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    Clinical Trial Results:
    An Open-label, Randomised, Three -Way, Cross-Over Study to Assess the Pharmacokinetics, Safety and Tolerability of Two Formulations of RBP-6300 10mg in Healthy Volunteers under a Naltrexone Block in the Presence and Absence of Food

    Summary
    EudraCT number
    		 2012-002408-42
    Trial protocol
    		 GB  
    Global end of trial date
    23 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RB-UK-12-0004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Reckitt Benckiser Pharmaceuticals, Inc
    Sponsor organisation address
    10710 Midlothian Turnpike, Suite 430, Richmond, VA, United States, 23235
    Public contact
    Director of Clinical Operations, Reckitt Benckiser Pharmaceuticals Inc., 01 804-594-2029,
    Scientific contact
    Director of Clinical Operations, Reckitt Benckiser Pharmaceuticals Inc., 01 804-594-2029,
    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
    27 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the relative bioavailability of buprenorphine after oral administration of RBP 6300 (Formualtion A) 10 mg as compared to RBP 6300 (Formualtion B) 10 mg, when administered in the fasted state. To assess the relative bioavailability of buprenorphine after oral administration of RBP 6300 (Formulation A) 10 mg to subjects who have been fed a high-fat breakfast as compared to fasted.
    Protection of trial subjects
    The Investigator was responsible for ensuring that the clinical study was performed in accordance with the protocol, current International Conference on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP), and applicable regulatory and country-specific requirements. GCP is an international, ethical, and scientific quality standard for designing, conducting, recording, and reporting studies that involve the participation of human subjects. Compliance with this standard provides the public assurance that the rights, safety, and well-being of study subjects are protected, consistent with the principles that originated in the Declaration of Helsinki, 1996, and that the clinical study data are credible. All informed consent documents and other documents used in the conduct of the study were approved by the IEC. Subjects were given consent documents to review before attending Screening. Prior to the Screening procedures, a medically qualified associate explained to each subject in a group setting the nature of the study, its purpose, procedures, expected duration, alternative therapies available, and the benefits and risks involved in study participation. Subjects were informed of their right to withdraw from the study at any time without prejudice. After this explanation, and before any study-specific procedures were performed, the subject voluntarily signed and dated the ICF to indicate their wish to participate in the study. The Investigator or designated subinvestigator also signed and dated the ICF. The time (hour and minute) the ICF was signed was also recorded by the subject and the person obtaining consent from the subject. Prior to participation in the study, the subject received a copy of the signed and dated ICF along with an emergency card with contact information for the Investigator and site staff in the event of a medical emergency during the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Sep 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: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    50
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 106 subjects were screened and 52 approved for participation. Two approved subjects were designated alternates who were not randomized or dosed.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All Subjects
    Arm description
    		 Subjects were randomized to 1 of 6 treatment arm combinations in this cross-over study. The three treatments (given in the assigned combination order) were 1). RBP-6300 Formulation A (10 mg buprenorphine hemiadipate HCl/10 mg naloxone HCl dihydrate) administered as an oral tablet after an overnight fast of at least 10 hours. 2). RBP-6300 Formulation B (10 mg buprenorphine hemiadipate HCl/10 mg naloxone HCl dihydrate) administered as an oral tablet after an overnight fast of at least 10 hours. 3). RBP-6300 Formulation A administered as an oral tablet within 30 minutes of starting and completing a high-fat breakfast following an overnight fast of at least 10 hours. A single oral tablet of each treatment was given at the beginning of each treatment period followed by a 14 day washout prior to starting the next treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RBP-6300 Formulation A
    Investigational medicinal product code
    Other name
    buprenorphine hemiadipate HCl , naloxone HCl dihydrate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each Formula A RBP-6300 tablet contains 10 mg buprenorphine hemiadipate HCl [7.20 mg buprenorphine free base] and 10 mg naloxone HCl dihydrate [8.18 mg naloxone free base]. Each dose was a single tablet taken orally in the am, either following a 10 hour fast or following a high-fat breakfast. Formula A has the same amount of buprenorphine and naloxone as Formula B. However Formula A contains fewer insoluble excipients than Formula B, thus reducing the potential harm to abusers.

    Investigational medicinal product name
    RBP-6300 Formulation B
    Investigational medicinal product code
    Other name
    buprenorphine hemiadipate HCl , naloxone HCl dihydrate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each Formula B RBP-6300 tablet contains 10 mg buprenorphine hemiadipate HCl [7.20 mg buprenorphine free base] and 10 mg naloxone HCl dihydrate [8.18 mg naloxone free base]. Each dose was a single tablet taken orally in the am following a 10 hour fast. Formula B has the same amount of buprenorphine and naloxone as Formula A. Formula B has been used in all previous clinical trials with RBP-6300 and contains more insoluble excipients than Formula A.

