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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, 4-way cross-over, multiple dose study to investigate the analgesic effects of buprenorphine and minacipran in healthy volunteers

    Summary
    EudraCT number
    		 2012-002302-43
    Trial protocol
    		 NL  
    Global end of trial date
    04 Oct 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2022
    First version publication date
    24 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DFP-06/CD/001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dr. Reddy's Laboratories Limited
    Sponsor organisation address
    8-2-337 Road no. 3, Banjara Hills , Hyderabad, India, 500034
    Public contact
    Geert Jan Groeneveld, Cente for Human Drug Research, 31 715246400, GGroeneveld@chdr.nl
    Scientific contact
    Geert Jan Groeneveld, Cente for Human Drug Research, 31 715246400, GGroeneveld@chdr.nl
    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 Oct 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Oct 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Oct 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To determine if the analgesic effects of co-administration of a single oral dose of milnacipran with a single intravenous dose of buprenorphine were higher than those of buprenorphine alone (potentiation) or higher than those of buprenorphine alone plus milnacipran alone (synergy) in healthy subjects. 2. To determine if the analgesic effects of co-administration of 8 days of milnacipran bid in combination with a single administration of buprenorphine were higher than those of buprenorphine alone (potentiation) or higher than those of buprenorphine alone plus multiple doses of milnacipran alone (synergy) in healthy subjects. 3. To investigate the safety and tolerability of co-administration of intravenous buprenorphine and oral milnacipran in healthy subjects. 4. To examine the potential pharmacokinetic interactions between intravenous buprenorphine and oral milnacipran in healthy subjects.
    Protection of trial subjects
    Subjects were given an oral and written explanation about the study. Only after they had given written acknowledgement of informed consent to participate did any trial-related procedure take place. All informed consent forms were signed in duplicate by the subject and the investigator or his delegate, with one original being retained at the investigational site.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Jun 2012
    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
    Netherlands: 11
    Worldwide total number of subjects
    11
    EEA total number of subjects
    11
    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)
    11
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study participants were recruited from CHDR volunteer database. The subjects were recruited after screening on the basis of inclusion and exclusion criteria as defined in the study protocol.

    Pre-assignment
    Screening details
    		 The subjects were screened on the basis of inclusion and exclusion criteria as defined in the protocol.

    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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Buprenorphine placebo+ Milnacipran 50 mg
    Arm description
    		 Milnacipran was administered twice daily. 3 different doses of Buprenorphine were used as follows: A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buprenorphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).

    Investigational medicinal product name
    Milnacipran
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered twice daily

    Arm title
    		 Buprenorphine active+ Milnacipran 25 mg
    Arm description
    		 Buprenorphine was administered on Day 1 and Day 8 and in three different doses: first a 30 minutes 0.5 μg/kg sub-therapeutic infusion followed 1.5 hours later by a second 30 minutes 1 μg/kg minimally-therapeutic infusion followed 1.5 hours later by the last 30 minutes 3 μg/kg therapeutic infusion. Milnacipran was administered twice daily (bid)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buprenorphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).

    Investigational medicinal product name
    Milnacipran
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered twice daily

    Arm title
    		 Buprenorphine active+ Milnacipran 50 mg
    Arm description
    		 Milnacipran was administered twice daily. 3 different doses of Buprenorphine were used as follows: A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buprenorphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).

    Investigational medicinal product name
    Milnacipran
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered twice daily

    Arm title
    		 Buprenorphine active+ Milnacipran placebo
    Arm description
    		 Milnacipran was administered twice daily. 3 different doses of Buprenorphine were used as follows: A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buprenorphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).

    Investigational medicinal product name
    Milnacipran
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered twice daily

    Number of subjects in period 1
    		Buprenorphine placebo+ Milnacipran 50 mg Buprenorphine active+ Milnacipran 25 mg Buprenorphine active+ Milnacipran 50 mg Buprenorphine active+ Milnacipran placebo
    Started
    11
    9
    10
    10
    Completed
    10
    9
    9
    10
    Not completed
    1
    0
    1
    0
         Consent withdrawn by subject
    1
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 11 11
    Age categorical
    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)
    		 11 11
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 24.2 ± 3.5 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 11 11

    End points

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    End points reporting groups
    Reporting group title
    Buprenorphine placebo+ Milnacipran 50 mg
    Reporting group description
    		 Milnacipran was administered twice daily. 3 different doses of Buprenorphine were used as follows: A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).

