Clinical trial NCT02445456
Conditions: Rectal Cancer
Keywords: Rectal cancer Sentinel Lymph Node Biopsy
Sponsor: Oxford University Hospitals NHS Trust
Start date: 2016-12-01; Completion date: 2020-12-01
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess whether the Sienna+/Sentimag system, which involves a magnetic tracer, is effective in identifying the sentinel lymph node in rectal cancer and whether it is then feasible to remove this lymph node during surgery to locally excise early rectal cancer.

Detailed description:
One issue in managing rectal cancer is identifying which patients will benefit from less radical surgery, which is much safer and better tolerated. However it does not remove lymph nodes where cancer cells may have spread. If lymph nodes containing cancer are left behind, the cancer may recur. So this surgery is only suitable in early rectal cancers not involving lymph nodes. Unfortunately, current investigations do not always accurately identify involved lymph nodes.

Sentinel lymph node biopsy (SLNB) is a technique to surgically remove the first lymph node where cancer cells spread. If this lymph node contains cancer, radical surgery is needed to reduce the risk of recurrence. However if it is clear, less radical surgery should be sufficient. This is standard practice for breast cancer and avoids unnecessary major surgery in many patients.

The investigators aim to assess whether SLNB is useful in rectal cancer. The investigators will determine whether the Sienna+/Sentimag system effectively identifies the sentinel lymph node, and whether the node can then be removed surgically.

The investigators will recruit patients in Oxford hospitals about to undergo surgery for rectal cancer. Patients will receive an injection of magnetic tracer during endoscopy prior to surgery. Some patients will have an extra MRI scan. During or after surgery, depending on the type of operation planned, a magnetic probe will be used to locate the sentinel lymph node in the tissue around the rectum. The removed specimen will be examined by a pathologist. Funding to undertake this study has been granted by the National Institute for Health Research (NIHR). Endomagnetics, the manufacturer, will supply the magnetic tracer and probe for use in this study.

If successful, the investigators will plan a larger clinical trial. This could have a major impact on improving outcomes for patients by allowing less radical surgery to be used where it is most appropriate.

Arms: arm 1: Patients with relatively advanced rectal cancer who are scheduled to undergo radical surgery to excise rectal tumour and mesorectum. They will receive endoscopic Sienna+ injection (magnetic tracer) 5 days before planned surgery. They will then undergo surgery to excise rectal cancer. The excised specimen will be examined using the Sentimag probe and by standard histology to assess for lymph nodes ex-vivo. arm 2: Patients with early rectal cancer scheduled to undergo local excision of a rectal tumour by transanal endoscopic microsurgery (TEM). They will receive endoscopic Sienna+ injection (magnetic tracer) 5 days before planned surgery, and have an MRI scan to assess tracer spread. They will then undergo TEM surgery to excise the rectal cancer. During surgery the Sentimag probe will be used to locate the sentinel lymph node so it can be surgically removed. The excised specimen will be examined by standard histology.
Interventions: intervention 1: Sienna+ injection intervention 2: MRI scan intervention 3: Surgery to excise rectal cancer intervention 4: Sentimag probe
Intervention descriptions: intervention 1: Endoscopic injection of magnetic tracer intervention 2: MRI scan of pelvis to detect spread of magnetic tracer intervention 3: Surgery as scheduled according to size and stage of rectal cancer. This will be either radical surgery or transanal endoscopic microsurgery (TEM) intervention 4: Probe to detect the previously injected magnetic tracer (Sienna+)

Protocol documents:
Prot_SAP_000.pdf: 
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Trial Title:  Feasibility of sentinel lymph node biopsy in rectal cancer 
Internal Reference Number / Short title:  SentiRect 
Ethics Ref: 15/SC/0317 
NCT number: NCT02445456 
Date and Version No: 15 March 2019, Version 1.3 
 
Chief Investigator: 
Chris Cunningham, Oxford University Hospitals NHS trust 
Investigators:  
Helen Jones, Oxford University Hospitals NHS trust 
Lai Mun Wang, Oxford University Hospitals NHS trust 
Mark Anderson, Oxford University Hospitals NHS trust  
Shazad Ashraf, University Hospitals Birmingham NHS trust 
 
Sponsor:  
Oxford University Hospitals NHS Foundation Trust 
 
Funder:  
Impact Acceleration Award Funding, NIHR Colorectal Therapies 
Healthcare Technology Cooperative, Leeds.  
Funding for research consumables from Endomagnetics, Cambridge.  
 
Chief Investigator Signature:  
 
The investigators declare no potential conflicts of interest. 
 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, host organisation, and members of the Research Ethics Committee, 
unless authorised to do so. 
 
 


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TABLE OF CONTENTS 
 
1. 
KEY TRIAL CONTACTS ..................................................................................................................... 3 
2. 
SYNOPSIS ....................................................................................................................................... 4 
3. 
ABBREVIATIONS ............................................................................................................................. 5 
4. 
BACKGROUND AND RATIONALE .................................................................................................... 7 
5. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS .................................................................. 8 
6. 
TRIAL DESIGN ................................................................................................................................. 9 
7. 
PARTICIPANT IDENTIFICATION ...................................................................................................... 9 
7.1. 
Trial Participants .......................................................................................................................... 10 
7.2. 
Inclusion Criteria .......................................................................................................................... 10 
7.3. 
Exclusion Criteria ......................................................................................................................... 10 
8. 
TRIAL PROCEDURES ..................................................................................................................... 10 
8.1. 
Recruitment ................................................................................................................................. 11 
8.2. 
Informed Consent ........................................................................................................................ 12 
8.3. 
Screening and Eligibility Assessment ........................................................................................... 12 
8.4. 
Randomisation, blinding and code-breaking ............................................................................... 12 
8.5. 
Baseline Assessments .................................................................................................................. 12 
8.6. 
Subsequent Visits ........................................................................................................................ 12 
8.7. 
Discontinuation/Withdrawal of Participants from Trial Treatment ............................................ 13 
8.8. 
Definition of End of Trial ............................................................................................................. 13 
9. 
IDENTIFICATION & DESCRIPTION OF THE INVESTIGATIONAL DEVICE ......................................... 14 
9.1. 
Device description ....................................................................................................................... 14 
9.2. 
Device Safety ............................................................................................................................... 14 
9.3. 
Device Accountability .................................................................................................................. 14 
10. 
NON-INVESTIGATIONAL MEDICINAL PRODUCT (NIMP) .............................................................. 14 
10.1. 
NIMP Description..................................................................................................................... 14 
11. 
SAFETY REPORTING ..................................................................................................................... 15 
11.1. 
Definitions ............................................................................................................................... 15 
11.2. 
Causality .................................................................................................................................. 16 
11.3. 
Procedures for Recording Adverse Events .............................................................................. 17 
11.4. 
Reporting Procedures for Serious Adverse Events .................................................................. 17 
11.5. 
Expectedness ........................................................................................................................... 18 
11.6. 
Safety Monitoring Committee ................................................................................................. 18 


