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    Clinical Trial Results:
    A PHASE II, RANDOMISED, SINGLE CENTRE, OPEN-LABEL, TWO-ARM STUDY TO DETERMINE THE SAFETY AND EFFICACY OF BUPRENORPHINE ORAL LYOPHILISATE (XPRENOR ®) IN COMPARISON WITH BUPRENORPHINE SUBLINGUAL TABLETS (SUBUTEX®)IN OPIOID-DEPENDENT PATIENTS

    Summary
    EudraCT number
    		 2012-003560-49
    Trial protocol
    		 GB  
    Global end of trial date
    22 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Apr 2022
    First version publication date
    25 Apr 2022
    Other versions
    Summary report(s)
    		 Espranor result summary
    Clinical Study Summary: MD2012/01XP

    Trial information

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    Trial identification
    Sponsor protocol code
    MD2012/01XP
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Macarthys Laboratories Limited (trading as Martindale Pharma)
    Sponsor organisation address
    Building A2, Glory Park, Wooburn Green, High Wycombe, United Kingdom, hp100df
    Public contact
    Ethypharm global headquarters, ETHYPHARM, +33 (0) 141121720, information@ethypharm.com
    Scientific contact
    Dr Mehemed OUZID, ETHYPHARM, +33 (0) 141121720, ouzid.mehemed@ethypharm.com
    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
    09 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective The primary objective of this study was to establish the safety profile of Xprenor compared to Subutex. Secondary objectives The secondary objectives of this study were to: 1. Establish the pharmacokinetic (PK) profile in terms of time to maximum concentration (Tmax) and maximum concentration (Cmax) for Xprenor and Subutex 2. Measure the disintegration and disappearance of Xprenor and Subutex from the mouth under normal administration conditions 3. Establish the suitability of the recommended initiation dose (2 to 4 mg) and maintenance doses (up to 24 mg) of Xprenor in opioid-dependent subjects. Exploratory objective The exploratory objective was to compare the dose requirements of Subutex vs. Xprenor.
    Protection of trial subjects
    The handling of data, including data quality control, were to comply with regulatory guidelines and local regulations where applicable, and the relevant Martindale Pharma’s SOPs and Working Instructions. All data were to be stored in an anonymous form in accordance with the data-protection regulations.
    Background therapy
    		 Xprenor: Starting dose of 2 to 4 mg/day, increasing in 2 to 6 mg steps up to 24 mg/day.
    Evidence for comparator
    		 Subutex: Starting dose of 2 to 4 mg/day, increasing in 2 to 8 mg steps up to 32 mg/day.
    Actual start date of recruitment
    14 Feb 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
    United Kingdom: 55
    Worldwide total number of subjects
    55
    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)
    55
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 55 subjects have been recruited by two centers.

    Pre-assignment
    Screening details
    		 A total of 55 subjects were screened, of these 17 subjects (30.9%) did not meet the inclusion/exclusion criteria and were Screen failures. There were 2 subjects that were randomised but did not receive study treatment: 1 subject was lost to follow-up and the other subject withdrew his consent.

    Pre-assignment period milestones
    Number of subjects started
    		 55
    Intermediate milestone: Number of subjects
    Patients randomised: 38
    Intermediate milestone: Number of subjects
    Patients who received medication: 36
    Number of subjects completed
    		 36

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen failure: 17
    Reason: Number of subjects
    		 Not treated: 2
    Period 1
    Period 1 title
    Titration/Maintenance/Extension periods (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-labelled study and no blinding was performed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Xprenor
    Arm description
    		 Eligible patients randomised to receive Xprenor
    Arm type
    		 Experimental

    Investigational medicinal product name
    Xprenor
    Investigational medicinal product code
    ND
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oromucosal use
    Dosage and administration details
    Started with an initial dose of 2 to 4 mg/day, with and then increased by 2 to 6 mg up to a maximum dose of 24 mg/day.

    Arm title
    		 Subutex
    Arm description
    		 Eligible patients radomised to receive Subutex
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Subutex
    Investigational medicinal product code
    ND
    Other name
    Buprenorphine
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Started with an initial dose of 2 to 4 mg/day, with additional doses up to an additional maximum of 4 mg on the first day if required up to a maximum dose of 32 mg/day.

