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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Saline Placebo- and Active-Controlled, Multicenter Study of HTX-011 via Local Administration for Postoperative Analgesia and Decreased Opioid Use Following Unilateral Open Inguinal Herniorrhaphy.

    Summary
    EudraCT number
    		 2017-001636-19
    Trial protocol
    		 BE  
    Global end of trial date
    29 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Feb 2019
    First version publication date
    15 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HTX-011-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03237481
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Heron Therapeutics, Inc.
    Sponsor organisation address
    4242 Campus Point Ct #200, San Diego, United States, 92121
    Public contact
    HTX-011-302 Team, Heron Therapeutics, Inc., 001 858251 4405,
    Scientific contact
    HTX-011-302 Team, Heron Therapeutics, Inc., 001 858251 4405,
    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
    13 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy and duration of analgesia following local administration of HTX-011 with saline placebo during the first 72 hours following unilateral open inguinal herniorrhaphy.
    Protection of trial subjects
    This study was conducted in compliance with the protocol and all applicable regulatory requirements in accordance with International Council for Harmonisation (ICH)/Good Clinical Practice (GCP) and in general conformity with the most recent version of the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jul 2017
    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
    Belgium: 4
    Country: Number of subjects enrolled
    United States: 414
    Worldwide total number of subjects
    418
    EEA total number of subjects
    4
    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)
    387
    From 65 to 84 years
    31
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were screened within 28 days prior to surgery. Subjects who met the Screening eligibility criteria were randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Group 1
    Arm description
    		 HTX-011, 2.5%/0.075% (bupivacaine/meloxicam doses), 10.3 mL, via instillation into the surgical site.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HTX-011
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release solution for injection
    Routes of administration
    Local use
    Dosage and administration details
    HTX-011, 2.5%/0.075% (bupivacaine/meloxicam doses), 10.3 mL, via instillation into the surgical site.

    Arm title
    		 Treatment Group 2
    Arm description
    		 Bupivacaine HCl without epinephrine 0.25%, 75 mg (30 mL), via injection into the surgical site.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bupivacaine hydrochloride, USP
    Investigational medicinal product code
    Other name
    Bupivacaine HCI
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    Bupivacaine HCl without epinephrine 0.25%, 75 mg (30 mL), via injection into the surgical site.

    Arm title
    		 Treatment Group 3
    Arm description
    		 Saline placebo, 10.3 mL, via instillation into the surgical site.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Local use
    Dosage and administration details
    Saline placebo, 10.3 mL, via instillation into the surgical site.

    Number of subjects in period 1
    		Treatment Group 1 Treatment Group 2 Treatment Group 3
    Started
    164
    172
    82
    Completed
    159
    170
    81
    Not completed
    5
    2
    1
         Consent withdrawn by subject
    3
    2
    1
         Lost to follow-up
    1
    -
    -
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Group 1
    Reporting group description
    		 HTX-011, 2.5%/0.075% (bupivacaine/meloxicam doses), 10.3 mL, via instillation into the surgical site.

    Reporting group title
    Treatment Group 2
    Reporting group description
    		 Bupivacaine HCl without epinephrine 0.25%, 75 mg (30 mL), via injection into the surgical site.

    Reporting group title
    Treatment Group 3
    Reporting group description
    		 Saline placebo, 10.3 mL, via instillation into the surgical site.

    Reporting group values
    		 Treatment Group 1 Treatment Group 2 Treatment Group 3 Total
    Number of subjects
    		 164 172 82 418
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 149 161 77 387
        From 65-84 years
    		 15 11 5 31
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.9 ( 13.29 ) 49.4 ( 11.26 ) 48.0 ( 14.59 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 8 3 23
        Male
    		 152 164 79 395

    End points

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    End points reporting groups
    Reporting group title
    Treatment Group 1
    Reporting group description
    		 HTX-011, 2.5%/0.075% (bupivacaine/meloxicam doses), 10.3 mL, via instillation into the surgical site.

