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    Clinical Trial Results:
    Use of Methylnaltrexone for the Treatment of Opioid Induced Constipation & Gastro-Intestinal Stasis in Intensive Care Patients (MOTION)

    Summary
    EudraCT number
    		 2014-004687-37
    Trial protocol
    		 GB  
    Global end of trial date
    28 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Oct 2018
    First version publication date
    24 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    14SM2335
    Additional study identifiers
    ISRCTN number
    		 ISRCTN75305839
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Joint Research Compliance Office, Imperial College London
    Sponsor organisation address
    Room 221, Medical School Building, St Mary's Campus, Norfolk Place, London, United Kingdom, W2 1PG
    Public contact
    Parind Patel, Imperial College Healthcare NHS Trust, +44 2083831878, parind.patel@nhs.net
    Scientific contact
    Parind Patel, Imperial College Healthcare NHS Trust, +44 2083831878, parind.patel@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
    20 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of Methylnaltrexone in producing laxation in patients sedated with opioid infusions.
    Protection of trial subjects
    All patients were treated in an intensive care unit with constant 1:1 nursing care to ensure safety and comfort, and minimise any distress.
    Background therapy
    		 In order to ensure that patients were treated as early as possible we compared Methylnaltrexone to Placebo in the management of OIC, after 48 hours of not opening bowels but having been given regular laxatives. If bowels were not opened after 72 hours of randomisation into the trial, rescue laxatives as per local ICU policy, were administered.
    Evidence for comparator
    		 Evidence to date suggests that Methylnaltrexone is beneficial in treating Opioid-Induced-Constipation (OIC) in patients when response to laxatives has not been sufficient. Constipation and gut dysfunction are a major concern in intensive care patients. There may also be additional benefits in reducing infection and immunosuppression, and hence an overall improvement in patient outcome. The efficacy and safety of Methylnaltrexone in the treatment of OIC have been evaluated in two multicentre, randomised, double-blind, placebo-controlled phase III trials involving adults with advanced illness (life expectancy of 1 - 6 months) who were receiving palliative care. Patients maintained their usual laxative regimen and the primary endpoint was rescue-free laxation. Secondary endpoints included time to laxation, pain scores, opioid withdrawal symptoms and adverse events. The landmark published trial compared Methylnaltrexone with placebo. Methylnaltrexone improved the laxation rate within four hours of the first dose compared with placebo [48% vs. 15% (p < 0.001)]. Of the patients who did respond within four hours of the first dose, half responded within 30 minutes. Case reports have also reported an immediate effect of Methylnaltrexone administration on bowel motility, with restored bowel function within 15 minutes of subcutaneous/intravenous injection. Finally, a retrospective chart review of 88 non–surgical critical care patients receiving Fentanyl infusions was conducted at the Hammersmith Hospital, Imperial College NHS Trust over a 10 week period in 2009. 15 patients met the criteria of constipation despite treatment with Senna and Sodium Docusate. Six of seven Methylnaltrexone patients responded to one or two doses with laxation within 24 hours versus 0/8 for conventional rescue therapy (p=0.001). There were no adverse effects from either rescue laxative therapies.
    Actual start date of recruitment
    14 Sep 2015
    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: 84
    Worldwide total number of subjects
    84
    EEA total number of subjects
    84
    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)
    48
    From 65 to 84 years
    35
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted in 4 ICUs within the UK with a target of recruiting 84 patients (allowing a drop out rate of 5%). The first patient was recruited on 14/09/2015 and the last patient was recruited on 15/07/2017, with a maximum follow up of 28 days in ICU.

    Pre-assignment
    Screening details
    		 All patients who were clinically judged to potentially be constipated due to opioids, were screened against the inclusion and exclusion criteria to be eligible for the study. A total of 609 patients were screened in the study between 22/09/2015 and 15/07/2017.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Unblinded research nurses were responsible for randomising patients and administering the study drug. Blinded nurses were responsible for data entry and bedside nurses who cared for patients were also blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Methylnaltrexone
    Arm description
    		 Methylnaltrexone
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methylnaltrexone
    Investigational medicinal product code
    Other name
    Methylnaltrexone Bromide
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients weighing 38-61kg received 8mg (0.4mls) Methylnaltrexone diluted in 50mls Normal Saline and patients weighing 62-114kg received 12mg (0.6mls) diluted in 50mls Normal Saline. In patients with severe renal impairment (creatinine clearance < 30ml/min), the dose of Methylnaltrexone administered was reduced to: 4mg (38-61kg) and 8mg (62-114kg). Study drug was administered over 15 minutes via an indwelling intravenous catheter.