    Investigational medicinal product name
    naltrexone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Naltrexone was administered both pre- and post-RBP-6300 dosing in order to minimize the occurrence of unacceptable AEs (eg, decreased respiration, nausea) often associated with the administration of buprenorphine in opiate-naive, healthy subjects. Naltrexone 100 mg was given at 13 hours [± 1 hour] and at 2 hours [± 15 minutes] predose. It was also given 50 mg at 12 hours [± 1 hour] and 24 hours [± 1 hour] post dose.

    Number of subjects in period 1
    		All Subjects
    Started
    50
    RBP-6300 Formulation A - Fasting
    47
    RBP-6300 Formulation B - Fasting
    47
    RBP-6300 Formulation A - High Fat
    44
    Completed
    41
    Not completed
    9
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    6
         Not specified
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 All subjects regardless of the order of the study interventions assigned in this cross-over trial.

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 50 50
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 50 50
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 34.1 (19 to 55) -
    Gender categorical
    Units: Subjects
        Female
    		 16 16
        Male
    		 34 34
    Race
    Units: Subjects
        White
    		 50 50
        Black or African American
    		 0 0
        Asian
    		 0 0
        American Indian or Alaska Native
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Other
    		 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 1
        Not Hispanic or Latino
    		 49 49
    Weight
    Units: kg
        arithmetic mean (full range (min-max))
    		 75.72 (54.8 to 96.4) -
    Height
    Units: cm
        arithmetic mean (full range (min-max))
    		 173 (149 to 191) -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (full range (min-max))
    		 25.2 (18.5 to 29.3) -

    End points

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    End points reporting groups
    Reporting group title
    All Subjects
    Reporting group description
    		 Subjects were randomized to 1 of 6 treatment arm combinations in this cross-over study. The three treatments (given in the assigned combination order) were 1). RBP-6300 Formulation A (10 mg buprenorphine hemiadipate HCl/10 mg naloxone HCl dihydrate) administered as an oral tablet after an overnight fast of at least 10 hours. 2). RBP-6300 Formulation B (10 mg buprenorphine hemiadipate HCl/10 mg naloxone HCl dihydrate) administered as an oral tablet after an overnight fast of at least 10 hours. 3). RBP-6300 Formulation A administered as an oral tablet within 30 minutes of starting and completing a high-fat breakfast following an overnight fast of at least 10 hours. A single oral tablet of each treatment was given at the beginning of each treatment period followed by a 14 day washout prior to starting the next treatment period.

    Subject analysis set title
    RBP-6300 Formulation A - Fasting
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    RBP-6300 Formulation A (10 mg buprenorphine hemiadipate HCl/10 mg naloxone HCl dihydrate) administered as an oral tablet after an overnight fast of at least 10 hours.

    Subject analysis set title
    RBP-6300 Formulation B - Fasting
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    RBP-6300 Formulation B (10 mg buprenorphine hemiadipate HCl/10 mg naloxone HCl dihydrate) administered as an oral tablet after an overnight fast of at least 10 hours.

    Subject analysis set title
    RBP-6300 Formulation A - High Fat
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    RBP-6300 Formulation A administered as an oral tablet within 30 minutes of starting and completing a high-fat breakfast following an overnight fast of at least 10 hours.

    Primary: Buprenorphine: Area under the plasma concentration-time curve from time 0 to 72 hours post dose (AUC0-72), AUC0-96, AUCinf, and AUClast

