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    Clinical Trial Results:
    An open randomised trial of patient controlled analgesia (PCA) versus routine care in patients with non-traumatic abdominal pain attending the Emergency Department. There is also a parallel, open randomised trial of patient controlled analgesia (PCA) versus routine care in patients with pain from traumatic injuries attending the Emergency Department which has been reported on elsewhere.

    Summary
    EudraCT number
    		 2011-000194-31
    Trial protocol
    		 GB  
    Global end of trial date
    30 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Nov 2019
    First version publication date
    16 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PenCTU/2010/CTIMP-004
    Additional study identifiers
    ISRCTN number
    		 ISRCTN25343280
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 R&D Number: 11/P/055, IRAS Number: 74960, REC Reference: 11/SC/0151, PenCTU Study Number: PenCTU/2010/CTIMP-004
    Sponsors
    Sponsor organisation name
    University Hospitals Plymouth NHS Trust (formerly Plymouth Hospitals NHS Trust)
    Sponsor organisation address
    Research Office, L2 MSCP, Bircham Park Offices, 1 Roscoff Rise, Derriford, Plymouth, United Kingdom, PL6 5FP
    Public contact
    Chris Hayward, Quality Assurance Manager, University of Plymouth, Peninsula Clinical Trials Unit (PenCTU), 01752 431020, christopher.hayward@pms.ac.uk
    Scientific contact
    Prof Jason Smith, Consultant in Emergency Medicine, University Hospitals Plymouth NHS Trust, Emergency Department, 01752 437629, jasonesmith@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
    30 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The research actually comprised two randomised controlled trials run in parallel, with two distinct patient populations, two different sample size calculations and the data were analysed independently in the two trials. The main objective was to compare patient controlled analgesia to nurse titrated analgesia (routine care) in adult emergency patients who present to the Emergency Department (ED) in moderate or severe pain from traumatic injury or with moderate or severe non-traumatic abdominal pain requiring IV analgesia and hospital admission. This EudraCT record has been populated with data from patients with non-traumatic abdominal pain. However, a publication link (https://www.ncbi.nlm.nih.gov/pubmed/26094763) is included under 'Online references' for the group with pain from traumatic injury.
    Protection of trial subjects
    The study is approved by the MHRA and the South Central - Southampton A Research Ethics Committee (NRES). Study monitoring is conducted by the Peninsula Clinical Trials Unit (PenCTU) and a Trial Steering Committee (TSC) and an Independent Data Monitoring Committee (IDMC) are set up for the study oversight.
    Background therapy
    		 Pain relief (morphine) administered by PCA.
    Evidence for comparator
    		 Pain relief (morphine) administered as per routine care (TAU).
    Actual start date of recruitment
    05 Jul 2011
    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: 209
    Worldwide total number of subjects
    209
    EEA total number of subjects
    209
    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)
    188
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 200 adult patients arriving at ED presenting with moderate or severe pain from non-traumatic abdominal pain will be targeted for recruitment. Expected duration of subject participation is 12 hours starting from the time that baseline VAS score is recorded, immediately after obtaining written informed consent

    Pre-assignment
    Screening details
    		 Patients between 18 and 75 years of age inclusive, Non-traumatic abdominal pain, Patients with moderate or severe pain who would routinely be prescribed IV morphine as part of standard care, Patients who are likely to remain in hospital for at least 12 hours from the time of enrolment, Provision of informed consent.

    Pre-assignment period milestones
    Number of subjects started
    		 209
    Number of subjects completed
    		 209

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment as Usual (TAU)
    Arm description
    		 Participants in the control group will continue to receive routine care as per local policy/protocol. In the ED, this comprises repeated doses of nurse-delivered IV morphine, as necessary to achieve adequate analgesia (VAS ≤44mm). Once admitted to an inpatient ward, routine care in accordance with local policy/protocol comprises further administration of opioid analgesia in the form of oral morphine solution, or subcutaneous morphine if nil by mouth, as required.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine sulphate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Tablet
    Routes of administration
    Intravenous use, Oral use, Subcutaneous use
    Dosage and administration details
    In the ED: Continued morphine sulphate IV solution 1mg/ml: delivered and titrated by nurse as necessary to achieve adequate analgesia (VAS ≤ 44mm), as per local policy/protocol. Once admitted to ward: Morphine sulphate 2mg/ml oral solution, 20-30mg, 2 hourly PRN, as per local policy/protocol Or, if patient is nil-by mouth: Morphine sulphate 10mg/ml subcutaneous injection, 5-12.5mg, 2 hourly, as per local policy/protocol.