    Arm title
    		 Normal Saline (Placebo)
    Arm description
    		 Normal Saline (Placebo)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal Saline (Placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo (Normal Saline) was prepared in an exactly identical syringe to study drug, containing Normal Saline. Placebo was administered over 15 minutes via an indwelling intravenous catheter.

    Number of subjects in period 1
    		Methylnaltrexone Normal Saline (Placebo)
    Started
    41
    43
    Completed
    39
    43
    Not completed
    2
    0
         Consent withdrawn by subject
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Methylnaltrexone
    Reporting group description
    		 Methylnaltrexone

    Reporting group title
    Normal Saline (Placebo)
    Reporting group description
    		 Normal Saline (Placebo)

    Reporting group values
    		 Methylnaltrexone Normal Saline (Placebo) Total
    Number of subjects
    		 41 43 84
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 25 23 48
        From 65-84 years
    		 16 19 35
        85 years +
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.6 ( 14.8 ) 58.6 ( 17.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 14 12 26
        Male
    		 27 31 58
    Reason for ICU admission
    Medical (non operative) includes: respiratory, post cardiac arrest, head injury, multiple trauma, infection, neurologic, cardiovascular, drug overdose, haemorrhage, post respiratory arrest, seizure disorder, aspiration/poisoning/toxicities, COPD, cardiogenic shock, gastrointestinal, neoplasm and rhythm disturbance. Surgical - emergency (operative) includes: cardiovascular, craniotomy, multiple trauma, head trauma, heart valve surgery, neurologic and respiratory. Surgical - elective (operative) incudes: heart valve surgery, respiratory and respiratory insufficiency.
    Units: Subjects
        Medical (non operative)
    		 31 34 65
        Surgical - emergency (operative)
    		 10 6 16
        Surgical - elective (operative)
    		 0 3 3
    Type of opioid
    Units: Subjects
        Fentanyl
    		 29 35 64
        Remifentanyl
    		 9 7 16
        Morphine
    		 2 0 2
        Remifentanyl until 1 hour before randomisation
    		 0 1 1
        Off opioids
    		 1 0 1
    Other sedatives
    Other sedatives include: propofol, midazolam, midazolam + propofol, midazolam + clonidine, propofol + clonidine, propofol + dexmedetomidine, ketamine
    Units: Subjects
        Other sedatives
    		 34 36 70
        None
    		 7 7 14
    Vasoactive drugs
    Vasoactive drugs include: noradrenaline, noradrenaline + vasopressin, noradrenaline + other, adrenaline, dobutamine, GTN, metaraminol, labetalol + hydralazine, noradrenaline + vasopressin + other, and other.
    Units: Subjects
        Vasoactive drugs
    		 25 27 52
        None
    		 16 16 32
    Selective Digestive Decontamination (SDD)
    Units: Subjects
        None
    		 37 33 70
        Selective Digestive Decontamination (SDD)
    		 4 10 14
    Traumatic Brain Injury (TBI)
    Units: Subjects
        Traumatic Brain Injury (TBI)
    		 8 7 15
        None
    		 33 36 69
    Richmond Agitation Sedation Score (RASS)
    Units: number
        median (inter-quartile range (Q1-Q3))
    		 -5.0 (-5.0 to -4.0) -4.0 (-5.0 to -4.0) -
    Total APACHE II Score
    Units: number
        arithmetic mean (standard deviation)
    		 18.0 ( 6.3 ) 18.2 ( 6.1 ) -
    Baseline opioid dose - Fentanyl
    Units: mcg/h
        median (inter-quartile range (Q1-Q3))
    		 100 (100 to 200) 150 (100 to 200) -
    Baseline opioid dose - Remifentanyl
    Units: mcg/h
        median (inter-quartile range (Q1-Q3))
    		 480 (292 to 684) 158 (96 to 301) -

    End points

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    End points reporting groups
    Reporting group title
    Methylnaltrexone
    Reporting group description
    		 Methylnaltrexone

    Reporting group title
    Normal Saline (Placebo)
    Reporting group description
    		 Normal Saline (Placebo)

