Single Arm, Prospective, Open Label, Multicenter Study Assessing the Safety and Effectiveness of IC2000 and SPY Fluorescence Imaging Systems in the Visualization of Lymphatic Vessels and Lymph Nodes During Lymphatic Mapping and Sentinel Lymph Node Biopsy in Subjects With Breast Cancer
Phase: PHASE3
Conditions: Breast Cancer, Lymph Node Mapping, Sentinel Lymph Node Biopsy
Sponsor: Novadaq Technologies ULC, now a part of Stryker



SPY® for Lymph Node Mapping  
Clinical Study Protocol SPY LNM 01 
  
Novadaq Technologies ULC. 
Version 7.0, August 13, 2020 
Page 5 of 67 
CONFIDENTIAL 
2. PROTOCOL SUMMARY 
 
2.1 Study Number and Title 
 
SPY LNM 01 (FILM-B): A Single Arm, Prospective, Open Label, Multicenter Study 
Assessing the Safety and Effectiveness of IC2000 and SPY Fluorescence Imaging 
Systems in the Visualization of Lymphatic Vessels and Lymph Nodes during 
Lymphatic Mapping and Sentinel Lymph Node Biopsy in Subjects with Breast Cancer 
 
Clinical Phase: Phase III - Investigational Device Study 
  
2.2 Study Objectives 
 
Primary 
• To assess the effectiveness of IC2000 and SPY-PHI (SPY Portable Handheld 
Imager; also called “IC2000 and SPY”) Fluorescence Imaging System in the 
identification of lymph nodes (histology confirmed lymph nodes), during lymphatic 
mapping and sentinel lymph node biopsy in subjects with early stage breast 
cancer. 
 
Secondary 
 
To evaluate the effectiveness of IC2000/SPY and Tc99m/Gamma Probe in the 
identification of at least one lymph node (histology confirmed lymph node) per 
subject.  
 
To evaluate the effectiveness of IC2000 and SPY as an intraoperative 
fluorescence visualization tool in delineation and mapping of lymphatic vessels in 
the identification of lymph nodes (histology confirmed lymph nodes). 
 
To confirm the safety of intradermal injection of IC2000 in intraoperative 
delineation and mapping lymphatic vessels and identification of lymph nodes. 
 
2.3 Study Design 
 
This is a prospective, open label, multicenter, non-inferiority within-patient study to 
determine the effectiveness of IC2000 (Indocyanine Green (ICG) for Injection) and 
the SPY Portable Handheld Imaging System (SPY-PHI) as an intraoperative 
fluorescence visualization tool, in the visual identification of lymphatic vessels and 
lymph nodes (LNs) during lymphatic mapping and sentinel lymph node biopsy (SLNB) 
procedures as confirmed by Technitium99m (Tc99m) and Gamma Probe. Enrollment 
will not exceed 1
 centers in North America. Prior to enrolling 
study subjects, participating surgeons at each center will be: 

SPY® for Lymph Node Mapping  
Clinical Study Protocol SPY LNM 01 
  
Novadaq Technologies ULC. 
Version 7.0, August 13, 2020 
Page 8 of 67 
CONFIDENTIAL 
2.4 Study Population 
To be eligible for the study, subjects must meet the following main inclusion criteria: 
 
18 years of age or older. 
 
Subjects with American Cancer Society Clinical Stage 0 Ductal Carcinoma in 
Situ (DCIS) (Stage 0, Tis, N0, M0), IA (T1*, N0, M0), IB ((T0, N1mi, M0) or 
T1*, N1mi, M0)) or Stage IIA (T0, N1**M0, or T1, N1**, M0 or T2, N0, M0)1 
breast cancer undergoing surgery to remove tumor draining LNs. 
Where: 
o Tis = Ductal carcinoma in situ 
o T0 = No evidence of primary tumor 
o T1 = Tumor ≤ 20 mm in greatest diameter 
o T1* = Includes T1mi   
o T2 = Tumor >20 mm but ≤ 50 mm in greatest diameter 
o N0 = No regional lymph node metastasisq1` 
o N1 = Metastasis to movable ipsilateral level I, II axillary LNs 
o N1** = T0 and T1 tumors with nodal micro-metastasis only are excluded 
from Stage IIA and are classified Stage IB. 
o mi = Micro-metastasis 
o M0 = Disease has not metastasized 
 
Subjects with clinically negative nodal status (N0) with or without neoadjuvant 
therapy. 
 