    Number of subjects in period 1 [1]
    		Xprenor Subutex
    Started
    23
    13
    Completed
    20
    10
    Not completed
    3
    3
         Consent withdrawn by subject
    2
    2
         Inadequate contraception
    -
    1
         Lost to follow-up
    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 total of 55 subjects were screened, of these 17 subjects (30.9%) did not meet the inclusion/exclusion criteria and were Screen failures. There were 2 subjects that were randomised but did not receive study treatment: 1 subject was lost to follow-up and the other subject withdrew his consent.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Xprenor
    Reporting group description
    		 Eligible patients randomised to receive Xprenor

    Reporting group title
    Subutex
    Reporting group description
    		 Eligible patients radomised to receive Subutex

    Reporting group values
    		 Xprenor Subutex Total
    Number of subjects
    		 23 13 36
    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)
    		 23 13 36
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 43.0 (26.0 to 58.0) 45.0 (23.0 to 53.0) -
    Gender categorical
    Units: Subjects
        Female
    		 3 2 5
        Male
    		 20 11 31
    Race
    Units: Subjects
        Asian
    		 0 1 1
        Caucasian
    		 15 9 24
        Other
    		 8 3 11
    Opioid dependance history
    Units: Subjects
        > 6-12 months
    		 1 0 1
        > 24 months
    		 22 13 35
    Type of opioid abused
    Units: Subjects
        Opioid painkiller addiction
    		 1 0 1
        Heroin addiction
    		 21 12 33
        Other
    		 1 1 2
    Height
    Units: cm
        median (full range (min-max))
    		 176.0 (154.0 to 192.0) 168.5 (153.0 to 199.0) -
    Weight
    Units: kg
        median (full range (min-max))
    		 73.4 (49.4 to 102.8) 64.1 (44.5 to 89.0) -
    BMI
    Units: KG/m2
        median (full range (min-max))
    		 23.5 (18.4 to 29.9) 21.6 (18.8 to 29.9) -
    Subject analysis sets

    Subject analysis set title
    Safety and Efficacy population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received at least one dose of the study medications.

    Subject analysis set title
    PK Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Population : 50% of all randomised subjects

    Subject analysis set title
    PK data after administration of both Xprenor and Subutex.
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects for which PK data were available following administration of both Xprenor and Subutex.

    Subject analysis sets values
    		 Safety and Efficacy population PK Population PK data after administration of both Xprenor and Subutex.
    Number of subjects
    36
    11
    5
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    36
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
    5
        Male
    31
    Race
    Units: Subjects
        Asian
    1
        Caucasian
    24
        Other
    11
    Opioid dependance history
    Units: Subjects
        > 6-12 months
    1
        > 24 months
    35
    Type of opioid abused
    Units: Subjects
        Opioid painkiller addiction
    1
        Heroin addiction
    33
        Other
    2
    Height
    Units: cm
        median (full range (min-max))
    175.5 (153.0 to 199.0)
    Weight
    Units: kg
        median (full range (min-max))
    71.4 (44.5 to 102.8)
    BMI
    Units: KG/m2
        median (full range (min-max))
    23.4 (18.4 to 29.9)

    End points

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    End points reporting groups
    Reporting group title
    Xprenor
    Reporting group description
    		 Eligible patients randomised to receive Xprenor

    Reporting group title
    Subutex
    Reporting group description
    		 Eligible patients radomised to receive Subutex

    Subject analysis set title
    Safety and Efficacy population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received at least one dose of the study medications.

    Subject analysis set title
    PK Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Population : 50% of all randomised subjects

    Subject analysis set title
    PK data after administration of both Xprenor and Subutex.
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects for which PK data were available following administration of both Xprenor and Subutex.

    Primary: Safety end points (AE)

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    End point title
    		 Safety end points (AE) [1]
    End point description
    To compare the incidence of AEs reported in Subutex and Xprenor arms compared to Subutex.
    End point type
    Primary
    End point timeframe
    All over the study
    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: Other method name: (specify) : Listing of events without statistical analysis (Medical Dictionary for Regulatory Activities (MedDRA, Version 15))
    End point values
    		 Xprenor Subutex
    Number of subjects analysed
    23
    13
    Units: Adverse events
        At least one AE
    17
    4
        AE severity Mild
    13
    1
        AE severity Moderate
    4
    3
        At least one Treatment-related TEAE
    16
    2
    No statistical analyses for this end point

    Primary: Safety end points (Oxygen desaturation)