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12. 
STATISTICS ................................................................................................................................... 18 
12.1. 
Description of Statistical Methods .......................................................................................... 18 
12.2. 
The Number of Participants .................................................................................................... 19 
12.3. 
The Level of Statistical Significance ......................................................................................... 19 
12.4. 
Criteria for the Termination of the Trial .................................................................................. 19 
12.5. 
Procedure for Accounting for Missing, Unused, and Spurious Data. ...................................... 19 
12.6. 
Inclusion in Analysis ................................................................................................................. 19 
12.7. 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan ........................ 20 
13. 
DATA MANAGEMENT .................................................................................................................. 20 
13.1. 
Source Data ............................................................................................................................. 20 
13.2. 
Access to Data ......................................................................................................................... 20 
13.3. 
Data Recording and Record Keeping ....................................................................................... 20 
14. 
QUALITY ASSURANCE PROCEDURES ........................................................................................... 21 
15. 
SERIOUS BREACHES ..................................................................................................................... 21 
16. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................................................... 21 
16.1. 
Declaration of Helsinki............................................................................................................. 21 
16.2. 
ICH Guidelines for Good Clinical Practice ................................................................................ 21 
16.3. 
Medical Device regulations ..................................................................................................... 21 
16.4. 
Approvals ................................................................................................................................. 22 
16.5. 
Reporting ................................................................................................................................. 22 
16.6. 
Participant Confidentiality ....................................................................................................... 22 
16.7. 
Expenses and Benefits ............................................................................................................. 22 
16.8. 
Other Ethical Considerations ................................................................................................... 22 
17. 
FINANCE AND INSURANCE .......................................................................................................... 22 
17.1. 
Funding .................................................................................................................................... 22 
17.2. 
Insurance ................................................................................................................................. 22 
18. 
PUBLICATION POLICY ................................................................................................................... 23 
19. 
REFERENCES ................................................................................................................................ 23 
20. 
APPENDIX A:  TRIAL FLOW CHART ............................................................................................... 24 
21. 
APPENDIX B:  SCHEDULE OF PROCEDURES ................................................................................. 25 
22. 
APPENDIX C:  AMENDMENT HISTORY ......................................................................................... 26 
 
1. KEY TRIAL CONTACTS 


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Chief Investigator 
Chris Cunningham 
Oxford University Hospitals NHS Foundation Trust 
Department of Colorectal Surgery 
Churchill Hospital 
Old Road 
Headington 
Oxford OX3 7LE 
Tel: 01865 235657 
Email:   chriscunningham@nhs.net  
Fax: 01865 235857 
 
Sponsor 
Ms Heather House 
R&D Lead 
Research and Development Department 
Joint Research Office 
Block 60, Churchill Hospital 
Headington 
Oxford OX3 7LE 
E-mail: ouh.sponsorship@ouh.nhs.uk  
Fax: 01865 572242 
 
2. SYNOPSIS 
Trial Title 
Feasibility study of sentinel lymph node mapping in rectal cancer 
Internal ref. no. (or 
short title) 
SentiRect Study 
Trial Design 
Feasibility: proof of principle 
Trial Participants 
Rectal cancer patients 
Planned Sample Size 
40 patients 
Treatment duration 
Single pre-operative administration 
Follow up duration 
2-3 weeks 
Planned Trial Period 
12 months 
 
Objectives 
Outcome Measures/Endpoints 
Primary 
 
Establish feasibility of identifying 
sentinel lymph node in rectal 
cancer:  
[A] Adverse or hypersensitivity 
reactions after Sienna+ tracer 
injection in rectal cancer patients.  
[B] Establish whether tracer is still 
present and detectable at the 
tumour injection site and in the 
lymph nodes at the time of surgery. 
[C] Determine the impact of 
Sienna+ injection on subsequent 
 
 
 
 
[A] Frequency of adverse or 
hypersensitivity reaction. 
 
[B] Frequency of tracer being 
detectable at the tumour injection 
site and in the lymph nodes at the 
time of surgery. 
[C] Surgeon’s assessment of any 
difficulties 
encountered 


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surgery (e.g. any difficulties due to 
discolouration or inflammation of 
tissue planes) 
attributable 
to 
prior 
Sienna+ 
injection. 
Secondary 
 
[A] 
Correlate 
histopathology 
findings with tracer uptake in the 
lymph nodes. 
 
[B] Radiologically evaluate the 
drainage pattern of Sienna+ tracer 
using a high resolution MRI, to 
establish a baseline for individual 
variation.   
EX-VIVO part of study:  
[C] Measure the distribution and 
spread of the Sienna+ tracer using 
the SentiMag hand-held probe in 
mesorectal specimen after rectal 
cancer surgery (in the pathology 
department). This is to establish a 
baseline in individual variation 
between specimens. 
[D] Assess the accuracy of the 
SentiMag hand-held probe/Sienna+ 
tracer in identifying "sentinel" 
lymph 
nodes. 
This 
will 
be 
determined in conjunction with a 
pathologist who will systematically 
identify 
lymph 
nodes 
in 
the 
standard manner. The level of 
tracer activity in each lymph node 
will be measured and correlated 
with position and tumour cell 
involvement.   
IN-VIVO part of study:  
 [E] Establish feasibility of sentinel 
lymph node biopsy during localised 
surgery for early rectal cancer using 
SentiMag 
hand-held 
probe 
to 
identify "peaks" of tracer activity 
intro-operatively. 
[A] 
Correlation 
between 
histopathology findings and tracer 
uptake (determined by Sentimag 
probe) in the lymph nodes. 
[B] High-resolution MRI mapping 
of the drainage pattern of Sienna+ 
tracer.  
 
 
EX-VIVO part of the study:  
[C] Mapping of the distribution of 
Sienna+ tracer in the mesorectal 
specimen 
using 
the 
SentiMag 
hand-held 
probe 
after 
rectal 
cancer surgery.  
 
 
[D] Accuracy of the SentiMag 
hand-held probe/Sienna+ tracer in 
identifying "sentinel" lymph nodes, 
determined by correlation with 
histopathology findings. 
 