Subjects with negative metastatic involvement (M0). 
 
Subjects of child-bearing potential must not be pregnant or lactating and must 
have a negative pregnancy test at Baseline. 
 
Have signed an approved informed consent form for the study. 
 
Be willing to comply with the protocol. 
 
Subjects meeting any of the following criteria will be excluded from the study: 
 
Have had prior axillary surgery or ipsilateral radiation in the breast(s) that is 
planned for this procedure. 
 
Advanced breast cancer subjects with stage IIB, III or IV. 
 
Known allergy or history of adverse reaction to ICG, iodine or iodine dyes. 
 
Subjects who have participated in another investigational study within 30 days 
prior to surgery. 
 
Pregnant or lactating subjects. 

SPY® for Lymph Node Mapping  
Clinical Study Protocol SPY LNM 01 
  
Novadaq Technologies ULC. 
Version 7.0, August 13, 2020 
Page 9 of 67 
CONFIDENTIAL 
 
Subjects who, in the Investigator's opinion, have any medical condition that 
may make the subject a poor candidate for the investigational procedure, or 
interferes with the interpretation of study results. 
 
2.5 Study Devices and Imaging Agents 
 
In this study, IC2000 and SPY-PHI will be assessed as an intraoperative fluorescence 
visualization tool in the identification of LNs during lymphatic mapping in subjects 
undergoing sentinel lymph node biopsy with early stage breast cancer. 
SPY-PHI is intended for intraoperative visual assessment of blood vessels and related 
tissue perfusion by surgeons.  It is an imaging system used in capturing and viewing 
fluorescent images for visual assessment of blood flow, as an adjunctive method for 
the evaluation of tissue perfusion, and related tissue-transfer circulation in tissue and 
free flaps during various surgical procedures. 
SPY-PHI allows for real time, intraoperative visualization and video of near infrared 
(NIR) fluorescence, which are acquired by using the imaging agent.  
The imaging agent used with SPY-PHI is Indocyanine Green (IC2000), which is a 
sterile, water-soluble tricarbocyanine dye with a peak spectral absorption at 
800-810 nm in blood plasma or blood. IC2000 contains not more than 5.0% sodium 
iodide. In this study, investigational ICG, IC2000, will be administered to subjects 
through an intradermal injection into the peri-areolar area of the breast. 
Tc-99m radioactive colloid injection is a clear, colorless aqueous solution and will be 
injected into the peri-areolar area of the breast as per standard of care. 
Tc99m will be used in conjunction with the Gamma Probe. Gamma Probes detect the 
presence of gamma rays emitted from radioactive isotopes in body organs or tissue . 
The system provides an increasing or decreasing sound and visual indicator (Count 
Bar) that vary in pitch as level of gamma radioactivity increases or decreases3. 
 
2.6 Study Variables 
 
Primary Variable 
• To assess the effectiveness of IC2000 and SPY-PHI (SPY Portable Handheld 
Imager; also called “IC2000 and SPY”) Fluorescence Imaging System in the 
identification of lymph nodes (histology confirmed lymph nodes), during lymphatic 
mapping and sentinel lymph node biopsy in subjects with early stage breast 
cancer. 
o Defined as the proportion of lymph nodes identified and excised by 
IC2000/SPY compared to the proportion of lymph nodes identified and 
excised by Tc99m/Gamma Probe, (histology confirmed lymph nodes). 
Denominator is the total number of lymph nodes identified and excised, 
inclusive of clinically suspicious lymph nodes (histology confirmed). 
 