    Reporting group title
    Treatment Group 2
    Reporting group description
    		 Bupivacaine HCl without epinephrine 0.25%, 75 mg (30 mL), via injection into the surgical site.

    Reporting group title
    Treatment Group 3
    Reporting group description
    		 Saline placebo, 10.3 mL, via instillation into the surgical site.

    Primary: Mean AUC0-72 of the NRS-A pain intensity score for HTX-011 compared with saline placebo

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    End point title
    		 Mean AUC0-72 of the NRS-A pain intensity score for HTX-011 compared with saline placebo [1]
    End point description
    Mean area under the curve (AUC) of the Numeric Rating Scale of pain intensity scores with activity (NRS-A) for HTX 011 compared with saline placebo.
    End point type
    Primary
    End point timeframe
    72 hours
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arm excluded from this Endpoint reported in previous Endpoint.
    End point values
    		 Treatment Group 1 Treatment Group 3
    Number of subjects analysed
    164
    82
    Units: NRS-A
        arithmetic mean (standard deviation)
    269.39 ( 173.719 )
    350.82 ( 171.224 )
    Statistical analysis title
    		 HTX-011 vs Saline Placebo
    Comparison groups
    Treatment Group 1 v Treatment Group 3
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 ANOVA
    Parameter type
    		 Least Squares Mean Difference (LSMD)
    Point estimate
    -81.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -125.83
         upper limit
    		 -37.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    22.592

    Secondary: Mean AUC0-72 of the NRS-A pain intensity score for HTX-011 compared with bupivacaine HCI

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    End point title
    		 Mean AUC0-72 of the NRS-A pain intensity score for HTX-011 compared with bupivacaine HCI [2]
    End point description
    Mean AUC0-72 of the NRS-A pain intensity scores for HTX-011 compared with bupivacaine HCI.
    End point type
    Secondary
    End point timeframe
    72 hours
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arm excluded from this Endpoint reported in subsequent Endpoint.
    End point values
    		 Treatment Group 1 Treatment Group 2
    Number of subjects analysed
    164
    82
    Units: NRS-A
        arithmetic mean (standard deviation)
    269.39 ( 173.719 )
    341.88 ( 158.303 )
    Statistical analysis title
    		 HTX-011 vs. Bupivacaine HCI
    Comparison groups
    Treatment Group 2 v Treatment Group 1
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Least Squares Mean Difference (LSMD)
    Point estimate
    -72.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -108.32
         upper limit
    		 -36.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.23

    Secondary: Mean total postoperative opioid consumption for HTX-011 compared with saline placebo

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    End point title
    		 Mean total postoperative opioid consumption for HTX-011 compared with saline placebo [3]
    End point description
    Mean total postoperative opioid consumption (in morphine equivalents) for HTX-011 compared with saline placebo.
    End point type
    Secondary
    End point timeframe
    72 hours
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arm excluded from this Endpoint reported in subsequent Endpoint.
    End point values
    		 Treatment Group 1 Treatment Group 3
    Number of subjects analysed
    164
    82
    Units: Milligram morphine equivalents (MME)
        arithmetic mean (standard deviation)
    10.85 ( 17.062 )
    17.53 ( 18.908 )
    Statistical analysis title
    		 HTX-011 vs. saline placebo
    Comparison groups
    Treatment Group 1 v Treatment Group 3
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Proportion of subjects who are opioid-free for HTX-011 compared with bupivacaine HCI.

