A Randomized, Controlled, Parallel, Multicenter Study Assessing Perfusion Outcomes With PINPOINT® Near Infrared Fluorescence Imaging in Low Anterior Resection
Phase: NA
Conditions: Rectal Cancer, Rectosigmoid Cancer
Sponsor: Novadaq Technologies ULC, now a part of Stryker

PINPOINT® in LAR (PILLAR III) 
Clinical Study Protocol PP PLR 03 
© 2015 NOVADAQ Technologies Inc. NOVADAQ, SPY Elite and PINPOINT are registered trademarks of Novadaq Technologies Inc. PILLAR, SPY PAQ 
and PINPOINT PAQ are trademarks of Novadaq Technologies Inc, 
Clinical Study Protocol 
PROTOCOL NUMBER 
PP PLR 03 
TITLE 
A Randomized, Controlled, Parallel, Multicenter Study Assessing 
Perfusion Outcomes with PINPOINT® Near Infrared Fluorescence 
Imaging in Low Anterior Resection. 
SHORT TITLE 
PILLAR III
PROTOCOL VERSION 
 April 15, 2016 
SPONSOR 
Novadaq Technologies Inc. 
5090 Explorer Dr., Ste. 202, 
Mississauga, Ontario, 
Canada, L4W 4T9 
Confidential 
This is a Novadaq Technologies Inc., document that contains confidential information. It is intended solely 
for the recipient clinical investigator(s) and must not be disclosed to any other party. 

4/15/2016

04/27/2016

4/27/2016

PINPOINT® in LAR (PILLAR III) 
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PROTOCOL SUMMARY 
Study Number and Title: 
PP PLR 03: A Randomized, Controlled, Parallel, Multicenter Study Assessing Perfusion Outcomes with 
PINPOINT® Near Infrared Fluorescence Imaging in Low Anterior Resection (PILLAR III). 
Clinical Phase: Pivotal Study/Non Significant Risk Medical Device 
Study Objectives: 
Primary: 
• To demonstrate an improvement in post-operative anastomotic leak rate in low anterior resection
procedures where colon and rectal tissue perfusion is evaluated using PINPOINT® endoscopic 
fluorescence imaging or SPY Elite® Intraoperative Imaging as an adjunct to standard surgical practice 
compared to surgical procedures performed according to standard surgical practice alone. 
Secondary: 
• To evaluate the ability of the PINPOINT system or SPY Elite system to provide sufficient visualization
for assessment of blood flow and related tissue perfusion during the procedure. 
• To evaluate the effectiveness of assessing perfusion of colon and rectal tissue using PINPOINT or
SPY Elite in reducing the rate of post-operative abscess requiring surgical management. 
Study Design 
This is a randomized, controlled, parallel, multicenter study to determine the reduction in post-operative 
anastomotic leak rate in low anterior resection (LAR) procedures where colon and rectal tissue perfusion 
is evaluated using PINPOINT or SPY Elite as an adjunct to standard surgical practice compared to 
surgical procedures performed according to standard surgical practice alone. The study is a two-stage 
adaptive design that allows a mid-trial reassessment of sample size. Therefore, a minimum of 450 and 
a maximum of 1000 subjects will be enrolled at up to 40 centers in North America. Prior to enrolling study 
subjects, participating surgeons at each center will be trained to perform perfusion assessment with 
PINPOINT. 
Screening: 
Patients scheduled for an open, or minimally invasive low anterior resection for a rectal or rectosigmoid 
neoplasm with curative intent with a planned anastomosis located 10 cm or less from the anal verge will 
be evaluated at baseline to determine if they meet the inclusion/exclusion criteria of the protocol. Subjects 
will be assessed to determine overall health status, including demographics, vital signs and predictive 
factors that may influence surgical outcomes. Eligible patients who provide informed consent will be 
considered for inclusion into the study. 
Day 0: 
During anesthesia, subjects will be randomized (1:1) to either the PERFUSION (PFN) Arm or the 
STANDARD (STD) Arm. Subjects in each arm will be randomized according to an independently 
generated randomization scheme to receive either perfusion assessment with PINPOINT and/or SPY 
Elite during the surgical procedure or to receive the standard of care procedure. Randomization will be 
stratified by site and by whether or not the patient received prior neoadjuvant therapy.  
Subjects in the PFN Arm will undergo a LAR according to the surgeon’s standard practice with the 
addition of intraoperative imaging using PINPOINT and/or SPY Elite NIR fluorescence imaging to assess 
colon and rectal tissue perfusion during the following steps of the procedure: 

 
 
 
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• perfusion of proximal transection margin after IMA ligation; prior to bowel transection 
• perfusion of the mucosal aspect of the completed anastomosis (with the exception of hand sewn 
coloanal anastomoses which will involve assessment of the mucosal aspect of the proximal colon only) 
 
Subjects in the PFN Arm may also undergo additional or repeat intraoperative imaging using PINPOINT 
and/or SPY Elite NIR fluorescence imaging based on the surgeon’s clinical judgment. 
 
Subjects in the STD Arm will undergo a LAR according to the surgeon’s standard practice only.  
 
All subjects will receive the hospital/institution and surgeon’s standard pre-operative, post-operative and 
post discharge care with the addition of any study specific requirements. An air leak test on all 
anastomoses (with the exception of hand sewn coloanal anastomosis when applicable) will be performed 
in the surgeon’s standard fashion. 
Details of the actual surgical technique will be documented post-operatively. The surgeon’s ability to 
sufficiently assess blood flow and related tissue perfusion using PINPOINT or SPY Elite will be recorded. 
The final height of the anastomosis from the anal verge will be determined by assessing the markings 
on the stapler or by rigid proctoscopy, at the discretion of the surgeon. The site of the proximal 
anastomosis segment and the level of the inferior mesenteric artery and vein ligation will also be 
recorded.  
Follow-up and Post-operative Complications: 
All subjects will be followed to monitor occurrence of post-operative complications up to Week 8 post- 
surgery (±14d). All subjects will have study specific follow-up visits on Day 1, date of discharge, Week 8 
and the date of ileostomy closure (if applicable). Subjects with a discharge date later than Week 8 who 
did not have an ileostomy, will be followed until the Week 8 visit. All subjects with a diverting ileostomy 
must have flexible sigmoidoscopy or proctoscopy and/or contrast enema to evaluate the anastomosis 
between 3 weeks postoperatively and the Week 8 visit (±14d).  
Subjects who present with a clinical suspicion of anastomotic leak during the study who do not require 
urgent reoperation will have a CT scan with PO and, if diverted or if necessary, rectal contrast to confirm. 
A leak is considered confirmed if any evidence of endoluminal contents (air, fluid, GI contents or contrast 
material) through the anastomosis is identified by imaging, drain output or at reoperation, or by 
endoscopic evidence of an anastomotic defect. All scans will be reviewed by an independent radiologist 
for confirmation. The presence of infection or abscess thought to be related to the anastomosis may be 
classified as an anastomotic leak at the surgeon’s discretion even if it cannot be definitively identified as 
visualized during an operation or by contrast extravasation. All anastomotic leaks will be followed until 
resolution. 
All adverse events and post-operative complications occurring during the study period will be reported 
and graded according to the Clavien-Dindo system (Table 2). 
Analysis of anastomotic leak rate will be based on the occurrence of a leak according to the protocol 
definition at any time during the study up to Week 8 (±14d).  

 
 
 
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Study Population: 
The study will enroll a minimum of 450 and maximum of 1000 subjects scheduled to undergo an open 
or minimally invasive LAR. To be eligible for the study, subjects must meet the following main inclusion 
criteria: 
• 18 years of age and older.  
• Undergoing open, or minimally invasive LAR for the treatment of rectal or rectosigmoid neoplasms. 
o 
Subjects with rectal or rectosigmoid neoplasm(s) may be treated with or without 
neoadjuvant therapy. Long-course neoadjuvant therapy must have been completed ≥6 
weeks prior to LAR surgery (Day 0). 
• Have a planned low circular stapled or transanally hand sewn anastomosis ≤10 cm from the anal 
verge, with or without reservoir/pouch. 
Subjects meeting any of the following criteria will be excluded from the study: 
• Undergoing stapled anastomosis with the use of an experimental or non-FDA approved stapler. 
• Undergoing ileoanal reconstruction, proctocolectomy, abdominoperineal resection, Hartmann’s 
procedure, Hartmann’s reversal or multiple synchronous colon resections (e.g., LAR and concomitant 
right colectomy). 
• Subject has received and completed a course of pelvic radiotherapy ≥ 6 months prior to LAR surgery 
(Day 0). 
• Subject has previously undergone a leftsided colon resection. 
• Subject has previously undergone a rectal resection. 
• Subject has recurrent rectal or rectosigmoid cancer. 
•  Has a diagnosis of locally advanced rectal or rectosigmoid cancer undergoing extended en bloc 
operations. 
• Has a diagnosis of Stage IV rectal or rectosigmoid cancer with any multifocal metastases or single site 
metastasis with tumor size of > 2 cm. 
    a. Intra operative incidental finding or preoperative suspicion of Stage IV cancer with isolated (single 
site) metastasis (≤ 2 cm) or limited metastases (≤3), with largest lesion ≤ 2 cm in size, does not exclude 
the subject. 
• Diagnosis of inflammatory bowel disease.Hepatic dysfunction defined as MELD Score >12.  
• Renal dysfunction with serum creatinine ≥ 2.0 mg/dL. 
• Known allergy or history of adverse reaction to ICG, iodine or iodine dyes. 
• Pregnant or lactating female. 
Study Devices: 
PINPOINT® Endoscopic Fluorescence Imaging System 
An endoscopic fluorescence imaging system for high definition (HD) visible (VIS) light and near infrared 
(NIR) fluorescence imaging that includes the following components: 
• A surgical endoscope optimized for VIS/NIR illumination and imaging.  
• A camera head that is also optimized for VIS/NIR imaging and mounts to the endoscope eyepiece  
• A flexible light guide cable. 
• An endoscopic Video Processor/Illuminator for VIS/NIR illumination to the surgical endoscope via a 
flexible light guide cable, and the image processing required to generate simultaneous, real-time HD 
video color and NIR fluorescence images. 
• A high-definition medical video recorder that allows the capture of still images and video. 
• The PINPOINT PAQ containing the imaging agent and aqueous solvent. 
SPY ELITE® Intraoperative Perfusion Assessment System. 
An open intraoperative fluorescence imaging system for HD and NIR fluorescence imaging that includes 
the following components: 
 
SPY Elite® Device 
 
SPY Elite® PAQ containing the imaging agent, aqueous solvent and sterile drape. 
The imaging agent used is indocyanine green (ICG), which is a sterile, water-soluble tricarbocyanine dye 
with a peak spectral absorption at 800-810 nm in blood plasma or blood. ICG contains not more than 

 
 
 
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5.0% sodium iodide. 
Study Variables: 
Primary: 
Incidence of post-operative anastomotic leak in each study arm. 
Secondary: 
• Proportion of PERFUSION arm subjects in whom the PINPOINT or SPY Elite system provided 
sufficient visualization for assessment of blood flow and related tissue perfusion during the procedure. 
• Incidence of post-operative abscess in each study arm. 
 