SPY® for Lymph Node Mapping  
Clinical Study Protocol SPY LNM 01 
  
Novadaq Technologies ULC. 
Version 7.0, August 13, 2020 
Page 10 of 67 
CONFIDENTIAL 
 
Secondary Variables 
 
To evaluate the effectiveness of IC2000/SPY and Tc99m/Gamma Probe in the 
identification of at least one lymph node (histology confirmed lymph node) per 
subject.  
o Defined as the proportion of subjects in which at least one lymph 
node is identified by IC2000/SPY, and Tc99m/Gamma Probe, (histology 
confirmed lymph nodes). Numerator is the number of subjects who have at 
least one lymph node identified by IC2000/SPY, and the number of 
subjects who have at least one lymph node identified by Tc99/Gamma 
Probe, respectively (histology confirmed). Denominator is the total number 
of subjects where mapping was attempted. 
 
To evaluate the effectiveness of IC2000 and SPY as an intraoperative 
fluorescence visualization tool in delineation and mapping of lymphatic vessels in 
the identification of lymph nodes (histology confirmed lymph nodes). 
o Defined as the proportion of lymph nodes identified by IC2000 and SPY 
(histology confirmed lymph nodes) by following a fluorescent lymphatic 
vessel compared to the proportion of lymph nodes identified by IC2000 and 
SPY (histology confirmed lymph nodes) with no lymphatic vessels visible 
by IC2000 and SPY. Denominator is the total number of lymph nodes 
identified by any method (histology confirmed). 
 
To confirm the safety of intradermal injection of IC2000 in intraoperative 
delineation and mapping lymphatic vessels and identification of lymph nodes. 
o Defined by the incidence of adverse events with IC2000. 
 
2.7 Study Procedures and Assessments 
 
The following assessments and procedures will be performed: 
 
Vital signs, height, weight, demographics, surgical predictive factors. 
 
Relevant medical history and underlying conditions. 
 
Assessment of eligibility criteria. 
 
Tc-99m radioactive colloid administration. 
 
Imaging agent (IC2000) administration. 
 
Mapping of lymphatic vessels using IC2000 and SPY-PHI. 
 
Identification of lymph nodes using IC2000 and SPY-PHI 
 
Excision of lymph nodes identified with IC2000 and SPY-PHI 
 
Confirmation and/or identification of lymph nodes with Tc-99m radioactive 
colloid and Gamma Probe ex-vivo and in-vivo.  
o LNs identified in-vivo by Tc99 and Gamma Probe will be excised under 
visual guidance of IC2000 and SPY. 

SPY® for Lymph Node Mapping  
Clinical Study Protocol SPY LNM 01 
  
Novadaq Technologies ULC. 
Version 7.0, August 13, 2020 
Page 12 of 67 
CONFIDENTIAL 
 
3.  TABLE OF CONTENTS 
2. PROTOCOL SUMMARY ........................................................................................... 5 
2.1 Study Number and Title .................................................................................. 5 
2.2 Study Objectives ............................................................................................ 5 
2.3 Study Design .................................................................................................. 5 
2.4 Study Population ............................................................................................ 8 
2.5 Study Devices and Imaging Agents ................................................................ 9 
2.6 Study Variables .............................................................................................. 9 
2.7 Study Procedures and Assessments ............................................................ 10 
2.8 Sample Size and Statistical Analysis ............................................................ 11 
2.9 Study Duration .............................................................................................. 11 
4. ABBREVIATIONS AND DEFINITIONS .................................................................. 14 
5. INTRODUCTION AND BACKGROUND ................................................................. 15 
5.1 Background .................................................................................................. 15 
5.2 Potential Risks and Benefits to Human Subjects.......................................... 26 
6. STUDY OBJECTIVES ............................................................................................. 28 
6.1 Objectives .................................................................................................... 28 
7. INVESTIGATIONAL PLAN ..................................................................................... 28 
7.1 Study Design Overview ................................................................................ 28 
7.2 Screening ..................................................................................................... 29 
7.3 Day 0 ............................................................................................................ 29 
7.4 Classification of LNs ..................................................................................... 31 
7.5 Follow-up and Post-operative Complications ............................................... 32 
8. SELECTION AND WITHDRAWAL OF SUBJECTS ............................................... 34 
8.1 Number of Subjects ...................................................................................... 34 
8.2 Inclusion Criteria ........................................................................................... 34 
8.3 Exclusion Criteria ......................................................................................... 34 
8.4 Withdrawal of Subjects ................................................................................. 35 
9. SUBJECT ENROLLMENT AND SUBJECT IDENTIFICATION PROCEDURES .... 35 
9.1 Subject Enrollment ....................................................................................... 35 
9.2 Subject Identification .................................................................................... 36 
10. STUDY TREATMENTS ......................................................................................... 37 
10.1 Device Descriptions .................................................................................... 37 
10.2 Imaging Agent Description ......................................................................... 39 
10.3 Installation, Training and Storage ............................................................... 41 
10.4 Concomitant Treatment .............................................................................. 42 
11. RISKS / PRECAUTIONS ...................................................................................... 42 
11.1 SPY-PHI System ........................................................................................ 42 
11.2 IC2000 (Indocyanine Green for Injection, USP) ......................................... 42 
12. STUDY PROCEDURES ........................................................................................ 44 
12.1 Schedule of Events .................................................................................... 44 