    Reporting group title
    Buprenorphine active+ Milnacipran 25 mg
    Reporting group description
    		 Buprenorphine was administered on Day 1 and Day 8 and in three different doses: first a 30 minutes 0.5 μg/kg sub-therapeutic infusion followed 1.5 hours later by a second 30 minutes 1 μg/kg minimally-therapeutic infusion followed 1.5 hours later by the last 30 minutes 3 μg/kg therapeutic infusion. Milnacipran was administered twice daily (bid)

    Reporting group title
    Buprenorphine active+ Milnacipran 50 mg
    Reporting group description
    		 Milnacipran was administered twice daily. 3 different doses of Buprenorphine were used as follows: A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).

    Reporting group title
    Buprenorphine active+ Milnacipran placebo
    Reporting group description
    		 Milnacipran was administered twice daily. 3 different doses of Buprenorphine were used as follows: A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).

    Subject analysis set title
    BUP+MIL-P vs BUP+MIL-25 after first bump
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of Buprenorphine +Milnacipran placebo and Buprenorphine + Milnacipran 25 mg

    Subject analysis set title
    BUP+MIL-P vs BUP+MIL-25 after second bump
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of Buprenorphine+ Milnacipran placebo and Buprenorphine+ Milnacipran 25 mg after second infusion of Buprenorphine

    Subject analysis set title
    BUP+MIL-P vs BUP+MIL-25 after third bump
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of Buprenorphine+ Milnapracin placebo and Buprenorphine+ Milnapracin 25 mg after third infusion of Buprenorphine

    Subject analysis set title
    BUP+MIL-P vs BUP+MIL-25
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of Buprenorphine + Milnacipran placebo and Buprenorphine+ Milnacipran 25 mg

    Subject analysis set title
    BUP+MIL-P vs BUP+MIL-50
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of Buprenorphine+ Milnacipran placebo and Buprenorphine+ Milnacipran 50 mg

    Subject analysis set title
    BUP+MIL-P vs BUP+MIL-50 after first bump
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of Buprenorphine+ Milnacipran placebo and Buprenorphine+ Milnacipran 50 mg after first infusion of Buprenorphine

    Subject analysis set title
    BUP+MIL-P vs BUP+MIL-50 after second bump
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of Buprenorphine+ Milnacipran placebo and Buprenorphine+ Milnacipran 50 mg after second infusion of Buprenorphine

    Subject analysis set title
    BUP+MIL-P vs BUP+MIL-50 after third bump
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of Buprenorphine+ Milnacipran placebo and Buprenorphine+ Milnacipran 25 mg after third infusion of Buprenorphine

    Subject analysis set title
    (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of treatments: (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50

    Subject analysis set title
    (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of treatments: (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 after first infusion of Buprenorphine

    Subject analysis set title
    (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of treatments: (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 after second infusion of Buprenorphine

    Subject analysis set title
    (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of treatments: (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 after third infusion of Buprenorphine

    Primary: Milnacipran AUC (0-t)- Day 1

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    End point title
    		 Milnacipran AUC (0-t)- Day 1 [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    AUC measured on administration of Milnacipran on Day 1
    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: Statistical Analysis has not been specified because the study population is small.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point for all baseline period arm is not reported as Milnacipran Placebo is administered to the subjects in one of the arms.
    End point values
    		 Buprenorphine placebo+ Milnacipran 50 mg Buprenorphine active+ Milnacipran 25 mg Buprenorphine active+ Milnacipran 50 mg
    Number of subjects analysed
    11
    9
    10
    Units: ng.hr/mL
        arithmetic mean (standard deviation)
    696.50 ± 160.60
    318.10 ± 102.30
    633.00 ± 154.00
    No statistical analyses for this end point