Safety:  
• Incidence of treatment related adverse device events and surgical complications. 
• Clavien-Dindo grading of post-operative complications. 
• Concomitant medications and procedures. 
Study Procedures and Assessments: 
The following tests and procedures will be performed: 
• Assessment of eligibility criteria. 
• Demographics, vital signs, height, weight, surgical predictive factors. 
• Hemoglobin measurement (pre-operative and Day 1). 
• Randomization to the PERFUSION or STANDARD Arm.  
• Low anterior resection according to surgeon’s standard practice inclusive of the hospital/institution’s 
standard pre-operative, post-operative and post discharge care. 
o 
Circular stapled or transanally hand sewn anastomosis. 
o 
Open or minimally invasive low anterior resection 
o 
Minimally invasive low anterior resection with or without hand-assist. 
o 
Minimally invasive low anterior resection with or without open-assist. 
o 
Conversion to open procedure. 
o 
Colorectal or coloanal reconstruction with or without reservoir/pouch. 
o 
Proximal diverting ileostomy as indicated. 
• PERFUSION Arm (only): 
o 
Imaging agent administration via central/peripheral IV line. 
o 
Perfusion assessments of colon transection margin prior to proximal transection. 
o 
Perfusion assessment of the proximal and distal mucosal aspect of completed 
anastomosis (except hand sewn coloanal anastomosis). 
• Assessment of adverse device effects up to 24 hrs. post-surgery. 
• Documentation of actual surgical technique. 
• Assessment of anastomotic leak, adverse events and other post-operative complications. 
o 
CT scan if clinical suspicion of anastomotic leak. 
• Classification of adverse events and post-operative complications using Clavien-Dindo system (Table 
2). 
• Ileostomy closure. 
o 
Routine endoscopy and/or contrast enema of anastomosis between 3 weeks post-
surgery and Week 8 visit if subject has an ileostomy. 
• Concomitant medications. 
• Follow-up visits on Day 1, date of discharge, Week 8, and date of ileostomy closure (if applicable). 
Subjects with a discharge date later than Week 8, who do not have an ileostomy, will have the last 
study visit at Week 8 visit. The last study visit for subjects with an ileostomy will occur on the date of 
closure, or at Week 8, whichever is earlier. 
Surgeon Qualification: 
• Training on use of PINPOINT by qualified Novadaq representatives.  
• Perform at least 3 perfusion assessment (proximal and transanal perfusion assessments) procedures 
with PINPOINT prior to enrolling subjects in the study. 
• Training on use of SPY Elite by qualified Novadaq representatives. 

 
 
 
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• Perform at least 3 perfusion assessment procedures (proximal only) with SPY Elite prior to using SPY 
Elite in the study. 
Sample Size and Statistical Analysis: 
The PILLAR III study is designed to allow a single mid-trial reassessment of sample size, employing the 
method of Mehta and Pocock22. A minimum of 450 and a maximum of 1000 subjects will be enrolled at 
up to 30 centers.. The trial will utilize a group sequential design with Pocock stopping boundaries with a 
planned sample size of 800 subjects. A futility boundary will also be incorporated.  A single interim 
analysis will be conducted on the first 450 subjects enrolled with assessment of the primary endpoint.  If 
the stopping boundary for trial success is not met at this interim analysis point and futility is not declared, 
the Mehta and Pocock method of sample size re-estimation based on promising zones will be applied to 
evaluate whether an increase in sample size above the planned 800 subjects is warranted (up to a 
maximum of 1.25 times the original planned sample size, i.e. 1000 subjects).  
  
At the time of the interim analysis, the primary objective null hypothesis will be tested against the one-
sided alternative hypothesis that the anastomotic leak rate in the PERFUSION arm is less than that 
experienced with the STANDARD surgical approach. If the p-value is less than a pre-specified threshold 
based on the Pocock stopping boundary, the null hypothesis will be rejected, whereas if the p-value is 
greater than the futility threshold, the trial will be considered futile. In either of these eventualities, no new 
enrollments will occur, and follow-up will only continue per regulatory requirements. However, if the p-
value falls between these two thresholds, an evaluation of conditional power will be made to determine 
if a re-estimated larger sample size is warranted.  The trial will then continue to either the planned sample 
size of 800 subjects or the re-estimated sample size of up to a maximum of 1000 subjects. 
A modified Intent-to-Treat (mITT) analysis population will be utilized for the primary analysis. The first 
two specified secondary objectives are intended to support product labeling. They will be tested in 
sequential fashion. i.e., if and only if the primary objective passes according to the criteria above, testing 
will proceed to the first secondary objective (proportion of PERFUSION arm subjects in whom the 
PINPOINT or SPY Elite system provided sufficient visualization for assessment of blood flow and related 
tissue perfusion during the procedure). If and only if that objective passes, testing will proceed to the 
second secondary objective (incidence of abscess requiring surgical management). The standard for 
“passing” the secondary objectives will be a p-value less than 0.025 one-sided. 
Study Duration: 
The study is expected to begin in the first half of 2015 and complete enrollment within 24 months. 
Therefore, the study is expected to complete in 2017.   

 
 
 
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TABLE OF CONTENTS 
PROTOCOL APPROVAL ..................................................................................................... 2 
PROTOCOL APPROVAL ..................................................................................................... 3 
PROTOCOL APPROVAL ..................................................................................................... 4 
PROTOCOL SUMMARY ...................................................................................................... 5 
ABBREVIATIONS AND DEFINITIONS .............................................................................. 13 
1 
INTRODUCTION AND BACKGROUND ................................................................. 14 
1.1 
Background ........................................................................................................... 14 
1.2 
Previous Human Experience ................................................................................ 15 
1.3 
Potential Risks and Benefits to Human Subjects ................................................ 16 
2 
STUDY OBJECTIVES ............................................................................................. 17 
2.1 
Objectives .............................................................................................................. 17 
2.1.1 
Primary Objective .................................................................................................... 17 
2.1.2 
Secondary Objectives .............................................................................................. 17 
3 
INVESTIGATIONAL PLAN ..................................................................................... 17 
3.1 
Study Design Overview ......................................................................................... 17 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................ 19 
4.1 
Number of Subjects ............................................................................................... 19 
4.2 
Inclusion Criteria ................................................................................................... 20 
4.3 
Exclusion Criteria .................................................................................................. 20 
4.4 
Withdrawal of Subjects ......................................................................................... 21 
5 
RANDOMIZATION, BLINDING AND SUBJECT IDENTIFICATION 
PROCEDURES ....................................................................................................... 21 
5.1 
Randomization ....................................................................................................... 21 
5.1.1 
Randomization Procedure ....................................................................................... 22 
5.2 
Subject Identification ............................................................................................ 22 
6 
STUDY TREATMENTS ........................................................................................... 23 
6.1 
PINPOINT Endoscopic Device Specifications ..................................................... 23 
6.2 
SPY Elite Intraoperative Device Specifications ................................................... 24 
6.3 
Imaging Agent Specifications............................................................................... 25 
6.3.1 
Installation, Training and Storage ............................................................................ 26 
6.4 
Concomitant Treatment ........................................................................................ 26 
7 
RISKS/PRECAUTIONS .......................................................................................... 27 
7.1 
PINPOINT System – Endoscopes, Camera and Video Processor Illuminator 
Unit ......................................................................................................................... 27 

 
 
 
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7.2 
SPY Elite System. .................................................................................................. 27 
7.3 
Imaging Agent (ICG) .............................................................................................. 27 
8 
STUDY PROCEDURES .......................................................................................... 28 
8.1 
Schedule of Events ............................................................................................... 28 
8.2 
Baseline/Screening Procedures (Day -30 to Day 0) ............................................ 30 
8.3 
Day 0 Procedures .................................................................................................. 30 
8.3.1 
ASCRS Guidelines for LAR ..................................................................................... 31 
8.3.2 
Perfusion Assessment ............................................................................................. 32 
8.3.2.1 
Imaging Agent Dosing and Administration ........................................................ 32 
8.3.2.2 
Proximal Transection Margin ............................................................................ 33 
8.3.2.3 
Anastomosis .................................................................................................... 34 
8.4 
Post-operative Follow-up Visits (Day 1 to Last Study Visit) ............................... 35 
8.5 
Image Acquisition and Transmission .................................................................. 36 
9 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS ........... 36 
9.1 
Definitions .............................................................................................................. 36 
9.1.1 
Adverse Event (AE) ................................................................................................. 36 
9.1.2 
Adverse Device Effect (ADE) ................................................................................... 37 
9.1.3 
Serious Adverse Event (SAE) .................................................................................. 37 
9.1.4 
Unanticipated Adverse Device Effect (UADE) .......................................................... 37 
9.2 
Adverse Event Descriptions ................................................................................. 38 
9.2.1 
Intensity ................................................................................................................... 38 
9.2.2 
Relationship ............................................................................................................ 38 
9.3 
Reporting and Evaluation of Serious Adverse Events and Unanticipated 
Adverse Device Effects ......................................................................................... 38 
9.4 
Surgical Complications: Special Instructions ..................................................... 38 
9.5 
Follow-up for Adverse Events and Adverse Device Effects ............................... 40 
9.6 
Reporting of Technical Complaints/Device Deficiencies .................................... 40 
9.6.1 
Definitions ............................................................................................................... 40 
9.6.2 
Reporting Procedures .............................................................................................. 40 
9.7 
ADEs, Technical Complaints/Device Deficiencies that are UADEs.................... 40 
10 
STATISTICAL CONSIDERATIONS ........................................................................ 41 
10.1 
Primary Objective .................................................................................................. 41 
10.2 
Hypotheses ............................................................................................................ 41 
10.3 
Statistical Analysis ................................................................................................ 41 
10.4 
Sample Size Considerations ................................................................................. 41 