SPY® for Lymph Node Mapping  
Clinical Study Protocol SPY LNM 01 
  
Novadaq Technologies ULC. 
Version 7.0, August 13, 2020 
Page 13 of 67 
CONFIDENTIAL 
12.2 Baseline/Screening Procedures (Day -30 to Day 0) ................................... 45 
12.3 Day 0 Procedures ....................................................................................... 45 
 Post-operative Follow-up Visits (Day of discharge to Day 30) ................... 47 
12.5 Histopathology of Excised LN..................................................................... 48 
12.6 Image Acquisition and Transmission .......................................................... 48 
13. EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS ........ 48 
13.1 Definitions .................................................................................................. 49 
13.2 Adverse Event Descriptions ....................................................................... 50 
13.3 Reporting and Evaluation of Serious Adverse Events and Unanticipated 
Adverse Device Effects .............................................................................. 51 
13.4 Follow-up for Adverse Device Effects and Adverse Events ........................ 51 
13.5 Reporting of Technical Complaints / Device Deficiencies ........................... 52 
13.6 ADEs Technical Complaints / Device Deficiencies that are UADEs ........... 52 
14. STATISTICAL CONSIDERATIONS ...................................................................... 52 
14.1 Analysis Populations .................................................................................. 52 
14.2 Demographic and Baseline Characteristics ................................................ 53 
14.3 Primary Objective ....................................................................................... 54 
14.4 Secondary Objectives ................................................................................ 54 
14.5 Other Analyses ………………………………………………………………….54 
14.6 Safety Objective ......................................................................................... 55 
14.7 Handling of Missing Data ........................................................................... 55 
14.8 Sample Size Considerations ...................................................................... 55 
15. ESTIMATED DURATION OF THE STUDY ........................................................... 56 
16. STUDY ETHICAL CONSIDERATIONS ................................................................ 56 
16.1 Ethical Conduct of the Study ...................................................................... 56 
16.2 Informed Consent ....................................................................................... 57 
16.3 Institutional Review Board, Ethics Committee, or Research Ethics Board 
(IRB) ........................................................................................................... 57 
16.4 Data and Safety Monitoring Board ............................................................. 57 
17. ADMINISTRATIVE PROCEDURES ...................................................................... 57 
17.1 Sponsor's Responsibilities .......................................................................... 57 
17.2 Investigator Training ................................................................................... 58 
17.3 Ongoing Communication of Safety Information during the Study ............... 58 
17.4 Study Monitoring ........................................................................................ 59 
17.5 Records Retention ...................................................................................... 59 
17.6 Investigator's Responsibilities ..................................................................... 59 
18. DATA MANAGEMENT ......................................................................................... 60 
19. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ......................... 61 
20. REFERENCES ...................................................................................................... 62 
 

