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    Clinical Trial Results:
    Relative bioavailability trial to investigate the pharmacokinetics of tapentadol following the administration of 3 prototype tapentadol 25 mg prolonged release (PR) granule formulations compared to a Palexia® PR 25 mg tablet in healthy adult subjects.

    Summary
    EudraCT number
    		 2012-005499-33
    Trial protocol
    		 DE  
    Global end of trial date
    15 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jun 2016
    First version publication date
    04 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HP5503-88
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1159-4436
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr. 6, Aachen, Germany, 52099
    Public contact
    Grünenthal Clinical Trial Helpdesk, Grünenthal GmbH, +49 241569 3223, Clinical-Trials@grunenthal.com
    Scientific contact
    Grünenthal Clinical Trial Helpdesk, Grünenthal GmbH, +49 241569 3223, Clinical-Trials@grunenthal.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000325-PIP01-08
    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
    25 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to assess the pharmacokinetics and relative bioavailability of tapentadol following administration of 3 prototype tapentadol PR granule formulations (test formulations) each containing 25 mg tapentadol, compared to 1 tablet of Palexia® PR 25 mg (reference formulation). This trial was conducted in two parts: Part 1 in fasted condition with a 4-treatment, 4-period crossover design Part 2 in fed condition with a 3-treatment, 3-period crossover design Each part includes a different set of male subjects. No endpoint was defined for this trial. The main pharmacokinetic target parameters were Cmax and AUC0-t for tapentadol. In addition, the analyses of AUC for tapentadol will be reported.
    Protection of trial subjects
    The trial was conducted according to ICH-GCP guidelines, the applicable local law, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. National regulations and national authorization was obtained.
    Background therapy
    		 Any prescribed or non-prescribed medications (excluding topical medications or nasal sprays without systemic effect) used on a regular basis within 14 days and Monoamine oxidase inhibitors used within 21 days before the Enrollment Visit were forbidden. Concomitant medications allowed during the trial were: • Paracetamol (e.g., for headache). • Treatments for nausea or vomiting, according to standard medical practice. • Topical medications without systemic effect. • Nasal sprays without systemic effect. • Naloxone, which may be administered as rescue medication for clinically significant respiratory depression requiring emergency medical intervention. Forbidden concomitant medication during the trial were: • Regular use of any prescribed or non-prescribed medications (excluding topical medications or nasal sprays without systemic effect) after the Enrollment Visit.
    Evidence for comparator
    		 PALEXIA® prolonged release is indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. The dosing regimen should be individualised according to the severity of pain being treated, the previous treatment experience and the ability to monitor the patient.
    Actual start date of recruitment
    27 Jan 2015
    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
    Germany: 48
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    48
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial started on 27 Jan 2015 with the first subject in (in Part 1) and was completed on 15 Jun 2015 with the last subject out (from Part 2). Each part of the trial included a different set of 24 healthy male subjects.

    Pre-assignment
    Screening details
    		 A total of 114 subjects signed an informed consent form and were involved in /undergoing the enrollment visit procedure. 66 subjects dropped out before allocation to treatment.

    Pre-assignment period milestones
    Number of subjects started
    		 114 [1]
    Number of subjects completed
    		 48

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Elevated systolic blood pressure and heart rate: 1
    Reason: Number of subjects
    		 Inclusion criteria not met/exclusion criteria met: 48
    Reason: Number of subjects
    		 Private reason: 8
    Reason: Number of subjects
    		 Supernumerous subject: 9
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 114 subjects signed an informed consent = Pre-assignment period. A total of 48 healthy Caucasian male subjects aged between 18 years and 55 years inclusive, with 24 subjects in Part 1 and Part 2, respectively, entered the 'Overall Trial' period and received IMP (Investigational medicinal product) Pharmacokinetic data was obtained for all of these subjects.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1_in fasted condition
    Arm description
    		 Part 1 had a 4-treatment, 4-period crossover single dose design to assess the relative bioavailability of 3 prototype tapentadol prolonged-release (PR) granule formulations (test formulations) compared to 1 tablet of Palexia® prolonged-release (PR) 25 mg (reference formulation) under fasted condition. This arm includes all subjects allocated to treatment sequences in Part 1 with at least 1 IMP administration. The treatment codes were defined as followed: C – Palexia® 25 mg prolonged-release tablet T1 – Tapentadol 25 mg prolonged-release granules 15% coating level T2 – Tapentadol 25 mg prolonged-release granules 20% coating level T3 – Tapentadol 25 mg prolonged-release granules 25% coating level
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tapentadol 25 mg prolonged-release granules 15% coating level
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of Tapentadol PR 25 mg granules with coating 15% under fasted condition.