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    End point title
    		 Buprenorphine: Area under the plasma concentration-time curve from time 0 to 72 hours post dose (AUC0-72), AUC0-96, AUCinf, and AUClast
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times. The PK parameters for any subjects who experienced emesis within 4 hours of administration of study treatment were excluded from the descriptive statistics and statistical analysis. Concentration-time data for subjects with quantifiable predose concentrations less than 5% of the respective Cmax were included in the PK and statistical analysis without adjustment. Data for subjects with quantifiable predose concentrations greater than 5% of the respective Cmax were excluded from the PK and statistical analysis. AUC0-96: Area under the plasma concentration-time curve from time 0 to 96 hours post dose AUCinf: Area under the plasma concentration-time curve from time 0 extrapolated to Infinity post dose AUClast: Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration
    End point type
    Primary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 hours (Day 4), post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [1]
    44 [2]
    43 [3]
    Units: hr*mg/mL
    arithmetic mean (standard deviation)
        AUC0-72
    12.205 ( 4.9607 )
    12.295 ( 5.6173 )
    15.932 ( 6.3917 )
        AUC0-96
    13.535 ( 5.4959 )
    13.54 ( 6.1411 )
    17.581 ( 7.1447 )
        AUCinf
    16.279 ( 6.0194 )
    16.7 ( 7.0443 )
    21.881 ( 8.0195 )
        AUClast
    14.181 ( 6.3366 )
    14.191 ( 6.9789 )
    18.743 ( 8.0898 )
    Notes
    [1] - PK population AUCinf: # subjects was 38
    [2] - PK population AUCinf: # subjects was 36
    [3] - PK population AUCinf: # subjects was 38
    Statistical analysis title
    		 AUC0-72: Formula A Fasting to Formula B Fasting
    Statistical analysis description
    Comparison of the natural log-transformed AUC tests was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 87 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation B - Fasting
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric LSMean ratio
    Point estimate
    1.0124
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9524
         upper limit
    		 1.0761
    Statistical analysis title
    		 AUC0-72: Formula A High Fat to Formula A Fasting
    Statistical analysis description
    Comparison of the natural log-transformed AUC tests was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 86 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation A - High Fat
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric LSMean ratio
    Point estimate
    1.323
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2433
         upper limit
    		 1.4079
    Statistical analysis title
    		 AUC0-92: Formula A Fasting to Formula B Fasting
    Statistical analysis description
    Comparison of the natural log-transformed AUC tests was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 87 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation B - Fasting
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric LSMean ratio
    Point estimate
    1.011
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9514
         upper limit
    		 1.0744
    Statistical analysis title
    		 AUC0-92: Formula A HIgh Fat to Formula A Fasting
    Statistical analysis description
    Comparison of the natural log-transformed AUC tests was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 86 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation A - High Fat
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric LSMean ratio
    Point estimate
    1.3131
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2344
         upper limit
    		 1.3969
    Statistical analysis title
    		 AUCinf: Formula A Fasting to Formula B Fasting
    Statistical analysis description
    Comparison of the natural log-transformed AUC tests was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 74 represents the sum of subjects contributing data in the two arms, not unique subjects. Note there were fewer subjects in each arm of the AUCinf calculation than in the other AUC measurements.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation B - Fasting
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric LSMean ratio
    Point estimate
    1.0264
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9539
         upper limit
    		 1.1043
    Statistical analysis title
    		 AUCinf: Formula A High Fat to Formula A Fasting
    Statistical analysis description
    Comparison of the natural log-transformed AUC tests was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 76 represents the sum of subjects contributing data in the two arms, not unique subjects. Note there were fewer subjects in each arm of the AUCinf calculation than in the other AUC measurements.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation A - High Fat
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric LSMean ratio
    Point estimate
    1.3321
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2382
         upper limit
    		 1.4332
    Statistical analysis title
    		 AUClast: Formula A Fasting to Formula B Fasting
    Statistical analysis description
    Comparison of the natural log-transformed AUC tests was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 87 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation B - Fasting
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric LSMean ratio
    Point estimate
    1.012
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9451
         upper limit
    		 1.0836
    Statistical analysis title
    		 AUClast: Formula A High Fat to Formula A Fasting
    Statistical analysis description
    Comparison of the natural log-transformed AUC tests was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 86 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation A - High Fat
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric LSMean ratio
    Point estimate
    1.345
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2546
         upper limit
    		 1.4418

    Secondary: Buprenorphine: Apparent clearance (CL/F)

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    End point title
    		 Buprenorphine: Apparent clearance (CL/F)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times. PK parameters for any subjects who experienced emesis within 4 hours of administration of study treatment were excluded from the descriptive statistics and statistical analysis. Concentration-time data for subjects with quantifiable predose concentrations less than 5% of the respective Cmax were included in the PK and statistical analysis without adjustment. Data for subjects with quantifiable predose concentrations greater than 5% of the respective Cmax were excluded from the PK and statistical analysis.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    38 [4]
    36 [5]
    38 [6]
    Units: L/hour
        arithmetic mean (standard deviation)
    519.99 ( 200.807 )
    521.46 ( 223.406 )
    382.43 ( 143.278 )
    Notes
    [4] - PK population
    [5] - PK population
    [6] - PK population
    No statistical analyses for this end point

    Secondary: Buprenorphine: Maximum observed plasma concentration (Cmax)

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    End point title
    		 Buprenorphine: Maximum observed plasma concentration (Cmax)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times. PK parameters for any subjects who experienced emesis within 4 hours of administration of study treatment were excluded from the descriptive statistics and statistical analysis. Concentration-time data for subjects with quantifiable predose concentrations less than 5% of the respective Cmax were included in the PK and statistical analysis without adjustment. Data for subjects with quantifiable predose concentrations greater than 5% of the respective Cmax were excluded from the PK and statistical analysis.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [7]
    44 [8]
    43 [9]
    Units: ng/mL
        arithmetic mean (standard deviation)
    1.545 ( 1.0075 )
    1.383 ( 0.9194 )
    1.466 ( 0.9581 )
    Notes
    [7] - PK population
    [8] - PK population
    [9] - PK population
    Statistical analysis title
    		 Cmax: Formula A Fasting to Formula B Fasting
    Statistical analysis description
    Comparison of the natural log-transformed Cmax tests was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 87 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation B - Fasting
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric LSMean ratio
    Point estimate
    1.1243
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9678
         upper limit
    		 1.3061
    Statistical analysis title
    		 Cmax: Formula A High Fat to Formula A Fasting
    Statistical analysis description
    Comparison of the natural log-transformed Cmax tests was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 86 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation A - High Fat
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Geometric LSMean ratio
    Point estimate
    0.9475
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8134
         upper limit
    		 1.1036

