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    Clinical Trial Results:
    An International, Randomised, Double blinded, Multi-centre, Active- and Placebo-controlled Dose Response Trial to Evaluate the Efficacy and Safety of SABER-Bupivacaine for Postoperative Pain Control in Patients Undergoing Primary, Elective, Open, Abdominal Hysterectomy

    Summary
    EudraCT number
    		 2007-006121-26
    Trial protocol
    		 DE   GB   HU   FR   SE   LV  
    Global end of trial date
    01 Jun 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Mar 2022
    First version publication date
    31 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BU-001-IM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00993226
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    DURECT Corporation
    Sponsor organisation address
    10260 Bubb Road, Cupertino, CA, United States, 95014
    Public contact
    Deborah Scott, DURECT Corporation, 001 408-777-1417, deborah.scott@durect.com
    Scientific contact
    Deborah Scott, DURECT Corporation, 001 408-777-1417, deborah.scott@durect.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Jun 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective is to identify the optimal dose of instilled SABER-Bupivacaine for postoperative pain control in abdominal hysterectomy for a non-malignant indication on the basis of efficacy, safety, and pharmacokinetics (PK) evaluations.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Harmonized Tripartite Guideline, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 May 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Hungary: 79
    Country: Number of subjects enrolled
    Latvia: 29
    Worldwide total number of subjects
    115
    EEA total number of subjects
    115
    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)
    114
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were screened 1 to 14 days before abdominal hysterectomy surgery at which time informed consent was obtained. Surgery was performed and the study drug was administered on Day 0.

    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, Assessor
    Blinding implementation details
    Participants were randomised in a double-blind manner and allocated to one of the three treatment arms in a ratio of 2:1:1. The random allocation of participants into treatment groups was based on a block randomisation list.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SABER-Bupivacaine
    Arm description
    		 5 mL, single dose instilled into surgical incision
    Arm type
    		 Experimental

    Investigational medicinal product name
    SABER-Bupivacaine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Instillation
    Dosage and administration details
    SABER-Bupivacaine 5.0 millilitre (mL) (600 [milligram] mg bupivacaine) was administered as a single instillation into the surgical wound following hysterectomy. Following the closure of the fascia, a 16G (large bore) needle was used to draw up the correct volume of room temperature SABER-Bupivacaine into a syringe. The needle was then removed and the investigational product was administered; after the closure of the fascia a single dose of 5.0 mL of SABER-Bupivacaine was instilled (no needle) covering the whole fascia area and ensuring containment of the entire dose.

    Arm title
    		 SABER-Placebo
    Arm description
    		 5 mL, single dose instilled into surgical incision
    Arm type
    		 Placebo

    Investigational medicinal product name
    SABER-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Instillation
    Dosage and administration details
    SABER-Placebo 5.0 mL was administered as a single instillation into the surgical wound following hysterectomy. Following the closure of the fascia, a 16G (large bore) needle was used to draw up the correct volume of room temperature SABER-Placebo into a syringe. The needle was then removed and the placebo was administered; after the closure of the fascia a single dose of 5.0 mL of SABER-Placebo was instilled (no needle) covering the whole fascia area and ensuring containment of the entire dose.

    Arm title
    		 Bupivacaine HCl
    Arm description
    		 0.25% 40 mL, single dose infiltrated peri-incisionally
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bupivacaine HCl
    Investigational medicinal product code
    Other name
    Marcain
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Infiltration
    Dosage and administration details
    The participant received 40 mL of standard bupivacaine HCl (Marcain; 100 mg bupivacaine HCl) following surgery, before wound closure, via infiltration: 10 mL was injected into the proximal muscle layer; 10 mL was injected into the distal layer, and 20 mL was injected into the subcutaneous layer.

    Number of subjects in period 1
    		SABER-Bupivacaine SABER-Placebo Bupivacaine HCl
    Started
    61
    27
    27
    Completed
    60
    26
    27
    Not completed
    1
    1
    0
         Consent withdrawn by subject
    1
    -
    -
         Adverse event, non-fatal
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SABER-Bupivacaine
    Reporting group description
    		 5 mL, single dose instilled into surgical incision

    Reporting group title
    SABER-Placebo
    Reporting group description
    		 5 mL, single dose instilled into surgical incision

    Reporting group title
    Bupivacaine HCl
    Reporting group description
    		 0.25% 40 mL, single dose infiltrated peri-incisionally

    Reporting group values
    		 SABER-Bupivacaine SABER-Placebo Bupivacaine HCl Total
    Number of subjects
    		 61 27 27 115
    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)
    		 60 27 27 114
        From 65-84 years
    		 1 0 0 1
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 46.7 (29 to 66) 44.3 (37 to 53) 45.1 (35 to 55) -
    Gender categorical
    Units: Subjects
        Female
    		 61 27 27 115
        Male
    		 0 0 0 0
    BMI
    Units: kg/m^2
        arithmetic mean (full range (min-max))
    		 26.1 (19 to 33.2) 26.2 (19.4 to 34.1) 27 (18.3 to 35) -