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    End point title
    		 Safety end points (Oxygen desaturation)
    End point description
    To examine potential oxygen desaturation (SpO2) up to 3 hours post-dose as measured by pulse oximetry continuously and at a series of time-points in each visit. PDPT : Post-Dose Period on Titration - PDPM : Post-Dose Period on Maintenance
    End point type
    Primary
    End point timeframe
    Continuous pulse oximetry :3 hours post-dose during active titration + Days 2 and 7 of Maintenance Period (D9-D14). Manual pulse oximetry : 0, 15, 30, 60 min post-study treatment during active titration + Days 2 and 7 of Maintenance Period (D9-D14).
    End point values
    		 Xprenor Subutex
    Number of subjects analysed
    23
    13
    Units: Seconds
    arithmetic mean (standard deviation)
        Dur. SpO2<90% 0 to 30 min PDPT Day 1
    8.1 ± 16.69
    158.3 ± 510.09
        Dur. SpO2<90% 0 to 30 min PDPT Day 2
    6.2 ± 10.39
    23.6 ± 29.96
        Dur. SpO2<90% 0 to 30 min PDPT Day 3
    5.0 ± 10.35
    21.7 ± 29.3
        Dur. SpO2<90% 0 to 30 min PDPT Day 5
    3.3 ± 5.77
    10.0 ± 14.14
        Dur. SpO2<90% 0 to 30 min PDPM Day 2
    6.1 ± 11.95
    177.0 ± 544.0
        Dur. SpO2<90% 0 to 30 min PDPM Day 7
    7.1 ± 13.47
    14.0 ± 31.25
        Dur. SpO2<90% 0 to 120 min PDPT Day 1
    0.0 ± 0.0
    0.5 ± 0.71
        Dur. SpO2<90% 0 to 120 min PDPT Day 2
    0.1 ± 0.28
    0.4 ± 0.79
        Dur. SpO2<90% 0 to 120 min PDPT Day 3
    0.6 ± 0.89
    0.0 ± 0.0
        Dur. SpO2<90% 0 to 120 min PDPT Day 5
    105.0 ± 0.00
    122.5 ± 137.89
        Dur. SpO2<90% 0 to 120 min PDPM Day 2
    68.0 ± 92.37
    499.3 ± 959.26
        Dur. SpO2<90% 0 to 120 min PDPM Day 7
    61.1 ± 88.94
    226.0 ± 281.46
    Statistical analysis title
    		 Pulse oximetry (SpO2 < 90% (0 to 30 min PDPT))
    Statistical analysis description
    Continuous oximetry saturation data (SpO2) records for all subjects by time post-dose, for each period of assessment.PDPT= Post Dose Period on Titration
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.6683
    Method
    		 ANOVA
    Confidence interval
    Notes
    [2] - Mean difference compared to ANOVA
    Statistical analysis title
    		 Pulse oximetry (SpO2 < 90% (0 to 120 min PDPT))
    Statistical analysis description
    Continuous oximetry saturation data (SpO2) records for all subjects by time post-dose, for each period of assessment. PDPT: Post Dose Period on Titration
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.3966
    Method
    		 ANOVA
    Confidence interval
    Notes
    [3] - Mean difference compared to ANOVA
    Statistical analysis title
    		 Pulse oximetry (SpO2 < 90% (0 to 30 min PDPM))
    Statistical analysis description
    Continuous oximetry saturation data (SpO2) records for all subjects by time post-dose, for each period of assessment. PDPM: Post Dose Period on Maintenance
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.0734
    Method
    		 ANOVA
    Confidence interval
    Notes
    [4] - Mean difference compared to ANOVA
    Statistical analysis title
    		 Pulse oximetry (SpO2 < 90% (0 to 120 min PDPM))
    Statistical analysis description
    Continuous oximetry saturation data (SpO2) records for all subjects by time post-dose, for each period of assessment. PDPM: Post Dose Period on Maintenance
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.5603
    Method
    		 ANOVA
    Confidence interval
    Notes
    [5] - Mean difference compared to ANOVA

    Primary: Safety end points (Respiration Rate)

