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    Clinical Trial Results:
    High Or Low Dose Syntocinon® for delay in labour: the HOLDS trial

    Summary
    EudraCT number
    		 2015-005537-50
    Trial protocol
    		 GB  
    Global end of trial date
    31 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Mar 2025
    First version publication date
    12 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15/BWH/P061
    Additional study identifiers
    ISRCTN number
    		 ISRCTN99841044
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Funders Reference: HTA 14/140/44, Sponsors Reference: 15/BWH/PO61
    Sponsors
    Sponsor organisation name
    Birmingham Women’s and Children’s NHS FT
    Sponsor organisation address
    Mindelsohn Way, Birmingham, United Kingdom, B15 2TG
    Public contact
    Ms Elizabeth Adey, Research and Development, Birmingham Women’s and Children’s NHS Foundation Trust, e.adey@nhs.net
    Scientific contact
    Ms Elizabeth Adey, Research and Development, Birmingham Women’s and Children’s NHS Foundation Trust, e.adey@nhs.net
    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
    03 Oct 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Sep 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This trial will assess whether high dose regimen oxytocin compared to standard (lower) dose regimen oxytocin will reduce the Caesarean section rate for women with confirmed delay in the first stage of labour,
    Protection of trial subjects
    The trial began recruiting on 30th June 2017 and recruitment was suspended for the first time on 17th October 2017 due to two unanticipated issues: -A site alerted us that clinicians could remove the label from the ampoule thus potentially unblinding the randomised treatment. The manufacturer resolved this by removing the original label and re-labelling the ampoules for the 900 treatment packs still stored with them, but 438 treatment packs had to be destroyed. -Routine monitoring processes uncovered a total of 233 temperature deviations outside the recommended range of 2-8C across 84% (16/19) of active sites. Extensive revisions to the guidelines for IMP monitoring and storage were introduced, including the use of buffered thermometers. Deviations were reduced to 38 across 29% (7/24) of sites. The buffered thermometers are set up to alarm if the temperature is recorded < 2 or > 30C (where there are no stability data and the ampoules cannot be used). The clinical staff would phone the 24/7 telephone randomisation system to halt recruitment in the site. This issue was submitted to the MHRA as a Serious Breach which was resolved when we submitted an amendment to restart the trial to HRA and the MHRA on the 20th February 2018. HRA approval was received on 8th June 2018. Local R&D approval was obtained and we re-started recruitment on 27th June 2018. In August 2018 it was identified that the IMP had been packaged in November 2016 by Sharp Services at ambient temperatures outside those recommended (2-8C), meaning potentially it should have been discarded and not used. The trial was suspended again and the matter was referred to the MHRA. In mid-September 2018, the matter was resolved when the MHRA decided that this process would not have had any detrimental effect on participants. The trial was further delayed due to the covid pandemic, meaning the trial awarded time and funding had been exhausted so we could not re-open.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 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: 120
    Worldwide total number of subjects
    120
    EEA total number of subjects
    0
    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)
    120
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 iHOLDs participants were recruited from obstetric departments in 21 participant hospitals across the UK.

    Pre-assignment
    Screening details
    		 In the first instance, arrangements were made for all nulliparous women to receive written information about the trial during the antenatal period, ideally at about 34 – 36 weeks. When admitted to the labour ward potential inclusion was then checked by the midwife responsible for her care, with final eligibility determined by an obstetrician.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The drug was prepared for trial use by Sharp Clinical Services, who blinded, labelled, packaged and distributed the treatment packs in temperatures compliant with the SPC (between 2-8C). Ampoules are only manufactured in 5 and 10iu and treatment packs contain 2 ampoules and will be stored in a fridge on Delivery Suite.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard Dose Regimen
    Arm description
    		 A standard dose of oxytocin starting at 2mu / min and increasing every 30 minutes up to a maximum of 32 mu / min.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oxytocin - Standard Regimen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Standard Strength Oxytocin Solution (10IU in 50mls) Regimen Time (Mins) - mu/min 0 min - 2 mu/min 30 mins - 4 mu/min 60 mins - 8 mu/min 90 mins - 12 mu/min 120 mins - 16 mu/min 150 mins - 20 mu/min 180 mins - 24 mu/min 210 mins - 28 mu/min 240 mins - 32 mu/min

