Safety and Feasibility Study of Magnetic Seed Markers to Localise Breast Cancers for Surgical Excision
Phase: NA
Conditions: Breast Cancer
Sponsor: Manchester University NHS Foundation Trust

	  
	  
	  
	  
	  
	  
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Study Title:  Phase I Safety and Feasibility Study of the use of Magnetic Marker 
Seeds to localise breast cancers  
 
 
Protocol Short Title/Acronym:  Magnetic seed localisation of breast cancers 
Ethics Ref:   
 
 
Insert 
Eudract Number:   
 
Not applicable 
Version No and Date:  
 
V2, 18th March 2016 
Chief Investigator:  
 
Mr J R Harvey  
Investigators:  
 
 
Dr Y. Lim, Mr J. Murphy, Dr A. Maxwell  
Sponsor:  
UHSM, Southmoor Road, Manchester, M23 9LT.  
Funder (if applicable): 
Endomagnetics Ltd, The Jeffreys Building, Cowley   
Road, Cambridge. CB4 0WS 
  
Confidentiality Statement 
This document contains confidential information that must not be disclosed to 
anyone other than the Sponsor, the Investigator Team, the Sponsoring Trust’s R&D 
Office (or a Southern Sector R&D Office, regulatory authorities, and members of the 
Health Research Authority or Local Research Network).   
 
	  

	  
	  
	  
	  
	  
	  
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Trial Personnel 
	  
Role in study: Chief Investigator 
Name: Mr James Harvey 
Address: UHSM, Nightingale Centre, Southmoor Road. Manchester. M23 9LT 
Telephone: 01612914441 
Fax: 01612914435 
Email:james.harvey@uhsm.nhs.uk 
 
 
 
Role in study: Co-investigator 
Name: Dr Yit Lim 
Address: UHSM, Nightingale Centre, Southmoor Road. Manchester. M23 9LT 
Telephone: 01612914436 
Fax: 01612914435 
Email:yit.lim@uhsm.nhs.uk 
 
 
 
Role in study: Co-investigator 
Name: Mr John Murphy 
Address: UHSM, Nightingale Centre, Southmoor Road. Manchester. M23 9LT 
Telephone: 01612914436 
Fax: 01612914435 
Email:john.murphy@uhsm.nhs.uk 
 
 
 
Role in study: Co-investigator 
Name: Dr Anthony Maxwell 
Address: UHSM, Nightingale Centre, Southmoor Road. Manchester. M23 9LT 
Telephone: 01612914460 
Fax: 01612914435 
Email:anthony.maxwell@manchester.ac.uk 
 
 
 

	  
	  
	  
	  
	  
	  
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Role in study: Statistician 
Name: Julie Morris 
Address: UHSM, 1st floor, Education & Research Centre, Manchester M23 9LT 
Telephone: 0161 2915815 
Email:Julie.morris@manchester.ac.uk 
 
 
 
 
 
 

	  
	  
	  
	  
	  
	  
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Signatures 
The approved protocol should be signed by author(s) and/or person(s) 
authorised to sign the protocol 
 
The Chief Investigator and UHSM as the Sponsors have discussed this protocol. 
The investigator agrees to perform the investigations and to abide by this protocol  
The investigator agrees to conduct the trial in compliance with the approved 
protocol, EU GCP and UK Regulations for CTIMPs (SI 2004/1031; as amended), the 
UK Data Protection Act (1998), the Trust Information Governance Policy (or other 
local equivalent), the Research Governance Framework (2005’ 2nd Edition; as 
amended), the Sponsor’s SOPs, and other regulatory requirements as amended. 
 
 
 
 
___________________________________  
 
_________________________ 
Chief Investigator signature 
 
 
 
 
Date 
 
Print name: 
 
 
 
 
 
 
___________________________________  
 
_________________________ 
Sponsor Representative signature 
 
 
 
Date 
 
Print name: 
 
 

	  
	  
	  
	  
	  
	  
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Contents 
1. 
Summary 
2. 
Glossary of Terms  
3.  
Background and Rationale 
 
4. 
Trial Objectives and Design 
 
4.1. Trial Objectives  
4.1.1 Primary and Secondary Endpoints/Outcome Measures  
4.2 Trial Design  
 
5. 
Selection and Withdrawal of Subjects  
5.1 Informed Consent 
5.2 Inclusion Criteria 
 
5.3 Exclusion Criteria 
 
5.4 Screening and Eligibility Assessment 
5.5 Identification and Selection of Participants 
5.6 Withdrawal of Subjects 
 
5.7 Expected Duration of Trial. 
 
 
6. 
Trial Procedures 
 
6.1 By Visit  
7. 
Assessment of Efficacy  
7.1 Primary Efficacy Parameters  
7.2. Secondary Efficacy Parameters 
 
 
8. 
Source Data 
9. 
Assessment of Safety 
 
 
9.1 Specification, Timing and Recording of Safety Parameters. 
 
9.2 Procedures for Recording and Reporting Adverse Events 
 
9.2.1 Adverse events that do not require reporting 
 
9.3 Urgent Safety Measures (USMs) 
 
 
10. 
Statistics 
 
10.1 Sample Size 
 
10.2 Randomisation 
10.3 Analysis 
 
11. 
Trial Steering Committee 

	  
	  
	  
	  
	  
	  
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12.  
Direct Access to Source Data and Documents 
13.  
Ethics and Regulatory Approvals 
14.  
Quality Assurance  
15.  
Data Handling 
 
16. 
Publication Policy  
17.  
Insurance and Indemnity  
18.  
Financial Aspects 
 

	  
	  
	  
	  
	  
	  
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1. Summary 
 
Title: 
Safety and feasibility study of Magnetic Seed markers 
to localise breast cancers for surgical excision 
Short title: 
Magnetic seeds to localise breast cancers 
Trial medication: 
N/A 
Phase of trial: 
I 
Objectives: 
 The Primary Endpoint  
An evaluation of the distribution of seed migrations to 
estimate the risk of markers migrating 
• A clinically significant distance (10mm or 
greater) 
• A clinically unsafe distance (40 mm or greater) 
Marker (seed) location will be compared 
radiographically between the post-placement image 
and the pre-operative image.  The position of the 
marker (seed) will be assessed in relation to 
anatomical landmarks and any change recorded in 
mm. 
Secondary research questions include; 
• Accuracy of initial placement – distance of the 
marker (seed) on radiographic imaging from the 
intended site of placement (e.g. lesion, marker 
clip, calcification); 
 
• Percentage magnetic markers (seeds) within 
target area;  
o The target area will be detected by 
mammography on the day of surgery and 
is defined as within 10mm of the target 
lesion. 
• Relationship between depth of marker (seed) 
and ease of transcutaneous detection; 

	  
	  
	  
	  
	  
	  