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    End point title
    		 Safety end points (Respiration Rate)
    End point description
    To monitor respiration rate (RR)
    End point type
    Primary
    End point timeframe
    0, 15, 30, and 60 minutes post-dosing at the first visit of the Titration Period, all other visits in the Titration Period when the buprenorphine dose was increased, and on Days 2 and 7 of the Maintenance Period.
    End point values
    		 Xprenor Subutex
    Number of subjects analysed
    23
    13
    Units: Breaths/min
    arithmetic mean (standard deviation)
        RR - Titration D1 - 0 min
    15.3 ± 2.03
    15.6 ± 2.97
        RR - Titration D1 - 15 min
    14.8 ± 2.28
    15.1 ± 2.47
        RR - Titration D1 - 30 min
    14.7 ± 2.20
    14.7 ± 2.10
        RR - Titration D1 - 60 min
    14.0 ± 2.07
    14.3 ± 2.14
        RR - Titration D7 - 0 min
    16.0 ± 0.00
    17.0 ± 1.41
        RR - Titration D7 - 15 min
    16.3 ± 1.15
    16.0 ± 2.83
        RR - Titration D7 - 30 min
    15.3 ± 0.58
    15.0 ± 1.41
        RR - Titration D7 - 60 min
    15.0 ± 1.41
    16.0 ± 2.83
        RR - Maintenance D2 - 0 min
    15.1 ± 1.98
    15.0 ± 1.84
        RR - Maintenance D2 - 15 min
    14.9 ± 2.02
    15.0 ± 1.84
        RR - Maintenance D2 - 30 min
    14.6 ± 1.77
    14.2 ± 2.09
        RR - Maintenance D2 - 60 min
    14.7 ± 1.73
    14.5 ± 2.34
        RR - Maintenance D7 - 0 min
    15.3 ± 2.74
    15.5 ± 2.59
        RR - Maintenance D7 - 15 min
    14.9 ± 2.20
    15.3 ± 2.26
        RR - Maintenance D7 - 30 min
    15.0 ± 1.67
    14.9 ± 2.56
        RR - Maintenance D7 - 60 min
    14.9 ± 1.67
    15.0 ± 2.56
    Statistical analysis title
    		 Respiration rate (RR) - 0 min
    Statistical analysis description
    The absolute respiration rate was to be statistically compared between Xprenor and Subutex groups on Maintenance Days 2 and 7 pre-dose, and at 15, 30, and 60 minutes post-dose treatment by analysis of variance (ANOVA).
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.8734 [7]
    Method
    		 ANOVA
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [6] - ANOVA
    [7] - P-value Comparison of Xprenor and Subutex at corresponding times for Maintenance Day 7
    Statistical analysis title
    		 Respiration rate (RR) - 15 min
    Statistical analysis description
    The absolute respiration rate was to be statistically compared between Xprenor and Subutex groups on Maintenance Days 2 and 7 pre-dose, and at 15, 30, and 60 minutes post-dose treatment by analysis of variance (ANOVA).
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.6072 [9]
    Method
    		 ANOVA
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [8] - ANOVA
    [9] - P-value Comparison of Xprenor and Subutex at corresponding times for Maintenance Day 7
    Statistical analysis title
    		 Respiration rate (RR) - 30 min
    Statistical analysis description
    The absolute respiration rate was to be statistically compared between Xprenor and Subutex groups on Maintenance Days 2 and 7 pre-dose, and at 15, 30, and 60 minutes post-dose treatment by analysis of variance (ANOVA).
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.8969 [11]
    Method
    		 ANOVA
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [10] - ANOVA
    [11] - P-value Comparison of Xprenor and Subutex at corresponding times for Maintenance Day 7
    Statistical analysis title
    		 Respiration rate (RR) - 60 min
    Statistical analysis description
    The absolute respiration rate was to be statistically compared between Xprenor and Subutex groups on Maintenance Days 2 and 7 pre-dose, and at 15, 30, and 60 minutes post-dose treatment by analysis of variance (ANOVA).
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.8986 [13]
    Method
    		 ANOVA
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [12] - ANOVA
    [13] - P-value Comparison of Xprenor and Subutex at corresponding times for Maintenance Day 7

    Secondary: Pharmacokinetic end points (Tmax)

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    End point title
    		 Pharmacokinetic end points (Tmax)
    End point description
    To evaluate and compare the pharmacokinetics between Subutex and Xprenor in terms of the maximum concentration (Cmax) and time to reach maximum concentration (Tmax) in opioid dependent patients.
    End point type
    Secondary
    End point timeframe
    Samples collected at 0, 5, 10, 15, 30, 60, 120, and 180 min on Day 1 of Titration Period and at 0, 5, 10, 15, 30, 60, 120, and 180 min post-study dosing on Days 2 and 7 of Maintenance Period and the last day of Extension Period (Days 27 to 29).
    End point values
    		 Xprenor Subutex
    Number of subjects analysed
    12
    6
    Units: Minutes
    median (full range (min-max))
        Buprenorphine
    60 (60 to 60)
    60 (60 to 60)
        Norbuprenorphine
    60 (60 to 60)
    120 (60 to 120)
    Statistical analysis title
    		 Pharmacokinetics
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05 [14]
    Method
    		 NA
    Confidence interval
    Notes
    [14] - Single dose pharmacokinetic parameters of Cmax, Tmax, and as data allows; AUC0-3, Kel, and t1/2 summarized using descriptive statistics (mean, SD, minimum, median, maximum geometric mean and CV%). Incurrent sample reanalysis (ISR) performed.