    Arm title
    		 High Dose Regimen
    Arm description
    		 High dose regimen of oxytocin starting at 4mU/min increasing every 30 minutes to a maximum of 64mU/min. The high dose regimen (i.e. double the concentration) has a higher starting dose, earlier attainment of conventional maximum doses (at 2 hours rather than over 4 hours) and the possible use of higher maximum doses of oxytocin compared to the standard regimen
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxytocin - High Regimen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Higher Strength Oxytocin Solution (20IU in 50mls) Regimen Time (Mins) - mu/min 0 min - 4 mu/min 30 mins - 8 mu/min 60 mins - 16 mu/min 90 mins - 24 mu/min 120 mins - 32 mu/min 150 mins - 40 mu/min 180 mins - 48 mu/min 210 mins - 56 mu/min 240 mins - 64 mu/min

    Number of subjects in period 1 [1]
    		Standard Dose Regimen High Dose Regimen
    Started
    58
    60
    Completed
    58
    60
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two participants at one centre have been excluded from analysis for the context of this report due to issues during randomisation and during data collection, one ppt did not give consent and a second was randomised twice and it was unknown which treatment she received.
    Period 2
    Period 2 title
    Primary Outcome (Birth)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard Dose Regimen
    Arm description
    		 A standard dose of oxytocin starting at 2mu / min and increasing every 30 minutes up to a maximum of 32 mu / min.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oxytocin - Standard Regimen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Standard Strength Oxytocin Solution (10IU in 50mls) Regimen Time (Mins) - mu/min 0 min - 2 mu/min 30 mins - 4 mu/min 60 mins - 8 mu/min 90 mins - 12 mu/min 120 mins - 16 mu/min 150 mins - 20 mu/min 180 mins - 24 mu/min 210 mins - 28 mu/min 240 mins - 32 mu/min

    Arm title
    		 High Dose Regimen
    Arm description
    		 High dose regimen of oxytocin starting at 4mU/min increasing every 30 minutes to a maximum of 64mU/min. The high dose regimen (i.e. double the concentration) has a higher starting dose, earlier attainment of conventional maximum doses (at 2 hours rather than over 4 hours) and the possible use of higher maximum doses of oxytocin compared to the standard regimen
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxytocin - High Regimen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Higher Strength Oxytocin Solution (20IU in 50mls) Regimen Time (Mins) - mu/min 0 min - 4 mu/min 30 mins - 8 mu/min 60 mins - 16 mu/min 90 mins - 24 mu/min 120 mins - 32 mu/min 150 mins - 40 mu/min 180 mins - 48 mu/min 210 mins - 56 mu/min 240 mins - 64 mu/min

    Number of subjects in period 2
    		Standard Dose Regimen High Dose Regimen
    Started
    58
    60
    Completed
    58
    60

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard Dose Regimen
    Reporting group description
    		 A standard dose of oxytocin starting at 2mu / min and increasing every 30 minutes up to a maximum of 32 mu / min.

    Reporting group title
    High Dose Regimen
    Reporting group description
    		 High dose regimen of oxytocin starting at 4mU/min increasing every 30 minutes to a maximum of 64mU/min. The high dose regimen (i.e. double the concentration) has a higher starting dose, earlier attainment of conventional maximum doses (at 2 hours rather than over 4 hours) and the possible use of higher maximum doses of oxytocin compared to the standard regimen