    Primary: Milnacipran tmax- Day 1

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    End point title
    		 Milnacipran tmax- Day 1 [3] [4]
    End point description
    End point type
    Primary
    End point timeframe
    Time to reach maximum plasma concentration (Cmax) on Day 1
    Notes
    [3] - 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: Statistical Analysis has not been specified because the study population is small.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point for all baseline period arm is not reported as Milnacipran Placebo is administered to the subjects in one of the arms.
    End point values
    		 Buprenorphine placebo+ Milnacipran 50 mg Buprenorphine active+ Milnacipran 25 mg Buprenorphine active+ Milnacipran 50 mg
    Number of subjects analysed
    11
    9
    10
    Units: hour
        arithmetic mean (standard deviation)
    3.156 ± 0.6175
    3.204 ± 0.8491
    3.17 ± 1.05
    No statistical analyses for this end point

    Primary: Milnacipran Cmax- Day 1

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    End point title
    		 Milnacipran Cmax- Day 1 [5] [6]
    End point description
    End point type
    Primary
    End point timeframe
    Cmax measured on Day 1
    Notes
    [5] - 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: Statistical Analysis has not been specified because the study population is small.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point for all baseline period arm is not reported as Milnacipran Placebo is administered to the subjects in one of the arms.
    End point values
    		 Buprenorphine placebo+ Milnacipran 50 mg Buprenorphine active+ Milnacipran 25 mg Buprenorphine active+ Milnacipran 50 mg
    Number of subjects analysed
    11
    9
    10
    Units: nanogram(s)/millilitre
        arithmetic mean (standard deviation)
    105.20 ± 26.93
    46.92 ± 15.92
    99.81 ± 37.20
    No statistical analyses for this end point

    Primary: Milnacipran AUC (0-t)- Day 8

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    End point title
    		 Milnacipran AUC (0-t)- Day 8 [7] [8]
    End point description
    End point type
    Primary
    End point timeframe
    Area under the curve (AUC (0-t)) on day 8
    Notes
    [7] - 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: Statistical Analysis has not been specified because the study population is small.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point for all baseline period arm is not reported as Milnacipran Placebo is administered to the subjects in one of the arms.
    End point values
    		 Buprenorphine placebo+ Milnacipran 50 mg Buprenorphine active+ Milnacipran 25 mg Buprenorphine active+ Milnacipran 50 mg
    Number of subjects analysed
    10
    9
    9
    Units: ng.hr/mL
        arithmetic mean (standard deviation)
    1281.0 ± 178.60
    629.20 ± 94.10
    1251.0 ± 306.70
    No statistical analyses for this end point

    Primary: Milnacipran tmax- Day 8

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    End point title
    		 Milnacipran tmax- Day 8 [9] [10]
    End point description
    End point type
    Primary
    End point timeframe
    Time taken to reach Cmax measured on Day 8 of the clinical trial
    Notes
    [9] - 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: Statistical Analysis has not been specified because the study population is small.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point for all baseline period arm is not reported as Milnacipran Placebo is administered to the subjects in one of the arms.
    End point values
    		 Buprenorphine placebo+ Milnacipran 50 mg Buprenorphine active+ Milnacipran 25 mg Buprenorphine active+ Milnacipran 50 mg
    Number of subjects analysed
    10
    9
    9
    Units: hour
        arithmetic mean (standard deviation)
    1.845 ± 1.02
    2.646 ± 0.4848
    3.104 ± 0.9775
    No statistical analyses for this end point

    Primary: Milnacipran Cmax- Day 8

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    End point title
    		 Milnacipran Cmax- Day 8 [11] [12]
    End point description
    End point type
    Primary
    End point timeframe
    Milnacipran Cmax measured on Day 8 of the study
    Notes
    [11] - 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: Statistical Analysis has not been specified because the study population is small.
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point for all baseline period arm is not reported as Milnacipran Placebo is administered to the subjects in one of the arms.
    End point values
    		 Buprenorphine placebo+ Milnacipran 50 mg Buprenorphine active+ Milnacipran 25 mg Buprenorphine active+ Milnacipran 50 mg
    Number of subjects analysed
    10
    9
    9
    Units: nanogram(s)/millilitre
        arithmetic mean (standard deviation)
    201.20 ± 58.51
    93.840 ± 11.69
    188.30 ± 66.65
    No statistical analyses for this end point