 
 
 
 
 
 
 
IN-VIVO part of study:  
 
[E] Number of TEM operations 
where the "sentinel" lymph node 
could be identified during surgery 
using the Sentimag probe, and 
then successfully removed. 
Device name 
Magtrace® tracer and SentiMag® magnetometer 
Device Manufacturer 
Endomagnetics, Cambridge 
Device Classification 
Class IIa device 
 
3. ABBREVIATIONS 
AE 
Adverse event 
AR  
Adverse reaction 


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CI 
Chief Investigator 
CRA 
Clinical Research Associate (Monitor) 
CRF 
Case Report Form 
CRO  
Contract Research Organisation 
CT 
Clinical Trials 
CTRG 
Clinical Trials and Research Governance 
DMC/DMSC 
Data Monitoring Committee / Data Monitoring and Safety Committee 
ERC 
Early rectal cancer 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
IB 
Investigators Brochure 
ICF 
Informed Consent Form 
ICG 
Indocyanine green 
ICH 
International Conference of Harmonisation 
IMP 
Investigational Medicinal Product 
IRB 
Independent Review Board 
MDT 
Multi-disciplinary team 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NHS 
National Health Service 
NIR 
Near infrared 
NRES 
National Research Ethics Service  
OXTREC 
Oxford Tropical Research Ethics Committee 
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 
SDV 
Source Data Verification 
SNLB 
Sentinel lymph node biopsy 
SOP 
Standard Operating Procedure 
SPIO 
Superparamagnetic iron oxide particles 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEM 
Transanal endoscopic microsurgery 


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TME 
Total mesorectal excision 
TMF 
Trial Master File 
TSG 
Oxford University Hospitals Trust / University of Oxford Trials Safety Group 
 
4. BACKGROUND AND RATIONALE 
The scientific rationale mainly comes from studies involving sentinel lymph node biopsy (SLNB) in breast 
cancer (Krag et al, 2010). No difference was seen in overall survival or disease free survival when women 
had SLNB compared to women who had SLNB and axillary node dissection (AND) in women with disease 
negative sentinel nodes. A further study in breast cancer patients with positive SLNB but no clinical 
evidence of lymph node involvement demonstrated that there was no difference in outcome when 
comparing those who had no further axillary surgery versus those who had subsequent completion 
axillary lymph node dissection (Giuliano et al, 2011). In both studies, a high proportion of patients were 
treated with adjuvant systemic chemotherapy and external beam radiation. These data strongly support 
the need for further research into the role of organ-preservation surgery in other cancer types.    
Sentinel node interrogation has yet to be fully evaluated in rectal cancer surgery due to technical 
limitations of obtaining SLNB from the mesorectum. As for breast cancer, rectal cancers can be excised 
by either radical or organ-preservation surgical techniques. Decision for either method is currently based 
on the risk of local recurrence or presence of lymph node metastasis. Radical surgery involves removal of 
the whole of the mesorectum and is associated with significantly worse functional outcome, morbidity 
and mortality. Current guidelines recommend that full thickness removal of the rectal tumour by 
transanal endoscopic microsurgery, TEM, is appropriate for small T1N0 cancers (less than 3 cm) where 
the risk of local recurrence (LR) is relatively low (NCCN guidelines, 2014). This surgery avoids removal of 
the whole mesorectum. The risk of LR increases with the depth of penetration of the rectal wall.  Results 
from the UK TEM database show that the risk of LR at 36 months trebles when comparing T1N0 to T2N0 
cancers of the same diameter (4.4% versus 14.3% respectively) (Bach et al, 2009). However, in 85% of 
rectal cancers that are T2N0 (based on tumours that are 2.1-3 cm diameter, with no lymphatic invasion) 
there is no LR at 36 months. There is a risk of subjecting patients to over-treatment in terms of surgery 
resulting in a significant risk of morbidity, mortality and impaired quality of life. On the other hand 
under-treatment of some “high risk” cancers would lead to recurrence. SLNB at TEM would potentially 
allow clinicians to excise T2 cancers in order to further stratify cancers based on future risk. This would 
avoid surgical over-treatment and under-treatment. 
Our research objective will be to assess the feasibility of using a magnetic non-radioactive iron-based 
tracer (Sienna+ or Magtrace) and a handheld magnetometer (SentiMag) to accurately define the position 
of sentinel lymph nodes in patients with operable rectal cancer.  This technology has already been 
successfully used in breast cancer patients in a UK multi-centre trial (Thill et al, 2014). The tracer is non-
radioactive and safe (there is an extremely low risk of a hypersensitivity reaction to iron-based 
compounds, magnetic tracer and superparamagnetic iron oxide (SPIOs)). Our research will be done in 
two stages. The first “ex-vivo” stage will involve mapping tracer activity in total mesorectal specimens 
from rectal cancer patients. These will be focused on patients with rectal cancers where standard radical 
surgery is recommended. In this group we will also inject indocyanine green dye (ICG) into the tumour 
during surgery to act as an adjunct to identifying the lymph nodes while we develop confidence with the 
Sentimag system. ICG is a widely-used dye with many applications in medicine, including SLN 


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identification, and has been used with some positive early results in rectal cancer (Cahill et al, 2012). The 
second stage would then involve an “in-vivo” study in patients with early rectal cancers (ERCs) that are 
suitable for TEM. We would use SentiMag technology to assess the feasibility and safety of SNLB in 
patients with ERC by taking lymph nodes with "peaks" of tracer activity from the mesorectum. After 
completion of this study, our intention will be to perform a clinical trial based on SLNB in rectal cancer 
patients. 
 There are no major ethical or legal issues associated with this study as SLNB is established in breast 
cancer practice. Our research will help to further define suitability for either localised or radical surgery 
in early rectal cancer patients. 
5. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
Objectives 
Outcome Measures/Endpoints  
Primary Objectives 
Establish feasibility of identifying sentinel lymph 
node in rectal cancer:  
[A] Adverse or hypersensitivity reactions after 
tracer injection in rectal cancer patients.  
[B] Establish whether tracer is still present and 
detectable at the tumour injection site and in the 
lymph nodes at the time of surgery. 
[C] Determine the impact of tracer injection on 
subsequent surgery (e.g. any difficulties due to 
discolouration or inflammation of tissue planes 
 
 
[A] Frequency of adverse or hypersensitivity 
reaction. 
[B] Frequency of tracer being detectable at the 
tumour injection site and in the lymph nodes at 
the time of surgery. 
[C] Surgeon’s assessment of any difficulties 
encountered attributable to prior tracer injection 
Secondary Objectives 
 [A] Correlate histopathology findings with tracer 
uptake in the lymph nodes. 
[B] Radiologically evaluate the drainage pattern 
of tracer using a high resolution MRI, to establish 
a baseline for individual variation.   
EX-VIVO part of study:  
[C] Measure the distribution and spread of the 
tracer using the SentiMag hand-held probe in 
mesorectal specimen after rectal cancer surgery 
(in the pathology department). This is to 
establish a baseline in individual variation 
between specimens. 
[D] Assess the accuracy of the SentiMag hand-
held probe/ tracer in identifying "sentinel" lymph 
nodes. This will be determined in conjunction 
 
 [A] Correlation between histopathology findings 
and tracer uptake (determined by Sentimag 
probe) in the lymph nodes. 
[B] High-resolution MRI mapping of the drainage 
pattern of tracer.  
EX-VIVO part of the study:  
 
[C] Mapping of the distribution of tracer in the 
mesorectal specimen using the SentiMag hand-
held probe after rectal cancer surgery.  
 