    End points

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    End points reporting groups
    Reporting group title
    SABER-Bupivacaine
    Reporting group description
    		 5 mL, single dose instilled into surgical incision

    Reporting group title
    SABER-Placebo
    Reporting group description
    		 5 mL, single dose instilled into surgical incision

    Reporting group title
    Bupivacaine HCl
    Reporting group description
    		 0.25% 40 mL, single dose infiltrated peri-incisionally

    Primary: Pain Intensity (PI)

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    End point title
    		 Pain Intensity (PI)
    End point description
    Mean PI on movement area under concentration-time curve (AUC) over the period 1 to 72 hours post-surgery. Participants assessed their pain intensity using an 11-point PI Numeric Rating Scale (PI-NRS) with NRS scores ranging from 0 (no pain) to 10 (worst pain possible). The AUC is computed for each participant using the standard trapezoidal rule and normalised by dividing by the time interval over which it is computed. This normalisation converts the AUC to the natural pain scale (NRS 0 to 10) to allow for better translation of the clinical treatment effect magnitude.
    End point type
    Primary
    End point timeframe
    1 to 72 hours after surgery
    End point values
    		 SABER-Bupivacaine SABER-Placebo Bupivacaine HCl
    Number of subjects analysed
    60
    27
    27
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Pain Intensity (PI)
    4.15 ( 1.74 )
    4.46 ( 1.48 )
    4.27 ( 1.69 )
    Statistical analysis title
    		 Statistical Analysis 1 for Pain Intensity (PI)
    Comparison groups
    SABER-Bupivacaine v SABER-Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.467
    Method
    		 t-test in analysis of variance (ANOVA)
    Parameter type
    		 Least-square (LS) Mean Difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.79
         upper limit
    		 0.36
    Variability estimate
    Standard deviation
    Dispersion value
    0.29
    Notes
    [1] - Exploratory comparison between SABER-Bupivacaine and Bupivacaine HCl not analyzed inferentially

    Primary: Supplemental Opioid Use

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    End point title
    		 Supplemental Opioid Use
    End point description
    Cumulative IV morphine-equivalent dose of opioid rescue medication.
    End point type
    Primary
    End point timeframe
    0 to 3 days after surgery
    End point values
    		 SABER-Bupivacaine SABER-Placebo Bupivacaine HCl
    Number of subjects analysed
    61
    27
    27
    Units: mg
        arithmetic mean (standard deviation)
    22.8 ( 24.3 )
    26.3 ( 25.7 )
    23.9 ( 25.9 )
    Statistical analysis title
    		 Statistical Analysis 1 for Supplemental Opioid Use
    Comparison groups
    SABER-Bupivacaine v SABER-Placebo
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.331
    Method
    		 t-test in ANOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.59
         upper limit
    		 2.58
    Variability estimate
    Standard deviation
    Dispersion value
    2.57
    Notes
    [2] - Exploratory comparison between SABER-Bupivacaine and Bupivacaine HCl was not analyzed inferentially.

    Secondary: Time to First Opioid Rescue Medication Usage

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    End point title
    		 Time to First Opioid Rescue Medication Usage
    End point description
    End point type
    Secondary
    End point timeframe
    0 to 14 days after surgery
    End point values
    		 SABER-Bupivacaine SABER-Placebo Bupivacaine HCl
    Number of subjects analysed
    61
    27
    27
    Units: hour
        arithmetic mean (standard deviation)
    7.71 ( 45.79 )
    1.53 ( 1.56 )
    25.94 ( 87.77 )
    No statistical analyses for this end point

    Secondary: Opioid Related Side Effects

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    End point title
    		 Opioid Related Side Effects
    End point description
    Opioid-related side effects were recorded 0 to 7 days after surgery. The Opioid-Related Symptom Distress Scale (OR-SDS) is a composite score computed from a questionnaire containing frequent opioid-related symptoms (Fatigue, Drowsiness, Inability to concentrate, Nausea, Dizziness, Constipation, Itching, Difficulty with urination, Confusion, Retching/vomiting). For each symptom, participants assigned integer scores to assess severity (none=0 to very severe=4), bothersomeness (none=0 to very much=5), and frequency (none=0 to almost constantly=4); participants reported number of Retching/vomiting episodes (none=0, 1 to 2 episodes=1, 3 to 4 episodes=2, 5 to 6 episodes=3, >6 episodes=4). On each day (Days 0 to 7), the score for each symptom was the mean of the 3 component scores, and the OR-SDS score was the overall mean of the 10 symptom scores, (values from 0 to 4; larger outcomes are worse). The mean of the daily OR-SDS score from Days 0 to 7 gave the overall OR-SDS Score.
    End point type
    Secondary
    End point timeframe
    0 to 7 days after surgery
    End point values
    		 SABER-Bupivacaine SABER-Placebo Bupivacaine HCl
    Number of subjects analysed
    53
    25
    23
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.28 ( 0.28 )
    0.34 ( 0.31 )
    0.27 ( 0.24 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    0 to 7 days after surgery
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    SABER-Bupivacaine
    Reporting group description
    		 -