    Secondary: Pharmacokinetic end points (Cmax)

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    End point title
    		 Pharmacokinetic end points (Cmax)
    End point description
    To evaluate and compare the pharmacokinetics between Subutex and Xprenor in terms of the maximum concentration (Cmax) and time to reach maximum concentration (Tmax) in opioid dependent patients.
    End point type
    Secondary
    End point timeframe
    Samples collected at 0, 5, 10, 15, 30, 60, 120, and 180 min on Day 1 of Titration Period and at 0, 5, 10, 15, 30, 60, 120, and 180 min post-study dosing on Days 2 and 7 of Maintenance Period and the last day of Extension Period (Days 27 to 29).
    End point values
    		 PK data after administration of both Xprenor and Subutex.
    Number of subjects analysed
    5
    Units: ng/ml
    median (standard deviation)
        Buprenorphine
    146.0 ± 88.2
        Norbuprenorphine
    109.09 ± 42.2
    No statistical analyses for this end point

    Secondary: Pharmacokinetic end points (AUC 0 to 3 h post-dose)

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    End point title
    		 Pharmacokinetic end points (AUC 0 to 3 h post-dose)
    End point description
    AUC0-3hr calculated using the linear trapezoidal rule from pre-dose to 3 hr post-dose or the time of the last quantifiable plasma concentration, respectively. For the purpose of calculating AUC0-3hr, when two consecutive plasma concentrations below the lower limit of quantification (LOQ) are encountered after Tmax all subsequent values are excluded from the analysis. Missing values are excluded from the analysis. All values <LOQ prior to Tmax will be set to zero. Cmax and AUC0-3hr data are summarised by treatment group and dose at each of the four sampling periods using standard dispersion parameters. Tmax Data will be summarised by treatment group and dose at each of the four sampling periods using median and ranges. A statistical comparison of median Tmax between these two treatments are undertaken using the Wilcoxon matched pairs signed rank test. An estimate of the median difference between pairs along with the 90% CIs obtained based on the Hodges Lehman estimator.
    End point type
    Secondary
    End point timeframe
    Samples collected at 0, 5, 10, 15, 30, 60, 120, and 180 min on Day 1 of Titration Period and at 0, 5, 10, 15, 30, 60, 120, and 180 min post-study dosing on Days 2 and 7 of Maintenance Period and the last day of Extension Period (Days 27 to 29).
    End point values
    		 PK data after administration of both Xprenor and Subutex.
    Number of subjects analysed
    5
    Units: min*ng/ml
    median (standard deviation)
        Buprenorphine
    156.0 ± 62.0
        Norbuprenorphine
    96.0 ± 39.4
    No statistical analyses for this end point

    Secondary: Efficacy end points (Likert scale)