    Investigational medicinal product name
    Tapentadol 25 mg prolonged-release granules 20% coating level
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of Tapentadol PR 25 mg granules with coating 20% under fasted condition.

    Investigational medicinal product name
    Tapentadol 25 mg prolonged-release granules 25% coating level
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of Tapentadol PR 25 mg granules with coating 25% under fasted condition.

    Investigational medicinal product name
    Palexia® 25 mg prolonged-release tablet
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of Palexia® PR 25 mg tablet under fasted condition.

    Arm title
    		 Part 2_in fed condition
    Arm description
    		 Part 2 had a 3-treatment, 3-period crossover single dose design to assess the relative bioavailability of 2 prototype tapentadol prolonged-release PR granule formulations (test formulations) compared to 1 tablet of Palexia® PR 25 mg (reference formulation) under fed condition. This arm includes all subjects allocated to treatment sequences in Part 2 with at least 1 IMP administration. The treatment codes were defined as followed: C – Palexia® 25 mg prolonged-release tablet T1 – Tapentadol 25 mg prolonged-release granules 15% coating level T2 – Tapentadol 25 mg prolonged-release granules 20% coating level
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tapentadol 25 mg prolonged-release granules 15% coating level
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of Tapentadol PR 25 mg granules with coating 15% under fed condition.

    Investigational medicinal product name
    Tapentadol 25 mg prolonged-release granules 20% coating level
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of Tapentadol PR 25 mg granules with coating 20% under fed condition.

    Investigational medicinal product name
    Palexia® 25 mg prolonged-release tablet
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received a single oral dose of Palexia® PR 25 mg tablet under fed condition.

    Number of subjects in period 1
    		Part 1_in fasted condition Part 2_in fed condition
    Started
    24
    24
    Completed
    23
    23
    Not completed
    1
    1
         Private reason
    1
    -
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1_in fasted condition
    Reporting group description
    		 Part 1 had a 4-treatment, 4-period crossover single dose design to assess the relative bioavailability of 3 prototype tapentadol prolonged-release (PR) granule formulations (test formulations) compared to 1 tablet of Palexia® prolonged-release (PR) 25 mg (reference formulation) under fasted condition. This arm includes all subjects allocated to treatment sequences in Part 1 with at least 1 IMP administration. The treatment codes were defined as followed: C – Palexia® 25 mg prolonged-release tablet T1 – Tapentadol 25 mg prolonged-release granules 15% coating level T2 – Tapentadol 25 mg prolonged-release granules 20% coating level T3 – Tapentadol 25 mg prolonged-release granules 25% coating level

    Reporting group title
    Part 2_in fed condition
    Reporting group description
    		 Part 2 had a 3-treatment, 3-period crossover single dose design to assess the relative bioavailability of 2 prototype tapentadol prolonged-release PR granule formulations (test formulations) compared to 1 tablet of Palexia® PR 25 mg (reference formulation) under fed condition. This arm includes all subjects allocated to treatment sequences in Part 2 with at least 1 IMP administration. The treatment codes were defined as followed: C – Palexia® 25 mg prolonged-release tablet T1 – Tapentadol 25 mg prolonged-release granules 15% coating level T2 – Tapentadol 25 mg prolonged-release granules 20% coating level

    Reporting group values
    		 Part 1_in fasted condition Part 2_in fed condition Total
    Number of subjects
    		 24 24 48
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 24 24 48
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41 ± 9.5 41 ± 10.1 -
    Gender categorical
    Units: Subjects
        Male
    		 24 24 48
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 177.4 ± 6.9 177 ± 5.5 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 80.95 ± 8.32 81.74 ± 7.59 -
    BMI
    Units: kg/m**2
        arithmetic mean (standard deviation)
    		 25.73 ± 2.17 26.11 ± 2.17 -

