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    Clinical Trial Results:
    MicroBubble detection and Ultrasound guided Biopsy of axillary Lymph nodes in patients with Early breast cancer.

    Summary
    EudraCT number
    		 2012-001889-14
    Trial protocol
    		 GB  
    Global end of trial date
    23 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Sep 2016
    First version publication date
    30 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Bubble2012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 R&D Protocol Number: A092595
    Sponsors
    Sponsor organisation name
    Cambridge University Hospitals NHS Foundation Trust
    Sponsor organisation address
    Cambridge Biomedical Campus, Hills Road, Cambridge, United Kingdom, CB2 0QQ
    Public contact
    Carrie Bayliss, Cambridge Clinical Trials Unit, 44 01223348158, carrie.bayliss@addenbrookes.nhs.uk
    Scientific contact
    Carrie Bayliss, Cambridge Clinical Trials Unit, 44 01223348158, carrie.bayliss@addenbrookes.nhs.uk
    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
    05 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Purpose of the trial: To improve the pre-operative diagnosis of axillary lymph node metastases in patients with breast cancer using an ultrasound contrast agent (SonoVue®) to detect the sentinel lymph node draining the breast and percutaneously removing it with a needle biopsy device. Primary objective: To assess the sensitivity of the microbubble guided biopsy technique in detecting metastatic sentinel lymph nodes.
    Protection of trial subjects
    Every effort was made throughout the trial to make the patient as comfortable as possible during the procedures. In Part 1 of the study, local anaesthesia of the retroareolar region at the site of the ultrasound microbubble agent was achieved with a subcutaneous injection of 2 mls 1% lidocaine. We noted that the patients in Part 1 of the study did experience a degree of discomfort during the micro bubble injection. Patients recruited to Part 2 of the study therefore had EMLA local anaesthetic cream applied to the areola 4 – 8 hours prior to the procedure, which reduced the pain experienced for this injection. For both parts of the study local anaesthetic was injected into the dermis and subcutaneous tissue of the axilla. In Part 2 of the study, prior to the vacuum assisted biopsy, a mean volume of 10mls of Lidocaine 1% and 1:200,000 adrenaline (range 5mls – 16mls) was injected into and around the axillary node prior to biopsy. Following the biopsy patients had the biopsy site compressed by hand for 10 minutes to reduce the chance of haematoma and help to minimise post biopsy discomfort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Dec 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 139
    Worldwide total number of subjects
    139
    EEA total number of subjects
    139
    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)
    82
    From 65 to 84 years
    56
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited who were scheduled to undergo surgical sentinel lymph node biopsy. This was a single centre study performed by members of the Cambridge Breast Unit in Addenbrooke’s Hospital, Cambridge.

    Pre-assignment
    Screening details
    		 Patients with newly diagnosed early breast cancer and recommended for SLNB as part of routine surgical management were eligible for recruitment to the study. Patients undergoing neoadjuvant chemotherapy (unless diagnosed with malignancy on VAB) were excluded from the study to avoid compromising accuracy of histological staging.

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

    Arms
    Arm title
    		 Single Arm Trial
    Arm description
    		 This was an open-label, non-randomised study. Thus all subjects were in the single arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sulphur Hexafluoride
    Investigational medicinal product code
    Other name
    SonoVue
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Following local anesthesia, Sulphur Hexafluoride microbubble 0.3 mls (SonoVue™ Bracco Imaging) was injected into the dermis at the junction between the edge of the areola and the breast. SonoVue™ is composed of phospholipid stabilised microbubbles containing sulphur hexafluoride gas. It comes in powder form and is reconstituted by mixing with 2mls of (0.9%) saline. The raised “bleb” of contrast was then massaged for a few seconds to encourage passage of microbubbles into the lymphatics. If the node was not visualized then additional injections of SonoVue™ were performed up to a maximum of 3 injections with a cumulative total of not more than 1ml.

    Number of subjects in period 1
    		Single Arm Trial
    Started
    139
    Completed
    137
    Not completed
    2
         Became ineligible
    1
         Physician decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 All consented subjects

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 139 139
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 82 82
        From 65-84 years
    		 56 56
        85 years and over
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.13 ( 11.53 ) -
    Gender categorical
    Units: Subjects
        Female
    		 139 139
        Male
    		 0 0
    Subject analysis sets

    Subject analysis set title
    Part 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects consenting to Part 1 of the study.