    Secondary: Buprenorphine: Time to maximum plasma concentration (Tmax)

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    End point title
    		 Buprenorphine: Time to maximum plasma concentration (Tmax)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times. Concentration-time data for subjects with quantifiable predose concentrations less than 5% of the respective Cmax were included in the PK and statistical analysis without adjustment. Data for subjects with quantifiable predose concentrations greater than 5% of the respective Cmax were excluded from the PK and statistical analysis.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [10]
    44 [11]
    43 [12]
    Units: hour
        median (full range (min-max))
    0.75 (0.5 to 4)
    0.75 (0.25 to 3)
    2 (0.5 to 10)
    Notes
    [10] - PK population
    [11] - PK population
    [12] - PK population
    Statistical analysis title
    		 Tmax: Formula A Fasting to Formula B Fasting
    Statistical analysis description
    Differences in Tmax across treatments ere tested using the nonparametric Wilcoxon signed rank test. Additionally, a 95% nonparametric CI was constructed for the median difference in the Tmax values based on the Hodges-Lehmann estimates. # subjects in this analysis: 87 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation B - Fasting
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7916 [13]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.125
         upper limit
    		 0.125
    Notes
    [13] - Statistical tests conducted were two-sided at an α level of 0.05.
    Statistical analysis title
    		 Tmax: Formula A High Fat to Formula A Fasting
    Statistical analysis description
    Differences in Tmax across treatments ere tested using the nonparametric Wilcoxon signed rank test. Additionally, a 95% nonparametric CI was constructed for the median difference in the Tmax values based on the Hodges-Lehmann estimates. # subjects in this analysis: 86 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation A - High Fat
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.0001 [14]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    1.375
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 2
    Notes
    [14] - Statistical tests conducted were two-sided at an α level of 0.05.

    Secondary: Buprenorphine: Apparent volume of distribution (Vz/F)

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    End point title
    		 Buprenorphine: Apparent volume of distribution (Vz/F)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times. PK parameters for any subjects who experienced emesis within 4 hours of administration of study treatment were excluded from the descriptive statistics and statistical analysis. Concentration-time data for subjects with quantifiable predose concentrations less than 5% of the respective Cmax were included in the PK and statistical analysis without adjustment. Data for subjects with quantifiable predose concentrations greater than 5% of the respective Cmax were excluded from the PK and statistical analysis.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    38 [15]
    36 [16]
    38 [17]
    Units: Liters
        arithmetic mean (standard deviation)
    26416.58 ( 9137.672 )
    26594.9 ( 9681.089 )
    20800.46 ( 8590.982 )
    Notes
    [15] - PK population
    [16] - PK population
    [17] - PK population
    No statistical analyses for this end point

    Secondary: Buprenorphine: Terminal phase half-life (T1/2)

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    End point title
    		 Buprenorphine: Terminal phase half-life (T1/2)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times. PK parameters for any subjects who experienced emesis within 4 hours of administration of study treatment were excluded from the descriptive statistics and statistical analysis. Concentration-time data for subjects with quantifiable predose concentrations less than 5% of the respective Cmax were included in the PK and statistical analysis without adjustment. Data for subjects with quantifiable predose concentrations greater than 5% of the respective Cmax were excluded from the PK and statistical analysis.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    42 [18]
    43 [19]
    43 [20]
    Units: hour
        arithmetic mean (standard deviation)
    39.352 ( 15.3397 )
    42.475 ( 19.5276 )
    42.513 ( 20.3092 )
    Notes
    [18] - PK population
    [19] - PK population
    [20] - PK population
    Statistical analysis title
    		 T1/2: Formula A Fasting to Formula B Fasting
    Statistical analysis description
    Comparison of observed values for T1/2 was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 85 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation B - Fasting
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Difference of LSMean
    Point estimate
    -2.667
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9.212
         upper limit
    		 3.879
    Statistical analysis title
    		 T1/2: Formula A High Fat to Formula A Fasting
    Statistical analysis description
    Comparison of observed values for T1/2 was performed using an analysis of variance (ANOVA) model with sequence, subject nested within sequence, treatment, and period as fixed effects. # subjects in this analysis: 85 represents the sum of subjects contributing data in the two arms, not unique subjects.
    Comparison groups
    RBP-6300 Formulation A - Fasting v RBP-6300 Formulation A - High Fat
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Difference of LSMean
    Point estimate
    2.882
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.735
         upper limit
    		 9.5

    Secondary: Naloxone: Area under the plasma concentration-time curve from time 0 to 72 hours post dose (AUC0-72), AUC0-96, AUCinf, and AUClast