    Primary: Buprenorphine Cmax after final IV infusion- Day 1

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    End point title
    		 Buprenorphine Cmax after final IV infusion- Day 1 [13] [14]
    End point description
    End point type
    Primary
    End point timeframe
    Cmax after 3rd IV infusion on Day 1
    Notes
    [13] - 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: Statistical Analysis has not been specified because the study population is small.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point for all baseline period arm is not reported as Buprenorphine Placebo is administered to the subjects in one of the arms.
    End point values
    		 Buprenorphine active+ Milnacipran 25 mg Buprenorphine active+ Milnacipran 50 mg Buprenorphine active+ Milnacipran placebo
    Number of subjects analysed
    9
    9
    9
    Units: nanogram(s)/millilitre
        arithmetic mean (standard deviation)
    0.375 ± 0.0197
    0.348 ± 0.0785
    0.369 ± 0.0566
    No statistical analyses for this end point

    Primary: Buprenorphine Cmax after final IV infusion- Day 8

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    End point title
    		 Buprenorphine Cmax after final IV infusion- Day 8 [15] [16]
    End point description
    End point type
    Primary
    End point timeframe
    Cmax after final infusion of Buprenorphine on Day 8
    Notes
    [15] - 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: Statistical Analysis has not been specified because the study population is small.
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point for all baseline period arm is not reported as Buprenorphine Placebo is administered to the subjects in one of the arms.
    End point values
    		 Buprenorphine active+ Milnacipran 25 mg Buprenorphine active+ Milnacipran 50 mg Buprenorphine active+ Milnacipran placebo
    Number of subjects analysed
    9
    9
    9
    Units: nanogram(s)/millilitre
        arithmetic mean (standard deviation)
    0.355 ± 0.0534
    0.389 ± 0.0720
    0.374 ± 0.0586
    No statistical analyses for this end point

    Secondary: Estimate of difference of electrical repeat pain AUC- DAY 1

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    End point title
    		 Estimate of difference of electrical repeat pain AUC- DAY 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 1, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm.mA
        number (not applicable)
    272
    -242
    621
    217
    -92
    -137
    -455
    317
    446
    514
    93
    729
    No statistical analyses for this end point

    Secondary: Estimate of difference of electrical repeat pain AUC- DAY 8

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    End point title
    		 Estimate of difference of electrical repeat pain AUC- DAY 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 8, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm.mA
        number (not applicable)
    -381
    -90
    -54
    -175
    -1394
    -1509
    -1424
    -1249
    -860
    -1118
    -693
    -769
    No statistical analyses for this end point

    Secondary: Estimate of difference of electrical single pain AUC- DAY 1

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    End point title
    		 Estimate of difference of electrical single pain AUC- DAY 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 1, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm.mA
        number (not applicable)
    -84
    -10
    232
    46
    -226
    -273
    -266
    -138
    -95
    -256
    -100
    72
    No statistical analyses for this end point

    Secondary: Estimate of difference of electrical single pain AUC- DAY 8

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    End point title
    		 Estimate of difference of electrical single pain AUC- DAY 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 8, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm.mA
        number (not applicable)
    -59
    -132
    13
    -59
    -341
    -364
    -290
    -368
    -28
    -101
    20
    -3
    No statistical analyses for this end point

    Secondary: Estimate of difference of pressure pain AUC- DAY 1

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    End point title
    		 Estimate of difference of pressure pain AUC- DAY 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 1, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm.mA
        number (not applicable)
    173
    -696
    -531
    -352
    -324
    50
    -658
    -362
    117
    425
    -301
    227
    No statistical analyses for this end point

    Secondary: Estimate of difference of pressure pain AUC- DAY 8

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    End point title
    		 Estimate of difference of pressure pain AUC- DAY 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 8, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm.kPa
        number (not applicable)
    -321
    -830
    316
    -278
    9
    -175
    -339
    542
    160
    559
    -787
    707
    No statistical analyses for this end point

    Secondary: Estimate of difference of cold pressor pain AUC- DAY 1

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    End point title
    		 Estimate of difference of cold pressor pain AUC- DAY 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 1, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm.s
        number (not applicable)
    113
    290
    -513
    -36
    60
    173
    464
    -455
    335
    479
    697
    -170
    No statistical analyses for this end point