    Reporting group values
    		 Standard Dose Regimen High Dose Regimen Total
    Number of subjects
    		 58 60 118
    Age categorical
    Units: Subjects
        <20
    		 4 5 9
        20 to <30
    		 27 29 56
        30 to < 40
    		 27 26 53
        40 and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28.7 ( 5.6 ) 28.7 ( 5.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 58 60 118
        Male
    		 0 0 0
    Ethnicity
    Units: Subjects
        UK (White)
    		 46 46 92
        South Asian (Asian)
    		 4 3 7
        Southern & Other European (White)
    		 3 4 7
        Northern European (White)
    		 2 2 4
        South East Asian (White)
    		 0 3 3
        African or African-Caribbean (Black)
    		 1 1 2
        Other Non-European (Other)
    		 0 1 1
        Don't Know / NA
    		 2 0 2
    Degree of Cervical Dilation (cm)
    Units: Subjects
        <6cm
    		 28 28 56
        >=6cm
    		 30 32 62
    BMI
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 24.7 ( 4.7 ) 25.6 ( 5.2 ) -
    Gestational Age at Randomisation (weeks)
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    		 39.57 (39.14 to 40.14) 39.43 (38.86 to 40.14) -

    End points

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    End points reporting groups
    Reporting group title
    Standard Dose Regimen
    Reporting group description
    		 A standard dose of oxytocin starting at 2mu / min and increasing every 30 minutes up to a maximum of 32 mu / min.

    Reporting group title
    High Dose Regimen
    Reporting group description
    		 High dose regimen of oxytocin starting at 4mU/min increasing every 30 minutes to a maximum of 64mU/min. The high dose regimen (i.e. double the concentration) has a higher starting dose, earlier attainment of conventional maximum doses (at 2 hours rather than over 4 hours) and the possible use of higher maximum doses of oxytocin compared to the standard regimen
    Reporting group title
    Standard Dose Regimen
    Reporting group description
    		 A standard dose of oxytocin starting at 2mu / min and increasing every 30 minutes up to a maximum of 32 mu / min.

    Reporting group title
    High Dose Regimen
    Reporting group description
    		 High dose regimen of oxytocin starting at 4mU/min increasing every 30 minutes to a maximum of 64mU/min. The high dose regimen (i.e. double the concentration) has a higher starting dose, earlier attainment of conventional maximum doses (at 2 hours rather than over 4 hours) and the possible use of higher maximum doses of oxytocin compared to the standard regimen

    Primary: Mode of Delivery of Birth

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    End point title
    		 Mode of Delivery of Birth [1]
    End point description
    The primary outcome was the effect on caesarean section rate of high does regimen versus standard dose regimen oxytocin. We also looked at what the mode of delivery was if not a CS.
    End point type
    Primary
    End point timeframe
    Collected at time of birth
    Notes
    [1] - 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 formal analyses was done for the trial due to low numbers given the trial closed early.
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
        Caesarean Section
    20
    16
        Spontaneous Vaginal Birth
    18
    20
        Instrumental
    20
    24
    No statistical analyses for this end point

    Secondary: Category of Emergency

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    End point title
    		 Category of Emergency
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at birth in women who had a caesarean section
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    20
    16
    Units: Women
        Category 1: Immediate threat to life
    6
    5
        Category 2: Maternal or fetal compromise
    11
    11
        Category 3: Early birth needed but no compromise
    3
    0
    No statistical analyses for this end point

    Secondary: Reason for Caesarean Section

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    End point title
    		 Reason for Caesarean Section
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at time of birth in women who had a caesarean.
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    20 [2]
    16 [3]
    Units: Women
        Delay in 1st stage
    13
    11
        Delay in 2nd stage
    20
    2
        Maternal Request
    1
    0
        Hyperstimulation
    1
    1
        CTG concerns without FBS
    16
    14
        Abnormal FBS
    0
    1
        Failed Instrumental
    5
    0
        Unsuitable for instrumental
    10
    10
        Other
    3
    2
    Notes
    [2] - More than one reason can be selected
    [3] - More than 1 reason can be selected
    No statistical analyses for this end point

    Secondary: Epidural Use during Labour

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    End point title
    		 Epidural Use during Labour
    End point description
    End point type
    Secondary
    End point timeframe
    Collected throughout birth
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
        Yes
    47
    46
    No statistical analyses for this end point