 
 
 
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10.5 
Adaptive Design and Analysis Plan ............................ Error! Bookmark not defined. 
10.6 
Study Populations for Analysis ............................................................................ 42 
10.6.1 Modified Intent-to-Treat (mITT) ................................................................................ 42 
10.6.2 As-Treated (AT) ....................................................................................................... 42 
10.6.3 Per-protocol (PP) ..................................................................................................... 43 
10.7 
Safety (S) ................................................................................................................ 43 
10.8 
Secondary Objectives ........................................................................................... 43 
10.9 
Handling of Missing Data ...................................................................................... 44 
10.10 Pooling of Site Data ............................................................................................... 44 
11 
ESTIMATED DURATION OF THE STUDY ............................................................. 44 
12 
STUDY ETHICAL CONSIDERATIONS ................................................................... 44 
12.1 
Ethical Conduct of the Study ................................................................................ 44 
12.2 
Informed Consent .................................................................................................. 45 
12.3 
Institutional Review Board, Ethics Committee, or Research Ethics Board 
(IRB) ....................................................................................................................... 45 
13 
ADMINISTRATIVE PROCEDURES ........................................................................ 45 
13.1 
Sponsor's Responsibilities ................................................................................... 45 
13.1.1 Public Disclosure of Clinical Trials ........................................................................... 45 
13.1.2 Study Supplies ........................................................................................................ 45 
13.1.3 Investigator Training ................................................................................................ 45 
13.1.3.1 Study Initiation Visit .......................................................................................... 45 
13.1.3.2 PINPOINT and SPY Elite System ..................................................................... 46 
13.1.4 Ongoing Communication of Safety Information During the Study ............................ 46 
13.1.5 Study Monitoring ..................................................................................................... 46 
13.1.6 Records Retention ................................................................................................... 46 
13.2 
Investigator's Responsibilities ............................................................................. 46 
13.2.1 Reporting and Recording of Study Data .................................................................. 46 
13.2.2 Source Documentation ............................................................................................ 46 
13.2.3 Study Devices ......................................................................................................... 47 
13.2.4 Records Retention ................................................................................................... 47 
13.3 
Data and Safety Review ........................................................................................ 47 
13.4 
Independent CT/Contrast Enema Scan Assessment .......................................... 48 
14 
DATA MANAGEMENT ........................................................................................... 48 
15 
POLICY FOR PUBLICATION AND PRESENTATION OF DATA ........................... 48 
16 
REFERENCES ........................................................................................................ 50 
 

 
 
 
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ABBREVIATIONS AND DEFINITIONS 
ADE 
Adverse device effect 
AE 
Adverse event 
AR 
Anterior Resection 
ASA 
American Society of Anesthesiologists 
AT 
As-Treated 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CT 
Computerized Tomography 
DSMC 
Data and Safety Monitoring Committee 
DRSI 
Disposable Rigid Scope Introducer 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HD 
High Definition 
IA 
Imaging Agent 
IBD 
Inflammatory Bowel Disease 
ICH 
International Conference on Harmonization 
ICG 
Indocyanine Green 
IMA 
Inferior Mesenteric Artery 
IMV 
Inferior Mesenteric Vein 
IPAA 
Ileal Pouch – Anal Anastomosis 
IR 
Independent Radiologist 
IRB 
Institutional Review Board 
IV 
Intravenous 
LAR 
Low Anterior Resection 
MELD 
Model for End-Stage Liver Disease 
mITT 
Modified Intent-to-Treat 
NGT 
Nasogastric Tube 
NIR 
Near-Infrared 
NPO 
Nil per Os 
PFN 
Perfusion  
PILLAR II 
Perfusion Assessment in Laparoscopic Left Anterior Resection Multicenter study  
PINPOINT 
PINPOINT Endoscopic Fluorescence Imaging System 
PO 
Per Os 
POD 
Post-operative Day 
PP 
Per-Protocol 
PSG 
PILLAR III Study Group 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
STD 
Standard 
US 
United States 
UADE 
Unanticipated Adverse Device Effect 
VIS 
Visible 

 
 
 
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1 INTRODUCTION AND BACKGROUND 
The study will be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and in compliance with the protocol, Good Clinical Practice (GCP) and all 
applicable regulations.  
1.1 Background 
This study will investigate the effectiveness of assessing perfusion of colon and rectal tissue using 
PINPOINT endoscopic fluorescence imaging (PINPOINT) or SPY Elite intraoperative imaging in 
reducing the post-operative anastomotic leak rate in low anterior resection (LAR). 
 
LAR with low colorectal or low coloanal anastomosis is an accepted surgical technique for 
surgically treating rectal and rectosigmoid neoplasms. The American Society of Colon and Rectal 
Surgeons defines LAR as a colorectal resection with anastomosis of the colon to the 
extraperitoneal rectum1 and defines an LAR with a coloanal anastomosis as a colorectal resection 
with anastomosis of colon to the anal canal circumferentially1. LAR may be accomplished by 
utilizing modern minimally invasive surgery techniques or by open surgery via laparotomy.  
Minimally invasive techniques for LAR include conventional laparoscopic or laparoscopic hand-
assisted procedures, and robotic surgery (da Vinci Surgery, Intuitive Surgical Inc.) or robotic-
assisted laparoscopic procedures. Minimally invasive techniques for colorectal surgery have 
become more accepted in recent years due to patient related benefits that include reduced post-
operative pain, earlier return of bowl function, shorter hospital stay and earlier ability to return to 
normal daily activities2-4. Laparoscopic surgery has also been shown to have lower post-operative 
complication and mortality rates as well as lower hospital costs4.  
Both minimally invasive and open methods are routinely performed. The decision to perform a 
minimally invasive or open procedure is made based on surgeon preference and training, surgical 
feasibility and patient anatomy and condition. Specifically, the tumor size and location, patient 
internal anatomy, obesity, and the effects of prior radiation will affect the ability of the surgeon to 
perform adequate resection in a minimally invasive fashion. These factors are considered when 
deciding to perform an open surgery versus a minimally invasive operation. Additionally, findings 
during a planned minimally invasive operation or a change in the patient’s operative condition 
may cause the surgeon to convert to an open procedure during the operation. Converted surgery 
can be expected in 6-24% of cases4. 
Minimally invasive and open LAR procedures are both considered to be oncologically safe for the 
patient. Data indicates that the oncologic outcomes between minimally invasive and open 
resections for treatment of primary rectal cancer are the same3. A recent retrospective 
comparative study has shown that there is no significant difference in the 5 year local recurrence 
rate and cancer free survival rate between laparoscopic and open surgery2.  
There are a number of complications that can occur after LAR, with anastomotic complications 
being the most serious. Anastomotic bleeding, leaks, strictures, and fistulas are complications 
that may be related to surgical technical factors such as tension, stapler malfunction and tissue 
ischemia; or to patient related factors such as male sex, local sepsis, poor nutrition, 
immunosuppression, morbid obesity and/or radiation exposure5. Anastomotic leak is considered 
the most dreaded of complications and is reported to occur 3-20% of the time in colorectal 
surgery6-10 and the risk increases for lower anastomoses. Anastomoses below 10 centimeters 

 
 
 
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(cm) from the anal verge have been shown to be a specific predictor of leak in a prospective 
study7. Another recent prospective randomized study in patients undergoing a colorectal resection 
(LAR, proctocolectomy, or Hartmann’s reversal, with low colorectal or coloanal anastomosis or 
ileoanal pouch anal anastomosis [IPAA] procedures) with planned anastomosis ≤10 cm from the 
anal verge demonstrated an overall leak rate of 12%11.  
Anastomotic leaks can be devastating for the patient as they can cause significant morbidity and 
increased mortality. Surgical risks are minimized as much as possible by using proper technique 
in constructing the anastomosis and by temporary ileostomy when felt to be necessary. One of 
the key technical issues in mitigating risk of anastomotic leak is ensuring adequate tissue 
perfusion in the region of the anastomosis. The blood supply of the distal and/or proximal 
segments of colon are thought to affect anastomotic healing and blood flow reduction at the rectal 
stump has been shown to be associated with an increased rate of anastomotic leak12. Standard 
surgical care includes an assessment which can include visualization by white light, palpation of 
the mesentery, bleeding from the cut edge when the colon or rectum is divided and visible blood 
flow from the cut marginal artery when dividing the colon and mesentery for the proximal margin 
of resection. These techniques are used variably by surgeons with no true objective measure to 
guide treatment. Intraoperative near infrared (NIR) fluorescence imaging to assess colon and 
rectal tissue perfusion is a relatively new technique that may help to reduce the risk of leaks 
occurring as a result of inadequate perfusion. Several studies published within the last 4-5 years 
have shown results that suggest NIR fluorescence imaging may play a role in reducing 
anastomotic leaks.  
PINPOINT acquires near-infrared (NIR) fluorescence images of an imaging agent (indocyanine 
green [ICG]) to allow for visual assessment of colon and rectal tissue perfusion during surgery. 
The recently completed PILLAR II Multicenter Study (PILLAR II) investigated the utility and 
feasibility of intra-operative perfusion assessment using PINPOINT in LAR procedures with a 
planned anastomosis 5-15 cm from the anal verge. Results indicate that PINPOINT is a safe and 
feasible tool for intra-operative assessment of tissue perfusion during colorectal resection and 
may lead to a decreased incidence of anastomotic leak13. 
1.2 Previous Human Experience 
Several studies using similar technology to PINPOINT and SPY Elite have been conducted to 
investigate the feasibility of using NIR ICG induced fluorescence angiography in assessing tissue 
perfusion during colorectal resection to potentially reduce the rate of anastomotic leak have been 
published.  
The PILLAR II study was conducted to demonstrate the utility and feasibility of intra-operative 
perfusion assessment using PINPOINT NIR ICG induced fluorescence angiography at the time 
of anastomosis creation13. 
One hundred and forty-seven patients were enrolled, of whom 139 were eligible for final analysis. 
The average age of patients was 58 ±14 years, and 53% of patients were male. Obesity (Body 
Mass Index [BMI] >30) was prevalent in 30% and the majority of patients were American Society 
of Anesthesiologists (ASA) II (53%). Diverticulitis (44%), rectal cancer (25%) and colon cancer 
(21%) were the most prevalent pre-operative diagnoses. Of the patients with rectal cancer (N=35), 
43% underwent pre-operative pelvic radiation. Cardiovascular disease (44%), and urogenital 
disease (40%) were the most prevalent comorbidities. 