    Secondary: Estimate of difference of cold pressor pain AUC- DAY 8

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    End point title
    		 Estimate of difference of cold pressor pain AUC- DAY 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 8, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm.s
        number (not applicable)
    554
    705
    415
    558
    641
    704
    751
    468
    601
    547
    691
    566
    No statistical analyses for this end point

    Secondary: Estimate of difference of delta electrical single pain AUC- DAY 1

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    End point title
    		 Estimate of difference of delta electrical single pain AUC- DAY 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 1, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm.mA
        number (not applicable)
    49.51
    29.91
    82.15
    53.86
    53.86
    197.35
    55.89
    -91.64
    -101.5
    259.20
    -290.4
    -273.2
    No statistical analyses for this end point

    Secondary: Estimate of difference of delta electrical single pain AUC- DAY 8

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    End point title
    		 Estimate of difference of delta electrical single pain AUC- DAY 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 8, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm.mA
        number (not applicable)
    23.34
    245.53
    71.73
    113.54
    60.88
    -43.52
    64.15
    162.00
    104.58
    -3.20
    139.72
    177.21
    No statistical analyses for this end point

    Secondary: Estimate of difference- Left Pupil/Iris Ratio- Day 1

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    End point title
    		 Estimate of difference- Left Pupil/Iris Ratio- Day 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 1, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: units
        number (not applicable)
    0.020
    0.028
    -0.013
    -0.007
    0.018
    0.019
    0.002
    0.033
    0.028
    0.022
    0.024
    0.039
    No statistical analyses for this end point

    Secondary: Estimate of difference- Left Pupil/Iris Ratio- Day 8

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    End point title
    		 Estimate of difference- Left Pupil/Iris Ratio- Day 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 8, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: units
        number (not applicable)
    -0.115
    0.065
    -0.029
    -0.070
    -0.048
    -0.077
    -0.047
    -0.018
    0.028
    0.004
    0.030
    0.050
    No statistical analyses for this end point

    Secondary: Estimate of difference- Right Pupil/Iris Ratio- Day 1

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    End point title
    		 Estimate of difference- Right Pupil/Iris Ratio- Day 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 1, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: units
        number (not applicable)
    0.016
    0.017
    -0.016
    -0.005
    0.015
    0.016
    0.007
    0.024
    0.021
    0.015
    0.020
    0.026
    No statistical analyses for this end point

    Secondary: Estimate of difference- Right Pupil/Iris Ratio- Day 8

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    End point title
    		 Estimate of difference- Right Pupil/Iris Ratio- Day 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 1, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: units
        number (not applicable)
    -0.128
    -0.054
    -0.032
    -0.072
    -0.052
    -0.097
    -0.043
    -0.015
    0.016
    -0.028
    0.030
    0.047
    No statistical analyses for this end point

    Secondary: Estimate of difference- Saccadic Inaccuracy - Day 1

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    End point title
    		 Estimate of difference- Saccadic Inaccuracy - Day 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 1, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: percent
        number (not applicable)
    0.1
    -0.5
    -0.2
    -0.2
    1.2
    1.4
    2.1
    0
    2.1
    2.3
    3.0
    1.1
    No statistical analyses for this end point

    Secondary: Estimate of difference- Saccadic Inaccuracy - Day 8

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    End point title
    		 Estimate of difference- Saccadic Inaccuracy - Day 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 8, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: percent
        number (not applicable)
    0.5
    0.2
    1.6
    0.8
    0.4
    0.3
    -0.2
    1.2
    0.5
    0.3
    0.2
    1.1
    No statistical analyses for this end point

    Secondary: Estimate of difference- Saccadic peak velocity- Day 1

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    End point title
    		 Estimate of difference- Saccadic peak velocity- Day 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 1, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: degree/second
        number (not applicable)
    -22.0
    -13.6
    -45.4
    -27.0
    -39.0
    -8.7
    -55.6
    -52.8
    -56.5
    -16.3
    -68.1
    -85.0
    No statistical analyses for this end point

    Secondary: Estimate of difference- Saccadic peak velocity- Day 8

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    End point title
    		 Estimate of difference- Saccadic peak velocity- Day 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 8, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: degree/second
        number (not applicable)
    -27.8
    24.1
    -9.0
    -4.2
    9.5
    -18.3
    32.7
    14.2
    13.9
    -19.6
    31.9
    29.5
    No statistical analyses for this end point