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    End point title
    		 Naloxone: Area under the plasma concentration-time curve from time 0 to 72 hours post dose (AUC0-72), AUC0-96, AUCinf, and AUClast
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times. The PK parameters for any subjects who experienced emesis within 4 hours of administration of study treatment were excluded from the descriptive statistics and statistical analysis. Concentration-time data for subjects with quantifiable predose concentrations less than 5% of the respective Cmax were included in the PK and statistical analysis without adjustment. Data for subjects with quantifiable predose concentrations greater than 5% of the respective Cmax were excluded from the PK and statistical analysis. AUC0-96: Area under the plasma concentration-time curve from time 0 to 96 hours post dose AUCinf: Area under the plasma concentration-time curve from time 0 extrapolated to Infinity post dose AUClast: Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 hours (Day 4), post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [21]
    43 [22]
    42 [23]
    Units: hr*pg/mL
    arithmetic mean (standard deviation)
        AUC0-72 (n=43, 43, 42)
    536.882 ( 379.091 )
    536.354 ( 380.102 )
    621.068 ( 350.954 )
        AUC0-96 (n=43, 43, 42)
    541.186 ( 382.039 )
    541.72 ( 383.261 )
    624.075 ( 351.424 )
        AUCinf (n=40, 39, 41)
    558.988 ( 392.757 )
    532.576 ( 384.951 )
    630.683 ( 354.287 )
        AUClast (n=43, 43, 42)
    512.556 ( 369.972 )
    514.805 ( 384.814 )
    600.107 ( 351.611 )
    Notes
    [21] - PK population AUCinf: # subjects was 40
    [22] - PK population AUCinf: # subjects was 39
    [23] - PK population AUCinf: # subjects was 41
    No statistical analyses for this end point

    Secondary: Naloxone: Apparent clearance (CL/F)

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    End point title
    		 Naloxone: Apparent clearance (CL/F)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    40 [24]
    39 [25]
    41 [26]
    Units: L/hour
        arithmetic mean (standard deviation)
    18128.5 ( 6292.69 )
    18900.8 ( 6242.62 )
    15596.4 ( 5875.31 )
    Notes
    [24] - PK population
    [25] - PK population
    [26] - PK population
    No statistical analyses for this end point

    Secondary: Naloxone: Maximum observed plasma concentration (Cmax)

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    End point title
    		 Naloxone: Maximum observed plasma concentration (Cmax)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [27]
    43 [28]
    42 [29]
    Units: pg/mL
        arithmetic mean (standard deviation)
    117.584 ( 59.6366 )
    114.488 ( 54.9768 )
    137.721 ( 131.51 )
    Notes
    [27] - PK population
    [28] - PK population
    [29] - PK population
    No statistical analyses for this end point

    Secondary: Naloxone: Time to maximum plasma concentration (Tmax)

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    End point title
    		 Naloxone: Time to maximum plasma concentration (Tmax)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [30]
    43 [31]
    42 [32]
    Units: hours
        median (full range (min-max))
    0.5 (0.25 to 12)
    0.5 (0.08 to 10)
    0.875 (0.25 to 10)
    Notes
    [30] - PK population
    [31] - PK population
    [32] - PK population
    No statistical analyses for this end point

    Secondary: Naloxone: Apparent volume of distribution (Vz/F)

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    End point title
    		 Naloxone: Apparent volume of distribution (Vz/F)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    40 [33]
    39 [34]
    41 [35]
    Units: liters
        arithmetic mean (standard deviation)
    281217.6 ( 148959.5 )
    267134.2 ( 113638.7 )
    200385 ( 79055.43 )
    Notes
    [33] - PK population
    [34] - PK population
    [35] - PK population
    No statistical analyses for this end point

    Secondary: Naloxone: Terminal phase half-life (T1/2)

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    End point title
    		 Naloxone: Terminal phase half-life (T1/2)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    41 [36]
    39 [37]
    41 [38]
    Units: hours
        arithmetic mean (standard deviation)
    10.941 ( 5.3226 )
    9.625 ( 2.5029 )
    9.061 ( 2.182 )
    Notes
    [36] - PK population
    [37] - PK population
    [38] - PK population
    No statistical analyses for this end point

    Secondary: Naloxone-3-Glucuronide: Area under the plasma concentration-time curve from time 0 to 72 hours post dose (AUC0-72), AUC0-96, AUCinf, and AUClast

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    End point title
    		 Naloxone-3-Glucuronide: Area under the plasma concentration-time curve from time 0 to 72 hours post dose (AUC0-72), AUC0-96, AUCinf, and AUClast
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 hours (Day 4), post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [39]
    44 [40]
    43 [41]
    Units: hr*pg/mL
    arithmetic mean (standard deviation)
        AUC0-72 (n=43, 44, 43)
    390626 ( 89104.2 )
    388016 ( 884449.9 )
    343377 ( 92323.5 )
        AUC0-96 (n=43, 44, 43)
    391305 ( 89619 )
    388920 ( 89401.2 )
    343911 ( 92602 )
        AUCinf (n=43, 43, 43)
    391536 ( 89784 )
    384388 ( 84678.6 )
    344084 ( 92695.7 )
        AUClast (n=43, 44, 43)
    388867 ( 89699.2 )
    386584 ( 89199.4 )
    341692 ( 92391.1 )
    Notes
    [39] - PK population
    [40] - PK population AUCinf: # subjects was 43
    [41] - PK population
    No statistical analyses for this end point