    End points

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    End points reporting groups
    Reporting group title
    Part 1_in fasted condition
    Reporting group description
    		 Part 1 had a 4-treatment, 4-period crossover single dose design to assess the relative bioavailability of 3 prototype tapentadol prolonged-release (PR) granule formulations (test formulations) compared to 1 tablet of Palexia® prolonged-release (PR) 25 mg (reference formulation) under fasted condition. This arm includes all subjects allocated to treatment sequences in Part 1 with at least 1 IMP administration. The treatment codes were defined as followed: C – Palexia® 25 mg prolonged-release tablet T1 – Tapentadol 25 mg prolonged-release granules 15% coating level T2 – Tapentadol 25 mg prolonged-release granules 20% coating level T3 – Tapentadol 25 mg prolonged-release granules 25% coating level

    Reporting group title
    Part 2_in fed condition
    Reporting group description
    		 Part 2 had a 3-treatment, 3-period crossover single dose design to assess the relative bioavailability of 2 prototype tapentadol prolonged-release PR granule formulations (test formulations) compared to 1 tablet of Palexia® PR 25 mg (reference formulation) under fed condition. This arm includes all subjects allocated to treatment sequences in Part 2 with at least 1 IMP administration. The treatment codes were defined as followed: C – Palexia® 25 mg prolonged-release tablet T1 – Tapentadol 25 mg prolonged-release granules 15% coating level T2 – Tapentadol 25 mg prolonged-release granules 20% coating level

    Subject analysis set title
    PK Set 1_fasting_15% coating (T1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a single dose of Tapentadol PR 25 mg granules with coating 15% under fasted condition. The Pharmacokinetic Set 1 (PK Set 1) comprised all subjects providing sufficient data, i.e., at least Cmax or AUC0-t, to compare at least 1 of the test formulations with the reference formulation in Part 1. They were included in the primary pharmacokinetic analyses of Part 1.

    Subject analysis set title
    PK Set 1_fasting_20% coating (T2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a single dose of Tapentadol PR 25 mg granules with coating 20% under fasted condition. The Pharmacokinetic Set 1 (PK Set 1) comprised all subjects providing sufficient data, i.e., at least Cmax or AUC0-t, to compare at least 1 of the test formulations with the reference formulation in Part 1. They were included in the primary pharmacokinetic analyses of Part 1.

    Subject analysis set title
    PK Set 1_fasting_25% coating (T3)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a single dose of Tapentadol PR 25 mg granules with coating 25% under fasted condition. The Pharmacokinetic Set 1 (PK Set 1) comprised all subjects providing sufficient data, i.e., at least Cmax or AUC0-t, to compare at least 1 of the test formulations with the reference formulation in Part 1. They were included in the primary pharmacokinetic analyses of Part 1.

    Subject analysis set title
    PK Set 2_fed_15% coating (T1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a single dose of Tapentadol PR 25 mg granules with coating 15% under fed condition. The Pharmacokinetic Set 2 (PK Set 2) comprised all subjects providing sufficient data, i.e., at least Cmax or AUC0-t, to compare at least 1 of the test formulations with the reference formulation in Part 2. They were included in the primary pharmacokinetic analyses of Part 2.

    Subject analysis set title
    PK Set 2_fed_20% coating (T2)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a single dose of Tapentadol PR 25 mg granules with coating 20% under fed condition. The Pharmacokinetic Set 2 (PK Set 2) comprised all subjects providing sufficient data, i.e., at least Cmax or AUC0-t, to compare at least 1 of the test formulations with the reference formulation in Part 2. They were included in the primary pharmacokinetic analyses of Part 2.

    Subject analysis set title
    PK Set 1_fasting _Palexia® PR 25 mg tablet (C)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a single dose of Palexia® PR 25 mg tablet under fasted condition. The Pharmacokinetic Set 1 (PK Set 1) comprised all subjects providing sufficient data, i.e., at least Cmax or AUC0-t, to compare at least 1 of the test formulations with the reference formulation in Part 1. They were included in the primary pharmacokinetic analyses of Part 1.

    Subject analysis set title
    PK Set 2_fed_Palexia® PR 25 mg tablet (C)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a single dose of Palexia® PR 25 mg tablet under fed condition. The Pharmacokinetic Set 2 (PK Set 2) comprised all subjects providing sufficient data, i.e., at least Cmax or AUC0-t, to compare at least 1 of the test formulations with the reference formulation in Part 2. They were included in the primary pharmacokinetic analyses of Part 2.