 
[D] Accuracy of the SentiMag hand-held probe/ 
tracer in identifying "sentinel" lymph nodes, 
determined by correlation with histopathology 


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with a pathologist who will systematically 
identify lymph nodes in the standard manner. 
The level of tracer activity in each lymph node 
will be measured and correlated with position 
and tumour cell involvement.   
IN-VIVO part of study:  
 [E] Establish feasibility of sentinel lymph node 
biopsy during localised surgery for early rectal 
cancer using SentiMag hand-held probe to 
identify 
"peaks" 
of 
tracer 
activity 
intro-
operatively.  
findings. 
 
 
 
IN-VIVO part of study:  
[E] Number of TEM operations where the 
"sentinel" lymph node could be identified during 
surgery using the Sentimag probe, and then 
successfully removed. 
Tertiary Objectives 
Not applicable 
Not applicable 
 
6. TRIAL DESIGN 
This is a clinical study assessing the feasibility of detecting and sampling sentinel lymph nodes in rectal 
cancer patients using a magnetic nanoparticle tracer (Sienna+ or Magtrace, class IIa device, CE-approved 
in Europe). See Appendix A for a flow diagram of the study schema.  
The study will be conducted in two phases. The first (ex-vivo) phase will assess the feasibility of detecting 
sentinel lymph nodes using tracer/SentiMag probe in patients undergoing radical surgery for rectal 
cancer. The second (in-vivo) phase will assess the feasibility of removing sentinel lymph nodes identified 
using tracer/SentiMag probe in patients undergoing less radical surgery for early rectal cancer.  
Expected duration of patient participation is 2-3 weeks, from pre-operative tracer injection till discharge 
from hospital following rectal cancer surgery. Standard practice includes a pre-operative clinic visit for 
discussion, visit to the endoscopy unit for endoscopic assessment of the tumour pre-operatively and 
hospital admission for surgery. There will be one additional visit for an MRI scan. This will be performed 
on the same day as the endoscopy visit or on the day of surgery.  
Screening of patients and provision of information about the study will occur during the pre-operative 
clinic visit. Consent will be taken on visit to the endoscopy unit and Sienna+ tracer will be injected during 
endoscopy. The Sentimag probe will be used during surgery and for second phase participants the 
sentinel lymph node will be removed. Pathological assessment of the removed specimen will be carried 
out after surgery. Patients will be monitored on the colorectal ward post-operatively until discharge.   
During each stage data will initially be recorded in hard copy on CRF then transferred to a secure 
electronic record.  
7. PARTICIPANT IDENTIFICATION 


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7.1. Trial Participants 
Participants diagnosed with rectal cancers that are operable and have no symptoms of intestinal 
obstruction.  
7.2. Inclusion Criteria 
• 
Participant is willing and able to give informed consent (in English) for participation in the trial. 
• 
Male or Female, aged 18 years and below 90 years of age. 
• 
Diagnosed with operable rectal cancer. 
• 
Discussion of case at the Oxford Colorectal Cancer MDT. 
• 
For in-vivo phase: Early rectal cancer and absence of lymph node involvement on staging MRI 
scan. 
• 
In the Investigator’s opinion, is able and willing to comply with all trial requirements. 
7.3. Exclusion Criteria 
The participant may not enter the trial if ANY of the following apply: 
• 
Female participant who is pregnant or lactating. 
• 
Known intolerance or hypersensitivity to iron or dextran compounds, magnetic tracers, or SPIOs. 
• 
For ex-vivo phase for ICG injection: known intolerance of iodine 
• 
For in-vivo phase: advanced rectal cancer or radiological nodal involvement on staging MRI scan 
• 
Cancer involvement of anal sphincter complex on clinical, radiological or endoscopic assessment. 
• 
Age less than 18 and greater than 90. 
• 
Adults who are not able to give consent or who are deemed vulnerable. 
 
8. TRIAL PROCEDURES 
Methodology training for investigators: At the start of the study, the principal investigators will undergo 
methodology training and practice the use of the hand held SentiMag probe device.  The chief 
investigator will standardize the sentinel lymph node biopsy technique during this feasibility study. 
Screening and preliminary discussion of research project with potential participant: During the standard 
pre-operative clinic visit patients who have been identified as potential participants will be screened and 
informed about the study by a clinician or colorectal specialist nurse. They will have an opportunity to 
ask questions and will be provided with an information sheet. 
Informed consent: In the endoscopy unit a clinician will discuss the study further and take consent if the 
patient is willing to proceed. A letter will be sent to the participant’s GP informing them of the study. 
Endoscopic injection of tracer and post-injection monitoring: The magnetic tracer will be injected 
approximately 5 days before surgery during endoscopic assessment of the tumour. The rectal tumour 