    Secondary: Naloxone-3-Glucuronide: Maximum observed plasma concentration (Cmax)

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    End point title
    		 Naloxone-3-Glucuronide: Maximum observed plasma concentration (Cmax)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [42]
    44 [43]
    43 [44]
    Units: pg/mL
        arithmetic mean (standard deviation)
    189833 ( 56207.23 )
    190464 ( 51991.93 )
    77190.7 ( 41626.66 )
    Notes
    [42] - PK population
    [43] - PK population
    [44] - PK population
    No statistical analyses for this end point

    Secondary: Naloxone-3-Glucuronide: Time to maximum plasma concentration (Tmax)

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    End point title
    		 Naloxone-3-Glucuronide: Time to maximum plasma concentration (Tmax)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [45]
    44 [46]
    43 [47]
    Units: hours
        median (full range (min-max))
    0.5 (0.25 to 2)
    0.5 (0.25 to 3)
    1.5 (0.25 to 4)
    Notes
    [45] - PK population
    [46] - PK population
    [47] - PK population
    No statistical analyses for this end point

    Secondary: Naloxone-3-Glucuronide: Terminal phase half-life (T1/2)

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    End point title
    		 Naloxone-3-Glucuronide: Terminal phase half-life (T1/2)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [48]
    43 [49]
    43 [50]
    Units: hours
        arithmetic mean (standard deviation)
    8.497 ( 2.5606 )
    8.255 ( 2.9189 )
    8.339 ( 2.5873 )
    Notes
    [48] - PK population
    [49] - PK population
    [50] - PK population
    No statistical analyses for this end point

    Secondary: Buprenorphine Hemiadipate: Area under the plasma concentration-time curve from time 0 to 72 hours post dose (AUC0-72), AUC0-96, AUCinf, and AUClast

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    End point title
    		 Buprenorphine Hemiadipate: Area under the plasma concentration-time curve from time 0 to 72 hours post dose (AUC0-72), AUC0-96, AUCinf, and AUClast
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 hours (Day 4), post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    37 [51]
    36 [52]
    28 [53]
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        AUC0-72 (n=37, 36, 28)
    1.006 ( 0.6769 )
    1.036 ( 0.5688 )
    1.671 ( 0.8329 )
        AUC0-96 (n=37, 36, 28)
    1.006 ( 0.6769 )
    1.036 ( 0.5689 )
    1.672 ( 0.8329 )
        AUCinf (n=33, 30, 19)
    1.036 ( 0.7017 )
    1.036 ( 0.5832 )
    1.8 ( 0.8657 )
        AUClast (n=43, 44, 43)
    0.863 ( 0.6558 )
    0.832 ( 0.5681 )
    1.327 ( 0.7492 )
    Notes
    [51] - PK population AUCinf: # subjects was 33 AUClast: # subjects was 43
    [52] - PK population AUCinf: # subjects was 30 AUClast: # subjects was 44
    [53] - PK population AUCinf: # subjects was 19 AUClast: # subjects was 43
    No statistical analyses for this end point

    Secondary: Buprenorphine Hemiadipate: Apparent clearance (CL/F)

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    End point title
    		 Buprenorphine Hemiadipate: Apparent clearance (CL/F)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    33 [54]
    30 [55]
    19 [56]
    Units: L/hour
        arithmetic mean (standard deviation)
    12696.7 ( 7618.39 )
    12110.1 ( 6588.64 )
    6282.36 ( 2571.67 )
    Notes
    [54] - PK population
    [55] - PK population
    [56] - PK population
    No statistical analyses for this end point

    Secondary: Buprenorphine Hemiadipate: Maximum observed plasma concentration (Cmax)

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    End point title
    		 Buprenorphine Hemiadipate: Maximum observed plasma concentration (Cmax)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [57]
    44 [58]
    43 [59]
    Units: ng/mL
        arithmetic mean (standard deviation)
    1.102 ( 0.8978 )
    0.978 ( 0.8173 )
    0.842 ( 0.7135 )
    Notes
    [57] - PK population
    [58] - PK population
    [59] - PK population
    No statistical analyses for this end point

    Secondary: Buprenorphine Hemiadipate: Time to maximum plasma concentration (Tmax)

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    End point title
    		 Buprenorphine Hemiadipate: Time to maximum plasma concentration (Tmax)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [60]
    44 [61]
    43 [62]
    Units: hours
        median (full range (min-max))
    0.5 (0.25 to 4)
    0.5 (0.25 to 3)
    1.25 (0.25 to 8)
    Notes
    [60] - PK population
    [61] - PK population
    [62] - PK population
    No statistical analyses for this end point