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o Marker (seed) depth to the nearest skin 
surface will be estimated sonographically 
o Ease of detection measured by ability to 
detect the marker (seed) with Sentimag 
detector and the time to detect marker 
(seed) in seconds; 
Other End-points 
• Safety and tolerability 
o Tissue responses as assessed by gross 
pathology and histology will be 
described 
o Adverse Effects profile will be monitored 
• Seed integrity post excision;  
• Number of days the marker (seed) was in place; 
• Mastectomy weight 
• Relationship between clinical characteristics 
and movement of the markers -- If any markers 
migrate a clinically significant distance, a 
qualitative assessment will be carried out to see 
if there is a possible relationship between 
clinical characteristics seen in patients and 
movement of the marker.  (e.g. Haematoma, 
placement of seed into fatty rather than soft 
tissue) 
 
Type of trial: 
Single site, single arm, open label safety and feasibility 
cohort study of using magnetic marker seeds to 
localise breast tumours. 
Trial 
design 
and 
methods: 
The magnetic marker system (Sentimark® Magnetic 
Marker System) is a sterile, single use device 
composed of a magnetic marker (seed) preloaded in a 
delivery system. The magnetic seed is approximately 
5mm long and 0.9mm in diameter. 
The seed is intended to be temporarily placed within 
the breast and removed within 28 days. The seed, 
when used in conjunction with the Sentimag® System 
(base unit and probe), can be used as a guide for the 
surgeon to facilitate excision of tissue. The Tissue 

	  
	  
	  
	  
	  
	  
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Marker (seed) is visible using ultrasound and 
mammography.  
The study is a first-in-human study using this particular 
magnetic seed and designed to test the feasibility and 
safety of using the marker (seed) in breast cancer 
patients. The data will support the application for a CE 
mark. 
The study will be carried out in patients requiring a 
mastectomy.  In this population, the full cycle of 
marker (seed) deployment and removal can be 
evaluated, but as the breast is being removed as part 
of the planned cancer treatment, patient treatment will 
be unaffected should the magnetic seed not perform 
as intended. 
Methods: 
The marker (seed) will be inserted by trained and 
qualified healthcare professionals under image 
guidance (ultrasound or radiography) and removed 
with the surgical mastectomy (breast) specimen.   
Sentimark will be placed in the lesion for which a 
patient is scheduled to have a mastectomy, a 
minimum of 2 days prior to surgery.  
The depth of lesion and marker will be recorded by the 
radiologist 
Confirmation of initial detectability with magnetometer 
immediately after placement and time to detection 
(seconds).  
Assessment of distance of the magnetic marker (seed) 
from lesion on pre-operative mammography. 
Check mammogram on morning of surgery to ensure 
Sentimark is still visible. 
Surgeon checks that Sentimark can be detected 
transcutaneously during surgery. 

	  
	  
	  
	  
	  
	  
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Surgeon performs mastectomy 
Record mastectomy weight. 25 patients (range of 
breast sizes (a minimum of three of each of small 
(<250g), and medium (250-500g), and five large 
(>500g) breasts). 
Perform pathology assessment of mastectomy tissue 
and record any unexpected tissue reaction to the 
Sentimark device (minimum 10 patients) 
All adverse events will be recorded from when the 
patient signs the informed consent until the final study 
visit. 
25 patients 
Trial 
duration 
per 
participant: 
6 weeks maximum 
Estimated total trial 
duration: 
Ten months 
Planned trial sites: 
Single – University Hospital of South Manchester 
Total 
number 
of 
participants 
planned: 
25 
Main 
inclusion/exclusion 
criteria: 
Inclusion criteria:  
• 
Participant is willing and able to give informed 
consent for participation in the study; 
• 
Female, aged 18 years or above; 
• 
Diagnosed with breast cancer (invasive or 
DCIS); 
• 
Willing to allow his or her General Practitioner 
and consultant, if appropriate, to be notified of 
participation in the study; 
• 
Undergoing mastectomy breast surgery. 
Exclusion criteria:   
• Patients with a Pacemaker or implanted device 
in the chest wall; 
• Patients requiring an MRI scan prior to surgery; 
• Patients with known coagulopathy or receiving 
anticoagulant medication including warfarin, 

	  
	  
	  
	  
	  
	  
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heparin, clopidogrel or rivaroxaban; 
• Patients receiving Neoadjuvant chemotherapy; 
• Patients who are pregnant or lactating; 
• Patients who have received Sienna (iron oxide) 
injection in the previous six months; 
• Patients with an existing breast haematoma 
close to the target lesion. 
• Patients with known hypersensitivity to stainless 
steel 
 
 
Statistical 
methodology 
and 
analysis: 
This protocol has been developed with Julie Morris 
Medical Statistician at Manchester University.  Simple 
descriptive summary statistics of the main parameters 
will be derived together with a graphical presentation 
of the raw data.  Percentages for categorical variables, 
means, standard deviations, medians and range 
values for quantitative factors will be calculated as 
appropriate. 95% confidence intervals will also be 
presented to provide a measure of accuracy for the 
estimates. 
The relationship between breast size and detectability 
of the seed by the magnetometer will be assessed 
using simple correlational analysis. 
The statistical software package, SPSS version 22, will 
be used for the statistical analysis. 
Sources of measurement error will be graphically 
displayed, reviewed and discussed as appropriate. 
 
 
 

	  
	  
	  
	  
	  
	  
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2. Glossary of Terms  
	  
AE 
Adverse Event 
AR  
Adverse Reaction 
CRF 
Case report form 
CI 
Chief Investigator 
CRA 
Clinical Research Associate (Monitor) 
CRF 
 
Case Report Form 
CRO  
Contract Research Organisation 
CT 
 
Clinical Trials 
CTA 
 
Clinical Trials Authorisation 
DCIS 
 
Ductal carcinoma in situ 
DSMB 
 
Data Safety Monitoring Board 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Products 
IRB 
Independent Review Board 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MRI 
Magnetic resonance imaging 
NHS 
National Health Service 
HRA 
Health Research Authority 
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SIL 
Subject Information Leaflet (see PIL) 
SmPC/SPC 
  Summary of Products Characteristics 
SOP 
Standard Operating Procedure 
SUSAR   
Suspected Unexpected Serious Adverse Reactions 
TMF 
Trial Master File 
U/S 
Ultrasound 
WLE 
Wide Local Excision (lumpectomy surgery) 
 
 
 
 

	  
	  
	  
	  
	  
	  