    Secondary: Estimate of difference- Saccadic reaction time- Day 1

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    End point title
    		 Estimate of difference- Saccadic reaction time- Day 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 1, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: second
        number (not applicable)
    -0.003
    0.002
    0.024
    0.008
    0.007
    0.004
    -0.002
    0.020
    0.013
    0.005
    0.006
    0.028
    No statistical analyses for this end point

    Secondary: Estimate of difference- Saccadic reaction time- Day 8

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    End point title
    		 Estimate of difference- Saccadic reaction time- Day 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on day 8, over approximately 5 hours following study drug/placebo administration
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: second
        number (not applicable)
    0.003
    -0.012
    -0.004
    -0.004
    0.004
    0.003
    -0.013
    0.021
    0.012
    0.012
    -0.006
    0.029
    No statistical analyses for this end point

    Secondary: Estimate of difference- Adaptive tracking- Day 1

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    End point title
    		 Estimate of difference- Adaptive tracking- Day 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on Day 1 approximately for over 5 hours following the administration of drug/placebo
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: percent
        number (not applicable)
    0.51
    -0.15
    -3.60
    -1.08
    -0.32
    2.80
    -2.90
    -0.88
    -0.72
    2.15
    -2.99
    -1.33
    No statistical analyses for this end point

    Secondary: Estimate of difference- Adaptive tracking- Day 8

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    End point title
    		 Estimate of difference- Adaptive tracking- Day 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on Day 8 approximately for over 5 hours following the administration of drug/placebo
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: percent
        number (not applicable)
    -0.50
    -0.07
    1.48
    -0.68
    -1.56
    0.47
    -1.92
    -3.22
    -1.56
    1.24
    -3.43
    -2.49
    No statistical analyses for this end point

    Secondary: Percent Estimate of difference- log transformed body sway- Day 1

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    End point title
    		 Percent Estimate of difference- log transformed body sway- Day 1
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on Day 1 approximately for over 5 hours following the administration of drug/placebo
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm
        number (not applicable)
    12.6
    7.8
    22.6
    14.2
    10.8
    -9.5
    34.3
    11.9
    25.2
    8.2
    54.6
    17.3
    No statistical analyses for this end point

    Secondary: Percent Estimate of difference- log transformed body sway- Day 8

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    End point title
    		 Percent Estimate of difference- log transformed body sway- Day 8
    End point description
    End point type
    Secondary
    End point timeframe
    Measured on Day 8 approximately for over 5 hours following the administration of drug/placebo
    End point values
    		 BUP+MIL-P vs BUP+MIL-25 after first bump BUP+MIL-P vs BUP+MIL-25 after second bump BUP+MIL-P vs BUP+MIL-25 after third bump BUP+MIL-P vs BUP+MIL-25 BUP+MIL-P vs BUP+MIL-50 BUP+MIL-P vs BUP+MIL-50 after first bump BUP+MIL-P vs BUP+MIL-50 after second bump BUP+MIL-P vs BUP+MIL-50 after third bump (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at first infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 2nd infusion (BUP+MIL-P)+(BUP-P+MIL-50)-PRE vs BUP+MIL-50 at 3rd infusion
    Number of subjects analysed
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    11
    Units: mm
        number (not applicable)
    6.3
    17.2
    15.4
    12.9
    -2.4
    -11.8
    5.7
    -0.3
    -4.1
    -17.1
    3.5
    2.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for adverse event reporting was throughout the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Buprenorphine placebo+ Milnacipran 50 mg
    Reporting group description
    		 Milnacipran was administered twice daily. 3 different doses of Buprenorphine were used as follows: A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).

    Reporting group title
    Buprenorphine active+ Milnacipran 25 mg
    Reporting group description
    		 Buprenorphine was administered on Day 1 and Day 8 and in three different doses: first a 30 minutes 0.5 μg/kg sub-therapeutic infusion followed 1.5 hours later by a second 30 minutes 1 μg/kg minimally-therapeutic infusion followed 1.5 hours later by the last 30 minutes 3 μg/kg therapeutic infusion. Milnacipran was administered twice daily (bid)

    Reporting group title
    Buprenorphine active+ Milnacipran 50 mg
    Reporting group description
    		 Milnacipran was administered twice daily. 3 different doses of Buprenorphine were used as follows: A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).