    Arm title
    		 Patient Controlled Analgesia (PCA)
    Arm description
    		 Participants in the a PCA group will receive a PCA device, via which they can administer further IV morphine boluses. The PCA device will remain in place for a minimum period of twelve hours, from the time of informed consent and collection of baseline VAS score provision.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Morphine sulphate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Morphine sulphate IV solution 1mg/ml: delivered via PCA device - 1mg bolus dose with 5 minute lock out for a minimum period of 12 hours (in the ED and on inpatient ward).

    Number of subjects in period 1
    		Treatment as Usual (TAU) Patient Controlled Analgesia (PCA)
    Started
    105
    104
    Completed
    97
    99
    Not completed
    8
    5
         VAS booklet lost
    3
    3
         Insufficient VAS data
    3
    -
         Local difficulties in implementing the protocol
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment as Usual (TAU)
    Reporting group description
    		 Participants in the control group will continue to receive routine care as per local policy/protocol. In the ED, this comprises repeated doses of nurse-delivered IV morphine, as necessary to achieve adequate analgesia (VAS ≤44mm). Once admitted to an inpatient ward, routine care in accordance with local policy/protocol comprises further administration of opioid analgesia in the form of oral morphine solution, or subcutaneous morphine if nil by mouth, as required.

    Reporting group title
    Patient Controlled Analgesia (PCA)
    Reporting group description
    		 Participants in the a PCA group will receive a PCA device, via which they can administer further IV morphine boluses. The PCA device will remain in place for a minimum period of twelve hours, from the time of informed consent and collection of baseline VAS score provision.

    Reporting group values
    		 Treatment as Usual (TAU) Patient Controlled Analgesia (PCA) Total
    Number of subjects
    		 105 104 209
    Age categorical
    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)
    		 94 94 188
        From 65-84 years
    		 11 10 21
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 69 70 139
        Male
    		 36 34 70
    Time of Recruitment
    Units: Subjects
        Morning (0600-1159)
    		 35 38 73
        Afternoon (1200-2200)
    		 62 61 123
        Excluded from Analysis
    		 8 5 13
    Recruitment Centre
    Units: Subjects
        Centre 1
    		 61 66 127
        Centre 2
    		 16 15 31
        Centre 3
    		 11 11 22
        Centre 4
    		 9 7 16
        Excluded from Analysis
    		 8 5 13
    Clinical Diagnosis
    Units: Subjects
        Bowel Pathology
    		 14 16 30
        Gall Bladder Pathology
    		 15 13 28
        Renal or Ureteric Pathology
    		 8 4 12
        Pancreatic Pathology
    		 8 9 17
        Appendix Pathology
    		 7 6 13
        Renal or Ureteric Pathology (Stone Passed)
    		 14 14 28
        Gynae Pathology (inc. Ovarian)
    		 7 4 11
        Oesophagitis or Gastritis
    		 4 4 8
        Abdominal Pain
    		 14 20 34
        Other (inc. Post-op Pain, Hepatic Neoplasm)
    		 6 9 15
        Excluded from Analysis
    		 8 5 13
    Pre-Admission Analgesia
    At least one dose in 24 hours before ED arrival.
    Units: Subjects
        Analgesic Gas
    		 3 7 10
        Non-Steroidal Anti-Inflammatory Drug
    		 15 9 24
        Paracetamol
    		 33 32 65
        Weak Opioid
    		 14 9 23
        Excluded from Analysis
    		 8 5 13
        No Pre-Admission Analgesia (in 24hrs of arrival)
    		 32 42 74
    Verbal Pain Score
    0-10 as recorded on hospital administration system
    Units: Score (0-10)
        median (inter-quartile range (Q1-Q3))
    		 8 (6 to 9) 8 (6 to 9) -
    Visual Analogue Pain Score
    At time of consent, cm
    Units: Centimeter
        median (inter-quartile range (Q1-Q3))
    		 6.1 (3.2 to 7.7) 4.8 (2.2 to 6.8) -
    Time from Arrival in ED to Randomisation
    Units: Minutes
        arithmetic mean (standard deviation)
    		 162.4 ± 83.9 164.7 ± 83.4 -
    Preadmission Analgesia: Participants with Pre-Admission Morphine
    Units: Subjects
        arithmetic mean (standard deviation)
    		 9.1 ± 6.1 8.9 ± 3.0 -
    Preadmission Analgesia: All Participants
    Units: Subjects
        arithmetic mean (standard deviation)
    		 3.3 ± 5.7 3.0 ± 4.8 -