SPY® for Lymph Node Mapping  
Clinical Study Protocol SPY LNM 01 
  
Novadaq Technologies ULC. 
Version 7.0, August 13, 2020 
Page 14 of 67 
CONFIDENTIAL 
4. ABBREVIATIONS AND DEFINITIONS 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ALND  
Axillary Lymph Node Dissection 
ASBrS 
American Society of Breast Surgeons 
AT 
As-treated 
BD 
Blue Dyes 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DCIS 
Ductal Carcinoma In-Situ 
DSMB 
Data and Safety Monitoring Board  
EC 
Ethics Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
H&E 
Hematoxylin and Eosin 
HD 
High Definition 
HSA 
Human Serum Albumin 
IA 
Imaging Agent 
IB 
Isosulfane Blue 
ICH 
International Conference on Harmonization  
ICG 
Indocyanine Green 
IRB 
Institutional Review Board 
LN 
Lymph Node 
MB 
Methylene Blue 
mITT 
Modified Intent-to-treat 
NIR 
Near-Infrared 
SADE 
Serious Adverse Device Effect  
SAE 
Serious Adverse Event 
SLN 
Sentinel Lymph Node 
SLNB  
Sentinel Lymph Node Biopsy 
SPY 
SPY Fluorescence Imaging Systems 
SPY-PHI 
SPY-PHI Open Field Handheld Fluorescence Imaging System 
Tc99m 
Technetium 99m 
Tc99m – TM Technetium 99m – Tilmanocept 
Tc99m – SC Technetium 99m – Sulfur Colloid 
US 
United States 
UADE 
Unanticipated Adverse Device Effect  
VIS 
Visible 

SPY® for Lymph Node Mapping  
Clinical Study Protocol SPY LNM 01 
  
Novadaq Technologies ULC. 
Version 7.0, August 13, 2020 
Page 34 of 67 
CONFIDENTIAL 
8. SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1 Number of Subjects 
 
Enrollment in the study will not exceed 
. 
 
8.2 Inclusion Criteria 
 
To be eligible for the study, a subject must meet all of the following criteria: 
 
18 years of age or older. 
 
Subjects with American Cancer Society Clinical Stage 0 Ductal Carcinoma in 
Situ (DCIS) (Stage 0, Tis, N0, M0), IA (T1*, N0, M0), IB ((T0, N1mi, M0) or 
T1*, N1mi, M0)) or Stage IIA (T0, N1**M0, or T1, N1**, M0 or T2, N0, M0)1  
breast cancer undergoing surgery to remove tumor draining LNs. 
Where: 
o 
Tis = Ductal carcinoma in situ 
o 
T0 = No evidence of primary tumor 
o 
T1 = Tumor ≤ 20 mm in greatest diameter 
o 
T1* = Includes T1mi   
o 
T2 = Tumor >20 mm but ≤ 50 mm in greatest diameter 
o 
N0 = No regional lymph node metastasis 
o 
N1 = Metastasis to movable ipsilateral level I, II axillary LNs 
o 
N1** = T0 and T1 tumors with nodal micro-metastasis only are excluded from 
Stage IIA and are classified Stage IB. 
o 
mi = Micro-metastasis 
o 
M0 = Disease has not metastasized 
 
Subjects with clinically negative nodal status (N0) with or without neoadjuvant 
therapy. 
 
Subjects with negative metastatic involvement (M0). 
 
Subjects of child-bearing potential must not be pregnant or lactating and must 
have a negative pregnancy test at Baseline. 
 
Have signed an approved informed consent form for the study. 
 
Be willing to comply with the protocol. 
 
8.3 Exclusion Criteria 
 
Subjects meeting any of the following criteria will be excluded from the study: 

SPY® for Lymph Node Mapping  
Clinical Study Protocol SPY LNM 01 
  
Novadaq Technologies ULC. 
Version 7.0, August 13, 2020 
Page 35 of 67 
CONFIDENTIAL 
 
Have had prior axillary surgery or ipsilateral radiation in the breast(s) that is 
planned for this procedure. 
 