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will be visualized by endoscopy, as per standard clinical practice. Up to 2ml tracer solution will be 
infiltrated systematically (in 4 quadrants) into the submucosa around the rectal tumour. After the 
procedure, patients will be monitored for 1 hour to ensure no hypersensitivity or adverse reactions occur 
and provided with a contact telephone number in case of any delayed reaction or side-effects on 
discharge.  
MRI scan of pelvis: On the same day as the endoscopy unit visit or the day of surgery, patients will 
undergo an MRI scan of the pelvis. This will be done 2-3 hours after the endoscopic injection of tracer or 
on the day of surgery. 
Rectal cancer surgery: Patients will undergo rectal cancer surgery according to their clinical indication. 
During surgery for the “ex-vivo” group, indocyanine green dye (ICG) will be injected near the tumour. At 
the conclusion of surgery the surgeon will make an assessment as to whether the tracer injection 
affected surgery, for example by causing inflammation in the tissue planes. 
Intra-operative detection of the sentinel lymph node using the Sentimag probe and excision of the 
identified node (second part participants only): During rectal cancer surgery, following excision of the 
tumour, the surgeon will use the hand held SentiMag probe to identify the sentinel lymph node. This will 
then be dissected and removed for subsequent histological analysis.  
Post-operative monitoring: Following surgery patients will be admitted to the colorectal ward for routine 
post-operative care. During this time they will be monitored and any adverse reactions or post-operative 
complications will be recorded. The patients’ participation in the study will cease when they are 
discharged from hospital.  
Ex-vivo detection of the sentinel lymph node in the surgical specimen using the Sentimag probe (first part 
only): The Sentimag probe will be used to measure the distribution of the tracer and to identify the 
sentinel lymph node in the specimen removed during the standard surgical procedure. A Near InfraRed 
(NIR) imaging system will also be used to assess the specimen to detect the distribution of ICG as an 
adjunct to identifying lymph nodes.   
Ex-vivo histological assessment of the surgical specimen: A colorectal pathologist will examine the tissue 
removed during surgery to identify all the lymph nodes present and whether or not they contain 
metastatic cancer deposits, according to standard practice. At the conclusion of the study the samples 
will be held in the cellular pathology department, in line with standard practice for diagnostic surgical 
specimens. 
8.1. Recruitment 
The identification of patients suitable for this study will take place at colorectal cancer multi-disciplinary 
meetings. This will involve reviewing the clinical, histological and radiological investigations with other 
surgeons, oncologists, radiologists and pathologists as part of the normal clinical review process. The 
principal investigators, who are part of the standard clinical care team for rectal cancer patients, are 
routinely present at this meeting.  
Identified potential participants will then be approached by the principal investigator during their routine 
pre-operative clinic visit, and screening will be performed at this time using a checklist. They will be 


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provided with an information sheet and given time to ask questions. Patients agreeing to participate will 
be recruited on their subsequent pre-operative visit to the endoscopy unit.  
8.2. Informed Consent 
The participant must personally sign and date the latest approved version of the Informed Consent form 
before any trial specific procedures are performed.  
Written and verbal versions of the Participant Information and Informed Consent will be presented to 
the participants detailing no less than: the exact nature of the trial; what it will involve for the 
participant; the implications and constraints of the protocol; the known side effects and any risks 
involved in taking part. It will be clearly stated that the participant is free to withdraw from the trial at 
any time for any reason without prejudice to future care, and with no obligation to give the reason for 
withdrawal. 
The participant will be allowed as much time as wished to consider the information, and the opportunity 
to question the Investigator, their GP or other independent parties to decide whether they will 
participate in the trial. Written Informed Consent will then be obtained by means of participant dated 
signature and dated signature of the person who presented and obtained the Informed Consent. The 
person who obtained the consent must be suitably qualified and experienced, and have been authorised 
to do so by the Chief/Principal Investigator. A copy of the signed Informed Consent will be given to the 
participant and a copy will go into the patient’s medical notes. The original signed form will be retained 
at the trial site. 
8.3. Screening and Eligibility Assessment 
Not applicable. Participation will be sought from patients that are diagnosed with rectal cancer and are 
discussed at the Colorectal MDT meeting. A simple checklist of inclusion and exclusion criteria will be 
used to screen the patients during their pre-operative clinic visit.  
8.4. Randomisation, blinding and code-breaking 
Not applicable  
8.5. Baseline Assessments 
Confirmation of operable rectal cancer at the Oxford Colorectal MDT discussion.  
8.6. Subsequent Visits 
[Visit 1: clinic] Potential participants will be informed about the study by the study investigators or the 
colorectal nurse specialists at their initial hospital clinic visit with the operating surgeon. This is part of 
the clinical work-up of a patient and therefore would not involve an additional visit for the participant. 
This visit will take place approximately 2-3 weeks prior to surgery. Information will only be given to 
patients who are already aware of their diagnosis. Patient information sheets will be given to the patient 
at this stage. Patients will be screened using the inclusion and exclusion checklist.  


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[Visit 2: endoscopy suite] Surgeons assess rectal cancers by endoscopic means in order to plan surgery. 
This is part of normal practice and will not involve an additional visit for the potential participant. This 
usually occurs a week before surgery. Informed consent will be obtained from participants at this stage. 
During the endoscopic procedure the tracer will be injected around the rectal tumour. Patients will be 
monitored for 1 hour following this for any adverse effect of the injection.  
[Visit 3: Radiology suite] Patients will have an MRI scan to assess tracer uptake into the mesorectum. This 
is not part of the standard routine care and will involve an additional hospital visit for the patient. This 
will be undertaken 2-3 hours after the endoscopic injection, on the same day as the endoscopy visit or 
prior to surgery on the day of surgery.   
[Visit 4: Admission to hospital for surgery]: This is part of normal practice and will not involve an 
additional visit for the potential participant. Sentinel node sampling will take place after surgery from the 
resected specimen (“ex-vivo” phase) or during surgery (“in-vivo” phase). Participants will be monitored 
during their post-operative stay in hospital as part of normal practice. The incidence of post-operative 
complications will be recorded on discharge. 
8.7. Discontinuation/Withdrawal of Participants from Trial Treatment 
Each participant has the right to withdraw from the trial at any time.  In addition, the Investigator may 
discontinue a participant from the trial at any time if the Investigator considers it necessary for any 
reason including: 
• 
Pregnancy 
• 
Ineligibility (either arising during the trial or retrospectively having been overlooked at screening) 
• 
Significant protocol deviation 
• 
Significant non-compliance with treatment regimen or trial requirements 
• 
An adverse event which requires discontinuation of the device or results in inability to continue 
to comply with trial procedures 
• 
Withdrawal of Consent 
• 
Loss to follow up 
No additional procedures or observations will continue to be required after the end of the study.  
Withdrawal from the study will result in the exclusion of the data for that participant from analysis.  
Withdrawn participants will be replaced by further recruitment to the study. 
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. 
8.8. Definition of End of Trial 
The end of trial is the date of the last participant discharged from hospital. 
 