 
 
 
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Laparoscopic resection was attempted in 86% and robotic surgery in 14% of the patients imaged. 
There was an overall conversion rate of 7.8% (N=12), of which 5 patients were imaged, and 7 
patients were dropped out of analysis due to intraoperative decision to not image. The splenic 
flexure was mobilized in 81% of patients, and a high ligation of the inferior mesenteric artery (IMA) 
was performed in 62% of cases.  Successful imaging was obtained in 98.6% of cases in which 
perfusion imaging was attempted. Imaging was unsuccessful in 2 patients secondary to 
equipment malfunction. Fluorescence angiography imaging changed the surgical plan in 11 
(7.9%) patients. This included revision of the point of proximal colon transection as indicated by 
perfusion assessment in 9 patients (6.5%); takedown and revision of anastomosis after transanal 
perfusion assessment in one patient; and confirmation of viability of anastomosis where there was 
concern based on white light imaging in one patient. The use of fluorescence angiography with 
findings of adequate perfusion altered the intraoperative plan for diversion to no diversion in this 
patient. There were no anastomotic leaks in the 11 patients in whom a change in the surgical plan 
occurred based on fluorescence angiography findings.  
Post-operative morbidity was reported in 17% of patients of which 12% was secondary to surgical 
procedure and 2 (1.4%) were severe in nature. There were only 2 (1.4%) anastomotic leaks 
reported, both diagnosed clinically and confirmed via radiological findings. Both patients had low 
ligation of IMA with an end-to-end anastomosis without diversion. One patient had rectal cancer 
with no history of pre-operative chemotherapy/radiation and underwent a laparoscopic low 
anterior resection with anastomosis at 6 cm, with splenic flexure mobilization, and had an 
operative time of 6 hours. A defect of the anastomosis on Computed Tomography (CT) scan 
obtained due to clinical suspicion on postoperative day 12 was discovered, and the patient was 
treated with a re-admission, antibiotics and transgluteal percutaneous drainage without diversion. 
The second patient had a diagnosis of diverticulitis, and underwent a laparoscopic anterior 
resection with anastomosis at 11cm and an operative time of 3 hours. Patient was diagnosed on 
post-operative day 12 by CT scan, which showed a small abscess containing air adjacent to the 
anastomosis and was treated with re-admission and antibiotics. Both patients had full resolution 
of symptoms and no further treatment was required.  
1.3 Potential Risks and Benefits to Human Subjects 
PINPOINT is classified by the United States Food and Drug Administration (FDA) as a Class II 
medical device with a Product Code of GCJ. PINPOINT is not identified as a significant risk device 
on the FDA Information Sheet titled "Significant Risk and Non-significant Risk Medical Device 
Studies". PINPOINT is a commercially available product in the United States (US). PINPOINT 
has a 510(k) clearance from the FDA for the following indication:   
“The PINPOINT system is intended to provide real-time endoscopic visible and endoscopic 
NIR fluorescence imaging. PINPOINT enables surgeons to perform routine visible light 
endoscopic procedures as well as further visually assess vessels, blood flow and related 
tissue perfusion with near infrared imaging during minimally invasive surgery”. 
SPY Elite is classified by the United States FDA as a Class II medical device with a Product Code 
of IZI. SPY Elite is a commercially available product in the United States. SPY Elite has a 510(k) 
clearance from the FDA for the following indication: 
“The SPY Elite System is an imaging system used in capturing and viewing fluorescence 
images for the visual assessment of blood as an adjunctive method for the evaluation of 

 
 
 
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tissue perfusion, and related tissue-transfer circulation in tissue and free flaps used in 
plastic, micro, reconstructive, gastrointestinal, and cardiovascular surgical procedures” 
The imaging agent, ICG is approved for human use by the FDA. The most serious risk of ICG 
when administered intravenously in humans, is anaphylactic death, which has been reported 
following ICG administration during cardiac catheterization14,15.  
These and other risks of the PINPOINT system or SPY Elite system in humans are described 
further in Section 7, Risks/Precautions. For more detailed information, please refer to the 
PINPOINT Operator’s Manual16 or SPY Elite Operator’s Manual18. 
 
2 STUDY OBJECTIVES 
2.1 Objectives 
2.1.1 
Primary Objective 
To demonstrate an improvement in post-operative anastomotic leak rate in low anterior resection 
procedures where colon and rectal tissue perfusion is evaluated using PINPOINT Endoscopic 
Fluorescence imaging or SPY Elite Intraoperative imaging as an adjunct to standard surgical 
practice compared to surgical procedures performed according to standard surgical practice 
alone. 
2.1.2 
Secondary Objectives 
To evaluate the ability of the PINPOINT system or SPY Elite system to provide sufficient 
visualization for assessment of blood flow and related tissue perfusion during the procedure. 
To evaluate the effectiveness of assessing perfusion of colon and rectal tissue using PINPOINT 
or SPY Elite in reducing the rate of post-operative abscess requiring surgical management. 
 
3 INVESTIGATIONAL PLAN 
3.1 Study Design Overview 
This is a randomized, controlled, parallel, multicenter study to determine the difference in post-
operative anastomotic leak rate in low anterior resection procedures where colon and rectal tissue 
perfusion is evaluated using PINPOINT and/or SPY Elite as an adjunct to standard surgical 
practice compared to surgical procedures performed according to standard surgical practice 
alone. The study incorporates a two-stage group sequential adaptive design that allows a single 
interim look and a mid-trial reassessment of sample size. The planned sample size is 800 subjects 
with a minimum of 450 and a maximum of 1000 subjects to be enrolled at up to 40 centers in 
North America. Prior to enrolling study subjects, participating surgeons at each center will be 
trained to perform perfusion assessment with PINPOINT and SPY Elite. 
Screening: 
Patients scheduled for a minimally invasive, or open low anterior resection (LAR) with a planned 
anastomosis located 10 cm or less from the anal verge will be evaluated at baseline to determine 
if they meet the inclusion/exclusion criteria of the protocol. Subjects will be assessed to determine 
overall health status, including demographics, vital signs and predictive factors that may influence 

 
 
 
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surgical outcomes. Eligible patients who provide informed consent will be considered for inclusion 
into the study. 
Day 0: 
During anesthesia, subjects will be randomized (1:1) to either the PERFUSION (PFN) Arm or 
the STANDARD (STD) Arm. Subjects in each group will be randomized according to an 
independently generated randomization scheme to receive perfusion assessment with 
PINPOINT and/or SPY Elite during the surgical procedure or to receive the standard of care 
procedure. Randomization will be stratified based on investigative site and prior neoadjuvant 
therapy. Subjects are considered enrolled upon randomization. 
FIGURE 1. Group Assignment and Randomization 
 
Subjects in the PFN Arm will undergo a LAR according to the surgeon’s standard practice with 
the addition of intraoperative imaging using PINPOINT and/or SPY Elite NIR fluorescence 
imaging to assess colon and rectal tissue perfusion during the following steps of the procedure: 
 
assessment of proximal transection margin of the colon after IMA ligation; prior to 
transection. 
 
assessment of the mucosal aspect of the completed anastomosis (with the exception of 
hand sewn coloanal anastomoses which will involve assessment of the mucosal aspect 
of the proximal colon only) 
 
Subjects in the STD Arm will undergo a LAR according to the surgeon’s standard practice only.  
 
All subjects will receive the hospital/institution and surgeon’s standard pre-operative, post-
operative and post discharge care with the addition of any study specific requirements. An air leak 
test on all anastomoses (with the exception of hand sewn coloanal anastomosis when applicable) 
will be performed in the surgeon’s standard fashion and documented. 

 
 
 
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The LAR procedure will adhere to the ASCRS Practice Parameters for the Management of Rectal 
Cancer19 and will include mobilization and early devascularization (e.g. IMA and IMV ligation) as 
well as splenic flexure mobilization. Details of the actual surgical technique including use of hand-
assisted technique and/or conversion to open, and any changes to the operative plan will be 
documented post-operatively. The surgeon’s ability to sufficiently assess blood flow and related 
tissue perfusion using PINPOINT and/or SPY Elite will be recorded for subjects in the PFN Arm. 
The final height of the anastomosis from the anal verge will be determined by assessing the 
markings on the stapler or by rigid proctoscopy at the discretion of the surgeon. The site of the 
proximal anastomosis segment and the level of the inferior mesenteric artery and vein ligation will 
be recorded17.  
Follow-up and Post-operative Complications: 
All subjects will be followed to monitor occurrence of adverse events (AE) and post-operative 
complications up to Week 8 (56 ±14 days) post-surgery. All subjects will have study specific 
follow-up visits on Day 1, date of discharge, Week 8 and the date of ileostomy closure (if 
applicable). Subjects with a discharge date later than Week 8, will be followed until discharge if 
the Investigator documents that the extended hospitalization is directly related to the surgical 
procedure or the PINPOINT and/or SPY Elite System. All subjects with a diverting ileostomy must 
have endoscopy and/or contrast enema of the anastomosis between 3 weeks post-surgery and 
the Week 8 visit (±14 days).  
Subjects who present with a clinical suspicion of anastomotic leak during the study who do not 
clinically require an urgent reoperation will have a CT scan with PO and, if necessary, rectal 
contrast to confirm. A leak is considered confirmed if endoluminal contents (air, fluid, GI contents 
or contrast material) through the anastomosis is identified by imaging, drain output or at 
reoperation. The scans will be reviewed by an independent radiologist for confirmation. The 
presence of infection or abscess thought to be related to the anastomosis may be classified as 
an anastomotic leak at the surgeon’s discretion even if it cannot be definitively identified as 
visualized during an operation or by contrast extravasation. All anastomotic leaks will be followed 
until resolution.   
For patients with a diverting ileostomy, a leak may be identified by direct visualization of an 
anastomotic defect via sigmoidoscopy or by rectal contrast imaging, regardless of presence or 
absence of clinical symptoms. 
All AE and post-operative complications occurring during the study period will be reported and 
graded according to the Clavien-Dindo system20. 
Analysis of anastomotic leak rate will be based on the occurrence of a leak according to the 
protocol definition at any time during the study up to Week 8.  
This study is evaluating the utility of the PINPOINT or SPY Elite system only, and therefore the 
study protocol describes the requirements and use of these devices only.  
4 SELECTION AND WITHDRAWAL OF SUBJECTS  
4.1 Number of Subjects 
A minimum of 450 and a maximum of 1000 subjects will be enrolled.  

