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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

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    Trial identification
    Sponsor protocol code
    R04341
    Additional study identifiers
    ISRCTN number
    		 ISRCTN12695929
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC number: 16/NW/0557
    Sponsors
    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
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    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?
    No
    General information about the trial
    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
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    36
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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.

    Pre-assignment
    Screening details
    		 42 patients screened, 41 eligible, 36 consented, 36 randomised.

    Pre-assignment period milestones
    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
    		 36

    Pre-assignment subject non-completion reasons
    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
    Period 1 title
    Baseline & Analysis (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 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 title
    		 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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    Baseline characteristics reporting groups
    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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    End points reporting groups
    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 )
    Statistical analysis title
    		 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
    36
    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
    Statistical analysis title
    		 Exploratory regression day time sBP (ABPM)
    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
    29
    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.
    Statistical analysis title
    		 Exploratory regression night time sBP (ABPM)
    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
    29
    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).
    Statistical analysis title
    		 Exploratory regression day time dBP (ABPM)
    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
    29
    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.
    Statistical analysis title
    		 Exploratory regression night time dBP (ABPM)
    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
    29
    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
    3
    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
    Statistical analysis title
    		 Exploratory regression central BP
    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
    22
    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.
    Statistical analysis title
    		 Exploratory regression PWV
    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
    22
    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
    Statistical analysis title
    		 Exploratory regression normalised AIO
    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
    22
    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

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    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
    Statistical analysis title
    		 Exploratory regression CO
    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
    35
    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.
    Statistical analysis title
    		 Exploratory regression CI
    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
    35
    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.
    Statistical analysis title
    		 Exploratory regression SVI
    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
    35
    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).
    Statistical analysis title
    		 Exploratory regression TRPI
    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
    35
    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)

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    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
    Statistical analysis title
    		 Exploratory regression RI
    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
    35
    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.
    Statistical analysis title
    		 Exploratory regression PI
    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
    35
    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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    Adverse events information [1]
    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 used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    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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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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