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9. IDENTIFICATION & DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
9.1. Device description 
This study will use Sienna+® or Magtrace® tracer which contains magnetised nanoparticles and a hand-
held SentiMag® probe within its CE market intended purpose for sentinel lymph node mapping. Lymph 
node mapping is used in cancer patients to identify the first lymph nodes that would be affected by 
spread of the cancer. Specifically, in this study, the device will be used to identify sentinel lymph nodes in 
the mesorectum of patients with rectal cancer.  
The tracer is a dark brown aqueous suspension of organically coated superparamagnetic iron oxide 
particles, supplied in a vial. It will be diluted and injected during endoscopy. The vials will be supplied 
directly and will not involve pharmacy. 
The manufacturer in Endomagnetics Limited, 325 Cambridge Science Park, Cambridge CB4 0WG. The 
Sienna+ product has been in use since 29 February 2012. On 31 October 2018 Endomagnetics 
discontinued Sienna+ and replaced it directly with Magtrace, which contains the same nanoparticle, in 
the same amount and concentration, but formulated in 0.3% saline rather than water.    
At the start of the study, the principal investigators will undergo methodology training and practice the 
use of the hand held SentiMag probe. 
9.2. Device Safety 
The tracer is supplied in vials with a long shelf life. The storage and handling procedures are 
straightforward; there are no temperature issues. The vials will be held in a secure storage area in the 
endoscopy department. The vial details and expiry date will be checked prior to administration in 
accordance with standard procedures. Details of the batch and injection will be recorded on the standard 
endoscopy documentation. Details of the injection will also be recorded on the CRF.  
The Sentimag includes a probe and a portable base unit that it connects to. There are no safety issues 
with either the tracer or the probe. 
9.3. Device Accountability  
The manufacturer (Endomagnetics) is responsible for the quality control of the tracer and 
probe.  
10. NON-INVESTIGATIONAL MEDICINAL PRODUCT (NIMP) 
10.1. 
NIMP Description 
Indocyanine green (ICG) dye is a tricarbocyanine dye with a peak spectral absorption in the near infrared 
(NIR) range. Following injection it can be visualised in the tissues using an NIR imaging system. ICG has a 
low molecular size so when injected subserosally or submucosally into the bowel it is rapidly taken up by 
the lymphatics and deposited in the local lymph nodes. It has been widely used for sentinel lymph node 
mapping in colorectal and other cancers, and is also commonly used as an indicator dye in many other 


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areas of medicine. ICG contains sodium iodide. It is safe for general use, but can cause allergic reactions 
in people with iodine sensitivity.   
ICG is supplied as a sterile water-soluble powder in 25mg vials. The vials are stored at room temperature. 
Prior to use the powder is dissolved in 10ml of sterile water. Once dissolved the ICG must be used within 
6 hours.    
11. SAFETY REPORTING 
11.1. 
Definitions 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs (including an abnormal laboratory findings) in 
participants, users or other persons whether or not related to the 
investigational medical device. This includes events related to the 
investigational device or comparator, events related to the procedures 
involved (any procedure in the protocol). For users or other persons 
this is restricted to events related to the investigational medical device. 
Adverse 
Device 
effect 
(ADE) 
 
An adverse event related to the use of an investigational medical 
device. This definition includes any events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, 
or operation, or any malfunction of the investigational device. This 
definition also includes any event resulting from user error or form 
intentional misuse of the investigational device. 
Serious 
Adverse 
Event 
(SAE) 
An adverse event that: 
• 
Led to death 
• 
Resulted in serious deterioration in the health of the subject 
that: 
o resulted in a life-threatening illness or injury 
o resulted in a permanent impairment of a body 
structure or a body function 
o required 
in-patient 
care 
or 
prolongation 
of 
hospitalisation 
o resulted in medical or surgical intervention to prevent 
life-threatening illness or injury or permanent 
impairment to a body structure or a body function. 
This includes device deficiencies that might have led to a serious 
adverse event if: 
a) suitable action had not been taken or 


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b) intervention had not been made or 
c) circumstances had been less fortunate.  
These are handled under the SAE reporting system. 
Planned hospitalisation for a pre-existing condition, or a procedure 
required by the trial protocol, without serious deterioration in health, 
is not considered a serious adverse event. 
Serious Adverse Device 
Effect (SADE) 
Any untoward medical occurrence that can be attributed wholly or 
partly to the device, which resulted in any of the characteristics of a 
serious adverse event as described above. 
Unanticipated Serious Adverse Device Effects (USADE) 
Any serious adverse device effect which, by its nature, incidence, 
severity or outcome, has not been identified  
Device deficiency 
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance.  Device deficiencies 
include malfunctions, use errors and inadequate labelling. 
Device deficiencies that did not lead to an adverse event, but could 
have led to a medical occurrence if suitable action had not been taken, 
or intervention had not been made or if circumstances had been less 
fortunate 
User error 
Act or omission of an act that results in a different medical device 
response than intended by the manufacturer or expected by the user.  
Use error includes slips, lapses and mistakes.  An unexpected 
physiological response of the subject does not itself constitute a use 
error. 
 
Severity definitions 
The following definitions will be used to determine the severity rating for all adverse events: 
Mild: awareness of signs or symptoms, that does not interfere with the subject’s usual activity or is 
transient that resolved without treatment and with no sequelae. 
Moderate: a sign or symptom, which interferes with the subject’s usual activity. 
Severe: incapacity with inability to do work or perform usual activities. 
11.2. 
Causality 
The relationship of each adverse event to the trial device may be determined by the manufacturer 
and/or a medically qualified Investigator according to the following definitions:  


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Not related: The event is clearly related to other factors such as the patients/participants clinical 
condition, therapeutic intervention, concomitant medication. 
Unlikely: The event is probably produced by other factors such as the patients/participants clinical 
condition, therapeutic intervention, concomitant medication and does not follow a known response 
pattern to the device 
Possibly: 
The 
event 
follows 
a 
reasonable 
temporal 
relationship 
form 
the 
time 
of 
placement/administration and/or follows a known response pattern to the device but could have been 
caused by other factors such as the patients/participants clinical condition, therapeutic intervention, 
concomitant medication. 
Most probable: The event follows a reasonable temporal relationship form the time of 
placement/administration and/or follows a known response pattern to the device and could not have 
been caused by other factors such as the patients/participants clinical condition, therapeutic 
intervention, 
concomitant 
medication. 
Further 
the 
event 
immediately 
follows 
the 
administration/placement of the device and improves on stopping or removing the device. 
11.3. 
Procedures for Recording Adverse Events 
All adverse events (including ADEs) and device deficiencies occurring during the course of the study will 
be recorded on the CRF whether or not attributed to the trial device. The information recorded will 
include but not be limited to: 
• 
A description of the event 
• 
The dates of the onset and resolution 
• 
Action taken 
• 
Outcome 
• 
Assessment of relatedness to the device 
• 
Whether the AE is serious or not 
• 
Whether the AE arises from device deficiency 
• 
Whether the AE arises from user error 
The severity of events will be assessed on the following scale:  1 = mild, 2 = moderate, 3 = severe. 
AEs/ADEs considered related to the device as judged by a medically qualified investigator or the Sponsor 
will be followed either until resolution, or the event is considered stable. 
It will be left to the Investigator’s clinical judgment to decide whether or not an AE/ADE is of sufficient 
severity to require the participant’s removal from treatment.  A participant may also voluntarily 
withdraw from treatment due to what he or she perceives as an intolerable AE/ADE.  If either of these 
occurs, the participant must undergo an end of trial assessment and be given appropriate care under 
medical supervision until symptoms cease, or the condition becomes stable. 
11.4. 
Reporting Procedures for Serious Adverse Events 
Reporting of all Serious Adverse Events will be done in accordance with the European Commission 
Guidelines on Medical Devices Serious Adverse Event Reporting (MEDDEV 2.7/3; December 2010). 


