Clinical Trial Results:
MicroBubble detection and Ultrasound guided Biopsy of axillary Lymph nodes in patients with Early breast cancer.
Summary
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EudraCT number |
2012-001889-14 |
Trial protocol |
GB |
Global end of trial date |
23 Sep 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Sep 2016
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First version publication date |
30 Sep 2016
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
Bubble2012
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Additional study identifiers
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ISRCTN number |
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US NCT number |
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WHO universal trial number (UTN) |
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Other trial identifiers |
R&D Protocol Number: A092595 | ||
Sponsors
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Sponsor organisation name |
Cambridge University Hospitals NHS Foundation Trust
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Sponsor organisation address |
Cambridge Biomedical Campus, Hills Road, Cambridge, United Kingdom, CB2 0QQ
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Public contact |
Carrie Bayliss, Cambridge Clinical Trials Unit, 44 01223348158, carrie.bayliss@addenbrookes.nhs.uk
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Scientific contact |
Carrie Bayliss, Cambridge Clinical Trials Unit, 44 01223348158, carrie.bayliss@addenbrookes.nhs.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
05 Sep 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Aug 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Sep 2015
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Was the trial ended prematurely? |
Yes
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General information about the trial
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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.
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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.
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Background therapy |
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Evidence for comparator |
- | ||
Actual start date of recruitment |
31 Dec 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 139
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Worldwide total number of subjects |
139
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EEA total number of subjects |
139
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
82
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From 65 to 84 years |
56
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85 years and over |
1
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Recruitment
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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
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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
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
Arms
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Arm title
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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
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Investigational medicinal product code |
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Other name |
SonoVue
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intradermal use
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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.
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
All consented subjects | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Part 1
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects consenting to Part 1 of the study.
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Subject analysis set title |
Part 2
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects consenting to Part 2 of the study.
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Subject analysis set title |
Part 2 Analysis Population
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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.)
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End points reporting groups
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Reporting group title |
Single Arm Trial
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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
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects consenting to Part 1 of the study.
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Subject analysis set title |
Part 2
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects consenting to Part 2 of the study.
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Subject analysis set title |
Part 2 Analysis Population
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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.)
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End point title |
Sensitivity | ||||||||||||
End point description |
Sensitivity of detecting pre-operative metastases using Microbubble Technique.
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End point type |
Primary
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End point timeframe |
Overall trial
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Notes [1] - This analysis only applies to the subjects included in the analysis population specified in the SAP. |
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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.
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Comparison groups |
Single Arm Trial v Part 2 Analysis Population
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Number of subjects included in analysis |
164
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
< 0.00001 | ||||||||||||
Method |
Exact binomial test, Clopper-Pearson CIs | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events are reported from time of consent to the study.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
Part 1 Safety
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Reporting group description |
All subjects in Part One who received any dose of SonoVue. | |||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part 2 Safety
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Reporting group description |
All subjects in Part Two who received any dose of SonoVue. | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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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. |