    Reporting group title
    Buprenorphine active+ Milnacipran placebo
    Reporting group description
    		 Milnacipran was administered twice daily. 3 different doses of Buprenorphine were used as follows: A. First 30 minute infusion: 0.5 μg/kg (sub-therapeutic dose). B. Second 30 minute infusion: 1 μg/kg (minimum therapeutic dose). C. Third 30 minute infusion: 3 μg/kg (clinically relevant therapeutic dose).

    Serious adverse events
    		 Buprenorphine placebo+ Milnacipran 50 mg Buprenorphine active+ Milnacipran 25 mg Buprenorphine active+ Milnacipran 50 mg Buprenorphine active+ Milnacipran placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Buprenorphine placebo+ Milnacipran 50 mg Buprenorphine active+ Milnacipran 25 mg Buprenorphine active+ Milnacipran 50 mg Buprenorphine active+ Milnacipran placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 11 (100.00%)
    9 / 9 (100.00%)
    10 / 10 (100.00%)
    10 / 10 (100.00%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    2 / 10 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    2
    1
    Chest discomfort
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    3 / 11 (27.27%)
    6 / 9 (66.67%)
    7 / 10 (70.00%)
    3 / 10 (30.00%)
         occurrences all number
    3
    6
    7
    3
    Feeling cold
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Feeling drunk
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    1
    Feeling hot
         subjects affected / exposed
    3 / 11 (27.27%)
    2 / 9 (22.22%)
    1 / 10 (10.00%)
    3 / 10 (30.00%)
         occurrences all number
    3
    2
    1
    3
    Feeling of relaxation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hot flush
         subjects affected / exposed
    2 / 11 (18.18%)
    3 / 9 (33.33%)
    2 / 10 (20.00%)
    2 / 10 (20.00%)
         occurrences all number
    2
    3
    2
    2
    Hyperhidrosis
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 9 (11.11%)
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    1
    2
    0
    Malaise
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    Thirst
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    1
    Reproductive system and breast disorders
    Ejaculation delayed
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    Testicular pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dry throat
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    2
    Dyspnoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Oropharyngeal discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Throat irritation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Bradyphrenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Daydreaming
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Delusional perception
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Disinhibition
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Disturbance in attention
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Inappropriate affect
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Initial insomnia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Heart rate increased
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    1
    Nervous system disorders
    Bradyphrenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Disturbance in attention
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 11 (18.18%)
    6 / 9 (66.67%)
    7 / 10 (70.00%)
    6 / 10 (60.00%)
         occurrences all number
    2
    6
    7
    6
    Dizziness postural
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Dyskinesia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    4 / 11 (36.36%)
    4 / 9 (44.44%)
    6 / 10 (60.00%)
    3 / 10 (30.00%)
         occurrences all number
    4
    4
    6
    3
    Paraesthesia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    0
    1
    Photophobia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Restlessness
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Somnolence
         subjects affected / exposed
    7 / 11 (63.64%)
    8 / 9 (88.89%)
    8 / 10 (80.00%)
    8 / 10 (80.00%)
         occurrences all number
    7
    8
    8
    8
    Speech disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Accommodation disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    2 / 10 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Abdominal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 9 (22.22%)
    2 / 10 (20.00%)
    3 / 10 (30.00%)
         occurrences all number
    1
    2
    2
    3
    Dry throat
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    1
    Epigastric discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    8 / 11 (72.73%)
    8 / 9 (88.89%)
    7 / 10 (70.00%)
    9 / 10 (90.00%)
         occurrences all number
    8
    8
    7
    9
    Salivary hypersecretion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    3 / 11 (27.27%)
    6 / 9 (66.67%)
    10 / 10 (100.00%)
    7 / 10 (70.00%)
         occurrences all number
    3
    6
    10
    7
    Skin and subcutaneous tissue disorders
    Piloerection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 9 (22.22%)
    2 / 10 (20.00%)
    3 / 10 (30.00%)
         occurrences all number
    1
    2
    2
    3
    Pruritus generalized
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Bladder spasm
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    Dysuria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary hesitation
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 9 (22.22%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    1
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    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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