    Primary: Rescue-free laxation

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    End point title
    		 Rescue-free laxation
    End point description
    The primary outcome event is significant laxation (at least 100mls volume) without rescue laxatives being given. The time to rescue free laxation is measured from randomisation. For patients with no event, the observation is censored at the date rescue laxatives were given. If non were given, this was censored at 96 hours after randomisation. If the first laxation volume is not reported, it is assumed not be a significant laxation since non-significant laxations were not being reported.
    End point type
    Primary
    End point timeframe
    Rescue-free laxation within 96 hours of randomisation
    End point values
    		 Methylnaltrexone Normal Saline (Placebo)
    Number of subjects analysed
    39
    43
    Units: subjects
        Rescue-free laxation within 96 hours
    12
    15
        Laxation after rescue laxatives
    10
    13
        No laxation
    2
    2
    Statistical analysis title
    		 Time to event
    Statistical analysis description
    The null hypothesis is that there is no difference in time to rescue free laxation in the Methylnaltrexone and Placebo groups. Allowing for a drop-out rate of 5% (patients who withdraw consent after regaining consciousness), with 42 subjects in each arm, this study had 85% power to detect a difference of 33% (48% vs, 15%) in the proportion of patients with rescue-free laxation within 12 hours at the 5% level (using a two-tailed log-rank test). Stratified by ICU.
    Comparison groups
    Methylnaltrexone v Normal Saline (Placebo)
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.816
         upper limit
    		 2.461

    Secondary: Gastric Residual Volume (GRV)

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    End point title
    		 Gastric Residual Volume (GRV)
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1-28 in ICU.
    End point values
    		 Methylnaltrexone Normal Saline (Placebo)
    Number of subjects analysed
    39
    43
    Units: mls
    median (inter-quartile range (Q1-Q3))
        GRV while on study drug
    0.0 (0.0 to 40.0)
    0.0 (0.0 to 25.0)
    Statistical analysis title
    		 Difference in GRV between treatments
    Comparison groups
    Methylnaltrexone v Normal Saline (Placebo)
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Toleration of enteral feed

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    End point title
    		 Toleration of enteral feed
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1-28 in ICU.
    End point values
    		 Methylnaltrexone Normal Saline (Placebo)
    Number of subjects analysed
    39
    43
    Units: days
        No. days enteral feed data available/applicable
    531
    707
        No. days full enteral feed achieved
    174
    225
    Statistical analysis title
    		 Difference in target enteral feed
    Comparison groups
    Methylnaltrexone v Normal Saline (Placebo)
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Requirement of prokinetics

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    End point title
    		 Requirement of prokinetics
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1-28 in ICU.
    End point values
    		 Methylnaltrexone Normal Saline (Placebo)
    Number of subjects analysed
    40
    43
    Units: Subjects
        Metoclopramide
    15
    13
        Erythromycin
    10
    7
    No statistical analyses for this end point

    Secondary: Average No. of bowel movements per day

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    End point title
    		 Average No. of bowel movements per day
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1-28 in ICU.
    End point values
    		 Methylnaltrexone Normal Saline (Placebo)
    Number of subjects analysed
    39
    43
    Units: Number
    median (inter-quartile range (Q1-Q3))
        Days 1-3 - no rescue
    0.33 (0.00 to 1.00)
    0.67 (0.00 to 1.67)
        Days 1-3 - after rescue(s)
    1.50 (0.50 to 2.50)
    1.33 (0.00 to 1.50)
        Days 4-28 - no rescue
    1.08 (0.33 to 1.80)
    2.00 (1.44 to 2.50)
        Days 4-28 - after rescue(s)
    1.18 (0.00 to 2.00)
    1.63 (1.00 to 2.42)
    Statistical analysis title
    		 Mean number of bowel movements per day
    Comparison groups
    Methylnaltrexone v Normal Saline (Placebo)
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - Days 1-3. P value Days 4-28 = 0.0055

    Secondary: Incidence of diarrhoea

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    End point title
    		 Incidence of diarrhoea
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1-28 in ICU.
    End point values
    		 Methylnaltrexone Normal Saline (Placebo)
    Number of subjects analysed
    39
    43
    Units: subjects
        Diarrhoea at least once
    23
    36
        Type 7 stool at least once
    23
    36
    Statistical analysis title
    		 Incidence of diarrhoea
    Comparison groups
    Methylnaltrexone v Normal Saline (Placebo)
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0152
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Change of opioid dose from baseline to 4 hours after first study drug dose

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    End point title
    		 Change of opioid dose from baseline to 4 hours after first study drug dose
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1-28 in ICU.
    End point values
    		 Methylnaltrexone Normal Saline (Placebo)
    Number of subjects analysed
    39
    43
    Units: subjects
        Total on fentanyl at baseline
    28
    35
        Fentanyl dose reduced
    1
    0
        Fentanyl dose remained same
    22
    30
        Fentanyl dose increased
    3
    3
        Total on remifentanyl at baseline
    9
    7
        Remifentanyl dose reduced
    3
    0
        Remifentanyl dose remained same
    3
    3
        Remifentanyl dose increased
    2
    1
    No statistical analyses for this end point