    Subject analysis set title
    Part 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects consenting to Part 2 of the study.

    Subject analysis set title
    Part 2 Analysis Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Consented Part 2 patients who underwent SonoVue injection and had both percutaneous biopsy and surgical pathology results excluding subjects who have chemotherapy prior to surgical excision and who are negative for malignancy at both the needle biopsy and on surgical excision. (This is due to the fact that the negative result at surgery after chemotherapy may be a false negative, as described in the protocol.)

    Subject analysis sets values
    		 Part 1 Part 2 Part 2 Analysis Population
    Number of subjects
    36
    103
    82
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.32 ( 10.97 )
    60.37 ( 11.67 )
    59.99 ( 11.96 )
    Gender categorical
    Units: Subjects
        Female
    36
    103
    82
        Male
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Single Arm Trial
    Reporting group description
    		 This was an open-label, non-randomised study. Thus all subjects were in the single arm.

    Subject analysis set title
    Part 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects consenting to Part 1 of the study.

    Subject analysis set title
    Part 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects consenting to Part 2 of the study.

    Subject analysis set title
    Part 2 Analysis Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Consented Part 2 patients who underwent SonoVue injection and had both percutaneous biopsy and surgical pathology results excluding subjects who have chemotherapy prior to surgical excision and who are negative for malignancy at both the needle biopsy and on surgical excision. (This is due to the fact that the negative result at surgery after chemotherapy may be a false negative, as described in the protocol.)

    Primary: Sensitivity

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    End point title
    		 Sensitivity
    End point description
    Sensitivity of detecting pre-operative metastases using Microbubble Technique.
    End point type
    Primary
    End point timeframe
    Overall trial
    End point values
    		 Single Arm Trial Part 2 Analysis Population
    Number of subjects analysed
    82 [1]
    82
    Units: Sensitivity
        number (confidence interval 95%)
    0.58824 (0.32925 to 0.81556)
    0.58824 (0.32925 to 0.81556)
    Notes
    [1] - This analysis only applies to the subjects included in the analysis population specified in the SAP.
    Statistical analysis title
    		 Primary Analysis Test
    Statistical analysis description
    Test of the null hypothesis that the sensitivity is less than or equal to 10%, using a one-sided exact binomial test at the 5% significance level. A p-value is reported. Note the analysis is not a comparison of two groups. This report lists two groups each of size 82 (and "subjects in this analysis" as 164) due to the validation requirements of the EudraCT system to have two comparison groups.
    Comparison groups
    Single Arm Trial v Part 2 Analysis Population
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.00001
    Method
    		 Exact binomial test, Clopper-Pearson CIs
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported from time of consent to the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Part 1 Safety
    Reporting group description
    		 All subjects in Part One who received any dose of SonoVue.

    Reporting group title
    Part 2 Safety
    Reporting group description
    		 All subjects in Part Two who received any dose of SonoVue.

    Serious adverse events
    		 Part 1 Safety Part 2 Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 102 (0.98%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Haematoma
    Additional description: Axillary haematoma following biopsy.
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
    Additional description: Given routine antiobiotics at end of breast and SLN surgical operation. Went into bronchospasm, crash team called; no action required. Patient kept in overnight (due to be a daycase) as a precaution and for allergy tests. Discharged well.
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Part 1 Safety Part 2 Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 102 (0.00%)
    General disorders and administration site conditions
    Chest discomfort
    Additional description: Heaviness in chest during procedure. Patient unsure whether related to procedure or heavy gardening session prior to examination. No indication that it was cardiac in origin. Resolved spontaneously.
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 102 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Mar 2014
    The reason for the amendment was to update the safety information in the Protocol and other trial documents to bring it in line with the latest version of the Reference Safety Information. Specifically the addition of two new expected adverse reactions: hypotension and vasovagal.

    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.
    Although sensitivity for detecting metastases is reasonable, the adverse effect of VAB on surgery is significant. We would therefore advocate the use of microbubble detection of SLN followed by core biopsy rather than VAB.
    For support, Contact us.
    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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