 
 
 
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4.2 Inclusion Criteria 
To be eligible for the study, a subject must fulfill all of the following criteria: 
1. Be 18 years of age or older. 
2. Be undergoing open, or minimally invasive LAR for the treatment of a rectal or rectosigmoid 
neoplasm. 
a. Subjects with rectal or rectosigmoid neoplasm(s) may be treated with or without 
neoadjuvant therapy. Long-course neoadjuvant therapy must have been 
completed ≥6 weeks prior to LAR surgery (Day 0). 
3. Have a planned low circular stapled or transanally hand sewn anastomosis ≤10 cm from the 
anal verge. 
4. Have a colorectal or coloanal reconstruction with or without reservoir/pouch. 
5. Subjects who are women of child-bearing potential must not be pregnant or lactating, must 
have a negative pregnancy test at Day 0.  
6. Have signed an approved informed consent form for the study.  
7. Be willing to comply with the protocol.  
4.3 Exclusion Criteria 
A subject meeting any of the following criteria will be excluded from the study: 
1. Undergoing stapled anastomosis with the use of an experimental or non-FDA approved 
stapler. 
2. Undergoing ileoanal reconstruction, total colectomy or proctocolectomy, abdominoperineal 
resection, Hartmann’s procedure, Hartmann’s reversal or multiple synchronous colon 
resections (e.g., LAR and concomitant right colectomy). 
3. Has received and completed a course of pelvic radiotherapy ≥ 6 months prior to LAR surgery 
(Day 0). 
4. Has previously undergone a left sided colon resection. 
5. Has previously undergone a rectal resection. 
6. Has recurrent rectal or rectosigmoid cancer. 
7. Has a diagnosis of locally advanced rectal or rectosigmoid cancer undergoing extended en 
bloc operations.  
8. Has a diagnosis of Stage IV rectal or rectosigmoid cancer with any multifocal metastases or 
single site metastasis with tumor size of > 2 cm 
 
 
a. Intraoperative incidental finding or preoperative suspicion of Stage IV cancer 
with isolated (single site) metastasis (≤ 2 cm) or limited metastases (≤3), with largest 
lesion ≤ 2 cm in size, does not exclude the subject. 
 
9. Has a diagnosis of inflammatory bowel disease (IBD). Subjects with rectal or rectosigmoid 
cancer neoplasms and IBD are excluded. 

 
 
 
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10. Has hepatic dysfunction defined as Model for End-Stage Liver Disease (MELD) Score >12.  
11. Renal dysfunction defined as creatinine ≥ 2.0 mg/dL. 
12. Has known allergy or history of adverse reaction to ICG, iodine or iodine dyes. 
13. Has, in the Investigator's opinion, any medical condition that makes the subject a poor 
candidate for the investigational procedure, or interferes with the interpretation of study 
results. 
14. Is actively participating in another investigational clinical study which, in the Investigator’s or 
Sponsor’s opinion, would interfere in this study.  
4.4 Withdrawal of Subjects 
Subjects can voluntarily withdraw (or be withdrawn) at any time during the study.  
Investigators may withdraw a subject from the study because: 
 
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 unacceptable 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 subject's Subject Completion case report form (CRF).  
Subjects who discontinue the study prematurely will not be replaced. 
5 RANDOMIZATION, BLINDING AND SUBJECT IDENTIFICATION PROCEDURES  
5.1 Randomization 
Patients will be prospectively randomized into the PILLAR III Clinical Trial.  Randomization will 
occur at the time of surgery, just after induction of anesthesia. Prior to surgery the patient will 
have provided written informed consent, completed all baseline procedures and met the 
requirements of the study inclusion and exclusion criteria. Randomization should be performed 
as closely as possible to the point of resection to minimize the incidence of dropout.   
Patients will be randomly assigned on a one to one (1:1) basis to either the PERFUSION group 
(PFN) or the STANDARD group (STD).  Randomization will be stratified by study site and within 
site by the patients history of prior neoadjuvant therapy (chemotherapy and/or radiation vs. non-
neoadjuvant therapy) to ensure a more even distribution of baseline neoadjuvant therapy between 
treatment groups. Permuted block randomization will be performed within strata. To minimize the 
opportunity for the sequence to be predicted, the block size will be variable and randomly chosen 
from small multiples of 2 (i.e. 2, 4 or 6).  The randomization schedules for all strata will be 
generated in advance by the contracted study statistician or designee using a computerized 

 
 
 
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random number generator. Investigational sites and the Study Sponsor will not have access to 
the randomization schedules.  
Randomization will be accomplished using a sequential numbered sealed envelope system. Due 
to stratification for prior neoadjuvant therapy, a box of envelopes will be supplied for each strata 
(one for subjects who have received prior neoadjuvant therapy and another for subjects who have 
not received prior neoadjuvant therapy). Envelope seals are broken and treatment assignment is 
made only after verification of proper informed consent execution and study eligibility. In order to 
prevent any attempts to subvert the randomization process, the subject’s initials, date of birth and 
date of randomization will be written on the randomization card. The randomization card will be 
signed by the study coordinator performing the randomization procedure and a second researcher 
who will witness the randomization procedure.  
5.1.1 
Randomization Procedure 
The study coordinator or a designee will log into the EDC system and be asked a series of 
questions verifying that the patient is eligible and that informed consent has been obtained prior 
to initiating the randomization process. Once the subject is under anaesthesia, the study 
coordinator will select the randomization envelope with the lowest randomization number from the 
neoadjuvant or non-neoadjuvant randomization box depending on if the subject has received prior 
neoadjuvant therapy or not. The study coordinator will then disclose the randomization 
assignment to the Investigator. The study coordinator will then write the subject’s initials, date of 
birth, and date of randomization on the randomization card. A second study coordinator or 
designee will witness the randomization procedure and will sign and date the randomization card 
verifying that the randomization procedure was followed correctly. The randomization card will be 
maintained in the subject’s file. As there is no ability for a sham comparison, the investigator 
cannot be blinded to the use of the PINPOINT or SPY Elite device. Patients will be blinded to their 
randomization assignment until after the procedure.  
A subject is not randomized until a randomization envelope seal has been broken. The 
randomization procedure should not be initiated unless the EDC system confirms that a patient is 
eligible and verifies baseline information. If any deviations occur (errors such as misplacing 
envelopes), or if the randomization assignment is made incorrectly, the clinical site will be required 
to contact the Sponsor and await guidance on how to proceed.    
If, at any time after randomization, the subject becomes ineligible or withdraws, the subject is still 
considered randomized. If an intraoperative decision is made to perform a procedure other than 
what was intended, the subject will be categorized with respect to the definitions outlined for the 
analysis populations (see the Statistical Methods Section 10.6).  
5.2 Subject Identification 
Screening ID Number:  All subjects screened for the study shall be assigned a 5-digit “screening” 
number on the Screening Log and if they are randomized, will subsequently be assigned a Subject 
Identification Number in the electronic data capture system.  The Screening Identification Number 
shall be unique and categorize a subject in sequence of screening by an “S” followed by a 5-digit 
number. The first 2 digits identify the site and the last three digits identify the subject. For example, 
the first subject screened at site 01 is identified as screening number S-01-001. The screening 
log shall be maintained by the site to identify those subjects that have failed screening with the 

 
 
 
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reason why they did not qualify for enrollment. The screening number will be assigned 
sequentially within each study center in order of subject presentation for screening. 
Enrolled Subject ID Number:  Once a subject is randomized, they will be assigned a Subject 
Identification Number which is also a 5-digit number. The first two digits of the Subject 
Identification Number identify the site and the last three digits identify the subject. Each site will 
be given a Site Identification Number.  For example, the first subject randomized at site 01 is 
identified as subject 01-001, the next subject as 01-002, etc.   
6 STUDY TREATMENTS 
6.1 PINPOINT Endoscopic Device Specifications 
PINPOINT is an endoscopic fluorescence imaging system for high definition (HD) visible (VIS) 
light and near-infrared (NIR) fluorescence imaging. PINPOINT includes the following 
components: 
 
A surgical endoscope optimized for VIS/NIR illumination and imaging, which is available in 
different diameters, lengths and directions of view (Model: SC9100, SC9130). 
 
A camera head that is also optimized for VIS/NIR imaging and mounts to the endoscope 
eyepiece (Model: PC9002). 
 
A flexible light guide cable (Model: PC9004). 
 
An endoscopic Video Processor / Illuminator (VPI) capable of providing VIS/NIR illumination 
to the surgical endoscope via a flexible light guide cable, and the image processing required 
to generate simultaneous, real-time HD video color and NIR fluorescence images (Model: 
PC9001). 
PINPOINT is designed to be connected to a medical-grade HD color monitor, such as those 
normally used in surgical endoscopy. 
 