    Secondary: Buprenorphine Hemiadipate: Apparent volume of distribution (Vz/F)

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    End point title
    		 Buprenorphine Hemiadipate: Apparent volume of distribution (Vz/F)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    33 [63]
    30 [64]
    19 [65]
    Units: liters
        arithmetic mean (standard deviation)
    7166.63 ( 4169.24 )
    7587.57 ( 5268.287 )
    8468.05 ( 5464.365 )
    Notes
    [63] - PK population
    [64] - PK population
    [65] - PK population
    No statistical analyses for this end point

    Secondary: Buprenorphine Hemiadipate: Terminal phase half-life (T1/2)

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    End point title
    		 Buprenorphine Hemiadipate: Terminal phase half-life (T1/2)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    33 [66]
    31 [67]
    22 [68]
    Units: hours
        arithmetic mean (standard deviation)
    0.417 ( 0.2047 )
    0.473 ( 0.2307 )
    1.174 ( 0.994 )
    Notes
    [66] - PK population
    [67] - PK population
    [68] - PK population
    No statistical analyses for this end point

    Secondary: Norbuprenorphine: Area under the plasma concentration-time curve from time 0 to 72 hours post dose (AUC0-72), AUC0-96, AUCinf, and AUClast

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    End point title
    		 Norbuprenorphine: Area under the plasma concentration-time curve from time 0 to 72 hours post dose (AUC0-72), AUC0-96, AUCinf, and AUClast
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 hours (Day 4), post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [69]
    43 [70]
    43 [71]
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        AUC0-72 (n=43, 43, 43)
    28.97 ( 9.136 )
    29.79 ( 10.5179 )
    32.819 ( 12.7461 )
        AUC0-96 (n=43, 43, 43)
    33.794 ( 10.4778 )
    34.942 ( 12.2799 )
    38.743 ( 15.0137 )
        AUCinf (n=38, 37, 39)
    43.891 ( 14.5846 )
    46.056 ( 16.673 )
    51.029 ( 21.2304 )
        AUClast (n=43, 43, 43)
    38.673 ( 12.949 )
    39.932 ( 15.1644 )
    44.967 ( 18.387 )
    Notes
    [69] - PK population AUCinf: # subjects was 38
    [70] - PK population AUCinf: # subjects was 37
    [71] - PK population AUCinf: # subjects was 39
    No statistical analyses for this end point

    Secondary: Norbuprenorphine: Maximum observed plasma concentration (Cmax)

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    End point title
    		 Norbuprenorphine: Maximum observed plasma concentration (Cmax)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 hours (Day 4), post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [72]
    43 [73]
    43 [74]
    Units: ng/mL
        arithmetic mean (standard deviation)
    1.287 ( 0.5964 )
    1.192 ( 0.578 )
    1.011 ( 0.4969 )
    Notes
    [72] - PK population
    [73] - PK population
    [74] - PK population
    No statistical analyses for this end point

    Secondary: Norbuprenorphine: Time to maximum plasma concentration (Tmax)

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    End point title
    		 Norbuprenorphine: Time to maximum plasma concentration (Tmax)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [75]
    43 [76]
    43 [77]
    Units: hours
        median (full range (min-max))
    1 (0.5 to 8)
    1.25 (0.5 to 6)
    3 (0.75 to 12)
    Notes
    [75] - PK population
    [76] - PK population
    [77] - PK population
    No statistical analyses for this end point

    Secondary: Norbuprenorphine: Terminal phase half-life (T1/2)

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    End point title
    		 Norbuprenorphine: Terminal phase half-life (T1/2)
    End point description
    PK parameters were calculated from the concentration-time data using noncompartmental methods (Phoenix® WinNonlin®, version 6.3) and actual sampling times.
    End point type
    Secondary
    End point timeframe
    Predose and 5 minutes and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day 5), 120 (Day 6), and 144 hours (Day 7) post dose. Dosing days included Day 1, Day 22 and Day 43
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    43 [78]
    43 [79]
    43 [80]
    Units: hours
        arithmetic mean (standard deviation)
    44.677 ( 14.9785 )
    43.902 ( 11.8023 )
    44.975 ( 17.4439 )
    Notes
    [78] - PK population
    [79] - PK population
    [80] - PK population
    No statistical analyses for this end point

