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    Clinical Trial Results:
    Phase II, single centre, double blinded, cross-over dose confirmation study using two morphine-naloxone i.v. solutions

    Summary
    EudraCT number
    		 2011-005903-34
    Trial protocol
    		 AT  
    Global end of trial date
    02 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Apr 2022
    First version publication date
    18 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KKSMUW2011-09
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    G.L. Pharma GmbH
    Sponsor organisation address
    Schlossplatz 1, Lannach, Austria, 8502
    Public contact
    G. L. Pharma GmbH, G. L. Pharma GmbH, +43 3136825770, office@gl-pharma.at
    Scientific contact
    G. L. Pharma GmbH, G. L. Pharma GmbH, +43 3136825770, office@gl-pharma.at
    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
    16 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the appropriate ratio of morphine and naloxone to suppress the pleasurable effects of intravenous morphine and precipitate withdrawal reactions.
    Protection of trial subjects
    health monitoring personnel, rescue medication, measurements of vital signs
    Background therapy
    		 diagnosis of opioid dependence currently undergoing morphine maintenance treatment
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 56
    Worldwide total number of subjects
    56
    EEA total number of subjects
    56
    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)
    56
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 2013 - 2015, Austria

    Pre-assignment
    Screening details
    		 vital signs, complete blood count, medical history, inclusion/exclusion criteria,

    Pre-assignment period milestones
    Number of subjects started
    		 56
    Intermediate milestone: Number of subjects
    oral morphine: 44
    Number of subjects completed
    		 44

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening failure: 10
    Reason: Number of subjects
    		 Consent withdrawn by subject: 2
    Period 1
    Period 1 title
    Morphine i.v.
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Morphine i.v.
    Arm description
    		 -
    Arm type
    		 Baseline

    Investigational medicinal product name
    Morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    individual doses

    Number of subjects in period 1 [1]
    		Morphine i.v.
    Started
    44
    Completed
    43
    Not completed
    1
         Consent withdrawn by subject
    1
    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: A number of 56 subjects were enrolled for screening. There were 10 screening failures, and 2 subjects withdraw their consent. Finally, 44 subjects started the baseline period.
    Period 2
    Period 2 title
    Morphine-Naloxone 100:1 vs. Morphine
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Morphine-Naloxone ratio 100:1 i.v.
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Morphine‐Naloxone 100:1 Ampoules / Solution for Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    individual doses

    Arm title
    		 Morphine Mono1
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    individual doses

    Number of subjects in period 2
    		Morphine-Naloxone ratio 100:1 i.v. Morphine Mono1
    Started
    43
    43
    Completed
    43
    42
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1
    Period 3
    Period 3 title
    Morphine-Naloxone 200:1 vs. Morphine
    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
    No

    Arm title
    		 Morphine-Naloxone ratio 200:1 i.v.
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Morphine‐Naloxone 200:1 Ampoules / Solution for Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    individual doses

    Arm title
    		 Morphine Mono2
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    individual doses

    Number of subjects in period 3
    		Morphine-Naloxone ratio 200:1 i.v. Morphine Mono2
    Started
    42
    42
    Completed
    40
    42
    Not completed
    2
    0
         Adverse event, non-fatal
    1
    -
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Morphine i.v.
    Reporting group description
    		 -

    Reporting group values
    		 Morphine i.v. Total
    Number of subjects
    		 44 44
    Age categorical
    all subjects
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 44 44
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 44 44

    End points

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    End points reporting groups
    Reporting group title
    Morphine i.v.
    Reporting group description
    		 -
    Reporting group title
    Morphine-Naloxone ratio 100:1 i.v.
    Reporting group description
    		 -

    Reporting group title
    Morphine Mono1
    Reporting group description
    		 -
    Reporting group title
    Morphine-Naloxone ratio 200:1 i.v.
    Reporting group description
    		 -

    Reporting group title
    Morphine Mono2
    Reporting group description
    		 -