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SAEs/SADEs that pose an immediate risk to patient health or safety, will be reported to R&D immediately 
or no later than 24 hours after the Investigator is aware and to the device manufacturer, competent 
authority and the REC within 2 calendar days of the Chief Investigator becoming aware of the event.   
All other reported SAEs/SADEs will be reported to R&D and competent authority within 7 calendar days 
of notification, if appropriate. This will not include SAEs that may be expected as part of the risks of 
routine care. Adverse device events (SADEs, USADEs) and device deficiencies will also be reported to the 
device manufacturer.  All SAEs will be followed up to resolution.   
SAEs/SADEs will be considered as any adverse event occurring from the injection of Sienna+ tracer during 
endoscopy to patient’s discharge from hospital following their scheduled surgery.   
11.5. 
Expectedness 
Expectedness will be determined according to the Manufacturers risk analysis report.  
Expected adverse reactions are uncommon but may include hypersensitivity reaction such as rash, 
itching, dizziness and lightheadedness. If inadvertent injection into the vascular system occurs 
anaphylactic reaction is possible. There may be brownish discolouration of the tissue around the 
injection site that may be noticeable at surgery.  
11.6. 
Safety Monitoring Committee 
The Oxford University Hospitals Trust Trials Safety Group (TSG) will conduct a review of all SAEs/SADEs 
for the trial reported during the quarter and cumulatively. The aims of this committee include: 
• 
To pick up any trends, such as increases in un/expected events, and take appropriate action 
• 
To seek additional advice or information from investigators where required 
• 
To evaluate the risk of the trial continuing and take appropriate action where necessary 
 
12. STATISTICS 
12.1. 
Description of Statistical Methods 
All data will be stored in an Excel worksheet and analysed using Excel and R.  
Frequency of event (adverse, hypersensitivity or complication) will equate to: number of adverse 
event/total number of recruited patients.  
Frequency of tracer detection at surgery (at tumour site and in lymph nodes) will equate to: number of 
operations where tracer seen/ total number of operations on recruited patients.   
Impact of tracer injection on subsequent surgery will be assessed by the surgeon's binary assessment as 
to whether surgery was more difficult than expected, and also free text comments to be analysed 
qualitatively.  


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A sentinel lymph node will be defined as the first lymph node draining the tumour and positivity defined 
according to the manufacturer’s instructions. A “positive” node will be defined as having over 10% of the 
tracer activity of the site of initial submucosal injection. A “negative” node will be defined as having less 
than 10% of the tracer activity of the site of initial submucosal injection. 
The detection rate for sentinel lymph nodes on MRI scan and Sentimag probe assessment will equate to: 
number of patients/specimens in whom a sentinel lymph node is identified/total number of examined 
patients/specimens.  
MRI and Sentimag mapping will be qualitatively compared for all relevant patients/specimens (as 
appropriate) to establish a baseline of individual variability.  
The presence and location of lymph nodes in the mesorectal specimen will be compared with the 
pathology findings for each patient in the ex-vivo part using correlation.   
The success rate for removing the sentinel lymph node during TEM surgery will equate to: number of 
patients in whom the sentinel lymph node was removed/total number of patients undergoing TEM 
operation. 
As this is a feasibility study, results will be continuously evaluated and adjustments made to the tracer 
dosage and timing of injection if indicated.      
12.2. 
The Number of Participants 
The first (ex-vivo) part of the study will recruit 20 patients due to have radical surgery for rectal cancer in 
order to establish the accuracy of sentinel node detection using Sienna+ tracer by ex-vivo specimen 
analysis. This number is based on previously published sentinel node studies in breast cancer and 
melanoma (O’Hea et al, 1992; Brouwer et al, 2012). The second (in-vivo) part will recruit a further 20 
patients, but these will be people with early rectal cancer scheduled for a less invasive TEM operation to 
treat their rectal cancer.  
12.3. 
The Level of Statistical Significance 
Not applicable for this proof of concept study 
12.4. 
Criteria for the Termination of the Trial 
Any serious adverse event will prompt a review of the study and possible termination.  
12.5. 
Procedure for Accounting for Missing, Unused, and Spurious Data. 
All available data will be used. Missing data will not be imputed. Spurious data will be re-checked, and if 
valid will be included in the analysis.  
12.6. 
Inclusion in Analysis 
All patients who receive the tracer injection will be included in the analysis.  


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12.7. 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan 
Not applicable. The analysis involves only simple statistical measures, and all proposed measures are 
necessary to determine feasibility.  
 
13. DATA MANAGEMENT 
13.1. 
Source Data 
Source documents are where data are first recorded, and from which participants’ CRF data are 
obtained. These include, but are not limited to, hospital records (from which medical history and 
previous and concurrent medication may be summarised into the CRF), clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. 
CRF entries will be considered source data if the CRF is the site of the original recording (e.g. there is no 
other written or electronic record of data).  All documents will be stored safely in confidential conditions. 
On all trial-specific documents, other than the signed consent, the participant will be referred to by the 
trial participant number/code, not by name. 
13.2. 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. Data will not be 
transferred outside of the UK.  
13.3. 
Data Recording and Record Keeping 
Data will be recorded using paper CRFs and entered into an Excel spreadsheet. Data from this study will 
be generated and analysed at the Oxford University Hospitals by the research investigators. Personal 
data will be stored and accessed by the investigators for less than 3 months. Research data will be stored 
for 10 years after the completion of the study.  
The participants will be identified by a unique trial specific number and/or code in any database.  The 
name and any other identifying detail will NOT be included in any trial data electronic file. 
All electronic data will be password-protected and anonymised. All hard copy files and data will be kept 
in a locked cabinet within a locked office with restricted access. Access to the data will be restricted to 
study team members. The NHS Code of Confidentiality will be followed. This study will follow the 
sponsor organisation’s policy regarding data storage and the NHS Code of Confidentiality. Information 
derived from the study will be stored on a single, secure (password encryption) NHS computer. This will 
be positioned within a secure location in the hospital.  
All participants will be informed using patient information sheets of how data will be stored. The 
principal investigators will constantly review the security of research data files.  
 


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14. QUALITY ASSURANCE PROCEDURES 
The trial will be conducted in accordance with the current approved protocol, ICH GCP, relevant 
regulations and standard operating procedures. 
Regular monitoring will be performed according to ICH GCP. 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. 
 