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    End point title
    		 Efficacy end points (Likert scale)
    End point description
    To evaluate and compare opioid withdrawal symptoms and satisfaction of treatment using medication hold and dose adequacy (Likert) scales between Subutex and Xprenor including; the examination of changes from Baseline and absolute scores between Maintenance Day 7 and the last day of the Extension Period for each treatment group. The subjects were to be asked to score the adequacy of ‘hold’ from their prescribed dose of study medication. There were 3 questions: 1. To assess adequacy of ‘hold’ on current dose of buprenorphine 2. To assess intensity of withdrawal symptoms on current dose of buprenorphine 3. To assess intensity of craving for heroin on current dose of buprenorphine Likert Scale: 4 = worst adequacy of hold/highest intensity of withdrawal/craving, 1 = best adequacy of hold/lowest intensity of withdrawal/craving
    End point type
    Secondary
    End point timeframe
    From baseline to the end of the study - TP=Titration Period - MP=Mainenance Period - EP=Extension Period
    End point values
    		 Xprenor Subutex
    Number of subjects analysed
    22
    11
    Units: Score Likert scale
    median (full range (min-max))
        Adequacy of Hold - TP Day 2
    3.0 (1 to 4)
    2.0 (1 to 4)
        Adequacy of Hold - TP Day 3
    2.0 (1 to 4)
    1.0 (1 to 4)
        Adequacy of Hold - TP Day 4
    1.5 (1 to 3)
    1.0 (1 to 3)
        Adequacy of Hold - TP Day 5
    2.0 (1 to 3)
    1.0 (1 to 3)
        Adequacy of Hold - TP Day 6
    2.0 (1 to 3)
    1.0 (1 to 3)
        Adequacy of Hold - TP Day 7
    1.0 (1 to 3)
    1.0 (1 to 3)
        Intensity of Withdrawal - TP Day 2
    2.0 (1 to 4)
    1.0 (1 to 3)
        Intensity of Withdrawal - TP Day 3
    2.0 (1 to 4)
    1.0 (1 to 4)
        Intensity of Withdrawal - TP Day 4
    1.0 (1 to 2)
    1.0 (1 to 2)
        Intensity of Withdrawal - TP Day 5
    1.0 (1 to 2)
    1.0 (1 to 2)
        Intensity of Withdrawal - TP Day 6
    1.0 (1 to 2)
    1.0 (1 to 2)
        Intensity of Withdrawal - TP Day 7
    1.0 (1 to 2)
    1.0 (1 to 2)
        Intensity of Craving - TP Day 2
    1.0 (1 to 4)
    1.0 (1 to 3)
        Intensity of Craving - TP Day 3
    1.0 (1 to 4)
    2.0 (1 to 4)
        Intensity of Craving - TP Day 4
    1.0 (1 to 3)
    1.0 (1 to 2)
        Intensity of Craving - TP Day 5
    1.0 (1 to 2)
    1.0 (1 to 2)
        Intensity of Craving - TP Day 6
    1.0 (1 to 2)
    1.0 (1 to 2)
        Intensity of Craving - TP Day 7
    1.0 (1 to 3)
    1.0 (1 to 2)
        Adequacy of Hold - MP Day 2
    1.0 (1 to 3)
    1.0 (1 to 3)
        Adequacy of Hold - MP Day 7
    1.0 (1 to 3)
    1.0 (1 to 3)
        Intensity of Withdrawal - MP Day 2
    1.0 (1 to 2)
    1.0 (1 to 2)
        Intensity of Withdrawal - MP Day 7
    1.0 (1 to 4)
    1.0 (1 to 2)
        Intensity of Craving - MP Day 2
    1.0 (1 to 2)
    1.0 (1 to 2)
        Intensity of Craving - MP Day 7
    1.0 (1 to 4)
    1.0 (1 to 2)
        Adequacy of Hold - EP Day 2
    1.0 (1 to 3)
    1.5 (1 to 3)
        Adequacy of Hold - EP Day 3
    1.0 (1 to 3)
    1.0 (1 to 2)
        Adequacy of Hold - EP Day 4
    1.0 (1 to 3)
    1.0 (1 to 2)
        Intensity of Withdrawal - EP Day 2
    1.0 (1 to 2)
    1.5 (1 to 2)
        Intensity of Withdrawal - EP Day 3
    1.0 (1 to 3)
    1.0 (1 to 1)
        Intensity of Withdrawal - EP Day 4
    1.0 (1 to 2)
    1.0 (1 to 1)
        Intensity of Craving - EP Day 2
    1.0 (1 to 2)
    1.5 (1 to 2)
        Intensity of Craving - EP Day 3
    1.0 (1 to 2)
    1.0 (1 to 1)
        Intensity of Craving - EP Day 4
    1.0 (1 to 1)
    1.0 (1 to 1)
    Statistical analysis title
    		 Likert Scale (Adequacy of Hold)
    Statistical analysis description
    The subjective 4 point assessments of hold, craving, and withdrawal symptoms were to be summarised by percentage. Also, for each of the 3 categories, the data were to be scored according to the four tick boxes (1 to 4) [‘Hold’, worst held 4; ‘Withdrawal’, severe symptoms 4; ‘Craving’, severe craving 4 ] and the scored data presented using standard descriptive statistics across each study period day, by treatment group Likert Scale: 4 = worst adequacy of hold/highest intensity of withdrawal/crav
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.603
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Likert Scale (Intensity of Withdrawal)
    Statistical analysis description
    The subjective 4 point assessments of hold, craving, and withdrawal symptoms were to be summarised by percentage. Also, for each of the 3 categories, the data were to be scored according to the four tick boxes (1 to 4) [‘Hold’, worst held 4; ‘Withdrawal’, severe symptoms 4; ‘Craving’, severe craving 4 ] and the scored data presented using standard descriptive statistics across each study period day, by treatment group Likert Scale: 4 = worst adequacy of hold/highest intensity of withdrawal/crav
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.062
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Likert Scale (Intensity of Craving)
    Statistical analysis description
    The subjective 4 point assessments of hold, craving, and withdrawal symptoms were to be summarised by percentage. Also, for each of the 3 categories, the data were to be scored according to the four tick boxes (1 to 4) [‘Hold’, worst held 4; ‘Withdrawal’, severe symptoms 4; ‘Craving’, severe craving 4 ] and the scored data presented using standard descriptive statistics across each study period day, by treatment group Likert Scale: 4 = worst adequacy of hold/highest intensity of withdrawal/crav
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.269
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Secondary: Efficacy end points (OOWS and SOWS )