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    End point title
    		 Proportion of subjects who are opioid-free for HTX-011 compared with bupivacaine HCI. [4]
    End point description
    Proportion of subjects who are opioid-free for HTX-011 compared with bupivacaine HCI.
    End point type
    Secondary
    End point timeframe
    72 hours
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not Applicable
    End point values
    		 Treatment Group 1 Treatment Group 2
    Number of subjects analysed
    164
    172
    Units: Subjects
    84
    69
    Statistical analysis title
    		 HTX-011 vs. bupivacaine HCI
    Comparison groups
    Treatment Group 1 v Treatment Group 2
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0486
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.111
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.003
         upper limit
    		 0.218

    Secondary: Mean total postoperative opioid consumption for HTX-011 compared with bupivacaine HCI

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    End point title
    		 Mean total postoperative opioid consumption for HTX-011 compared with bupivacaine HCI [5]
    End point description
    Mean total postoperative opioid consumption (in morphine equivalents) for HTX-011 compared with bupivacaine HCI.
    End point type
    Secondary
    End point timeframe
    72 hours
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arm excluded from this Endpoint reported in subsequent Endpoint.
    End point values
    		 Treatment Group 1 Treatment Group 2
    Number of subjects analysed
    164
    172
    Units: Milligram morphine equivalents (MME)
        arithmetic mean (standard deviation)
    10.85 ( 17.062 )
    14.51 ( 18.185 )
    Statistical analysis title
    		 HTX-011 vs. bupivacaine HCI
    Comparison groups
    Treatment Group 1 v Treatment Group 2
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Incidence of Treatment-Emergent Adverse Events (TEAs)

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    End point title
    		 Incidence of Treatment-Emergent Adverse Events (TEAs)
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Group 1 Treatment Group 2 Treatment Group 3
    Number of subjects analysed
    163
    172 [6]
    82
    Units: Subjects reporting TEAEs
    119
    127
    61
    Notes
    [6] - One subject was randomized to HTX-011, but received bupivacaine HCl (Safety Population N=173).
    No statistical analyses for this end point

    Secondary: Incidence of Serious Adverse Events (SAEs)

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    End point title
    		 Incidence of Serious Adverse Events (SAEs)
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Group 1 Treatment Group 2 Treatment Group 3
    Number of subjects analysed
    163
    172 [7]
    82
    Units: Subjects reporting SAEs
    2
    1
    1
    Notes
    [7] - One subject was randomized to HTX-011, but received bupivacaine HCl (Safety Population N=173).
    No statistical analyses for this end point

    Secondary: Incidence of Opioid-related Adverse Events (ORAEs)

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    End point title
    		 Incidence of Opioid-related Adverse Events (ORAEs)
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Group 1 Treatment Group 2 Treatment Group 3
    Number of subjects analysed
    163
    172 [8]
    82
    Units: Subjects reporting ORAEs
    53
    73
    36
    Notes
    [8] - One subject was randomized to HTX-011, but received bupivacaine HCl (Safety Population N=173).
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    28 days
    Adverse event reporting additional description
    For each Preferred Term (PT), subjects are included only once, even if they experienced multiple events in that PT.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Treatment Group 1
    Reporting group description
    		 HTX 011, HTX-011 2.5%/0.075% (bupivacaine/meloxicam doses), 10.3 mL, via instillation into the surgical site.

    Reporting group title
    Treatment Group 2
    Reporting group description
    		 Bupivacaine HCI without epinephrine 0.25%, 75 mg (30 mL), via injection into the surgical site.

    Reporting group title
    Treatment Group 3
    Reporting group description
    		 Saline placebo, 10.3 mL, via instillation into the surgical site.