    Secondary: Duration of first stage of labour

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    End point title
    		 Duration of first stage of labour
    End point description
    End point type
    Secondary
    End point timeframe
    During labour
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    41
    42
    Units: minute
        arithmetic mean (standard deviation)
    818 ( 221 )
    888 ( 249 )
    No statistical analyses for this end point

    Secondary: Duration of second stage of labour

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    End point title
    		 Duration of second stage of labour
    End point description
    End point type
    Secondary
    End point timeframe
    During labour
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    43
    44
    Units: minute
        arithmetic mean (standard deviation)
    144 ( 64 )
    150 ( 77 )
    No statistical analyses for this end point

    Secondary: Duration of third stage of labour

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    End point title
    		 Duration of third stage of labour
    End point description
    End point type
    Secondary
    End point timeframe
    During Labour
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: minute
        arithmetic mean (standard deviation)
    8 ( 16 )
    8 ( 7 )
    No statistical analyses for this end point

    Secondary: Time from randomisation to Birth

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    End point title
    		 Time from randomisation to Birth
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Birth
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    57
    60
    Units: minute
        median (inter-quartile range (Q1-Q3))
    431 (349 to 548)
    368 (242 to 608)
    No statistical analyses for this end point

    Secondary: Degree of perineal trauma

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    End point title
    		 Degree of perineal trauma
    End point description
    End point type
    Secondary
    End point timeframe
    During labour
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
        None (intact perineum)
    14
    20
        First Degree
    2
    3
        Second Degree
    17
    16
        Third Degree
    2
    1
        Fourth Degree
    0
    1
        Missing
    3
    3
        NA (CS)
    20
    16
    No statistical analyses for this end point

    Secondary: Fetal blood sampling during labour or significant STAN event

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    End point title
    		 Fetal blood sampling during labour or significant STAN event
    End point description
    End point type
    Secondary
    End point timeframe
    During labour
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    9
    12
    No statistical analyses for this end point

    Secondary: Abnormal cardiogram leading to immediate birth without FBS

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    End point title
    		 Abnormal cardiogram leading to immediate birth without FBS
    End point description
    End point type
    Secondary
    End point timeframe
    During labour
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    13
    18
    No statistical analyses for this end point

    Secondary: Women with blood loss > 500ml (PPH)

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    End point title
    		 Women with blood loss > 500ml (PPH)
    End point description
    End point type
    Secondary
    End point timeframe
    During labour
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    27
    25
    No statistical analyses for this end point

    Secondary: IV Antibiotics for suspected or confirmed chorioamnionitis

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    End point title
    		 IV Antibiotics for suspected or confirmed chorioamnionitis
    End point description
    End point type
    Secondary
    End point timeframe
    Until discharge
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    3
    1
    No statistical analyses for this end point

    Secondary: Active management of third stage of labour

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    End point title
    		 Active management of third stage of labour
    End point description
    End point type
    Secondary
    End point timeframe
    During labour
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    55
    55
    No statistical analyses for this end point

    Secondary: Length of stay after birth in hospital

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    End point title
    		 Length of stay after birth in hospital
    End point description
    End point type
    Secondary
    End point timeframe
    From birth until discharge
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: day
        median (inter-quartile range (Q1-Q3))
    1.5 (1 to 3)
    1 (1 to 2)
    No statistical analyses for this end point

    Secondary: Rotation Required

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    End point title
    		 Rotation Required
    End point description
    For instrumental births
    End point type
    Secondary
    End point timeframe
    During labour
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    7
    4
    No statistical analyses for this end point

    Secondary: Ventouse

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    End point title
    		 Ventouse
    End point description
    In instrumental births
    End point type
    Secondary
    End point timeframe
    During labour
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    23 [4]
    24 [5]
    Units: women
        No
    19
    20
        Successful
    3
    2
        Failed
    1
    2
    Notes
    [4] - Only women with successful or failed instrumental birth
    [5] - Only women with successful or failed instrumental birth
    No statistical analyses for this end point