    Primary: No endpoints have been defined for this trial.

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    End point title
    		 No endpoints have been defined for this trial. [1]
    End point description
    End point type
    Primary
    End point timeframe
    No endpoints have been defined for this trial.
    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: In HP5503-88 (exploratory Phase I trials) endpoints were specified using PK variables. The primary and secondary trial objectives were defined and appropriate analysis of data reported in pre-defined endpoint sections.
    End point values
    		 Part 1_in fasted condition Part 2_in fed condition
    Number of subjects analysed
    24
    24
    Units: not applicable
    24
    24
    No statistical analyses for this end point

    Other pre-specified: Primary statistical analysis of pharmacokinetic parameters_Cmax

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    End point title
    		 Primary statistical analysis of pharmacokinetic parameters_Cmax
    End point description
    Pharmacokinetic analysis of Cmax of tapentadol. The Pharmacokinetic Sets (PK Set) comprised all subjects providing sufficient data, i.e., at least Cmax or AUC0-t, to compare at least 1 of the test formulations with the reference formulation for the Pharmacokinetic Sets of Part 1 (PK Set 1) and Part 2 (PK Set 2), respectively. Note: Due to the crossover design, the same subjects received different treatments within each part. The number of subjects included in the treatment comparisons of Cmax is 23 in Part 1 and 23 in Part 2 instead of the automatically calculated 46.
    End point type
    Other pre-specified
    End point timeframe
    Blood for pharmacokinetic analysis was taken up to 32 hours after IMP administration.
    End point values
    		 PK Set 1_fasting_15% coating (T1) PK Set 1_fasting_20% coating (T2) PK Set 1_fasting_25% coating (T3) PK Set 2_fed_15% coating (T1) PK Set 2_fed_20% coating (T2) PK Set 1_fasting _Palexia® PR 25 mg tablet (C) PK Set 2_fed_Palexia® PR 25 mg tablet (C)
    Number of subjects analysed
    23
    23
    23
    23
    23
    23
    23
    Units: ng/mL
        least squares mean (confidence interval 90%)
    4.9244 (4.7032 to 5.1559)
    4.7657 (4.5517 to 4.9898)
    4.3973 (4.1999 to 4.6041)
    9.9601 (9.4558 to 10.4913)
    8.3541 (7.9311 to 8.7997)
    4.5882 (4.3821 to 4.8039)
    9.8553 (9.3563 to 10.3809)
    Statistical analysis title
    		 ANOVA_PK Set 1_T1/C_Cmax
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter Cmax in the Pharmacokinetic Set of Part 1 (PK Set 1). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with Cmax as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects.
    Comparison groups
    PK Set 1_fasting_15% coating (T1) v PK Set 1_fasting _Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.0733
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.0058
         upper limit
    		 1.1453
    Statistical analysis title
    		 ANOVA_PK Set 1_T2/C_Cmax
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter Cmax in the Pharmacokinetic Set of Part 1 (PK Set 1). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with Cmax as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects.
    Comparison groups
    PK Set 1_fasting_20% coating (T2) v PK Set 1_fasting _Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.0387
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9734
         upper limit
    		 1.1084
    Statistical analysis title
    		 ANOVA_PK Set 1_T3/C_Cmax
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter Cmax in the Pharmacokinetic Set of Part 1 (PK Set 1). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with Cmax as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects.
    Comparison groups
    PK Set 1_fasting_25% coating (T3) v PK Set 1_fasting _Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9584
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8981
         upper limit
    		 1.0227
    Statistical analysis title
    		 ANOVA_PK Set 2_T1/C_Cmax
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter Cmax in the Pharmacokinetic Set of Part 2 (PK Set 2). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with Cmax as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects.
    Comparison groups
    PK Set 2_fed_15% coating (T1) v PK Set 2_fed_Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.0106
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9391
         upper limit
    		 1.0876
    Statistical analysis title
    		 ANOVA_PK Set 2_T2/C_Cmax
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter Cmax in the Pharmacokinetic Set of Part 2 (PK Set 2). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with Cmax as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects.
    Comparison groups
    PK Set 2_fed_20% coating (T2) v PK Set 2_fed_Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.8477
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.7877
         upper limit
    		 0.9122

