/m^2) standardised differences	-0.08 ± 0.17	-0.13 ± 0.14
TPRI (mmHg ml^-1 min^-1 kg^-1) differences	140.35 ± 1508.87	574.92 ± 963.77
TPRI (mmHg ml^-1 min^-1 kg^-1) standardised diffs	2.89 ± 23.58	9.25 ± 16.61

Notes
[19] - n missing = 1
[20] - For CO, CI and TRPI: n=12, n missing = 0 For SVI: n=11, n missing = 1

Exploratory regression CO

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[21]

P-value

= 0.8731

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

0.84

Variability estimate

Standard error of the mean

Dispersion value

0.38

Notes
[21] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size.

Exploratory regression CI

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[22]

P-value

= 0.8808

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.34

upper limit

0.4

Variability estimate

Standard error of the mean

Dispersion value

0.18

Notes
[22] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size.

Exploratory regression SVI

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

= 0.4211

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

1.93

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

6.75

Variability estimate

Standard error of the mean

Dispersion value

2.36

Notes
[23] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size. Note: for SVI exploratory regression analysis the group numbers are n=23 for L-citrulline and n=11 for placebo (overall n=34).

Exploratory regression TRPI

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[24]

P-value

= 0.6493

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-135.64

Confidence interval

level

95%

sides

2-sided

lower limit

-738.18

upper limit

466.89

Variability estimate

Standard error of the mean

Dispersion value

295.43

Notes
[24] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size.

Secondary: Uteroplacental measurements (continuous)

Top of page

End point title

Uteroplacental measurements (continuous)

End point description

Within-patient change in RI and PI was calculated by subtracting each patient’s visit 1 RI or PI measurement from their visit 3 RI or PI measurement. Standardised within-patient change in RI and PI measurements was calculated by dividing each patient’s change in RI or PI measurement by the number of days between visit 3 and visit 1. Within-patient change and standardised within-patient change from visit 1 to visit 3 of RI and PI was presented using mean and 95% confidence interval for each treatment group separately. (See supplementary material for confidence intervals).

End point type

Secondary

End point timeframe

Change in uteroplacental blood flow measurements (uterine artery resistance index (RI) and pulsatility index (PI)) from randomisation (visit 1) to 8 weeks (visit 3).

End point values	Arm A	Arm B
Number of subjects analysed	23 ^[25]	12 ^[26]
Units: Ratio
arithmetic mean (standard deviation)
RI differences	-0.1 ± 0.11	-0.08 ± 0.09
RI standardised differences	-0.002 ± 0.002	-0.001 ± 0.002
PI differences	-0.43 ± 0.43	-0.37 ± 0.34
PI standardised differences	-0.01 ± 0.01	-0.01 ± 0.01

Notes
[25] - n missing = 1
[26] - n missing = 0

Exploratory regression RI

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[27]

P-value

= 0.7345

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.05

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.03

Notes
[27] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size.

Exploratory regression PI

Statistical analysis description

Comparison groups

Arm A v Arm B

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[28]

P-value

= 0.8704

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

0.21

Variability estimate

Standard error of the mean

Dispersion value

0.11

Notes
[28] - Exploratory regression analyses. These analyses are viewed as entirely hypothesis generating, rather than confirmatory analyses, in light of the small sample size.

Secondary: Uteroplacental measurments (discrete)

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End point title

Uteroplacental measurments (discrete)

End point description

Presence/absence of notching. Bilateral notching is defined as “L Notch” = Yes and “R Notch” = Yes, and change in bilateral notching is defined as patients with bilateral notching at visit 1 no longer having bilateral notching at visit 3.

End point type

Secondary

End point timeframe

Change in uteroplacental blood flow measurements ( presence of bilateral notching) from randomisation (visit 1) to 8 weeks (visit 3).