    Secondary: Forceps

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    End point title
    		 Forceps
    End point description
    In instrumental births
    End point type
    Secondary
    End point timeframe
    During labour
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    23 [6]
    24 [7]
    Units: women
        No
    4
    2
        Successful
    15
    22
        Failed
    3
    0
    Notes
    [6] - Only women with successful or failed instrumental birth
    [7] - Only women with successful or failed instrumental birth
    No statistical analyses for this end point

    Secondary: Primary reason for Instrumental Birth

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    End point title
    		 Primary reason for Instrumental Birth
    End point description
    In instrumental birth
    End point type
    Secondary
    End point timeframe
    At birth
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    23 [8]
    24 [9]
    Units: women
        CTG Concerns without resort to FBS
    18
    12
        Abnormal FBS (<= 7.20)
    0
    1
        Delay in 2nd stage
    14
    15
        Pushing challenges
    2
    1
        Other
    1
    2
    Notes
    [8] - Only women with successful or failed instrumental birth. Can select more than 1 reason.
    [9] - Only women with successful or failed instrumental birth. Can select more than 1 reason.
    No statistical analyses for this end point

    Secondary: Neonatal: Gender

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    End point title
    		 Neonatal: Gender
    End point description
    Measured in babies
    End point type
    Secondary
    End point timeframe
    At birth
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: babies
        Female
    31
    29
        Male
    27
    31
    No statistical analyses for this end point

    Secondary: Neonatal: Birthweight

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    End point title
    		 Neonatal: Birthweight
    End point description
    Neonatal outcome
    End point type
    Secondary
    End point timeframe
    At birth
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    3.52 ( 0.44 )
    3.51 ( 0.42 )
    No statistical analyses for this end point

    Secondary: Apgar score at 5 minutes

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    End point title
    		 Apgar score at 5 minutes
    End point description
    End point type
    Secondary
    End point timeframe
    At birth
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: score
        median (inter-quartile range (Q1-Q3))
    10 (9 to 10)
    9.5 (9 to 10)
    No statistical analyses for this end point

    Secondary: Arterial cord blood gases when collected

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    End point title
    		 Arterial cord blood gases when collected
    End point description
    End point type
    Secondary
    End point timeframe
    At birth
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    32
    34
    Units: pH
        arithmetic mean (standard deviation)
    7.22 ( 0.1 )
    7.22 ( 0.09 )
    No statistical analyses for this end point

    Secondary: Venous cord blood gases when collected

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    End point title
    		 Venous cord blood gases when collected
    End point description
    End point type
    Secondary
    End point timeframe
    At Birth
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    35
    39
    Units: pH
        arithmetic mean (standard deviation)
    7.27 ( 0.09 )
    7.29 ( 0.07 )
    No statistical analyses for this end point

    Secondary: Breastfeeding rates on discharge from hospital

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    End point title
    		 Breastfeeding rates on discharge from hospital
    End point description
    End point type
    Secondary
    End point timeframe
    At discharge
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: Babies
    42
    50
    No statistical analyses for this end point

    Secondary: Discharge home with mother

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    End point title
    		 Discharge home with mother
    End point description
    End point type
    Secondary
    End point timeframe
    At discharge
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: Babies
    58
    60
    No statistical analyses for this end point

    Secondary: Resuscitation

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    End point title
    		 Resuscitation
    End point description
    End point type
    Secondary
    End point timeframe
    At birth
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: Babies
    8
    6
    No statistical analyses for this end point

    Secondary: Reason for neonatal review on ward

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    End point title
    		 Reason for neonatal review on ward
    End point description
    Excluding routine baby check
    End point type
    Secondary
    End point timeframe
    From birth to discharge
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: babies
        Infection
    13
    6
        Other
    5
    7
        Baby not reviewed
    36
    45
    No statistical analyses for this end point