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3. 
Background and Rationale 
Breast Cancer 
Breast cancer is a heterogeneous disease, with great diversity in the site, size and 
progression of tumours. Some are palpable and discovered by the patient, though 
many are first detected during mammogram screening. For such cancers, 
localisation is necessary prior to surgery, to guide surgeons to the target excision 
site.  
Wire Guided Localisation 
Traditionally, localisation involves radiographic-guided insertion of a wire into the 
breast, with positioning of the wire tip at the centre of the lesion. However, this 
procedure carries several logistical limitationsi,ii stemming from the fact that wire 
localisation must be performed on the day of surgery. This is to minimise risk of wire 
migration or dislodgementiii, a significant possibility due to the external section of 
wire left protruding from the breast. Same-day appointments demand excellent 
coordination between radiological departments and operating theatres to ensure 
that disruption to procedure scheduling is minimised. Delays may result from 
technically difficult proceduresiv, leading to over-running radiology appointments 
that have a knock on effect on operating lists. Additionally, cancelled operations 
can result in preceding wire guidance procedures becoming unnecessary, resulting 
in wasted staff hours. 
Another limitation of wire guidance occurs because the wire directs surgeons along 
a linear route. Lesions are found at a point along the wire, though it can be difficult 
to determine how far along they are found. For this reason, surgeons making initial 
incisions may be dictated by the visual trajectory of the wire, rather than the 
location of the lesioni. This can lead to excessive dissection and sub optimal 
cosmetic results. 
Radioactive Seed Localisation 
Radioactive seed localisation (RSL) is a localisation technique that is less commonly 
used in the UK. A radioactive seed can be inserted up to 5 days before surgery, 
thus eliminating the requirement for radiology appointments on the same day as the 
patient’s operation. The seed is detected in theatre using a handheld gamma probe. 
The gamma probe directs the surgeon to a single specific point via the shortest 
route, whereas, wires often transect the breast, meaning that surgeons commonly 
end up dissecting across normal tissue to locate the tip of the wire. In addition, with 
RSL, there is no distraction from external projections of wire, so the surgeon is 
guided purely by the audible response to the seed. It is hypothesised that the 

	  
	  
	  
	  
	  
	  
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advantages of RSL will lead to improved surgical techniques and reduce pressures 
on theatre schedulingi. 
However, up to now, there is little evidence demonstrating clear superiority in 
surgical outcome of one localisation technique. Several studies have found lower 
positive margin rates in patients undergoing RSL versus wire guidancev,vi,vii. This 
means that edges of excised tissues less commonly involves cancerous tissue, 
suggesting that RSL more accurately localises cancerous lesions. Conversely, many 
more studies, including one of the largest trials to date, conclude there is no 
variability in surgical outcomei,v,viii,ix.   
Regardless of stance on surgical outcome, all studies noted that RSL offers 
significant improvements in scheduling of appointments and patient conveniencei,ii, 
v-ix. 
However, radioactive techniques are not without limitations. Several studies have 
evaluated the use of standard radioisotope and blue dye injections for sentinel node 
biopsyx,xi,xii. Each study commented on the complex legislation regulating use of 
radioisotopes, particularly with regards to operator training and correct disposal and 
handling. In addition, radioisotope use increases patient and healthcare worker 
radiation exposure which, though minimal, would be preferable to avoid. 
Iron Oxide Use in Breast Surgery 
Several studies have investigated the use of liquid injections of iron oxide rather 
than traditional radioisotope and blue dye injections, in sentinel node 
identificationx,xi,xii. Following iron oxide injections, a handheld magnetometer was 
used to detect the location of iron oxide in the lymph nodes. All studies concluded 
that iron oxide particles performed equally as well as standard radioisotope & blue 
dye injections in sentinel node identification, demonstrating potential for more 
widespread use of the technique.  
In addition, Ahmed et al tested localisation of cancerous lesions using a magnetic 
tracer injection. The tracer successfully localised all tumours and resulted in 
appropriate excisional margins, without excess tissue excisionx; thus demonstrating 
the feasibility of magnetic tracer localisation of tumours. 
Sentimark Magnetic Localisation 
The localisation method with which this project is concerned has similar principles 
to RSL. However, instead of radioactive seeds, a soft magnetic seed called 
Sentimark, is placed into the breast. The seed is similar to a biopsy clip and can be 
detected using a handheld magnetometer called Sentimag. The Sentimag probe 

	  
	  
	  
	  
	  
	  
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emits an alternating magnetic field that detects the magnetic response of the 
Sentimark seed. The magnetometer produces an audible response when held close 
to the Sentimark seed and can be used by surgeons to locate target excision sites. 
Sentimark is inserted about a week before operation, ideally during a biopsy 
appointment, for patient convenience. 
This study will be the first to investigate magnetic seed localisation of tumours. It is 
hypothesised that using magnetic seeds rather than injections with a magnetic 
tracer will allow more accurate detection and localisation using the Sentimag probe. 
This is because the probe is detecting the magnetic field produced by a single 
discrete object, rather than a collection of iron oxide-containing liquid which may 
disperse throughout the breast. 
Summary of Localisation Techniques 
The coordination and scheduling difficulties encountered in wire guided localisation, 
alongside the logistical and safety issues of radioisotope usage, highlight a 
requirement for further innovation and acquisition of new technologies in the field of 
localisation. It is hoped that magnetic seed localisation can act as a feasible 
alternative to existing technologies. Use of magnetism in localisation techniques 
offers a potential alternative to wire guidance and RSL.  
An important consideration with the deployment of the new seed is whether the size 
and shape of the seed are sufficiently similar to previous designs to show similar 
migration patterns, as movement of the seed prior to surgery can cause incomplete 
lesion excision with en-suing requirements for re-operation or an increased risk of 
recurrence.  
The migration performance of Sentimark in an implantation trial in goats, mean 
migration of 0.95mm with a range 0 to 3.6mm (N=10), was very similar to that 
observed by Alderliesten, et al.xiii who report a mean migration of 0.8mm, range 0 to 
2.8mm (N=10) for RSL seeds which was considered “clinically negligible” in RSL of 
human breast lesions. However, confirmation is required that the magnetic marker 
performs as expected in the clinic.  
The study will test a soft magnetic seed (Sentimark) and its accompanying handheld 
magnetic probe (Sentimag) with particular consideration for its safety and 
performance once placed into human breast tissue. 

	  
	  
	  
	  
	  
	  
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Device 
The device to be studied is a small (5mm x 0.9mm) metal magnetic marker (seed) 
that has soft magnetic properties. This means that when exposed to a magnetic 
field it becomes magnetic. The magnetism can then be detected using a 
magnetometer and probe which gives an audible and visual signal of the strength of 
response from the seed and as it is directional this can accurately guide the user to 
the site of the magnetic seed. The magnetometer is a CE approved device and is 
used worldwide for detecting iron oxide in sentinel lymph node biopsy procedures, 
and is proven in clinical practice. The seed itself will be deployed by a radiologist 
into the centre of the tumour site using a similar technique to that used to currently 
place a wire into the breast. The seed itself is cylindrical and in in vivo studies in 
goats have shown similar migration performance to that seen with radioactive seeds 
in human breast tissue. 
The seed has also been tested in animal tissue models by UHSM radiologists and 
surgeons, and in these models it can be safely deployed by the radiologists using 
existing techniques. The device was detected and surgical resection was performed 
with 100% accuracy on all specimens. There is no radiation exposure from this 
device. 
 