    Serious adverse events
    		 Treatment Group 1 Treatment Group 2 Treatment Group 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 163 (1.23%)
    1 / 173 (0.58%)
    1 / 82 (1.22%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 173 (0.58%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia, obstructive
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 173 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 173 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Incision site haematoma
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 173 (0.00%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 173 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 163 (0.00%)
    0 / 173 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment Group 1 Treatment Group 2 Treatment Group 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    119 / 163 (73.01%)
    127 / 173 (73.41%)
    61 / 82 (74.39%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 163 (1.23%)
    5 / 173 (2.89%)
    6 / 82 (7.32%)
         occurrences all number
    2
    5
    6
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    15 / 163 (9.20%)
    16 / 173 (9.25%)
    6 / 82 (7.32%)
         occurrences all number
    15
    16
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    24 / 163 (14.72%)
    42 / 173 (24.28%)
    13 / 82 (15.85%)
         occurrences all number
    24
    42
    13
    Headache
         subjects affected / exposed
    21 / 163 (12.88%)
    24 / 173 (13.87%)
    10 / 82 (12.20%)
         occurrences all number
    21
    24
    10
    Dysgeusia
         subjects affected / exposed
    15 / 163 (9.20%)
    21 / 173 (12.14%)
    3 / 82 (3.66%)
         occurrences all number
    15
    21
    3
    Tremor
         subjects affected / exposed
    7 / 163 (4.29%)
    12 / 173 (6.94%)
    8 / 82 (9.76%)
         occurrences all number
    7
    12
    8
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    3 / 163 (1.84%)
    6 / 173 (3.47%)
    5 / 82 (6.10%)
         occurrences all number
    3
    6
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    30 / 163 (18.40%)
    37 / 173 (21.39%)
    28 / 82 (34.15%)
         occurrences all number
    30
    37
    28
    Constipation
         subjects affected / exposed
    28 / 163 (17.18%)
    41 / 173 (23.70%)
    15 / 82 (18.29%)
         occurrences all number
    28
    41
    15
    Vomiting
         subjects affected / exposed
    7 / 163 (4.29%)
    12 / 173 (6.94%)
    4 / 82 (4.88%)
         occurrences all number
    7
    12
    4
    Skin and subcutaneous tissue disorders
    Skin odour abnormal
         subjects affected / exposed
    13 / 163 (7.98%)
    1 / 173 (0.58%)
    1 / 82 (1.22%)
         occurrences all number
    13
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jun 2017
    The primary changes in this amendment are presented below: • Revised the key secondary efficacy endpoints as follows: - Moved the endpoint on mean AUC0-72 of the NRS-A for HTX-011 vs bupivacaine HCl to be the first (#1) key secondary endpoint. - Added a key secondary endpoint (#3) on the proportion of subjects who are opioid-free through 72 hours for HTX-011 vs bupivacaine HCl. - Moved the endpoint on mean total postoperative opioid consumption through 72 hours for HTX-011 compared with bupivacaine HCl to be a key secondary efficacy endpoint (#4). - Revised the analysis plan for testing key secondary endpoints to be hierarchical testing. • Reduced the number of other (non-key) secondary efficacy endpoints. • Moved the secondary study objective on efficacy and duration of analgesia for HTX-011 vs bupivacaine HCl to be the first secondary objective. • Increased the sample size of the HTX-011 group (from 150 subjects to 200 subjects) and the bupivacaine HCl group (from 100 subjects to 200 subjects). • Increased the volume of saline placebo to be administered (from 6.8 mL to 10.3 mL). • Revised instructions on administering HTX-011 and saline placebo via instillation. • Added acetaminophen as a rescue medication. • Removed acetaminophen from the list of prohibited medications. • Revised the instructions for postoperative pain management after 72 hours and included an appendix with discharge instructions for subjects who were medically ready for discharge. • Added an exclusion criterion for systemic steroids administered within 5 half-lives or 10 days prior to administration of study drug, whichever was longer (exclusion criterion #12). • Clarified the prescribed activity for NRS-A. • Clarified how to perform NRS-R assessments.
    30 Jul 2017
    The primary changes in this amendment are presented below: • Reduced the study sample size from 500 subjects to 400 subjects. The randomization scheme will remain the same. • Added Local Anesthetic Systemic Toxicity (LAST) assessments. • Added body temperature measurement and increased the number of vital sign assessment timepoints. • Specified the route of administration for acetaminophen (oral) as a rescue medication for postoperative pain. • Clarified that intraoperative safety monitoring would be in accordance with ASA standards, which is consistent with the European Board of Anaesthesiology (EBA) recommendations for minimal monitoring during Anaesthesia and Recovery. • Clarified study suspension and study stopping criteria. • Provided rationale for fentanyl dosing during surgery. • Provided additional details regarding Sponsor safety oversight.

    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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