15. SERIOUS BREACHES 
A serious breach is defined as “A breach of GCP or the trial protocol which is likely to affect to a 
significant degree –  
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial”. 
In the event that a serious breach is suspected the Sponsor must be contacted within 1 working day. In 
collaboration with the C.I., the serious breach will be reviewed by the Sponsor and, if appropriate, the 
Sponsor will report it to the REC committee, Regulatory authority and the NHS host organisation within 
seven calendar days. 
 
16. ETHICAL AND REGULATORY CONSIDERATIONS 
16.1. 
Declaration of Helsinki 
The Investigator will ensure that this trial is conducted in accordance with the principles of the 
Declaration of Helsinki. These details are provided in the protocol.   
16.2. 
ICH Guidelines for Good Clinical Practice 
The Investigator will ensure that this trial is conducted in full conformity with relevant regulations and 
with the ICH Guidelines for Good Clinical Practice (CPMP/ICH/135/95) July 1996. 
16.3. 
Medical Device regulations 
The Investigator will ensure that this trial is conducted in full conformity with: 
• 
European Commission Medical Device Guidelines relating to the application of the EU Directives 
on Medical Devices 
• 
Guide to European Medical Device Trials and BS EN ISO 14155 


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16.4. 
Approvals 
The protocol, informed consent form, participant information sheet and any proposed advertising 
material will be submitted to an appropriate Research Ethics Committee (REC), regulatory authorities 
(MHRA in the UK), and host institution(s) for written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
16.5. 
Reporting 
The CI shall submit once a year throughout the clinical trial, or on request, an Annual Progress Report to 
the REC, host organisation and Sponsor.  In addition, an End of Trial notification and final report will be 
submitted to the MHRA, the REC, host organisation and Sponsor. 
16.6. 
Participant Confidentiality 
The trial staff will ensure that the participants’ anonymity is maintained.  The participants will be 
identified only by initials and a participants ID number on the CRF and any electronic database.  All 
documents will be stored securely and only accessible by trial staff and authorised personnel. The trial 
will comply with the Data Protection Act, which requires data to be anonymised as soon as it is practical 
to do so. 
16.7. 
Expenses and Benefits 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of 
receipts, or a mileage allowance provided as appropriate. 
16.8. 
Other Ethical Considerations 
No other ethical declarations to declare in relation to this study.  
 
17. FINANCE AND INSURANCE 
17.1. 
Funding 
This study has received a £5000 Impact Acceleration Award from the NIHR Colorectal Therapies 
Healthcare Technology Cooperative, Leeds.  
Funding for the use of research devices and consumables will be provided by Endomagnetics, Cambridge 
17.2. 
Insurance 
NHS bodies are legally liable for the negligent acts and omissions of their employees. If you are harmed 
whilst taking part in a clinical trial as a result of negligence on the part of a member of the trial team this 
liability cover would apply. 


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Non-negligent harm is not covered by the NHS indemnity scheme. The Oxford University NHS Trust, 
therefore, cannot agree in advance to pay compensation in these circumstances. 
In exceptional circumstances an ex-gratia payment may be offered. 
18. PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and 
any other publications arising from the study.  Authors will acknowledge the source of funding for the 
study. Authorship will be determined in accordance with the ICMJE guidelines and all other contributors 
will be acknowledged. 
 
19. REFERENCES 
1. 
Bach SP, Hill J, Monson JR, Simson JN, Lane L, Merrie A, et al. A predictive model for local 
recurrence after transanal endoscopic microsurgery for rectal cancer. The British journal of surgery. 
2009;96(3):280-90. 
2. 
Brouwer OR, Klop WM, Buckle T, Vermeeren L, van den Brekel MW, Balm AJ, et al. Feasibility of 
sentinel node biopsy in head and neck melanoma using a hybrid radioactive and fluorescent tracer. 
Annals of surgical oncology. 2012;19(6):1988-94. 
3. 
Cahill RA, Anderson M, Wang LM, Lindsey I, Cunningham C, Mortensen NJ. Near-infrared (NIR) 
laparoscopy for intraoperative lymphati road-mapping and sentinel node identification during definitive 
surgical resection of early-stage colorectal neoplasia. Surgical Endoscopy. 2012;26:197-204. 
4. 
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. Annals of surgical 
oncology. 2014;21(4):1237-45. 
5. 
Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, et al. Axillary 
dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a 
randomized clinical trial. JAMA : the journal of the American Medical Association. 2011;305(6):569-75. 
6. 
Krag DN, Anderson SJ, Julian TB, Brown AM, Harlow SP, Costantino JP, et al. Sentinel-lymph-node 
resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients 
with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. The lancet 
oncology. 2010;11(10):927-33. 
7. 
http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf  [cited 2014]. 
8. 
O'Hea BJ, Hill AD, El-Shirbiny AM, Yeh SD, Rosen PP, Coit DG, et al. Sentinel lymph node biopsy in 
breast cancer: initial experience at Memorial Sloan-Kettering Cancer Center. Journal of the American 
College of Surgeons. 1998;186(4):423-7. 
9. 
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. 
 
 


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20. APPENDIX A:  TRIAL FLOW CHART 
 
 
 
 


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21. APPENDIX B:  SCHEDULE OF PROCEDURES 
 
Procedures 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Informed consent 
 
 
 
 
Demographics 
 
 
 
 
Medical history 
 
 
 
 
Concomitant medications 
 
 
 
 
Laboratory tests 
 
 
 
 
Eligibility assessment 
 
 
 
 
Initial visit and discussion at 
Colorectal clinic 
 
 
 
 
Endoscopy 
suite 
(Sienna+ 
injection) 
 
 
 
 
Radiology, MRI pre-op assessment  
 
 
 
 
Admission for surgery 
 
 
 
 
Adverse event assessments  
 
 
 
 
 
 
 
 


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22. APPENDIX C:  AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version No. 
Date issued 
Author(s) 
of 
changes 
Details of Changes made 
1 
1.1 
25 June 2015 
H Jones 
Addition of comment in 11.2 that 
data will not be transferred outside 
the UK 
2 
1.2 
2 April 2017 
H Jones 
Addition of MRI scan and ICG 
injection during surgery for Group A 
patients, removal of interim analysis 
after 10 patients, change in tracer 
dosage specification 
3 
1.3 
15 March 2019 
H Jones 
Sienna tracer has been withdrawn by 
the company and directly replaced by 
Magtrace. Time for patient to wait in 
endoscopy after injection reduced to 
1 hour.  
 
Protocol amendments must be submitted to the Sponsor for approval prior to submission to the REC 
committee or MHRA.