PINPOINT Procedure Kits with Introducer containing the imaging agent, aqueous solvent and 
disposable rigid scope introducer (DRSI)21. 
PINPOINT is connected to a high-definition medical video recorder (Sony HVO-1000) that allows 
the capture of still images and video during operation. 
PINPOINT acquires NIR fluorescence images of an imaging agent (ICG) to allow for visual 
assessment of vessels, blood flow and related tissue perfusion during minimally invasive, or open 
surgery. For the purpose of this study, PINPOINT will be used to assess perfusion of colon and 
rectal tissue during low anterior resection procedures. 
PINPOINT Procedure Kits are supplied as part of the PINPOINT System. The PINPOINT PAQ® 
contains 6 procedure kits and is indicated for use exclusively with PINPOINT.  
Each PINPOINT PAQ® (Product code: PP9036) contains: 
 
One box of sterile indocyanine green for injection, USP that contains: 
o Six single use 25 mg vials of ICG 
o Six single use 10 ml ampules of sterile Aqueous solvent 

 
 
 
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 
Twelve 3 ml syringes, sterile 
 
Twelve 10 ml syringes, sterile 
 
Six 3-way stopcocks, sterile 
 
Twelve needles, 18G, 1 inch, sterile 
 
Labels for syringes 
The PINPOINT Operator’s Manual describes the contents, use and storage of the PINPOINT 
PAQ’s. Instructions for preparation, handling and administration of ICG are also provided in the 
PINPOINT Operator’s Manual. 
PINPOINT allows simultaneous display of multiple images. Real time NIR fluorescence video 
images are acquired by using the imaging agent and may be viewed in two ways: 
PINPOINT image: 
NIR fluorescence is superimposed in pseudo-color (green) on a white light 
image 
SPY image: 
 
A black and white NIR fluorescence image is displayed 
 
PINPOINT also operates as a conventional endoscopic imaging system and provides illumination 
for real-time color (white light) HD video imaging in the area of interest.   
PINPOINT is a commercially available product in the United States (US). PINPOINT has a 510(k) 
clearance from the FDA for the following indication:   
“The PINPOINT system is intended to provide real-time endoscopic visible and endoscopic 
NIR fluorescence imaging. PINPOINT enables surgeons to perform routine visible light 
endoscopic procedures as well as further visually assess vessels, blood flow and related 
tissue perfusion with near infrared imaging during minimally invasive surgery”. 
PINPOINT is manufactured by Novadaq Technologies Inc. (Novadaq). Please refer to the current 
version of the PINPOINT Operator’s Manual16 for a full description and specifications of the 
system.  
6.2 SPY Elite Intraoperative Device Specifications 
SPY Elite is an intraoperative fluorescence imaging system that allows surgeons to capture, 
review, print and archive high-quality fluorescence images of blood flow in vessels and micro-
vessels, tissue and organ perfusion, in real-time during the course of performing a wide variety of 
surgical procedures. 
The SPY Elite System consists of the following components: 
 
SPY Elite Device 
 
SPY Elite Kit 
The SPY Elite device consists of the following components: 
 
An imaging head and camera system capable of capturing, archiving and replaying  
fluorescence images, an articulating arm and a mobile cart (LC3000) 
 
A touch screen monitor, glide-pad and keyboard 

 
 
 
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 
SPY Elite Imaging System Software and SPY Elite analysis tool kit 
 
SPY Elite PAQs containing the imaging agent, aqueous solvent and sterile drapes 
SPY Elite PAQs are supplied as part of the SPY Elite System. The SPY Elite PAQ® contains 6 
procedure kits and is indicated for use exclusively with SPY Elite 
Each SPY Elite procedure kit (Product code: LC3201) contains: 
 
One 25 mg vial of sterile indocyanine green for injection, USP 
 
One ampule Sterile Aqueous Solvent 
 
One SPY Elite Sterile Drape 
 
One SPY Elite Kit IFU 
 
SPY Elite is an open-field NIR fluorescence system that utilizes the same mode of action as the 
PINPOINT System to allow for visual assessment of vessels, blood flow and related tissue 
perfusion during gastrointestinal procedures. For the purpose of this study, SPY Elite may only 
be used to assess perfusion of the colon prior to proximal transection during the low anterior 
resection procedures at the investigator’s discretion. 
SPY Elite allows for real time NIR fluorescence video images which are acquired by using the 
imaging agent and may be viewed in SPY image mode (A black and white NIR fluorescence 
image)  
SPY Elite is classified by the United States FDA as a Class II medical device with a Product Code 
of IZI. SPY Elite is a commercially available product in the United States. SPY Elite has a 510(k) 
clearance from the FDA for the following indication: 
“The SPY Elite System is an imaging system used in capturing and viewing fluorescence 
images for the visual assessment of blood as an adjunctive method for the evaluation of 
tissue perfusion, and related tissue-transfer circulation in tissue and free flaps used in 
plastic, micro, reconstructive, gastrointestinal, and cardiovascular surgical procedures”. 
SPY Elite is manufactured by Novadaq Technologies Inc. (Novadaq). Please refer to the current 
version of the SPY Elite Operator’s Manual19 for a full description and specifications of the system.  
6.3 Imaging Agent Specifications 
The imaging agent (IA), ICG (indocyanine green for injection, USP) 25 mg for Injection in the form 
of a sterile lyophilized powder containing indocyanine green with no more than 5% sodium iodide 
is approved by the FDA for determining cardiac output, hepatic function and liver blood flow, and 
for ophthalmic angiography via intravascular administration14,15. ICG is also approved under a 
510(k) by the FDA for assessing blood flow and tissue perfusion in a variety of surgical and non-
surgical procedures16,18. ICG can be administered intravenously or intra-arterially. It absorbs light 
in the near-infrared region at 806 nm, and emits fluorescence (light) at a slightly longer 
wavelength, 830 nm. When injected intravenously, ICG rapidly and extensively binds to plasma 
proteins and is confined to the intravascular compartment with minimal leakage into the 
interstitium. This property makes it an ideal agent for the acquisition of high quality images of the 
vasculature (i.e., for NIR fluorescence angiography). 

 
 
 
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The imaging agent is supplied as part of the PINPOINT PAQ or SPY Elite PAQ for 
distribution with PINPOINT or SPY Elite and is indicated for use exclusively with 
PINPOINT or SPY Elite.  
6.3.1 
Installation, Training and Storage 
PINPOINT (and SPY Elite, if requested) will be installed by Novadaq representatives. The 
Investigator(s) and study staff shall be required to participate in training on the operational and 
procedural use of PINPOINT and SPY Elite as it relates to the conduct of this study. Training will 
be provided by Novadaq.  
Prior to enrollment, participating Investigator surgeons must be experienced in the use of 
PINPOINT for assessing perfusion of colon and rectal tissue via participation in the PILLAR II 
study or via current ongoing use of a PINPOINT system installed at the study center.  
Participating Investigators must also be experienced in the use of SPY Elite for assessing 
perfusion of colon and rectal tissue (proximal imaging only) via current ongoing use of a SPY Elite 
system at the study center, prior to utilizing SPY Elite in the study. 
Investigator surgeons new to this technique will receive PINPOINT (and SPY Elite, if requested) 
training consisting of the following: 
 
Didactic training on product and procedure. 
 
Hands on training session with clinical educators on site. 
 
Guidance on use of PINPOINT and interpretation of the images with a clinical educator during 
a minimum of 3 cases prior to study enrollment. 
 
Guidance on use of SPY Elite and interpretation of the images with a clinical educator during 
a minimum of 3 cases prior to the use of SPY Elite in the study. 
Supporting personnel operating and cleaning PINPOINT or SPY Elite will also receive training 
and be familiar with all applicable aspects of the operation and cleaning of the system. 
PINPOINT and SPY Elite should be stored at room temperature in a secure and limited access 
area available to study staff.  
6.4 Concomitant Treatment 
Any concomitant medications the subject is receiving at the start of the study (Day 0) or given for 
any reason during the study must be recorded in the CRF and source documents with the 
exception of routine medications given for preparation of surgery, during surgery and post-
operative care. These include but are not limited to the following: 
 
Sedatives and anesthetics 
 
Anticoagulants 
 
Prophylactic antibiotics 
 
Laxatives, diuretics and antacids 
 
Routine post-operative pain medications 

 
 
 
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The drug name, start and stop dates, indication, dose, frequency, and route information will be 
recorded for concomitant medications. 
Other surgical and diagnostic procedures (e.g., endoscopy) concomitant to the LAR that take 
place during the study must be recorded in the CRF and in the source document, including start 
and stop dates. 
7 RISKS/PRECAUTIONS 
Refer to the PINPOINT Operator’s Manual for a full description of the risks and precautions 
associated with all components of PINPOINT. The entire PINPOINT Operator’s Manual should 
be read before using PINPOINT. Failure to follow the instructions and warnings in the manual 
may result in unsafe operation of the system and/or injury to the patient or operator. 
Refer to the SPY Elite Operator’s Manual for a full description of the risks and precautions 
associated with all components of SPY Elite. The entire SPY Elite Operator’s Manual should be 
read before using SPY Elite. Failure to follow the instructions and warnings in the manual may 
result in unsafe operation of the system and/or injury to the patient or operator. 
7.1 PINPOINT System – Endoscopes, Camera and Video Processor Illuminator Unit 
PINPOINT is classified by the FDA as a Class II medical device with a Product Code of GCJ. 
PINPOINT is not identified as a significant risk device on the FDA Information Sheet titled 
"Significant Risk and Non-significant Risk Medical Device Studies".  
PINPOINT should only be used according to its approved Indication for Use and according to the 
study procedures described in this protocol. 
7.2 SPY Elite System. 
SPY Elite is classified by the FDA as a Class II medical device with a Product Code of IZI. SPY 
Elite is not identified as a significant risk device on the FDA Information Sheet titled "Significant 
Risk and Non-significant Risk Medical Device Studies".  
SPY Elite should only be used according to its approved Indication for Use and according to the 
study procedures described in this protocol. 
7.3 Imaging Agent (ICG) 
Systemic ICG, which is administered intravenously, is associated with some risks. ICG contains 
sodium iodide and should be used with caution in patients who have a history of allergy to iodides 
or iodinated imaging agents. Anaphylactic or urticarial reactions have been reported in patients 
with and without history of allergy to iodides. Anaphylactic deaths have been reported following 
ICG administration during cardiac catheterization14,15. 
Radioactive iodine uptake studies should not be performed for at least 1 week following ICG 
administration14,15. 
Animal reproduction studies have not been conducted with ICG. It is not known whether ICG can 
cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. It 

 
 
 
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is not known whether ICG is secreted in human milk. Women who are pregnant or lactating are 
excluded from this study. 
Subjects will most likely be administered ICG through a central line routinely placed for standard 
of care. Should a peripheral line be placed solely for the purpose of ICG intravenous 
administration, risks associated with intravenous injection include pain, bruising, ecchymosis, 
thrombosis, hematoma, infection, infiltration and/or extravasation. 
8 STUDY PROCEDURES 
8.1 Schedule of Events 
Table 1 presents the schedule of events for this study.  