Study Population 
Adult women with capacity to consent who have a proven breast cancer requiring 
breast removing mastectomy surgery. 
Potential Risks to Patients 
The device itself is a small piece of metal and in itself does not offer a likely safety 
risk. 
• 
Migration of the seed – the seed is cylindrical and therefore once placed in 
the breast it has the potential to migrate along the path of the needle that 
was used to deploy it. When deployed into mammary soft tissue in animal 
models the device has not migrated. This study will involve placing the 
device in women having mastectomy so even if the device migrates it will not 
affect patient’s cancer care (as the whole breast will be removed along with 
the device no matter where it is located in the breast). 
• 
Failure to detect the seed – the seed is small and the magnetic field 
generated is proportional to the size of the seed. This study aims to assess 
whether the seed can be detected in all sizes of breast as in some cases it 

	  
	  
	  
	  
	  
	  
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may be possible that the seed lies too deep in the breast to be detected 
using the magnetometer. To ensure safe resection of the cancer, each 
patient in this study will be under-going a planned mastectomy, to ensure 
that the device is fully removed even if detection should fail. 
• 
Tissue acceptance – the seed is produced from a single material and has 
demonstrated biocompatibility through ISO-10993 biocompatibility 
evaluation including demonstration of tissue acceptance in mammary tissue 
of goats (28-day implantation period). Bone wax is used as a terminal plug 
for Sentimark device. Bone wax is commonly used for the same purpose in 
brachytherapy and RSL needles. Some reaction to bone wax may occur, 
such as an allergic reaction or foreign body reactions (e.g. granulomas), as 
bone wax is a minimally resorbable implantable substance.  
 
Potential Benefits 
The study will be carried out in patients requiring a mastectomy.  In this population, 
the full cycle of marker (seed) deployment and removal can be evaluated, but as the 
breast is being removed as part of the planned cancer treatment, patient treatment 
will be unaffected should the magnetic seed not perform as intended. However, 
there will be no direct benefit for patients taking part in the study and the potential 
benefits of this study are limited to the advancement of medical knowledge. If the 
study confirms that the magnetic marker (seed) is safe and the method is feasible, 
the device has the potential to be used for localisation of breast cancers for 
lumpectomy surgery.  

	  
	  
	  
	  
	  
	  
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4. 
Trial Objectives and Design  
4.1. Trial Objectives 
Aims of the feasibility study: 
• 
Assess migration of Sentimark magnetic marker (seed) between deployment 
and surgery; 
• 
Investigate the accuracy of magnetic marker (seed) placement; 
• 
Assess the ability to transcutaneously detect the Sentimark device; 
• 
Examine the safety profile and Adverse Effects of Sentimark device use; 
• 
Explore the relationship between mastectomy weight, depth of lesion and 
ability to detect the magnetic seed using Sentimag probe; 
• 
Determine marker seed integrity in vivo.  
 
4.1.1 Primary and Secondary Endpoints/Outcome Measures  
The Primary Endpoint:  
An evaluation of the distribution of seed migrations to estimate the risk of markers 
migrating 
• A clinically significant distance (10mm or greater); 
• A clinically unsafe distance (40 mm or greater). 
Marker (seed) location will be compared radiographically between the post-
placement image and the pre-operative image.  The position of the marker (seed) 
will be assessed in relation to anatomical landmarks and any change recorded in 
mm. 
Secondary research questions include: 
• Accuracy of initial placement – distance of the marker (seed) on radiographic 
imaging from the intended site of placement (e.g. lesion, marker clip, 
calcification); 
• Percentage magnetic markers (seeds) within target area.  
o The target area will be detected by mammography on the day of 
surgery and is defined as within 10mm of the target lesion. 
• Relationship between depth of marker (seed) and ease of transcutaneous 
detection; 
o Marker (seed) depth to the nearest skin surface will be estimated 
sonographically 

	  
	  
	  
	  
	  
	  
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o Ease of detection measured by ability to detect the marker (seed) with 
Sentimag detector and the time to detect marker (seed) in seconds 
 
Other Endpoints: 
• Safety and tolerability; 
o Tissue responses as assessed by gross pathology and histology will 
be described 
o Adverse Effects profile will be monitored 
• Seed integrity post excision;  
• Number of days the marker (seed) was in place; 
• Mastectomy weight; 
• Relationship between clinical characteristics and movement of the markers -- 
If any markers migrate a clinically significant distance, a qualitative 
assessment will be carried out to see if there is a possible relationship 
between clinical characteristics seen in patients and movement of the 
marker.  (e.g. Haematoma, placement of seed into fatty rather then soft 
tissue). 
4.2  
Study Design 
This is a single site, single arm, unblinded safety and feasibility cohort study 
investigating the use of magnetic marker seeds to localise breast tumours. 
Expected duration of patient participation – Four to six weeks. This will equate to a 
2-4 week period between invitation to join study and Study visit 2 when surgery 
occurs. And a 2-3 week period between surgery and the final follow-up Study visit 
3. 
Invitation – occurs immediately after surgical discussion on the patient’s surgical 
plan for removal of the breast cancer. Patient given an information leaflet about 
study. 
• 
Follow-up phone call to patient more than 24 hours after invitation; 
• 
Study visit 1 – Consultation with patient – consent taken for study. Eligibility 
confirmed and baseline data recorded. Placement of Sentimark device, 
mammogram taken to check placement, detectability of device confirmed, 
ultrasound performed to confirm depth of clip; 
• 
Study visit 2 – day of surgery – check mammogram (this can occur on the 
day before surgery if the patients requires attendance for Sentinel Node 

	  
	  
	  
	  
	  
	  
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Biopsy as part of routine clinical care the day before surgery), check 
detectability of Sentimark seed, surgery performed; 
• 
Study visit 3 – Routine follow-up appointment – Adverse effects recorded, 
oncological outcomes recorded and mastectomy weight. 
5.  
Selection and Withdrawal of Subjects  
5.1  
Informed Consent 
• 
Consent for the study will be taken by a Consultant Breast Surgeon. This 
consultant will be authorised to take consent by the Chief Investigator of the 
study and will have received training about the study and written information 
about the study. This consent process will take place at Study Visit 1, more 
than 24 hours after initial invitation to take part in the study. 
5.2  
Inclusion Criteria  
• 
Participant is willing and able to give informed consent for participation in the 
study; 
• 
Female, aged 18 years or above; 
• 
Diagnosed with breast cancer (invasive or DCIS); 
• 
Willing to allow his or her General Practitioner and consultant, if appropriate, 
to be notified of participation in the study; 
• 
Undergoing mastectomy breast surgery. 
5.3  
Exclusion Criteria  
• 
Patients with a Pacemaker or implanted device in the chest wall; 
• 
Patients requiring an MRI scan prior to surgeryi; 
• 
Patients with known coagulopathy or receiving anticoagulant medication 
including warfarin, heparin, clopidogrel or rivaroxaban; 
• 
Patients receiving Neoadjuvant chemotherapy; 
• 
Patients who are pregnant or lactating; 
• 
Patients who have received Sienna (iron oxide) injection in the previous six 
months; 
• 
Patients with an existing breast haematoma close to the target lesion. 
• 
Patients with known hypersensitivity to stainless steel. 
5.4  
Screening and Eligibility Assessment 
• 
Potential participants will be identified by the Research nurses at the Breast 
Multidisciplinary Meeting which occurs every morning in the Nightingale 
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
i	  If	  the	  patient	  requires	  a	  MRI	  scan	  for	  another	  reason,	  the	  scan	  can	  be	  performed	  safely	  in	  line	  with	  the	  MRI	  
conditional	  information	  provided	  for	  Sentimark	  

	  
	  
	  
	  
	  
	  