    Other pre-specified: Primary statistical analysis of pharmacokinetic parameters_AUC0-t

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    End point title
    		 Primary statistical analysis of pharmacokinetic parameters_AUC0-t
    End point description
    Pharmacokinetic analysis of AUC0-t of tapentadol. The Pharmacokinetic Sets (PK Set) comprised all subjects providing sufficient data, i.e., at least Cmax or AUC0-t, to compare at least 1 of the test formulations with the reference formulation for the Pharmacokinetic Sets of Part 1 (PK Set 1) and Part 2 (PK Set 2), respectively. Note: Due to the crossover design, the same subjects received different treatments within each part. The number of subjects included in the treatment comparisons of AUC0-t is 23 in Part 1 and 23 in Part 2 instead of the automatically calculated 46.
    End point type
    Other pre-specified
    End point timeframe
    Blood for pharmacokinetic analysis was taken up to 32 hours after IMP administration.
    End point values
    		 PK Set 1_fasting_15% coating (T1) PK Set 1_fasting_20% coating (T2) PK Set 1_fasting_25% coating (T3) PK Set 2_fed_15% coating (T1) PK Set 2_fed_20% coating (T2) PK Set 1_fasting _Palexia® PR 25 mg tablet (C) PK Set 2_fed_Palexia® PR 25 mg tablet (C)
    Number of subjects analysed
    23
    23
    23
    23
    23
    23
    23
    Units: h·ng/mL
        least squares mean (confidence interval 90%)
    58.5895 (56.5522 to 60.7002)
    61.4336 (59.2974 to 63.6468)
    64.6398 (62.3921 to 66.9685)
    96.0943 (93.0071 to 99.284)
    91.2479 (88.3163 to 94.2767)
    64.8975 (62.6408 to 67.2355)
    101.264 (98.0107 to 104.6253)
    Statistical analysis title
    		 ANOVA_PK Set 1_T1/C_AUC0-t
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter AUC0-t in the Pharmacokinetic Set of Part 1 (PK set 1). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with AUC0-t as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects.
    Comparison groups
    PK Set 1_fasting_15% coating (T1) v PK Set 1_fasting _Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9028
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8587
         upper limit
    		 0.9491
    Statistical analysis title
    		 ANOVA_PK Set 1_T2/C_AUC0-t
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter AUC0-t in the Pharmacokinetic Set of Part 1 (PK set 1). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with AUC0-t as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects.
    Comparison groups
    PK Set 1_fasting_20% coating (T2) v PK Set 1_fasting _Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9466
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9004
         upper limit
    		 0.9952
    Statistical analysis title
    		 ANOVA_PK Set 1_T3/C_AUC0-t
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter AUC0-t in the Pharmacokinetic Set of Part 1 (PK set 1). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with AUC0-t as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects.
    Comparison groups
    PK Set 1_fasting_25% coating (T3) v PK Set 1_fasting _Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.996
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9474
         upper limit
    		 1.0471
    Statistical analysis title
    		 ANOVA_PK Set 2_T1/C_AUC0-t
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter AUC0-t in the Pharmacokinetic Set of Part 2 (PK set 2). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with AUC0-t as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects.
    Comparison groups
    PK Set 2_fed_15% coating (T1) v PK Set 2_fed_Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9489
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9062
         upper limit
    		 0.9937
    Statistical analysis title
    		 ANOVA_PK Set 2_T2/C_AUC0-t
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter AUC0-t in the Pharmacokinetic Set of Part 2 (PK set 2). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with AUC0-t as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects.
    Comparison groups
    PK Set 2_fed_20% coating (T2) v PK Set 2_fed_Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9011
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8605
         upper limit
    		 0.9436

    Other pre-specified: Primary statistical analysis of pharmacokinetic parameters_AUC