    Secondary: Subjects with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Subjects with Treatment-Emergent Adverse Events (TEAEs)
    End point description
    Treatment-emergent AEs (TEAEs) were defined as AEs (any untoward medical occurrence) that either commenced following initiation of randomised study treatment or were present prior to randomised study treatment but increased in frequency or severity following initiation of randomised study treatment. TEAEs that occurred following administration of study treatment in Period 1 but before administration of study treatment in Period 2 were attributed to the treatment administered in Period 1 (and the same for Period 2). If the time was missing for an AE on Day 1 of any period, then the AE was attributed to the treatment administered on that day. The investigator assessed whether a TEAE was likely related to study treatment, and also the severity rating for the TEAE (mild, moderate or severe).
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 10
    End point values
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Number of subjects analysed
    47 [81]
    47 [82]
    44 [83]
    Units: subjects
        At least one TEAE
    35
    36
    25
        TEAE considered related to treatment
    26
    20
    15
        Severe TEAE
    0
    0
    0
        TEAE leading to withdrawal
    4
    2
    0
    Notes
    [81] - Safety population: All subjects who received at least 1 dose of study treatment
    [82] - Safety population: All subjects who received at least 1 dose of study treatment
    [83] - Safety population: All subjects who received at least 1 dose of study treatment
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 10
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    RBP-6300 Formulation A - Fasting
    Reporting group description
    		 RBP-6300 Formulation A (10 mg buprenorphine hemiadipate HCl/10 mg naloxone HCl dihydrate) administered as an oral tablet after an overnight fast of at least 10 hours.

    Reporting group title
    RBP-6300 Formulation B - Fasting
    Reporting group description
    		 RBP-6300 Formulation B (10 mg buprenorphine hemiadipate HCl/10 mg naloxone HCl dihydrate) administered as an oral tablet after an overnight fast of at least 10 hours.

    Reporting group title
    RBP-6300 Formulation A - High Fat
    Reporting group description
    		 RBP-6300 Formulation A administered as an oral tablet within 30 minutes of starting and completing a high-fat breakfast following an overnight fast of at least 10 hours.

    Serious adverse events
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 RBP-6300 Formulation A - Fasting RBP-6300 Formulation B - Fasting RBP-6300 Formulation A - High Fat
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 47 (74.47%)
    36 / 47 (76.60%)
    25 / 44 (56.82%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 47 (27.66%)
    12 / 47 (25.53%)
    8 / 44 (18.18%)
         occurrences all number
    13
    15
    10
    Catheter site pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    1
    Feeling hot
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 47 (2.13%)
    1 / 44 (2.27%)
         occurrences all number
    1
    2
    1
    Feeling cold
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Feeling of relaxation
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Gravitational oedema
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Hunger
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    Infusion site rash
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    1
    0
    1
    Cough
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Nightmare
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    Periorbital contusion
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 47 (25.53%)
    6 / 47 (12.77%)
    9 / 44 (20.45%)
         occurrences all number
    12
    6
    9
    Somnolence
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 47 (6.38%)
    4 / 44 (9.09%)
         occurrences all number
    1
    4
    5
    Loss of consciousness
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    Disturbance in attention
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    4 / 47 (8.51%)
    4 / 47 (8.51%)
    0 / 44 (0.00%)
         occurrences all number
    5
    5
    0
    Dysgeusia
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    Lethargy
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    Nervousness
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    Photophobia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 47 (2.13%)
    3 / 44 (6.82%)
         occurrences all number
    3
    2
    3
    Nausea
         subjects affected / exposed
    9 / 47 (19.15%)
    10 / 47 (21.28%)
    3 / 44 (6.82%)
         occurrences all number
    9
    11
    3
    Abdominal distension
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 47 (4.26%)
    1 / 44 (2.27%)
         occurrences all number
    1
    2
    1
    Abdominal pain upper
         subjects affected / exposed
    2 / 47 (4.26%)
    5 / 47 (10.64%)
    1 / 44 (2.27%)
         occurrences all number
    2
    5
    1
    Dyspepsia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    4 / 47 (8.51%)
    4 / 47 (8.51%)
    1 / 44 (2.27%)
         occurrences all number
    4
    4
    1
    Abdominal pain
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 47 (4.26%)
    0 / 44 (0.00%)
         occurrences all number
    1
    2
    0
    Diarrhoea
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 47 (4.26%)
    0 / 44 (0.00%)
         occurrences all number
    2
    2
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Bladder disorder
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    1
    Tendon pain
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    Muscle twitching
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    1
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jan 2013
    The first amendment, dated 28 January 2013, was approved prior to the initiation of study conduct at Celerion. The purpose of the amendment was to change the PI for the study.
    15 Aug 2013
    The second amendment, dated 15 August 2013, was issued to change the clinical facility and PI, change the Medical Monitor, move urine PK from secondary objectives to exploratory objectives, add metabolic profiling as an exploratory objective, clarify urine aliquotting procedures, clarify collection of temperature, define the number of completers required, and add details regarding total blood volume collected. Changes to the procedures for the fed conditions and the volume of water provided at study treatment administration were updated to match the appropriate guidelines. The following changes were also made to make the study procedures more consistent with the other trials in the clinical program:  Naltrexone dosing regimen was changed.  Inclusion/Exclusion criteria were changed.  Telemetry and ECGs were added.  Clinical laboratory tests were changed.

    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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