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Breast Unit, UHSM. Potential study participants will be patients who are 
newly diagnosed with breast cancer and screening will occur in this pre-clinic 
MDT meeting to see if they meet the eligibility criteria for the study. These 
patients will have a clinical consultation with a Breast Care Nurse and Breast 
Surgeon later the same day and their cancer diagnosis and care will be 
discussed. At the end of this discussion they will be offered further 
discussion about this study which they could be eligible for. The study will be 
briefly introduced by the clinician and then if the patient is potentially 
interested, they will be given a Patient Information Leaflet about the study 
and made aware that the study is completely optional and in the next few 
days the Research Nurse will contact them to ask if they are potentially 
interested in taking part. 
• 
Patients interested in taking part in the study will return for a further follow-up 
visit to discuss the study further and to confirm eligibility and to consent to 
the study at this point.  
• 
The screening process will include collection of the following data; 
• 
Demographics – age, sex, BMI; 
• 
Current medications including anticoagulant medication; 
• 
Pre-operative histology of the breast cancer; 
• 
Oncological information – size and location of lesion on imaging, clinical 
findings, radiological score; 
• 
Medical history – including implantable devices such as pacemakers or 
defibrillators; 
• 
Confirmation from Surgical team that pre-operative MRI will not be required.  
• 
Pregnancy test for premenopausal women. 
5.5 
 Selection of Participants  
Potential participants will be identified by the Research nurses at the Breast 
Multidisciplinary Meeting which occurs every morning in the Nightingale Breast Unit, 
UHSM.  
5.6 
 Withdrawal of Subjects  
Safety of the study participants will be monitored by the Chief Investigator. It is 
unlikely there will be Serious Adverse Events directly related to the Sentimark as it is 
similar to devices currently in use to mark breast cancer location. The study 
involves an intervention of Sentimark placement within the breast. Patients may 
withdraw consent to have this procedure performed in which case this will be 
recorded and the patient will be withdrawn from the study and will be replaced by 
another subject. If a patient withdraws consent to the study once the Sentimark has 
been placed, they will be withdrawn from the study but information on the cancer 

	  
	  
	  
	  
	  
	  
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excision surgery will be recorded to ensure the Sentimark magnetic marker (seed) 
was removed as part of the breast cancer surgery. 
Each participant has the right to withdraw study at any time.  In addition, the 
investigator may discontinue a participant from the study at any time if the 
investigator considers it necessary for any reason including:  
• 
Ineligibility (either arising during the study or retrospective having been 
overlooked at screening); 
• 
Significant protocol deviation; 
• 
Significant non-compliance with treatment regimen or study requirements; 
• 
An adverse event which requires discontinuation of the study medication or 
results in inability to continue to comply with study procedures; 
• 
Disease progression which requires discontinuation of the study medication 
or results in inability to continue to comply with study procedures; 
• 
Consent withdrawn; 
• 
Lost to follow up. 
 
It is understood by all concerned that an excessive rate of withdrawals can render 
the study un-interpretable; therefore, unnecessary withdrawal of patients should be 
avoided.  Should a patient decide to withdraw from the study, all efforts will be 
made to report the reason for withdrawal as thoroughly as possible.  
Withdrawal from the study will result in exclusion of the data for that participant 
from analysis.   
The reason for withdrawal will be recorded in the CRF.   
If the participant is withdrawn due to an adverse event, the investigator will arrange 
for follow-up visits or telephone calls until the adverse event has resolved or 
stabilised.   
5.7 
Expected Duration of Trial 
Expected duration of patient participation – Four to six weeks. This will equate to a 
2-4 week period between invitation to join study and Study visit 2 when surgery 
occurs. Study visit 1 will occur a minimum of 2 days prior to surgery. Surgery will 
not be delayed beyond 31 days from decision to treat the cancer with mastectomy. 
There will be a 2-3 week period between surgery and the final follow-up Study visit 
3, the end of the study will be confirmed as when post-operative histology has been 
recorded and any plans for re-excision surgery are known. 
 

	  
	  
	  
	  
	  
	  
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6. 
Trial Procedures  
Assessments 
Baseline Visit 1 
Surgery Visit 2 
Post surgery Visit 3  
(2-3 wks post surgery) 
Informed consent 
X 
  
  
Medical history 
X 
  
  
Pregnancy test (if pre 
menopausal) 
X 
  
  
CRF/eCRF completion 
including data transfer and 
query resolution 
X 
X  
X 
Concomitant medication 
check  
X 
 X 
 X 
Review/reporting of patient 
AEs/SAEs 
  
X 
X 
Place sentimark lesion and 
ultrasound 
 X 
  
  
Localise lesion during surgery 
  
X 
  
Check detectability of seed 
with magnetometer 
X 
X 
  
Data collection in theatre 
  
 X 
  
Record migration of clip 
  
 X 
   
Mammogram 
X 
X 
  
Mastectomy specimen x-ray 
  
X 
  
	  

	  
	  
	  
	  
	  
	  
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7.  
Assessment of Efficacy  
7.1  
Primary Efficacy Parameters 
The Primary Endpoint:  
An evaluation of the distribution of seed migrations to estimate the risk of markers 
migrating 
• A clinically significant distance (10mm or greater); 
• A clinically unsafe distance (40 mm or greater). 
Marker (seed) location will be compared radiographically between the post-
placement image and the pre-operative image.  The position of the marker (seed) 
will be assessed in relation to anatomical landmarks and any change recorded in 
mm. 
Formally the 95% CI if 0 out of 25 seeds migrate >10mm is 0-13%. However, 
findings will be considered in conjunction with other observations: 
• The observed distribution of migration (e.g. how variable is this distribution 
and how close does it lie to the limits) 
• For any seeds migrating >10mm, a qualitative assessment of underlying 
characteristics such as haematoma or placement into fatty tissue (both 
reported as causes of migration in RSL procedures) 
• Abnormal tissue responses will be assessed by gross pathology and 
histology, as part of the safety endpoint. 
7.2  
Secondary Efficacy Parameters 
Secondary Research Questions: 
• Accuracy of initial placement – distance of the marker (seed) on radiographic 
imaging from the intended site of placement (e.g. lesion, marker clip, 
calcification); 
• Percentage magnetic markers (seeds) within target area;  
o The target area will be detected by mammography on the day of 
surgery and is defined as within 10mm of the target lesion 
• Relationship between depth of marker (seed) and ease of transcutaneous 
detection; 
o Marker (seed) depth to the nearest skin surface will be estimated 
sonographically 
o Ease of detection measured by ability to detect the marker (seed) with 
Sentimag detector and the time to detect marker (seed) in seconds 

	  
	  
	  
	  
	  
	  