PINPOINT® in LAR (PILLAR III) 
                                                    
Clinical Study Protocol PP PLR 03 
 
 
© 2015 NOVADAQ Technologies Inc. NOVADAQ, SPY Elite and PINPOINT are registered trademarks of Novadaq Technologies Inc. PILLAR, SPY PAQ and PINPOINT PAQ are trademarks of Novadaq 
Technologies Inc, 
TABLE 1.  Schedule of Events 
Procedure 
Baseline 
(Day -30 to 
Day 0) 
Day 0  (Operative Phase) 
Post-Operative Follow-Up 
Pre-Op 
Intra-Op 
Post-Op 
Day 1 
(24±12 
hrs.) 
Date of 
Dischargea 
Ileostomy 
Endoscopy/ 
Contrast 
Enema 
(Week 3 to 
Week 8 ±14d) 
Week 8 
(56±14d) 
Informed consent 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Vital signs, height, weight 
X 
 
 
 
 
 
 
 
Surgical risk factors 
X 
 
 
 
 
 
 
 
Pre-operative diagnosis 
X 
 
 
 
 
 
 
 
Pregnancy test (record in source only) 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Serum sodium, bilirubin, creatinine and INR for 
MELD Score  
X 
 
 
 
 
 
 
 
Hemoglobin, Albumin, Pre-albumin 
 
X 
Xc 
 
X 
 
 
 
Randomization (in OR, during anesthesia) 
 
 
X 
 
 
 
 
 
LAR surgical procedure 
 
 
X 
 
 
 
 
  
Imaging agent administration (treatment group only) 
 
 
X 
 
 
 
 
 
Perfusion Assessment (Perfusion arm only) 
  Proximal transection margin 
  Mucosal aspect of completed anastomosis 
 
 
 
X 
X 
 
 
 
 
 
Document actual surgical technique 
 
 
 
X 
 
 
 
 
Anastomotic leak assessment  
 
 
 
X 
X 
X 
 
X 
Surgical Complication assessment/grading 
 
 
X 
X 
X 
X 
 
X 
Endoscopy and/or contrast enema - Ileostomy 
subjects (between 3 & 8 wks.) 
 
 
 
 
 
 
Xb 
 
Concomitant medications and procedures 
X 
X 
X 
X 
X 
X 
 
X 
Adverse events/adverse device effects 
 
X 
X 
X 
X 
X 
 
Xd 
a 
Subjects with a discharge date later than Week 8, who did not have an ileostomy, will be followed until Week 8 ±14d. 
 
b 
All subjects with a diverting ileostomy must have endoscopy and/or contrast enema between 3 weeks post-surgery and the Week 8 visit. 
c 
Hemoglobin measurement at time of anastomosis if subject had any hypotensive events or blood loss over 500 ml at time of anastomosisd All subjects with adverse events thought to be related to the LAR 
procedure or the PINPOINT or SPY Elite system will be followed until resolution or deemed chronic.

PINPOINT® in LAR (PILLAR III) 
                                                    
Clinical Study Protocol PP PLR 03 
 
 
© 2015 NOVADAQ Technologies Inc. NOVADAQ and PINPOINT are registered trademarks of Novadaq Technologies Inc. PINPOINT 
and PINPOINT PAQ a 
8.2 Baseline/Screening Procedures (Day -30 to Day 0) 
After signing the informed consent form, subjects will be assigned a screening number (see 
Section 5.2) and be evaluated for eligibility into the study.  
The following procedures will be conducted during the baseline assessment: 
 
Collection of demographics, surgical risk factors, pre-operative diagnosis. 
 
Vital signs (heart rate and blood pressure), height and weight. 
 
Serum tests (bilirubin,sodium,creatinine and INR) for MELD Score 
The following online calculator from the OPTN website should be used to calculate the  
MELD Score:  
o   https://optn.transplant.hrsa.gov/resources/allocation-calculators/meld-calculator/ 
 
Pregnancy test (urine test or institution standard of care) for females of childbearing potential. 
 
8.3 Day 0 Procedures 
On Day 0, the following will be completed before randomization and surgery: 
 
Serum hemoglobin, prealbumin, and albumin measurement. 
During anesthesia, subjects will be randomized as described in Section 5.1. Subjects are 
considered enrolled upon randomization. 
According to the randomization assignment, subjects in the PERFUSION arm will receive 
perfusion assessment with PINPOINT and/or SPY Elite during surgery and undergo surgery 
according to the surgeon’s standard practice. Subjects randomized to the Standard arm will 
undergo the surgery according to the surgeon’s standard practice only. All subjects will receive 
the hospital/institution and surgeon’s standard pre-operative and post-operative care with the 
addition of any study specific requirements. The LAR will be performed according to guidelines 
from the American Society of Colorectal Surgeons (ASCRS) to minimize variability. The LAR 
procedure may include the following: 
 
Circular stapled or transanally hand sewn anastomosis 
 
Open or minimally invasive low anterior resection 
 
Minimally invasive with or without hand-assist low anterior resection. 
 
Minimally invasive with or without open-assist low anterior resection. 
 
Conversion to open procedures. 
 
Transabdominal and/or transanal total mesorectal excision. 
 
Colorectal or coloanal reconstruction with or without reservoir/pouch. 
 
Ileostomy as required. 
An intra-operative measurement of hemoglobin should be performed at the time of anastomosis 
if the subject experiences a hypotensive event requiring intraoperative management (e.g. use of 
vasopressors) or blood loss greater than 500 ml at the time of anastomosis. 
Either during or immediately post-operatively, the details of the surgery will be documented. The 
following elements must be included and recorded in the Operative case report form (CRF): 

 
 
 
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 
Actual procedure at start of operation/time of randomization 
o Occurrence of intra-operative conversion to open operation. Defined as the 
occurrence of an unplanned incision or an incision made longer or earlier than planned 
to facilitate dissection or mobilization. The use of a limited laparotomy wound to 
facilitate a low stapled anastomosis and/or specimen extraction is permissible and not 
defined as an open conversion. 
 
Level of inferior mesenteric artery (IMA) and vein (IMV) ligation. 
o High (proximal to left colonic take-off), mid (just distal to left colic takeoff) or low (colon 
marginal vessels).  
 
Final level of anastomosis from the anal verge (determined by assessing the markings on the 
stapler or by rigid proctoscopy at the discretion of the surgeon). 
 
Site of the proximal anastomosis segment (descending, sigmoid or transverse colon). 
 
Use of pelvic drains (yes or no). 
 
Ileostomy procedure performed or not performed. 
 
Revisions to the anastomosis. 
 
Criteria used to determine the point of proximal and distal transection. 
 
Criteria used in decision to divert. 
 
Occurrence of significant intra-operative hypotension events (e.g. use of vasopressors). 
 
Results of air leak test. 
 
Assessment of proximal and distal anastomotic donut (for completeness). 
 
Assessment of PINPOINT and/or SPY Elite to provide visualization of blood flow. 
 
Concomitant medications and procedures as described in Section 7.2. 
 
Adverse events according to Section 9. 
 
8.3.1 ASCRS Guidelines for LAR 
In order to minimize variability in the surgical approach, clinical guidelines from the ASCRS will 
be followed. Any deviations from the ASCRS guidelines will be recorded in the Intraoperative 
comments section of the Operative CRF. Refer to ASCRS Practice Parameters for the 
Management of Rectal Cancer (revised) for more detailed guidelines19. 
The following guidelines are recommended: 
 
A surgical exploration involving a thorough assessment of the peritoneal cavity and 
abdominal organs to detect or rule out synchronous lesions, advanced malignant disease 
or coexisting pathology. 
 
Total mesorectal excision for tumors of the middle and lower thirds of the rectum, and 
tumor-specific mesorectal excision extending at least 5 cm below the distal margin of the 
tumor for tumors of upper third of the rectum. 
 
For most rectal cancers, a 2-cm distal mural margin with a total mesorectal excision is 
adequate and a 1-cm distal mural margin is acceptable for cancers located at or below the 
mesorectal margin. 
 
Proximal vessel ligation at origin of superior rectal artery and resection of all associated 
lymphatic drainage 

 
 
 
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 
In absence of clinical involvement, an extended lateral lymph node dissection in addition 
to TME is not necessary. 
 
Definitive resection should be offered to subjects with an apparent complete clinical 
response to neoadjuvant therapy. 
 
Intraoperative anastomotic leak testing should be performed. 
 
A diverting ostomy should be considered for subjects undergoing a TME for rectal cancer. 
 
Routine prophylactic oophorectomy is not necessary, but oophorectomy is advised for 
grossly abnormal ovaries or contiguous extension of a rectal cancer. 
 
Adjuvant chemoradiotherapy is recommended for subjects with stage III or high-risk stage 
II rectal cancer who have not received neoadjuvant therapy. 
 
Adjuvant chemoradiotherapy is recommended for subjects with stage III or high-risk stage 
II rectal cancer previously treated with neoadjuvant therapy. 
 
Surgical report should include information regarding the diagnostic workup, intraoperative 
findings, and technical details of procedure. 
 