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    End point title
    		 Efficacy end points (OOWS and SOWS )
    End point description
    Evaluate and compare the scores on the OOWS and SOWS from baseline to end of study between Subutex and Xprenor, including examination of changes from Baseline. Subjective and Objective Opioid Withdrawal Scales (SOWS and OOWS scores) : - SOWS scale: 5 point scale (from 0 to 4) on 16 parameters assessing withdrawal (Section 9.5.1.1). For each parameter: 0 = not at all, 1 = a little, 2 = moderate, 3 = quite a bit, and 4 = extremely, so the lower the overall SOWS score, the fewer the withdrawal symptoms the subject felt they were experiencing - OOWS scale: 13 parameters with 1 of 2 ratings (either 0 or 1) ascribed to each. In each case, the ‘0' corresponded to either the absence of the withdrawal sign, or, in the case of rhinorrhea, < 3 sniffs, so the lower the mean OOWS score, the fewer opioid withdrawal signs were observed by the PI (or her/his designee). Parameter: 0 = not at all, 1 = a little, 2 = moderate, 3 = quite a bit, and 4 = extremely.
    End point type
    Secondary
    End point timeframe
    From baseline to end of study.
    End point values
    		 Xprenor Subutex
    Number of subjects analysed
    22
    11
    Units: Score
    median (full range (min-max))
        SOWS Titration Day 2
    4.0 (0 to 25)
    4.0 (0 to 13)
        SOWS Titration Day 3
    4.0 (0 to 23)
    2.0 (0 to 33)
        SOWS Titration Day 4
    0.0 (0 to 14)
    0.0 (0 to 3)
        SOWS Titration Day 5
    1.0 (0 to 12)
    0.0 (0 to 2)
        SOWS Titration Day 6
    1.0 (0 to 7)
    0.0 (0 to 4)
        SOWS Titration Day 7
    0.0 (0 to 4)
    1.0 (0 to 3)
        SOWS Maintenance Day 2
    0.0 (0 to 6)
    1.0 (0 to 6)
        SOWS Maintenance Day 7
    0.0 (0 to 1)
    0.0 (0 to 3)
        OOWS Titration Day 2
    1.0 (0 to 9)
    0.0 (0 to 4)
        OOWS Titration Day 3
    0.0 (0 to 5)
    1.0 (0 to 4)
        OOWS Titration Day 4
    0.0 (0 to 7)
    0.0 (0 to 1)
        OOWS Titration Day 5
    0.0 (0 to 5)
    0.0 (0 to 2)
        OOWS Titration Day 6
    0.0 (0 to 2)
    0.0 (0 to 1)
        OOWS Titration Day 7
    0.0 (0 to 1)
    0.0 (0 to 1)
        OOWS Maintenance Day 2
    0.0 (0 to 1)
    0.0 (0 to 1)
        OOWS Maintenance Day 7
    0.0 (0 to 1)
    0.0 (0 to 1)
    Statistical analysis title
    		 SOWS Maintenance D2
    Statistical analysis description
    Subjective and Objective Opioid Withdrawal Scales
    Comparison groups
    Subutex v Xprenor
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.8336
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 SOWS Maintenance D7
    Statistical analysis description
    Subjective and Objective Opioid Withdrawal Scales
    Comparison groups
    Subutex v Xprenor
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.8963
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 OOWS Maintenance D2
    Statistical analysis description
    Subjective and Objective Opioid Withdrawal Scales
    Comparison groups
    Subutex v Xprenor
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 1
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 OOWS Maintenance D7
    Statistical analysis description
    Subjective and Objective Opioid Withdrawal Scales
    Comparison groups
    Subutex v Xprenor
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7609
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Secondary: Efficacy end points (Study drug oral disintegration time)