Advanced breast cancer subjects with stage IIB, III or IV. 
 
Known allergy or history of adverse reaction to ICG, iodine or iodine dyes. 
 
Subjects who have participated in another investigational study within 30 days 
prior to surgery. 
 
Pregnant or lactating subjects. 
 
Subjects who, in the Investigator's opinion, have any medical condition that 
may make the subject a poor candidate for the investigational procedure, or 
interferes with the interpretation of study results. 
 
8.4 Withdrawal of Subjects 
 
Subjects can voluntarily withdraw (or be withdrawn) at any time during the study. 
Investigators may withdraw a subject from the study due to: 
 
A new health condition, diagnosis or finding appears that is suspected to 
require care or medication prohibited by the protocol. 
o 
e.g. the planned surgical procedure is modified to a procedure 
prohibited by the protocol. 
 
The subject has intolerable adverse events. 
 
It is in the subject’s best interest according to the Investigator’s clinical 
judgment. 
If a subject is prematurely withdrawn from the study, the reason(s) for withdrawal must 
be recorded on the relevant page of the subject's Study Completion CRF. 
Subjects who discontinue the study prematurely will not be replaced. The Sponsor may 
stop the study at any time. 
 
9. SUBJECT ENROLLMENT AND SUBJECT IDENTIFICATION PROCEDURES 
9.1 Subject Enrollment 
 
Enrollment will occur on the day of surgery. Prior to surgery, the subject will have provided 
written informed consent, completed all baseline procedures and met all the requirements 
of inclusion and exclusion. Enrollment should be performed as closely as possible to the 
surgical procedure to minimize the incidence of dropout. Enrollment is completed only 
after verification of proper informed consent and study eligibility. 
 
 

SPY® for Lymph Node Mapping  
Clinical Study Protocol SPY LNM 01 
Novadaq Technologies ULC. 
Version 7.0, August 13, 2020 
Page 57 of 67 
CONFIDENTIAL 
 
16.2 Informed Consent 
 
The informed consent forms used for the study must comply with applicable laws and 
regulations. An Investigator must explain the medical aspects of the study, including the 
nature of the study and procedure, orally and in writing, in such a manner that the subject 
is aware of potential benefits and risks. Other elements of the informed consent process 
may be delegated by the Investigator. Subjects must be informed about all aspects of the 
clinical study that are necessary to make the decision to participate in the clinical trial. 
Subjects must be informed that participation is voluntary and that they may withdraw from 
the study at any time, without prejudice. Documentation of the discussion and the date of 
informed consent must be recorded in the source documentation. Subjects must give 
informed consent in writing. 
The informed consent process must be conducted, and the form must be signed, before 
the subject undergoes any screening procedures that are performed solely for the 
purpose of determining eligibility for the study. 
 
16.3 Institutional Review Board, Ethics Committee, or Research Ethics Board (IRB) 
 
The protocol, protocol amendments (as specified by the IRB), and the informed consent 
form for the proposed study, along with any other documents required by the center's 
IRB must be submitted by the Investigator to the center's duly constituted IRB for review 
and approval. The Investigator must also ensure that the IRB reviews the progress of the 
study on a regular basis and, if necessary, renews its approval of the study on an annual 
basis. A copy of each IRB approval letter must be forwarded to the Sponsor before the 
study is implemented. Documentation of subsequent reviews of the study must also be 
forwarded to the Sponsor. 
 
16.4 Data and Safety Monitoring Board 
 
The study will be reviewed on an as needed basis by an independent Data and Safety 
Monitoring Board (DSMB). The statistician will prepare a report for the DSMB in advance 
of the scheduled review meeting using the report template provided by the DSMB. A 
DSMB charter will outline specific safety and data monitoring procedures. 
 
17. ADMINISTRATIVE PROCEDURES 
 
17.1 Sponsor's Responsibilities 
 
17.1.1 Public Disclosure of Clinical Trials 
 
The Sponsor will submit information about this protocol to the appropriate web-based 
national clinical trial registry and results database in each applicable regulatory region