    End points

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    End points reporting groups
    Reporting group title
    Treatment as Usual (TAU)
    Reporting group description
    		 Participants in the control group will continue to receive routine care as per local policy/protocol. In the ED, this comprises repeated doses of nurse-delivered IV morphine, as necessary to achieve adequate analgesia (VAS ≤44mm). Once admitted to an inpatient ward, routine care in accordance with local policy/protocol comprises further administration of opioid analgesia in the form of oral morphine solution, or subcutaneous morphine if nil by mouth, as required.

    Reporting group title
    Patient Controlled Analgesia (PCA)
    Reporting group description
    		 Participants in the a PCA group will receive a PCA device, via which they can administer further IV morphine boluses. The PCA device will remain in place for a minimum period of twelve hours, from the time of informed consent and collection of baseline VAS score provision.

    Primary: Total pain experienced: Primary and Sensitivity Analyses

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    End point title
    		 Total pain experienced: Primary and Sensitivity Analyses
    End point description
    The primary outcome measure is the visual analogue pain rating scale (VAS) as a unidimensional measure of pain. The primary endpoint will be the difference between the intervention (PCA) and control (TAU) groups with regard to overall pain experience over the 12 hour period, captured by using a standardised area under the curve (max score 100) of the participant-recorded hourly serial VAS pain measurements. Sensitivity 1 = Pain scored as zero for periods of sleep. Sensitivity 2 = Missing pain scores from theatre withdrawals imputed using linear interpolation from last recorded pain score to zero at 12 hr time point. Sensitivity 3 = Includes data from site who had local difficulties in implementing the protocol. Sensitivity 4 = Excludes data from 35 participants with >5 minutes between time of first pain score and time of randomisation.
    End point type
    Primary
    End point timeframe
    On obtaining informed consent, the participant will mark their VAS pain score. Participants are then prompted to record their VAS pain score at hourly intervals by a bleep from the electronic timer.
    End point values
    		 Treatment as Usual (TAU) Patient Controlled Analgesia (PCA)
    Number of subjects analysed
    97
    99
    Units: Pain score
    arithmetic mean (standard deviation)
        Primary Analysis
    47.3 ± 24.7
    35.3 ± 25.8
        Sensitivity 1
    37.7 ± 21.5
    28.2 ± 22.3
        Sensitivity 2
    46.7 ± 24.7
    34.7 ± 25.5
        Sensitivity 3
    47.7 ± 24.6
    35.2 ± 25.6
        Sensitivity 4
    49.2 ± 23.3
    36.7 ± 25.7
    Statistical analysis title
    		 Adjusted Analysis
    Statistical analysis description
    Adjusted for stratification variables (time of first pain score and recruitment centre) and baseline pain score.
    Comparison groups
    Treatment as Usual (TAU) v Patient Controlled Analgesia (PCA)
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 11.9
    Notes
    [1] - Primary analyses undertaken on an ‘intention-to-treat’ (ITT) basis.

    Secondary: Total morphine

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    End point title
    		 Total morphine
    End point description
    None.
    End point type
    Secondary
    End point timeframe
    Sum of pre-admission morphine, morphine from time of admission to time of recruitment, and morphine delivered during 12 hour study period.
    End point values
    		 Treatment as Usual (TAU) Patient Controlled Analgesia (PCA)
    Number of subjects analysed
    97
    99
    Units: milligram(s)
        arithmetic mean (standard deviation)
    23.6 ± 13.1
    36.1 ± 22.4
    No statistical analyses for this end point