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8.  
Source Data 
• 
Medical records; 
• 
Histopathology reports; 
• 
Specimen x-rays and mammograms; 
• 
CRF. 
All documents will be stored safely in confidential conditions.  On all study-specific 
documents, other than the signed consent, the participant will be referred to by the 
study participant number/code, not by name. 
9.  
Assessment of Safety  
9.1  
Specification, Timing and Recording of Safety Parameters.  
All Serious Adverse Events (SAEs) will be reported immediately to the Sponsor of 
the study. Refer to SOP 2a Safety Reporting for clinical trials conducted at UHSM. 
European Commission guidance on Medical Devices MEDDEV 2.7/3 Revision 3 May 
2015 will be used for reporting all Adverse Events under directives 90/385/EEC and 
93/42/EEC. 
Serious Adverse Events are defined as: 
• Adverse Event that: 
o Led to a death, 
o Led to a serious deterioration in health that either: 
• Resulted in a life-threatening illness or injury, or 
• Resulted in a permanent impairment of a body structure or a 
body function, or 
• Required in-patient hospitalization or  
• Prolongation of existing hospitalization,  
• Or resulted in medical or surgical intervention to prevent life 
threatening illness or injury or permanent impairment to a body 
structure or a body function. 
o Led to foetal distress, foetal death or a congenital abnormality or birth 
defect 
NOTE 1: This includes device deficiencies that might have led to a serious adverse 
event if a) suitable action had not been taken or b) intervention had not been made 

	  
	  
	  
	  
	  
	  
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or c) if circumstances had been less fortunate. These are handled under the SAE 
reporting system. 
NOTE 2: A planned hospitalization for pre-existing condition, or a procedure 
required by the Clinical Investigation Plan, without a serious deterioration in health, 
is not considered to be a serious adverse event. 
 
Device deficiency 
Inadequacy of an investigational medical device related to its identity, quality, 
durability, reliability, safety or performance. This may include malfunctions, use 
error, or inadequacy in the information supplied by the manufacturer. 
 
Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device. 
NOTE 1- This includes any adverse event resulting from insufficiencies or 
inadequacies in the instructions for use, the deployment, the implantation, the 
installation, the operation, or any malfunction of the investigational medical device. 
 
Serious Adverse Device Effect (SADE) 
 
Adverse device effect that has resulted in any of the consequences characteristic of 
a serious adverse event. 
 
Unanticipated Serious Adverse Device Effect (USADE) 
 
Serious adverse device effect which by its nature, incidence, severity or outcome 
has not been identified in the current version of the risk analysis report. 
NOTE: Anticipated SADE (ASADE): an effect which by its nature, incidence, severity 
or outcome has been previously identified in the risk analysis report 
 
REPORTABLE EVENTS UNDER ANNEX 7 AND ANNEX X OF DIRECTIVES 
90/385/EEC AND 93/42/EEC RESPECTIVELY 
 
For the purpose of this guidance and based on the definitions above, the following 
events are considered reportable events in accordance with Annex 7, section 2.3.5 
and Annex X, section 2.3.5 of the above mentioned Directives 5 : 
- any SAE, 
- any Device Deficiency that might have led to a SAE if: 
a) suitable action had not been taken or 
b) intervention had not been made or 
c) if circumstances had been less fortunate 
- new findings/updates in relation to already reported events. 

	  
	  
	  
	  
	  
	  
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All SAEs and SARs will be reported immediately to the Chief Investigator of the 
Study, Mr James Harvey, and the Research & Development Office. 
Adverse Events requiring reporting: 
• Migration of Sentimark magnetic marker (seed) >10mm from cancer location;  
• Haematoma following Sentimark placement surgical treatment;  
• Sentimark device not resected from breast during cancer surgery.  
 
9.2 Procedures for Recording and Reporting Adverse Events 
 
All Serious Adverse Events (SAEs) should be reported immediately to the Sponsor. 
The immediate reports should be followed promptly by detailed, written reports 
using the MEDDEV Summary Reporting Form. The immediate and follow-up reports 
should identify subjects by unique code numbers assigned to the trial subjects’ 
names, personal identification numbers, and/or addresses.   
 
9.2.1Reporting Timelines 
 
Report by sponsor to National Competent Authorities (NCA). 
 
The sponsor must report to the NCAs where the clinical investigation has 
commenced: 
• - for all reportable events as described which indicate an imminent risk of 
death, serious injury, or serious illness and that requires prompt remedial 
action for other patients/subjects, users or other persons or a new finding to 
it: immediately, but not later than 2 calendar days after awareness by 
sponsor of a new reportable event or of new information in relation with an 
already reported event. 
• - any other reportable events as described or a new finding/update to it: 
immediately, but not later than 7 calendar days following the date of 
awareness by the sponsor of the new reportable event or of new information 
in relation with an already reported event. 
• Any other reportable events as described or a new finding/update to the 
event: immediately, following the date the sponsor becomes aware of the 
new reportable event or of new information in relation with an already 
reported event. 
 
 
 

	  
	  
	  
	  
	  
	  
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9.2.2 Causality Assessment 
 
The relationship between the use of the medical device and the occurrence of each 
adverse event shall be assessed and categorized. During causality assessment 
activity, clinical judgement shall be used and the relevant documents, such as the 
Investigator’s Brochure, the Clinical Protocol or the risk Analysis Report shall be 
consulted, as all the foreseeable serious adverse events and the potential risks are 
listed and assessed there. The presence of confounding factors, such as 
concomitant medication/treatment, the natural history of the underlying disease, 
other concurrent illness or risk factors shall also be considered. 
The above considerations apply also to the serious adverse events occurring in the 
comparison group. 
For the purpose of harmonising reports, each SAE will be classified according to 
five different levels of causality. The sponsor and the investigators will use the 
following definitions to assess the relationship of the serious adverse event to the 
investigational medical device. 
 
1) Not related: relationship to the device or procedures can be excluded when: 
- the event is not a known side effect of the product category the device belongs to 
or of similar devices and procedures; 
- the event has no temporal relationship with the use of the investigational device or 
the procedures; 
- the serious event does not follow a known response pattern to the medical device 
(if the response pattern is previously known) and is biologically implausible; 
- the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the serious event; 
- the event involves a body-site or an organ not expected to be affected by the 
device or procedure; 
- the serious event can be attributed to another cause (e.g. an underlying or 
concurrent illness/ clinical condition, an effect of another device, drug, treatment or 
other risk factors); 
- the event does not depend on a false result given by the investigational 
device used for diagnosis 17, when applicable; 
- harms to the subject are not clearly due to use error; 
- In order to establish the non-relatedness, not all the criteria listed above might be 
met at the same time, depending on the type of device/procedures and the serious 
event. 
2) Unlikely: the relationship with the use of the device seems not relevant and/or the 
event can be reasonably explained by another cause, but additional information 
may be obtained. 