End point values	Arm A	Arm B
Number of subjects analysed	24	12
Units: persons
Visit 1 notchings present	10	2
Visit 3 notchings present	5	0
Change in notchings	5	2

No statistical analyses for this end point

Secondary: Plasma ADMA and Arginie

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End point title

Plasma ADMA and Arginie

End point description

Within-patient change in plasma ADMA concentration and Arginine concentration was calculated by subtracting each patient’s visit 1 concentrations from their visit 3 concentrations. Standardised within-patient change in concentration was calculated by dividing each patient’s change in concentration by the number of days between visit 3 and visit 1. Within-patient change and standardised within-patient change from visit 1 to visit 3 of ADMA concentration and Arginine concentrations was presented using mean and 95% confidence interval for each treatment group separately. (See supplementary material for confidence intervals).

End point type

Secondary

End point timeframe

Change in plasma ADMA and arginine concentrations between randomisation (visit 1) and the 8 week clinic visit (visit 3)

End point values	Arm A	Arm B
Number of subjects analysed	21 ^[29]	11 ^[30]
Units: μmol/L
arithmetic mean (standard deviation)
Plasma ADMA differences	0.01 ± 0.05	-0.01 ± 0.05
Plasma ADMA standardised differences	0.0002 ± 0.0008	-0.0002 ± 0.0008
Arginine differences	6.86 ± 36.34	-2.55 ± 13.34
Arginine standardised differences	0.14 ± 0.62	-0.04 ± 0.23

Notes
[29] - Plasma ADMA: n=19, n missing=5 Arginine: n=21, n missing = 3
[30] - Plasma ADMA: n=8, n missing=4 Arginine: n=11, n missing = 1

No statistical analyses for this end point

Secondary: Antihypertensive therapy

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End point title

Antihypertensive therapy

End point description

Antihypertensive therapy (AHT) information was used to determine whether patients were taking antihypertensive therapy at visit 1 or visit 3, for at least one of “Methyldopa”, “Labetalol”, “Beta blocking agent” or “Calcium channel antagonist”. The number of patients who are taking antihypertensive therapy at visit 1 is presented for each treatment group separately. The number of patients who are taking antihypertensive therapy at visit 3 will be presented for each treatment group separately. The number of patients who change from taking (any) antihypertensive therapy from visit 1 to visit 3 is presented for each treatment group separately

End point type

Secondary

End point timeframe

Change in antihypertensive therapy from visit 1 to visit 3.

End point values	Arm A	Arm B
Number of subjects analysed	24 ^[31]	12 ^[32]
Units: persons
Visit 1 AHT	16	6
Visit 3 AHT	13	6

Notes
[31] - AHT: Visit 1 only n = 3, visit 1 & 3 n = 13 (overall n = 16)
[32] - AHT: Visit 1 only n = 0, visit 1 & 3 n = 6 (overall n = 6)

No statistical analyses for this end point

Post-hoc: Pregnancy outcomes (continuous)

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End point title

Pregnancy outcomes (continuous)

End point description

Post- hoc summaries for the status and outcomes after giving birth. Continous outcomes presented with means and standard deviation. Categorical outcomes present using frequencies.

End point type

Post-hoc

End point timeframe

Status and outcomes of pregnancy after giving birth.

End point values	Arm A	Arm B
Number of subjects analysed	24	12
Units: (see below)
arithmetic mean (standard deviation)
Gestational age (days)	264.0 ± 12.2	259.8 ± 12.1
Birthweight (grams)	2846.8 ± 622.1	3123.6 ± 707.8

No statistical analyses for this end point

Post-hoc: Pregnancy outcomes (discrete)

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End point title

Pregnancy outcomes (discrete)

End point description

Post- hoc summaries for the status and outcomes after giving birth. Continous outcomes presented with means and standard deviation. Categorical outcomes present using frequencies.

End point type

Post-hoc

End point timeframe

Status and outcomes of pregnancy after giving birth.

End point values	Arm A	Arm B
Number of subjects analysed	24	12
Units: persons
Live born: Yes	24	12
Gender: Female	14	5
Gender: Male	10	7
Magnesium sulfate required: Yes	1	0
Steroids required: Yes	5	2
Preeclampsia: Yes	5	3
Chronic hypertension: Yes	24	12
SGA by population centile: Yes	7	3
FGR: Yes	7	3
Pregestational diabetes: Yes	3	3
Gestational diabetes: Yes	4	0
Perinatal outcome: Alive	24	12
Perinatal survival: Yes	24	12

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

The appearance or worsening of any undesirable sign, symptom, or medical condition occurring after the study has commenced, even if not considered to be related to the study. See uploaded results for details of non-serious adverse events.