    Secondary: Admitted to NNU

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    End point title
    		 Admitted to NNU
    End point description
    End point type
    Secondary
    End point timeframe
    From birth to discharge
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: babies
    3
    3
    No statistical analyses for this end point

    Secondary: Level of NNU Care received

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    End point title
    		 Level of NNU Care received
    End point description
    End point type
    Secondary
    End point timeframe
    from birth to discharge
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    3
    3
    Units: babies
        Transitional
    2
    1
        Special Care (Level 1)
    0
    1
        HDC (Level 2)
    1
    0
        Intensive Care (Level 3)
    0
    0
        Missing
    0
    1
    No statistical analyses for this end point

    Secondary: Maternal: Headache

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    End point title
    		 Maternal: Headache
    End point description
    End point type
    Secondary
    End point timeframe
    From birth to discharge
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    1
    0
    No statistical analyses for this end point

    Secondary: Maternal: Nausea

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    End point title
    		 Maternal: Nausea
    End point description
    End point type
    Secondary
    End point timeframe
    from birth to discharge
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    7
    5
    No statistical analyses for this end point

    Secondary: Maternal: Vomiting

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    End point title
    		 Maternal: Vomiting
    End point description
    End point type
    Secondary
    End point timeframe
    from birth to discharge
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    5
    6
    No statistical analyses for this end point

    Secondary: Maternal: Tachycardia/Bradycardia

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    End point title
    		 Maternal: Tachycardia/Bradycardia
    End point description
    End point type
    Secondary
    End point timeframe
    from birth to discharge
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    12
    6
    No statistical analyses for this end point

    Secondary: Maternal: Uterine Tachysystole

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    End point title
    		 Maternal: Uterine Tachysystole
    End point description
    End point type
    Secondary
    End point timeframe
    During birth
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    18
    24
    No statistical analyses for this end point

    Secondary: Maternal: Uterine Hyperstimulation

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    End point title
    		 Maternal: Uterine Hyperstimulation
    End point description
    End point type
    Secondary
    End point timeframe
    during birth
    End point values
    		 Standard Dose Regimen High Dose Regimen
    Number of subjects analysed
    58
    60
    Units: women
    14
    16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All events will be documented in the medical notes from randomisation until discharge from hospital.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Trial Specific
    Dictionary version
    1.0
    Reporting groups
    Reporting group title
    Standard Dose Regimen
    Reporting group description
    		 A standard dose of oxytocin starting at 2mu / min and increasing every 30 minutes up to a maximum of 32 mu / min.

    Reporting group title
    High Dose Regimen
    Reporting group description
    		 High dose regimen of oxytocin starting at 4mU/min increasing every 30 minutes to a maximum of 64mU/min. The high dose regimen (i.e. double the concentration) has a higher starting dose, earlier attainment of conventional maximum doses (at 2 hours rather than over 4 hours) and the possible use of higher maximum doses of oxytocin compared to the standard regimen

    Serious adverse events
    		 Standard Dose Regimen High Dose Regimen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 58 (25.86%)
    7 / 60 (11.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Intensive care - Mother
    Additional description: Admission to HDU/ITU
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intensive care - Neonatal
    Additional description: Neonatal intensive care
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Postpartum haemorrhage
    Additional description: Triggering massive obstetric haemorrhage
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice neonatal
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis neonatal
    Additional description: Suspected sepsis
         subjects affected / exposed
    6 / 58 (10.34%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Standard Dose Regimen High Dose Regimen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 58 (44.83%)
    30 / 60 (50.00%)
    Pregnancy, puerperium and perinatal conditions
    Uterine hyperstimulation
         subjects affected / exposed
    14 / 58 (24.14%)
    16 / 60 (26.67%)
         occurrences all number
    14
    16
    Uterine tachysystole
         subjects affected / exposed
    18 / 58 (31.03%)
    24 / 60 (40.00%)
         occurrences all number
    18
    24