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    End point title
    		 Primary statistical analysis of pharmacokinetic parameters_AUC
    End point description
    Pharmacokinetic analysis of AUC of tapentadol. The Pharmacokinetic Sets (PK Set) comprised all subjects providing sufficient data, i.e., at least Cmax or AUC0-t, to compare at least 1 of the test formulations with the reference formulation for the Pharmacokinetic Sets of Part 1 (PK Set 1) and Part 2 (PK Set 2), respectively. Subjects were excluded from the statistical analysis of AUC if the proportion of the extrapolated area of the AUC exceeded 20%. Therefore, the number of subject was reduced to N=22 in the subgroup "PK Set 1_fasting_20% coating versus Palexia® PR" and to N=21 in the subgroup "PK Set 1_fasting_25% coating versus Palexia® PR". Note: Due to the crossover design, the same subjects received different treatments within each part. The number of subjects included in the treatment comparisons of AUC is not correct as automatically calculated by the system. The correct figure is always given in the analysis description of the different treatment comparisons.
    End point type
    Other pre-specified
    End point timeframe
    Blood for pharmacokinetic analysis was taken up to 32 hours after IMP administration.
    End point values
    		 PK Set 1_fasting_15% coating (T1) PK Set 1_fasting_20% coating (T2) PK Set 1_fasting_25% coating (T3) PK Set 2_fed_15% coating (T1) PK Set 2_fed_20% coating (T2) PK Set 1_fasting _Palexia® PR 25 mg tablet (C) PK Set 2_fed_Palexia® PR 25 mg tablet (C)
    Number of subjects analysed
    23
    22 [2]
    21 [3]
    23
    23
    23
    23
    Units: h·ng/mL
        least squares mean (confidence interval 90%)
    62.8281 (60.6197 to 65.117)
    67.6169 (65.1447 to 70.1828)
    73.4931 (70.7294 to 76.3648)
    99.8591 (96.6037 to 103.2241)
    97.4753 (94.2977 to 100.7599)
    70.5312 (68.0521 to 73.1007)
    105.0618 (101.6369 to 108.6021)
    Notes
    [2] - 1 subject was excluded from the statistical analysis of AUC as AUC%extr exceeded 20%.
    [3] - 2 subjects were excluded from the statistical analysis of AUC as AUC%extr exceeded 20%.
    Statistical analysis title
    		 ANOVA_PK Set 1_T1/C_AUC
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter AUC in the Pharmacokinetic Set of Part 1 (PK Set 1). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with AUC as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects. Note: 23 subjects were included in this treatment comparison.
    Comparison groups
    PK Set 1_fasting_15% coating (T1) v PK Set 1_fasting _Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.8908
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8469
         upper limit
    		 0.937
    Statistical analysis title
    		 ANOVA_PK Set 1_T2/C_AUC
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter AUC in the Pharmacokinetic Set of Part 1 (PK Set 1). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with AUC as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects. Note: 22 subjects were included in this treatment comparison.
    Comparison groups
    PK Set 1_fasting_20% coating (T2) v PK Set 1_fasting _Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9587
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9105
         upper limit
    		 1.0094
    Statistical analysis title
    		 ANOVA_PK Set 1_T3/C_AUC
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter AUC in the Pharmacokinetic Set of Part 1 (PK Set 1). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with AUC as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects. Note: 21 subjects were included in this treatment comparison.
    Comparison groups
    PK Set 1_fasting_25% coating (T3) v PK Set 1_fasting _Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.042
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9888
         upper limit
    		 1.098
    Statistical analysis title
    		 ANOVA_PK Set 2_T1/C_AUC
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter AUC in the Pharmacokinetic Set of Part 2 (PK Set 2). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with AUC as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects. Note: 23 subjects were included in this treatment comparison.
    Comparison groups
    PK Set 2_fed_15% coating (T1) v PK Set 2_fed_Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9505
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.907
         upper limit
    		 0.996
    Statistical analysis title
    		 ANOVA_PK Set 2_T2/C_AUC
    Statistical analysis description
    The statistical analysis of pharmacokinetic parameters was an analysis of variance (ANOVA) of the parameter AUC in the Pharmacokinetic Set of Part 2 (PK Set 2). The analysis has been performed using log transformed values. The ANOVA model was fitted to the data with AUC as the dependent variable, and the effects due to treatment sequence group, period, treatment, and subjects nested within sequence as fixed effects. Note: 23 subjects were included in this treatment comparison.
    Comparison groups
    PK Set 2_fed_20% coating (T2) v PK Set 2_fed_Palexia® PR 25 mg tablet (C)
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9278
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8854
         upper limit
    		 0.9722