	  
	  
	  
	  
	  
	  
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3) Possible the relationship with the use of the investigational device is weak but 
cannot be ruled out completely. Alternative causes are also possible (e.g. an 
underlying or concurrent illness/ clinical condition or/and an effect of another 
device, drug or treatment). Cases were relatedness cannot be assessed or no 
information has been obtained should also be classified as possible. 
4) Probable the relationship with the use of the investigational device seems 
relevant and/or the event cannot reasonably explained by another cause, but 
additional information may be obtained. 
5) Causal relationship: the serious event is associated with the investigational 
device or with procedures beyond reasonable doubt when: 
- the event is a known side effect of the product category the device belongs to or 
of similar devices and procedures; 
- the event has a temporal relationship with investigational device use/application or 
procedures; 
- the event involves a body-site or organ that 
a) the investigational device or procedures are applied to; 
b) the investigational device or procedures have an effect on; 
- the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
- the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
- other possible causes (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled 
out; 
- harm to the subject is due to error in use; 
- the event depends on a false result given by the investigational device used for 
diagnosis, when applicable; 
- In order to establish the relatedness, not all the criteria listed above might be met 
at the same time, depending on the type of device/procedures and the serious 
event. The sponsor and the investigators will distinguish between the serious 
adverse events related to the investigational device and those related to the 
procedures (any procedure specific to the clinical investigation). An adverse event 
can be related both to procedures and the investigational device. Complications of 
procedures are considered not related if the said procedures would have been 
applied to the patients also in the absence of investigational device use/application. 
In some particular cases the event may be not adequately assessed because 
information is insufficient or contradictory and/or the data cannot be verified or 
supplemented. The sponsor and the Investigators will make the maximum effort to 
define and categorize the event and avoid these situations. Where the sponsor 

	  
	  
	  
	  
	  
	  
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remains uncertain about classifying the serious event, it should not exclude the 
relatedness and classify the event as “possible”. 
Particular attention shall be given to the causality evaluation of unanticipated 
serious adverse (device) events. The occurrence of unanticipated events related to 
the use of the device (USADE) could suggest that the clinical investigation places 
subjects at increased risk of harm than was to be expected beforehand. 
 
9.2.3 Reporting Form 
 
The reporting form template for the summary SAE tabulation is given in the 
Appendix of this document. 
The table gives a cumulative overview of the reportable events per clinical 
investigation and will be updated and transmitted to participating NCAs each time a 
new reportable event or a new finding to an already reported event is to be 
reported. More detailed information has to be provided on request of an NCA, if so 
requested by using the individual reporting form. The sponsor shall identify the 
new/updated information in the status column of the tabular form featured in the 
Appendix as: 
a = added = new reportable event; 
m = modified = new finding/update to an already reported event; 
u = unchanged. 
Changes in a line should be highlighted in bold and/or colour in the respective 
column. 
The reporting form is study specific and covers only a given clinical investigation, 
defined by a distinct clinical investigation plan. English is the recommended 
language for the reporting form. The report should be sent by email in Excel to the 
participating NCAs, or an equivalent format which allows using the inserted filters. 
The reporting to MHRA shall use the form template for the summary SAE tabulation 
as given in the Appendix of MEDDEV 2.7.3 December 2010. 
Safety Oversight: 
The Trial Steering Committee will meet once all patients have completed the study 
or earlier if considered necessary by the Chief Investigator. They will consider all 
Serious adverse events and adverse events and the main safety and efficacy 
outcomes. Notably they will discuss:  
Morbidity and safety of seed placement – recording of any morbidity as a result of 
Study visit 1 or 2; 
Detectability of the seed in the breast. – measured at Study visits 1 and 2 using the 
hand-held magnetometer; 
Assessment of migration of the seed from time of deployment to time of surgery. 
Measured on difference in position of magnetic marker (seed) from the cancer 

	  
	  
	  
	  
	  
	  
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between Study Visits 1 and 2, and assessed on mammograms by a Consultant 
Radiologist.  
If any markers migrate a clinically significant distance, a qualitative assessment will 
be carried out to see if there is a possible relationship between clinical 
characteristics seen in patients and movement of the marker.  (e.g. Haematoma, 
placement of seed into fatty rather then soft tissue) 
Adverse tissue responses as assessed by gross pathology and histopathology. 
9.2.4 Adverse Events that do not require reporting  
n/a 
9.3 Urgent safety measures (USMs) 
For any safety issues during the study, refer to SOP 2d Urgent Safety Measures  
10.  
Statistics 
10.1 Sample Size 
This protocol has been developed with Julie Morris Medical Statistician at 
Manchester University.   
The sample size has been set at 25 patients to achieve a balance between having 
sufficient numbers to observe any unexpected patterns of seed migration and 
keeping to a minimum the number of patients exposed to any risk through 
participating in the study as no direct benefit is to be expected for participants who 
consent to taking part in the trial. 
RSL seeds are a product similar in size and shape to Sentimark, in widespread 
clinical use in the same indication, and considered to be safe and effective. In the 
literature Alderliestenxiii, et al. [2011] report a mean migration of 0.8mm, range 0 to 
2.8mm (N=10) for RSL seeds which was considered “clinically negligible” by the 
authors.  
Migration of Sentimark in preclinical studies where the seed is deployed in soft 
mammary tissue showed a mean migration of 0.95mm, range 0 to 3.6mm (N=10) 
and no abnormal tissue reaction. Migration observed is substantially similar to that 
reported by Alderliesten et al for RSL seeds.  
From the experience with RSLs, clinically significant migration of radioseeds 
(greater than 1cm) in larger studies has been reported in 3/456 placements (Grayxiv 
et al [2004], Sungxv et al [2013]). However when it does occur the reason is often 
either a pre-existing or newly formed haematoma or placement of the seed into fatty 
rather than soft tissue.   

	  
	  
	  
	  
	  
	  
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For this reason, clinical characteristics of patients in whom a seed migrates more 
than 1cm will be carefully evaluated. 
Formally, the 95% CI if 0 out of 25 seeds migrate >10mm is 0-13%. However, 
findings will be considered in conjunction with other observations including: 
• The observed distribution of migration (e.g. how variable is this distribution 
and how close does it lie to the limits) 
• For any seeds migrating >10mm, a qualitative assessment of underlying 
characteristics such as haematoma or placement into fatty tissue (both 
reported as causes of migration in RSL procedures) 
• Abnormal tissue responses will be assessed by gross pathology and 
histology, as part of the safety endpoint. 
10.2  Randomisation 
No randomisation is required. 
10.3 Analysis 
Simple descriptive summary statistics of the main parameters will be derived 
together with a graphical presentation of the raw data. Percentages for categorical 
variables, means, standard deviations, medians and range values for quantitative 
factors will be calculated as appropriate. 95% confidence intervals will also be 
presented to provide a measure of accuracy for the estimates. 
The relationship between breast size and detectability of the seed by the 
magnetometer will be assessed using simple correlational analysis. 
The statistical software package, SPSS version 22, will be used for the statistical 
analysis. 
Sources of measurement error will be graphically displayed, reviewed and 
discussed as appropriate. 

	  
	  
	  
	  
	  
	  
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11. 
Trial Steering Committee  
The Trial Steering Committee will consist of; 
• 
Lay member who has already been involved in design of the study and of the 
Patient Information Leaflet. 
• 
Chief Investigator and co-investigators – Mr J. Harvey, Dr Y. Lim, Dr A. 
Maxwell, Mr J. Murphy. 
• 
Independent Chairman. 
• 
Statistician – Julie Morris. 
• 
Endomag - Scientific Representative. 
 