    Reporting group title
    SABER-Placebo
    Reporting group description
    		 -

    Reporting group title
    Bupivacaine HCl
    Reporting group description
    		 -

    Serious adverse events
    		 SABER-Bupivacaine SABER-Placebo Bupivacaine HCl
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 60 (11.67%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    ECG QT prolonged
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ECG abnormal
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal neoplasm
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 27 (0.00%)
    0 / 27 (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
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 27 (0.00%)
    0 / 27 (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
    Laryngeal oedema
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 27 (0.00%)
    0 / 27 (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
    Haematoma infection
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         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
    		 SABER-Bupivacaine SABER-Placebo Bupivacaine HCl
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 60 (81.67%)
    24 / 27 (88.89%)
    24 / 27 (88.89%)
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences all number
    4
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    7 / 60 (11.67%)
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    7
    0
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    0
    Injury, poisoning and procedural complications
    Incision site haematoma
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    0
    Post procedural contusion
         subjects affected / exposed
    36 / 60 (60.00%)
    9 / 27 (33.33%)
    0 / 27 (0.00%)
         occurrences all number
    37
    9
    0
    Post procedural discharge
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 27 (3.70%)
    2 / 27 (7.41%)
         occurrences all number
    4
    1
    2
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 27 (3.70%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 60 (15.00%)
    3 / 27 (11.11%)
    4 / 27 (14.81%)
         occurrences all number
    9
    3
    4
    Somnolence
         subjects affected / exposed
    5 / 60 (8.33%)
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    5
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 60 (16.67%)
    4 / 27 (14.81%)
    3 / 27 (11.11%)
         occurrences all number
    10
    4
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 60 (11.67%)
    3 / 27 (11.11%)
    7 / 27 (25.93%)
         occurrences all number
    8
    3
    7
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    9 / 60 (15.00%)
    8 / 27 (29.63%)
    4 / 27 (14.81%)
         occurrences all number
    9
    8
    5
    Nausea
         subjects affected / exposed
    8 / 60 (13.33%)
    6 / 27 (22.22%)
    9 / 27 (33.33%)
         occurrences all number
    9
    6
    9
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         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
    25 Aug 2008
    This amendment was made to change all text pertaining to the use of 15 mg morphine tablets as rescue therapy. Due to the unavailability of the 15 mg dose in some of the participating countries, 10 mg tablets were used to ensure that all countries were adhering to the same rescue medication regimen. Additionally, this amendment clarified the timings for the evaluation of home readiness via Post- Anaesthetic Discharge Scoring System.
    20 Jan 2009
    In addition to the correction of some administrative errors, this amendment detailed, added, or clarified: the addition of the long-term safety visit, that the participant’s evaluability would be decided at the Blinded Data Review Meeting, the allowance of intravenous morphine administration post-operatively to optimise the participant’s pain treatment, the recording of background treatment (in the electronic case report form, not the electronic Diary [eDiary]), flexibility regarding the taking of PK blood samples, the use of alternative anaesthesia during surgery, the causality statement for adverse events, the definition of “at rest”, the recording of concomitant illness (not past illness) and additional information regarding the safety of benzyl alcohol was added. Additionally, exclusion criterion number 16 was added to the protocol in this amendment. The schedule of assessments was updated in accordance with the changes.
    25 Mar 2009
    This amendment introduced the magnetic resonance imaging scan at the 6 month follow-up visit and the benzyl alcohol concentration measurements and analysis at selected sites. Eighty-one (81) participants were randomised according to the protocol version 5.0 including amendments 1 to 3.
    13 Jul 2009
    In addition to a clarification of some text, this amendment detailed that paracetamol should only be taken on Days 0 to 2 (72 hours) instead of Days 0 to 7. The paracetamol background treatment was not limited to orally administered paracetamol and was administered immediately after surgery to ensure that there was sufficient pain relief from background medication and subsequent adherence to the protocol. The amendment also detailed the removal of the baseline blood-draw as it was identical to the screening blood-draw and that alternative syringes were packed with the Investigational Medicinal Product (IMP) to avoid application of the incorrect volume of IMP following surgery. Additionally, anti-emetic use was clarified. Thirty-four (34) participants were randomised according to protocol version 5.0 including amendments 1 to 4.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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