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    End point title
    		 Efficacy end points (Study drug oral disintegration time)
    End point description
    Study Drug Oral Disintegration Time : To establish the time required for (a) disintegration (partial) of the test medications Subutex and Xprenor, and (b) complete disappearance, when placed in the therapeutic area of administration (Subutex, sublingually i.e. under the tongue; Xprenor, oro-mucosally, i.e. on the tongue). The oral disintegration speed of Xprenor and Subutex was to be assessed visually at the following time points using a stop watch: 0, 15 and 30 seconds, 1, 2, 3, 5, 10, and 15 minutes on Days 1, 7, 9, and 14. The same person was to assess the complete course of 1 tablet disintegration. Separate measurements were taken for the time to partial disintegration (no longer able to remove from the mouth) and time to completely disintegrate.
    End point type
    Secondary
    End point timeframe
    From baseline to end of study, on Days 1, 7, 9, and 14
    End point values
    		 Xprenor Subutex
    Number of subjects analysed
    23
    13
    Units: Minutes
    median (full range (min-max))
        Partial disintegration at Titration D1
    0.3 (0.25 to 0.50)
    0.3 (0.25 to 1.00)
        Complete disintegration at Titration D1
    2.0 (1.00 to 15.00)
    5.0 (2.00 to 15.00)
        Partial disintegration at Titration D7
    0.3 (0.25 to 0.50)
    0.3 (0.25 to 0.50)
        Complete disintegration at Titration D7
    2.0 (1.00 to 10.00)
    10.0 (3.00 to 10.00)
        Partial disintegration at Maintenance D2
    0.25 (0.25 to 0.25)
    0.3 (0.25 to 0.50)
        Complete disintegration at Maintenance D2
    2.0 (1.00 to 10.00)
    10.0 (3.00 to 15.00)
        Partial disintegration at Maintenance D7
    0.3 (0.25 to 0.50)
    0.3 (0.25 to 2.00)
        Complete disintegration at Maintenance D7
    2.0 (1.00 to 10.00)
    7.5 (3.00 to 15.00)
        Partial disintegration All periods
    0.3 (0.25 to 0.50)
    0.3 (0.25 to 2.00)
        Complete disintegration All periods
    2.0 (1.00 to 15.00)
    10.0 (2.00 to 15.00)
    Statistical analysis title
    		 Drug Disintegration Status Post-dose
    Statistical analysis description
    Times of both partial and complete oral disintegration for each study drug summarised separately. Proportion of all treatments at each time point with whole disintegration determined separately for Xprenor and Subutex (phase and dose). Disintegration time records inadvertently recorded after a second dose on Titration Day 1 not included. Mean and median time to whole, partial, complete disintegration determined separately for Xprenor and Subutex and compared using Cox model for multiple events.
    Comparison groups
    Xprenor v Subutex
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.0001
    Method
    		 Cox
    Parameter type
    		 Cox proportional hazard
    Confidence interval
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were to be monitored throughout the study from the time the subject signed the ICF.
    Adverse event reporting additional description
    AEs and SAEs were reported until the end of the Extension Period. All AE’s were to be recorded within 24 h of when the site became aware of it. Life-threatening or fatal AEs were to be reported to Aptiv Solutions within 2 hours of knowledge of the event if this occurred before recognised recurrence of the disease.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Subutex
    Reporting group description
    		 Subjects who had received Subutex

    Reporting group title
    Xprenor
    Reporting group description
    		 Subjects who had received Xprenor

    Reporting group title
    Extension
    Reporting group description
    		 Subjects entered until Extension period (during which all Xprenor randomized subjects were to be transferred to Subutex)

    Serious adverse events
    		 Subutex Xprenor Extension
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 23 (0.00%)
    0 / 32 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Subutex Xprenor Extension
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 13 (30.77%)
    17 / 23 (73.91%)
    13 / 32 (40.63%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 23 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Chest discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 23 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 32 (3.13%)
         occurrences all number
    0
    2
    2
    Fatigue
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 23 (8.70%)
    2 / 32 (6.25%)
         occurrences all number
    0
    4
    4
    Feeling hot
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 23 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    Vessel puncture site reaction
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    2 / 32 (6.25%)
         occurrences all number
    0
    3
    3
    Nasal congestion
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 23 (8.70%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 23 (8.70%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 23 (13.04%)
    1 / 32 (3.13%)
         occurrences all number
    0
    4
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 23 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    2
    0
    2
    Depressed mood
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 23 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    Restlessness
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 23 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 23 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    3
    0
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 23 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Blood pressure diastolic decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 23 (4.35%)
    1 / 32 (3.13%)
         occurrences all number
    3
    3
    3
    Blood pressure increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 32 (3.13%)
         occurrences all number
    0
    2
    2
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 23 (8.70%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    Heart rate decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Mean cell volume abnormal
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 23 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 23 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 23 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    Arthropod bite
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 23 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    Laceration
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
    4 / 23 (17.39%)
    1 / 32 (3.13%)
         occurrences all number
    6
    6
    6
    Hyperaesthesia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Migraine
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 23 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Foreign body sensation in eyes
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 23 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 23 (8.70%)
    1 / 32 (3.13%)
         occurrences all number
    0
    3
    3
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 23 (8.70%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 23 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    2
    0
    2
    Toothache
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 32 (3.13%)
         occurrences all number
    0
    2
    2
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 23 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    3
    0
    3
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 23 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 23 (8.70%)
    1 / 32 (3.13%)
         occurrences all number
    0
    3
    3
    Pruritus
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Skin irritation
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 23 (13.04%)
    1 / 32 (3.13%)
         occurrences all number
    0
    4
    4
    Back pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle twitching
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    1 / 32 (3.13%)
         occurrences all number
    0
    2
    2
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Cellulitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 23 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 23 (4.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 23 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2012
    Amendment 1 (Protocol version12)
    28 Nov 2012
    Amendment 2 (Protocol version 13)
    04 Apr 2013
    Amendment 3 (Protocol version 15)
    01 Aug 2013
    Amendment 4 (Protocol version 16)

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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