    Secondary: Total morphine during 12 hour study period

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    End point title
    		 Total morphine during 12 hour study period
    End point description
    None.
    End point type
    Secondary
    End point timeframe
    Dose information will be recorded on hospital drug charts by staff responsible for clinical management of the patient as per routine practice. PCA usage will be obtained from the PCA devices which log dosage every hour.
    End point values
    		 Treatment as Usual (TAU) Patient Controlled Analgesia (PCA)
    Number of subjects analysed
    97
    99
    Units: milligram(s)
        arithmetic mean (standard deviation)
    10.7 ± 9.6
    23.6 ± 20.3
    No statistical analyses for this end point

    Secondary: Percentage of study period with pain VAS >4.4cm

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    End point title
    		 Percentage of study period with pain VAS >4.4cm
    End point description
    None.
    End point type
    Secondary
    End point timeframe
    VAS score collected at hourly intervals during the 12 hour study period.
    End point values
    		 Treatment as Usual (TAU) Patient Controlled Analgesia (PCA)
    Number of subjects analysed
    97
    99
    Units: millimeter(s)
        arithmetic mean (standard deviation)
    46.9 ± 30.5
    32.6 ± 32.5
    No statistical analyses for this end point

    Secondary: Percentage of study period asleep

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    End point title
    		 Percentage of study period asleep
    End point description
    VAS sheet will have a tickbox used by the participant to indicate periods of sleep. When a participant hears a bleep reminder after waking from a period of sleep, s/he will complete the appropriate VAS score as usual (i.e. on the sheet corresponding to the display on the timer) and will then indicate their prior period of sleep by ticking the tickbox on the previous relevant sheet(s).
    End point type
    Secondary
    End point timeframe
    Participants will retrospectively record periods of sleep on the VAS pain score sheet.
    End point values
    		 Treatment as Usual (TAU) Patient Controlled Analgesia (PCA)
    Number of subjects analysed
    97
    99
    Units: hour
        arithmetic mean (standard deviation)
    18.6 ± 19.2
    19.7 ± 18.7
    No statistical analyses for this end point

    Secondary: Length of hospital stay

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    End point title
    		 Length of hospital stay
    End point description
    None.
    End point type
    Secondary
    End point timeframe
    Following the participant’s discharge, the length of stay in hospital will be obtained from the Patient Administration System (PAS) (or equivalent) by the RN and recorded in the CRF.
    End point values
    		 Treatment as Usual (TAU) Patient Controlled Analgesia (PCA)
    Number of subjects analysed
    97
    99
    Units: day
        arithmetic mean (standard deviation)
    3.6 ± 3.0
    3.3 ± 3.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs reported to Sponsor and PenCTU within 24hrs. Sponsor will report fatal/ life-threatening SUSARS to the MHRA and REC within 7 days.
    Adverse event reporting additional description
    SUSARs which are not fatal or life-threatening are reported by the sponsor to the MHRA and REC within 15 days after the sponsor first becomes aware of the reaction.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Both Arms - TAU and PCA
    Reporting group description
    		 -

    Serious adverse events
    		 Both Arms - TAU and PCA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 209 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Both Arms - TAU and PCA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 209 (2.39%)
    Skin and subcutaneous tissue disorders
    Urticaria
    Additional description: Urticaria at canulation site
         subjects affected / exposed
    1 / 209 (0.48%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    4 / 209 (1.91%)
         occurrences all number
    4
    Rash
         subjects affected / exposed
    1 / 209 (0.48%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2011
    Protocol V2.0, 16 Nov 2011: the protocol has been amended for two primary reasons: 1) to slightly alter the trial entry criteria to enhance recruitment and to clarify existing criteria 2) to introduce an additional, non interventional, questionnaire based follow up study investigating frequency of chronic pain development six months after participation in the main, interventional phase of the trial. The opportunity has been taken also to update contact details following changes to email addresses
    23 Apr 2012
    Protocol V3.0, 23 Apr 2012: References to Derriford Hospital as the sole Investigator Site have been modified / removed to reflect REC approval of additional sites. An additional VAS score collected after the 12 hour study period also added.
    26 Jun 2012
    Protocol V4.0, 26 Jun 2012: Remove the question relating to morphine-related adverse events from the additional follow-up questionnaire.

    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.
    See publication for strengths and limitations of the study - https://www.ncbi.nlm.nih.gov/pubmed/26094712

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26094763
    http://www.ncbi.nlm.nih.gov/pubmed/26094712
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