    Primary: AUC(0-20) of SOWS-G

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    End point title
    		 AUC(0-20) of SOWS-G [1]
    End point description
    Signs and symptoms of opiate‐withdrawal, according to Short Opiate Withdrawal Scale ‐ German (SOWS‐G), AUC of Total Score between 0 and 20 minutes after application of study drug.
    End point type
    Primary
    End point timeframe
    0 and 20 minutes after application of study drug
    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: The study was carried out in a cross-over design. No statistical analysis was reported to prevent automated summing up of the arms population. For the primary endpoint SOWS-G , 42 subjects were included. The analysis was pre-specified, the analysis type was superiority with a p-value of < 0.05. The method used was Wilcoxon (Mann-Whitney).
    End point values
    		 Morphine-Naloxone ratio 100:1 i.v. Morphine-Naloxone ratio 200:1 i.v. Morphine Mono1 Morphine Mono2
    Number of subjects analysed
    42
    40
    42
    40
    Units: total score * minutes
        geometric mean (standard deviation)
    239 ( 127 )
    104 ( 110 )
    21 ( 37 )
    18 ( 36 )
    No statistical analyses for this end point

    Primary: AUC of Pupil diameter

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    End point title
    		 AUC of Pupil diameter [2]
    End point description
    Pupil diameter, mean of left and right eye, AUC between 0 and 20 minutes after application of study drug.
    End point type
    Primary
    End point timeframe
    0-20 minutes after administration of study drug
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The study was carried out in a cross-over design. No statistical analysis was reported to prevent automated summing up of the arms population. For the primary endpoint pupil diameter, 42 subjects were included. The analysis was pre-specified, the analysis type was superiority with a p-value of < 0.05. The method used was Wilcoxon (Mann-Whitney).
    End point values
    		 Morphine-Naloxone ratio 100:1 i.v. Morphine-Naloxone ratio 200:1 i.v. Morphine Mono1 Morphine Mono2
    Number of subjects analysed
    41
    40
    41
    40
    Units: mm * minutes
        geometric mean (standard deviation)
    17.1 ( 10.5 )
    13.7 ( 11.2 )
    -10.2 ( 8.2 )
    -10.6 ( 10.3 )
    No statistical analyses for this end point

    Secondary: AUC(0-20) of OOWS

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    End point title
    		 AUC(0-20) of OOWS
    End point description
    Objective Opiate Withdrawal Scale
    End point type
    Secondary
    End point timeframe
    0-20 minutes
    End point values
    		 Morphine-Naloxone ratio 100:1 i.v. Morphine-Naloxone ratio 200:1 i.v. Morphine Mono1 Morphine Mono2
    Number of subjects analysed
    42
    40
    42
    40
    Units: total score * minutes
        geometric mean (standard deviation)
    131 ( 43 )
    68 ( 42 )
    7 ( 11 )
    5 ( 9 )
    No statistical analyses for this end point

    Secondary: AUC(0-20) of Wang scale

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    End point title
    		 AUC(0-20) of Wang scale
    End point description
    Wang Scale (third)
    End point type
    Secondary
    End point timeframe
    0-20 minutes
    End point values
    		 Morphine-Naloxone ratio 100:1 i.v. Morphine-Naloxone ratio 200:1 i.v. Morphine Mono1 Morphine Mono2
    Number of subjects analysed
    23
    21
    23
    21
    Units: total score * minutes
        geometric mean (standard deviation)
    253 ( 148 )
    67 ( 77 )
    2 ( 7 )
    1 ( 2 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    full report
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    all subjects
    Reporting group description
    		 -

    Serious adverse events
    		 all subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 44 (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
    		 all subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 44 (47.73%)
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 44 (4.55%)
         occurrences all number
    2
    Dysgeusia
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Coma
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Injection site erythema
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Injection site urticaria
         subjects affected / exposed
    5 / 44 (11.36%)
         occurrences all number
    7
    Injection site plaque
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    2 / 44 (4.55%)
         occurrences all number
    2
    Flatulence
         subjects affected / exposed
    3 / 44 (6.82%)
         occurrences all number
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 44 (4.55%)
         occurrences all number
    2
    Enteritis
         subjects affected / exposed
    2 / 44 (4.55%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    8 / 44 (18.18%)
         occurrences all number
    9
    Vomiting
         subjects affected / exposed
    2 / 44 (4.55%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    2 / 44 (4.55%)
         occurrences all number
    3
    Urticaria
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 44 (2.27%)
         occurrences all number
    1
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 44 (2.27%)
         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
    26 Jul 2012
    Change of principal investigator
    30 Aug 2013
    Addition of an additional questionnaire for the subjects
    15 Apr 2014
    Adjustments to safety reporting and informed consent
    17 Oct 2014
    Change of principal investigator

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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