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2016
    Made in response to review by the MHRA: o Changes to the description of the monitoring in labour that is undertaken to both mother and baby o Clarity of the descriptions for adverse drug reactions and events and reporting arrangements Other: • Addition of a minimisation algorithm to the randomisation • Addition of exclusion criteria of full cervical dilation of the woman • Faxing of consent and randomisation forms to the Trial Office for in house monitoring purposes • Clarity around the data collection items ( for mother: use of epidural analgesia during labour, degree of perineal trauma (First, second, third, fourth), active management of third stage of labour, for the baby: gender and birthweight, resuscitation, reason for review on the postnatal ward (excluding routine baby check), reason and level of neonatal care, duration of respiratory support, days to full oral feeds, SARNAT grade) • Membership of the Trial Steering and Data Monitoring Committees as these have been agreed by the NIHR • Minor amendments and correction of minor mistakes found within the protocol
    15 Apr 2021
    • Trial logo replaced • Minor amendments and correction of minor mistakes found within the protocol Contacts and Roles: Contacts updated, including the removal of contact details for committee members Background: Updated with data from a published trial Trial Aim and Objectives: Updated to include summary of pilot study Trial Design: Changes to eligibility criteria Treatment Allocation: • Instructions added for daily IMP temperature logging and reporting • Addition of the following sections: Drug interaction or contraindications, treatment modification, cessation of treatment/continuation after the trial • Withdrawal of trial/treatment and change of status within the trial section replaced Adverse Event Reporting: Restructuring of section and addition of new information and instructions for SAE reporting Data Management: • Addition of case report form schedule and summary of data collection points, personnel and training requirements • Removal of duplicated section (long term storage of data) Statistical Methods and analysis: • Additions to description of statistical analysis outline plan • Amendments to primary outcome analysis and subgroup analysis sections Data Access and Quality Assurance: Addition of ethical considerations section Organisation and Responsibilities: Update to centre eligibility rules, PI and Research Midwife responsibilities Regulatory and Ethical Approval: Amendments to funding and cost implications section regarding financial support for sites Reporting, Publications and Notification of results: Replaced text for authorship and publication policy

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Oct 2017
    A site alerted us that clinicians could remove the label from the ampoule thus potentially unblinding the randomised treatment. The manufacturer resolved this by removing the original label and re-labelling the ampoules for the 900 treatment packs still stored with them, but 438 treatment packs had to be destroyed. Routine monitoring processes uncovered a total of 233 temperature deviations outside the recommended range of 2-8oC across 84% (16/19) of active sites. Extensive revisions to the guidelines for Investigational Medicinal Product (IMP) monitoring and storage were introduced, including the use of buffered thermometers. Deviations were reduced to 38 across 29% (7/24) of sites. The buffered thermometers are set up to alarm if the temperature is recorded < 2oC or > 30oC (where there are no stability data and the ampoules cannot be used). The clinical staff would phone the 24/7 telephone randomisation system to halt recruitment in the site. This issue was submitted to the MHRA as a Serious Breach which was resolved when we submitted an amendment to restart the trial to Health Research Authority (HRA) and the MHRA on the 20th February 2018. HRA approval was received on 8th June 2018. Local Research & Development (R&D) approval was obtained and we re-started recruitment on 27th June 2018.
    27 Jun 2018
    01 Aug 2018
    In August 2018 it was identified that the IMP had been packaged in November 2016 by Sharp Services at ambient temperatures outside those recommended (2-8oC), meaning potentially it should have been discarded and not used. The trial was suspended again and the matter was referred to the MHRA. In mid-September2018, the matter was resolved when the MHRA decided that this process would not have had any detrimental effect on participants. However, the trial awarded time and funding had been exhausted so we could not re-open. Further funding was identified in October 2020 for HOLDS and the intention was to run HOLDS concurrently with iHOLDS (HTA 17/137/02). Funding started in October 2019, with recruitment due to begin in July 2020 which was then delayed by the impact of the COVID-19 pandemic. We restarted recruitment to the trial in June 2022.
    01 Jun 2022

    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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