The function of the committee is to ensure ongoing safety of the study to patients 
and to monitor ongoing efficacy of the device. The committee will convene after all 
patients have completed the study (or earlier at the request of the Chief Investigator) 
to review the primary end-point, discuss the safety of the Study, to perform the 
qualitative assessment of clinical characteristics for seeds migrating more than 
10mm and to evaluate the overall feasibility and safety of the device based on the 
end-points recorded. 
12. 
Direct Access to Source Data and Documents 
The Investigator(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspections by providing the Sponsor(s), Regulators and REC direct 
access to source data and other documents (e.g. patients’ case sheets, X-ray 
reports, histology reports etc.). 
13. 
Ethics and Regulatory Approvals 
The trial will be conducted in compliance with the principles of the Declaration of 
Helsinki (specifying which amendment), the principles of GCP and all of the 
applicable regulatory requirements. The study protocol and other documentation 
will be submitted to the REC. Any subsequent protocol amendments will be 
submitted to the REC and Regulatory Authorities for approval, and will comply with 
regulations. 
The protocol will be submitted for MHRA approval and assessment as part of CE 
marking process for the Sentimark device. Results of the study will form part of the 
CE marking application to Endomag’s notified body for the Sentimark device. 
The Chief Investigator will submit a final report at conclusion of the trial to the 
Sponsor and the REC within the timelines defined in the Regulations. 

	  
	  
	  
	  
	  
	  
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14. 
Quality Control 
Monitoring of this trial will be to ensure compliance with Good Clinical Practice and 
scientific integrity will be managed and oversight retained, by Mr James Harvey and 
the Trial Steering Committee, as per the study monitoring plan. Data will be 
evaluated for compliance with the protocol and accuracy in relation to source 
documents. Following written standard operating procedures, the monitors will 
verify that the clinical trial is conducted and data are generated, documented and 
reported in compliance with the protocol, GCP and the applicable regulatory 
requirements.  
There is a requirement for the maintenance of an updated training record for each 
member of the research team and retention of GCP training certificates which must 
be less than 2 years old. 
15. 
Data Handling and Management 
The Chief Investigator will act as custodian for the trial data. The following 
guidelines will be strictly adhered to: 
• 
Patient data will be anonymised.  
• 
All anonymised data will be stored on a password protected computer; 
• 
All trial data will be stored in line with the Medicines for Human Use (Clinical 
Trials).  
Amended Regulations 2006 and the Data Protection Act and archived in line with 
the Medicines for Human Use (Clinical Trials) Amended Regulations 2006 as defined 
in the Kings Health Partners Clinical Trials Office Archiving SOP. 
 
Data Management 
Given the small number of patients within the study a paper CRF will be maintained 
for all Study Patients. 
16. 
Publication Policy  
It is intended that the results of the study will be reported and disseminated at 
international conferences and in peer-reviewed scientific journals. 
17. 
Insurance / Indemnity  
NHS indemnity will cover the Indemnity for the study. The provider of the Sentimark 
device has indemnity to cover use of the Sentimark device. 
18. 
Financial Aspects  
Funding to conduct the trial is provided by Endomagnetics Ltd, The Jeffreys 
Building, St John’s Innovation Park, Cowley Road, Cambridge, CB4 0WS. 

	  
	  
	  
	  
	  
	  
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References 
 
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
i Sharek D, Zuley ML, Zhang JY, Soran A, Ahrendt GM, Ganott MA. Radioactive 
seed localisation versus wire localisation for lumpectomies: a comparison of 
outcomes. AJR AM J Roentgenol. 2015 Apr;204(4):872-7	  
ii Murphy JO, Moo T-A, King T a, Van Zee KJ, Villegas K a, Stempel M, et al. 
Radioactive seed localization compared to wire localization in breast-conserving 
surgery: initial 6-month experience. Ann Surg Oncol [Internet]. 2013;20(13):4121–7. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/23943024	  
iii Kaul D, Fallenberg E, Diekmann F, Budach V, Maurer M. Dislocability of 
localization devices for nonpalpable breast lesions: experimental results. Radiol Res 
Pract [Internet]. 2014;2014:425823. Available from: 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3964887&tool=pmcentr
ez&rendertype=abstract	  
iv Banitalebi H, Skaane P. Migration of the breast biopsy localization wire to the 
pulmonary hilus. Acta radiologica. 2005. p. 28–31.	  
v Gray RJ, Salud C, Nguyen K, Dauway E, Friedland J, Berman C, et al. Randomized 
prospective evaluation of a novel technique for biopsy or lumpectomy of 
nonpalpable breast lesions: radioactive seed versus wire localization. Annals of 
surgical oncology. 2001.  	  
vi Hughes JH, Mason MC, Gray RJ, McLaughlin SA, Degnim AC, Fulmer JT, et al. A 
multi-site validation trial of radioactive seed localization as an alternative to wire 
localization. Breast J. 2008;14(2):153–7.	  
vii Ocal K, Dag A, Turkmenoglu O, Gunay EC, Yucel E, Duce MN. Radioguided 
occult lesion localisation versus wire-guided localisation for non-palpable breast 
lesions: Randomized controlled trial. Clinics. 2011;66:1003–7.	  
viii Lovrics PJ, Goldsmith CH, Hodgson N, McCready D, Gohla G, Boylan C, et al. A 
Multicentered, Randomized, Controlled Trial Comparing Radioguided Seed 
Localization to Standard Wire Localization for Nonpalpable, Invasive and in situ 
Breast Carcinomas. Annals of Surgical Oncology. 2011. p. 3407–14. 	  
ix Dauer LT, Thornton C, Miodownik D, et al. Radio-active seed localization with I-
125 for nonpalpable lesions prior to breast lumpectomy and/or excisional biopsy: 
methodology, safety, and experience of initial year. Health Phys 2013: 105:356-365 	  
x Ahmed M, Anninga B, Goyal S, Young P, Pankhurst QA, Douek M, the MagSNOLL 
Trialists Group (2015). Magnetic sentinel node and occult lesion localization in 
breast cancer (MagSNOLL Trial). Br J Surg. 102: 646–652. doi: 10.1002/bjs.9800	  
xi Douek M, Klaase J, Monypenny I, Kothari A, Zechmeister K, Brown D, et al. 
Sentinel node biopsy using a magnetic tracer versus standard technique: the 
SentiMAG Multicentre Trial. Ann Surg Oncol [Internet]. 2014;21(4):1237–45. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/24322530	  
xii Thill M, Kurylcio A, Welter R, van Haasteren V, Grosse B, Berclaz G, et al. The 
Central-European SentiMag study: Sentinel lymph node biopsy with 
superparamagnetic iron oxide (SPIO) vs. radioisotope. Breast. 2014;23(2):175–9.	  
xiii T. Alderliesten et al., Radioactive Seed Localization of Breast Lesions: An 
Adequate Localization Method without Seed Migration, The Breast Journal, (2011) 
Vol.17 No.6, 594-601	  

	  
	  
	  
	  
	  
	  
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xiv R.J. Gray et al., Radioactive seed localization of nonpalpable breast lesions is 
better than wire localization The American Journal of Surgery, (2004), 188, 377-380	  
xv J.S. Sung et al., Safety and efficacy of radioactive seed localization with I-125 
prior to lumpectomy and/or excisional biopsy European J. of Radiology, (2013) 82, 
1453-1457