Adverse event reporting additional description

Medical conditions/diseases present before starting the study will only be considered as adverse events if they worsen after the start of the study. Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or symptoms, are considered clinically significant, or require therapy.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

L-citrulline safety set

Reporting group description

Any participant who recieved at least 1 dose of L-citrulline.

Reporting group title

Placebo safety set

Reporting group description

Any participant who recieved at least one dose of placebo.

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: Non-serious adverse events not coded using MedDRA so these are included in the main study report which is attached.

Serious adverse events	L-citrulline safety set	Placebo safety set
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 24 (0.00%)	1 / 12 (8.33%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Pregnancy, puerperium and perinatal conditions
Foetal disorder
Additional description: Fetal ventriculomegaly diagnosed on fetal MRI on 8th May 2018. Participant delivered on 26th May 2018. Baby well at birth and will have neonatal follow-up.
subjects affected / exposed	0 / 24 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	L-citrulline safety set	Placebo safety set
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 24 (0.00%)	0 / 12 (0.00%)

More information

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Were there any global substantial amendments to the protocol? Yes

19 Mar 2017

Amendment 2: Submitted to meet MHRA conditions on initial approval Approved by MHRA – 19/03/2017 Approved by REC – 27/03/2017 Approved by HRA – 23/03/2017 (initial approval) IB document update -As per MHRA recommendations to clarify stability data testing. Contact card - This was omitted from the original application in error. Change to participant questionnaire - Removal of question 1

23 Mar 2017

Amendment 1: Inclusion of IRAS ID on patient information sheets. Approved by HRA – 23/03/2017 (initial approval) Approved by MHRA – N/A Approved by REC – N/A

03 Jul 2017

Amendment 3: Submitted to amend the protocol Approved by MHRA – 18/08/2017 Approved by REC – 03/07/2017 Approved by HRA - 31/08/2017 Protocol - ABPM will now be issued at study visit 1 and 3 Patient information sheets ABPM will now be issued at study visit 1 and 3 Change of PI at St Thomas’ Hospital

24 Aug 2017

Amendment 4: Submitted to amend PISCs Approved by HRA and REC - 24/08/2017 Approved by MHRA – N/A Amendment to Patient Information sheets to clarify what scans are optional research scans and inclusion of further data protection information

17 Nov 2017

Amendment 5: Submitted to clarify that other sites within MFT can identify patients for CHERRY and amend the Sponsor name throughout the protocol Approved by MHRA – N/A Approved by REC – 17/11/2017 Approved by HRA – 23/11/2017

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Feasibility study on the effects of L-citrulline on uteroplacental and cardiovascular function in hypertensive pregnant women.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Diastolic blood pressure

Primary: Diastolic blood pressure

Primary: Recrutiment rates

Primary: Recrutiment rates

Primary: Acceptability of intervention

Primary: Acceptability of intervention

Secondary: Ambulatory BP monitor

Secondary: Ambulatory BP monitor

Secondary: Cardiovascular compliance

Secondary: Cardiovascular compliance

Secondary: Vascular compliance

Secondary: Vascular compliance

Secondary: Uteroplacental measurements (continuous)

Secondary: Uteroplacental measurements (continuous)

Secondary: Uteroplacental measurments (discrete)

Secondary: Uteroplacental measurments (discrete)

Secondary: Plasma ADMA and Arginie

Secondary: Plasma ADMA and Arginie

Secondary: Antihypertensive therapy

Secondary: Antihypertensive therapy

Post-hoc: Pregnancy outcomes (continuous)

Post-hoc: Pregnancy outcomes (continuous)

Post-hoc: Pregnancy outcomes (discrete)

Post-hoc: Pregnancy outcomes (discrete)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Feasibility study on the effects of L-citrulline on uteroplacental and cardiovascular function in hypertensive pregnant women.