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any adverse event starting at the time of the first intake of tapentadol formulation until the time of the subject-related end of trial, including the washout between periods.
    Adverse event reporting additional description
    The absolute and relative frequencies of subjects with any TEAEs were determined within each treatment. If an adverse event lasted longer than 1 treatment period (including washout) then it was assigned to the treatment of the period in which it first occurred.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Part 1_in fasted condition_overall
    Reporting group description
    		 Part 1 had a 4-treatment, 4-period crossover single dose design to assess the relative bioavailability of 3 prototype tapentadol PR granule formulations (test formulations) compared to 1 tablet of Palexia® PR 25 mg (reference formulation) under fasted condition. This arm includes all subjects allocated to treatment sequences in Part 1 with at least 1 IMP administration.

    Reporting group title
    Part 2_in fed condition_overall
    Reporting group description
    		 Part 2 had a 3-treatment, 3-period crossover single dose design to assess the relative bioavailability of 2 prototype tapentadol PR granule formulations (test formulations) compared to 1 tablet of Palexia® PR 25 mg (reference formulation) under fed condition. This arm includes all subjects allocated to treatment sequences in Part 2 with at least 1 IMP administration.

    Reporting group title
    Part 1_fasting_15% coating (T1)
    Reporting group description
    		 All subjects which received a single dose of tapentadol PR 25 mg granules with coating 15% under fasted condition

    Reporting group title
    Part 1_fasting_20% coating (T2)
    Reporting group description
    		 All subjects which received a single dose of tapentadol PR 25 mg granules with coating 20% under fasted condition

    Reporting group title
    Part 1_fasting_25% coating (T3)
    Reporting group description
    		 All subjects which received a single dose of tapentadol PR 25 mg granules with coating 25% under fasted condition

    Reporting group title
    Part 1_fasting _Palexia® PR 25 mg tablet (C)
    Reporting group description
    		 All subjects which received a single dose of Palexia® PR 25 mg tablet under fasted condition

    Reporting group title
    Part 2_fed_15% coating (T1)
    Reporting group description
    		 All subjects which received a single dose of tapentadol PR 25 mg granules with coating 15% under fed condition

    Reporting group title
    Part 2_fed_20% coating (T2)
    Reporting group description
    		 All subjects which received a single dose of tapentadol PR 25 mg granules with coating 20% under fed condition

    Reporting group title
    Part 2_fed_Palexia® PR 25 mg tablet (C)
    Reporting group description
    		 All subjects which received a single dose of Palexia® PR 25 mg tablet under fed condition

    Serious adverse events
    		 Part 1_in fasted condition_overall Part 2_in fed condition_overall Part 1_fasting_15% coating (T1) Part 1_fasting_20% coating (T2) Part 1_fasting_25% coating (T3) Part 1_fasting _Palexia® PR 25 mg tablet (C) Part 2_fed_15% coating (T1) Part 2_fed_20% coating (T2) Part 2_fed_Palexia® PR 25 mg tablet (C)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Part 1_in fasted condition_overall Part 2_in fed condition_overall Part 1_fasting_15% coating (T1) Part 1_fasting_20% coating (T2) Part 1_fasting_25% coating (T3) Part 1_fasting _Palexia® PR 25 mg tablet (C) Part 2_fed_15% coating (T1) Part 2_fed_20% coating (T2) Part 2_fed_Palexia® PR 25 mg tablet (C)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 24 (41.67%)
    6 / 24 (25.00%)
    4 / 23 (17.39%)
    5 / 24 (20.83%)
    0 / 23 (0.00%)
    4 / 23 (17.39%)
    4 / 24 (16.67%)
    2 / 23 (8.70%)
    1 / 23 (4.35%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    5 / 24 (20.83%)
    0 / 24 (0.00%)
    2 / 23 (8.70%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    6
    0
    2
    2
    0
    2
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 24 (12.50%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    2 / 23 (8.70%)
    2 / 24 (8.33%)
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    3
    3
    0
    1
    0
    2
    2
    1
    0
    Feeling hot
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    1 / 23 (4.35%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 24 (4.17%)
    2 / 23 (8.70%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    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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