    Secondary: Incidence of Clostridium difficile infection: PCR or Toxin positive

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    End point title
    		 Incidence of Clostridium difficile infection: PCR or Toxin positive
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1-28 in ICU
    End point values
    		 Methylnaltrexone Normal Saline (Placebo)
    Number of subjects analysed
    39
    43
    Units: % of patients
        Percentage of patients - infection reported
    8
    16
    No statistical analyses for this end point

    Secondary: Mortality: 28 days

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    End point title
    		 Mortality: 28 days
    End point description
    End point type
    Secondary
    End point timeframe
    Survival status at 28 days post-randomisation
    End point values
    		 Methylnaltrexone Normal Saline (Placebo)
    Number of subjects analysed
    39
    43
    Units: subjects
        Died <28 days
    10
    2
        Alive at 28 days
    29
    41
    No statistical analyses for this end point

    Secondary: Expected numbers of deaths in each treatment group (based on baseline assessments)

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    End point title
    		 Expected numbers of deaths in each treatment group (based on baseline assessments)
    End point description
    It was assessed whether risk of death at entry to the study might explain the observed difference in mortality between the two arms. This was done using the following measures: Knaus, APACHE UK 2013, APACHE UK 2015, ICNARC model 2013, ICNARC model 2015 and SAPSII score. The expected numbers based on APACHE UK 2015 are reported here.
    End point type
    Secondary
    End point timeframe
    Expected number of deaths from baseline risk
    End point values
    		 Methylnaltrexone Normal Saline (Placebo)
    Number of subjects analysed
    38
    42
    Units: Number
        Expected number of deaths
    11
    12
        Observed number of deaths
    10
    2
    No statistical analyses for this end point

    Secondary: Incidence of Ventilator Associated Penumonia (VAP)

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    End point title
    		 Incidence of Ventilator Associated Penumonia (VAP)
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1-7 in ICU.
    End point values
    		 Methylnaltrexone Normal Saline (Placebo)
    Number of subjects analysed
    41
    43
    Units: subjects
    median (inter-quartile range (Q1-Q3))
        Randomisation
    6.0 (5.0 to 7.0)
    6.0 (4.0 to 6.0)
        Day 1
    6.0 (4.0 to 7.0)
    6.0 (5.0 to 6.0)
        Day 4
    6.0 (5.0 to 7.0)
    6.0 (4.0 to 7.0)
        Day 7
    7.0 (5.0 to 8.0)
    6.0 (5.0 to 7.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Days 1-28 in ICU. Fatal or life threatening SAEs were reported on the day that local sites became aware of the event (within 24 hours).
    Adverse event reporting additional description
    Clinical outcomes from ICU admission were exempt from adverse event reporting, unless the investigator deemed the event to be related to the administration of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Methylnaltrexone
    Reporting group description
    		 Methylnaltrexone

    Reporting group title
    Normal Saline (Placebo)
    Reporting group description
    		 Normal Saline (Placebo)

    Serious adverse events
    		 Methylnaltrexone Normal Saline (Placebo)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 43 (4.65%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Perforated abdominal viscous (perforated colon on CT)
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Methylnaltrexone Normal Saline (Placebo)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 40 (22.50%)
    12 / 43 (27.91%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 40 (20.00%)
    11 / 43 (25.58%)
         occurrences all number
    8
    11
    Rectal cancer metastatic
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 43 (2.33%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Rash over torso
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 43 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2016
    Changes made to trial protocol: - Page 7 - Change of wording under population eligibility; removal of ‘from admission to ICU’ - Page 14 - Change of wording under design, regarding possible addition of new sites. Change of ‘GICU’ to ‘ICU’ so that CICU patients can be included in the study - Page 15 - Change of inclusion criteria; removal of ‘following ICU admission’ and change in exclusion criteria - ‘abdominal surgery’ to ‘GI tract surgery’ - Other administrative changes
    16 Jun 2016
    Addition of 2 sites: - Royal Surrey County Hospital (never recruited in the end) - Nottingham University Hospitals (never came on board)
    07 Sep 2016
    Addition of one participating site: - Queen Elizabeth Hospital, King's Lynn
    30 Jan 2017
    - Changes to trial protocol inclusion criteria, to additionally include ICU patients sedated with opioids for a total of 12 hours (consecutive or non-consecutive) in the past 48 hours. - Wording changes in Patient Information Sheets and Consent Forms. - Notification of updated SmPC for Relistor (Methylnaltrexone) that will be used for the next safety reporting period.
    10 Jan 2018
    To amend trial protocol definition of “end of trial” to allow for retrospective mortality outcome data collection, to be added to our analyses.

    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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