8.3.2 Perfusion Assessment 
Subjects randomized to the PFN Arm will receive intraoperative imaging using PINPOINT or SPY 
Elite NIR fluorescence imaging to assess colon tissue perfusion of proximal transection margin 
after IMA ligation; prior to transection. 
Subjects randomized to the PFN Arm will also receive intraoperative imaging using PINPOINT 
endoscopic fluorescence imaging to assess perfusion of the mucosal aspect of the completed 
anastomosis (with the exception of coloanal anastomosis when applicable). 
Subjects randomized to the PFN Arm may receive additional intraoperative imaging or repeat 
imaging based on the surgeon’s judgment. 
At the completion of the procedure, an assessment regarding the ability of the PINPOINT or SPY 
Elite system to provide sufficient visualization for assessment of blood flow and related tissue 
perfusion will be made by the surgeon for subjects in the PFN Arm. 
8.3.2.1 Imaging Agent Dosing and Administration 
The ICG solution will be prepared and administered by the appropriate qualified study and/or 
operating room personnel. Refer to Chapter 4, Handling and Preparation and Administration of 
ICG in the PINPOINT and SPY Elite Operator’s Manual for complete detailed instructions.  
The dose for imaging of the proximal colon is 3.0 ml ± 1.0 ml of a 2.5 mg/ml concentration of ICG. 
The amount of ICG administered may be adjusted within this range to allow for surgeon 
preference for brightness. Additional imaging studies may be performed within minutes, once the 
blood volume of ICG from the initial injection has reached a concentration that will not interfere 
with the subsequent images. The plasma half-life of ICG is approximately 1-3 minutes. It is 
possible that subsequent doses of ICG may need to be reduced for the additional imaging studies. 
The dose for transanal imaging of the completed anastomosis is 3.0 ml ± 1.0 ml of a 2.5 mg/ml 
solution of ICG. Transanal imaging after anastomosis may require a lower dosage of ICG, 

 
 
 
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depending on residual fluorescence from previous imaging.  
ICG is administered as a tight bolus through a peripheral or central intravenous (IV) line in order 
to ensure that the total dose of ICG is infused into the circulation as quickly as possible. It is 
important that the ICG bind to the plasma proteins in the blood as rapidly as possible to provide 
a clear, bright, useful image.  
This is followed immediately by a 10 ml saline flush. The flush ensures rapid infusion of the 
imaging agent into the circulation. Opening an IV to flush is not an adequate substitute for a bolus 
injection of the flush solution. For optimum fluorescence imaging, the IV tubing needs to be 
cleared of any imaging agent as quickly as possible. 
8.3.2.2 Proximal Transection Margin 
At the point of the procedure when the colon/rectum has been mobilized and dissected fully and 
appropriately, the distal rectal transection has been completed, the IMA and IMV have been 
ligated, and the surgeon is prepared for proximal resection and subsequent low anastomosis, 
perfusion assessment will be performed. 
Perfusion assessment of the proximal transection margin may be made with PINPOINT or SPY 
Elite depending on Investigator preference and approach (open vs minimally invasive). 
The location of proximal transection will be based on clinical judgment and will include 
consideration of the following factors: 
 
A minimum distance of 5 cm from the tumor for the proximal resection margin. 
 
Sufficient bowel length to ensure a tension-free anastomosis. 
 
Preservation of bowel length. 
 
Adequate blood supply through visual inspection and palpation using the following 
assessment techniques where appropriate: 
o pink tissue with 1-2 second refill. 
o bleeding (bright red) from the cut edge or from abrasion or stabbing with needle. 
o presence of blood in bowel vasculature. 
ICG will be administered and the surgeon will assess perfusion of the tissue around (proximal and 
distal to) the planned transection margin. 
Perfusion imaging of the proximal transection margin may be performed intracorporeally or 
extracorporeally depending on Investigator preference. If proximal imaging is performed 
extracorporeally, all fluorescent lights must be turned off to minimize background noise.  
The PINPOINT imaging head will be positioned between 5 cm and 30 cm (~2-12 inches) from the 
planned transection margin with the camera head positioned parallel to the area being imaged 
and planned transection margin centered in the field of view. The area being imaged must remain 
in focus throughout the imaging procedure.  
If the Investigator chooses to utilize SPY Elite for proximal imaging, the following procedure will 
be followed. The SPY Elite Imaging head will be positioned parallel to the proximal colon, 
approximately 30 cm (~12 inches) from the bowel, with the proximal transection margin centered 

 
 
 
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in the field of view. SPY Elite imaging may be performed for proximal transection margin imaging 
in open procedures or for extracorporeal minimally invasive procedures. 
When positioning is complete, the subject will receive an intravenous injection of ICG followed by 
an injection of saline flush solution. The dose and time of injection will be recorded. The image 
sequence will be recorded from the point of administration of saline flush, through the ICG wash-
in, perfusion assessment and final point of proximal transection 
Perfusion at the planned point of transection will be characterized as follows: 
Inadequate – the absence of fluorescence, or spotty and/or patchy areas of green fluorescence. 
Adequate – pale, dull, or faded green fluorescence. 
Optimal – vivid, bright green fluorescence that entirely saturates the area of interest.  
Proximal transection should be made within the area of optimal perfusion (bright fluorescence) 
when possible, with consideration given to the factors for determining the location of proximal 
transection detailed above. An imaging guide will be provided to all investigators to serve as a 
guideline for the interpretation of perfusion images. The clinical reasons for choosing the 
transection point will be recorded. 
8.3.2.3 Anastomosis 
Perfusion of the proximal and (where appropriate) distal sides of the mucosal aspect of the 
completed anastomosis will be assessed using PINPOINT only. The distal assessment will be 
performed after the standard air leak test (when performed) has been completed (air leak test can 
be omitted in hand sewn coloanal anastomoses). In the case of a hand sewn coloanal 
anastomosis, the assessment will involve assessment of the mucosal aspect of the proximal colon 
only.  
The PINPOINT endoscope will be inserted into the anus via the Novadaq disposable rigid scope 
introducer (DRSI) provided as part of the PINPOINT Procedure Kit. Refer to the current version 
of the Instructions for Use for a full description of the DRSI21. The PINPOINT scope will be 
advanced to the point of the anastomosis under white light. The PINPOINT imaging head will be 
positioned approximately 5- 15 cm (~2-6 inches) from the completed anastomosis. The area being 
imaged must remain in focus throughout the imaging procedure. Sufficient insufflation is required 
for adequate assessment. ICG will be administered and the surgeon will assess the perfusion on 
the proximal and distal sides of the staple or suture line as inadequate, adequate or optimal. The 
flow sequence (proximal vs distal first) will also be recorded. The image sequence will be recorded 
from the ICG wash-in to perfusion assessment. 
Note that it is important to image all portions of the completed anastomosis. If a colonic j-pouch 
or end to side anastomosis has been done, imaging and perfusion assessment may need to be 
performed intracorporeally as well as following completion of the anastomosis to ensure 
visualization of perfusion of all at risk areas (i.e., the entire conduit in the case of a pouch). 
Additional imaging studies should be completed as necessary and the image sequences 
recorded.  

 
 
 
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Similar to perfusion imaging of the proximal bowel, perfusion of the mucosal aspect of the 
anastomosis will be characterized as follows: 
Inadequate – the absence of fluorescence, or spotty and/or patchy areas of green fluorescence 
Adequate – pale, dull or faded green fluorescence. 
Optimal – vivid, bright green fluorescence that entirely saturates the area of interest  
Refer to the perfusion imaging guide for guidance on interpretation of perfusion images. 
A diverting ostomy will be based on clinical judgment in conjunction with perfusion assessment of 
the anastomosis. A diverting ostomy should be considered for all anastomoses located less than 
7 cm to the anal verge. A diverting ostomy should be performed for all anastomoses with poor 
perfusion located less than 7 cm to the anal verge. 
At the completion of the procedure, an assessment regarding the ability of the PINPOINT and 
SPY Elite (if applicable) system to provide sufficient visualization for assessment of blood flow 
and related tissue perfusion will be made by the surgeon. 
8.4 Post-operative Follow-up Visits (Day 1 to Last Study Visit) 
Subjects will have standard of care assessments throughout the study according to the 
hospital/institutions standard procedures as well as study specific visits on postoperative Day 1, 
the date of discharge, Week 8 (56 ±14 days) and the date of ileostomy closure, if applicable.  
Subjects will be assessed for the following throughout the study: 
 
Serum hemoglobin measurement (Day 1). 
 
Evidence of anastomotic leak. 
 
Assessment and grading of post-operative complications. 
 
Concomitant medications and procedures as described in Section 7.2. 
 
Adverse events according to Section 9. 
Although the patient may be seen by various individuals post-surgery, the study-specific visits 
must be conducted by a surgeon who is part of the study and has signed the Signature and 
Delegation Log. Any complications and outcomes of study required assessments between visits 
will be documented at the study required visits. 
Subjects with a discharge date later than Week 8, who did not have an ileostomy, will have the 
last study visit on Week 8 ±14 days.  
Diverted patients should receive routine endoscopic and/or contrast enema evaluation of the 
anastomotic region, between 3 weeks post-surgery and the Week 8 visit. 
Subjects who present with a clinical suspicion of anastomotic leak during the study will have a CT 
scan with PO and, if necessary (e,g., presence of a diverting ileostomy), rectal contrast to confirm. 

 
 
 
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8.5 Image Acquisition and Transmission  
Videos of the image sequences acquired using PINPOINT and SPY Elite will be recorded to a 
medical grade video recorder. All required images will be provided to the Sponsor by the 
Investigative Center. Image files will be identified using the subject I.D. number and initials only 
(no information identifying the subject shall be included in the files). 
9 EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS 
All untoward medical occurrences either observed by the Investigator or one of his/her medical 
collaborators, or reported by the subject spontaneously, or in response to the direct question 
below, will be reported as follows: 
 
All events occurring before randomization should be recorded in the source documents and 
will be considered part of the subject’s case history. 
 
Events occurring as a result of the surgery will be reported as adverse events related to the 
surgical procedure in the adverse event CRF. 
 
All adverse events occurring during the study will be recorded as adverse events on the 
adverse event CRF.  
 
Events related to the use of PINPOINT or SPY Elite will be recorded as adverse device effects 
in the description of event section of the adverse event CRF. 
 
Events related to PINPOINT or SPY Elite that affect a user of the device (non-patient) are 
recorded on the technical complaint form. 
In an attempt to optimize consistency of AE reporting across centers, the subjects must be asked 
a standard question to elicit events. At each clinic evaluation of the subject, study personnel will 
ask the following questions: “Have you had any problems since your last visit?” 
AEs reported on the CRF will include the date of onset, severity, relationship to PINPOINT or SPY 
Elite, relationship to surgical procedure, date of resolution (or the fact that it is ongoing or has 
become chronic), action taken, and whether the AE is serious or not. 
9.1 Definitions 
9.1.1 Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs 
(including an abnormal laboratory findings) in subjects whether or not related to the investigational 
medical device.  
 
 
Includes events related to the PINPOINT or SPY Elite.  
 
Includes events related to procedures involved (any procedure in the clinical investigation 
plan). 
 
Postoperative nausea or vomiting occurring during the first 24 to 48 hours, and post-

 
 
 
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operative pain related to surgical procedure is not considered an adverse event. 
9.1.2  Adverse Device Effect (ADE) 
Any adverse event related to the use of PINPOINT or SPY Elite (includes imaging agent and all 
hardware components).  
 
Includes any event that is a result of a use error or intentional misuse.  
ADEs that affect subjects will be recorded as ADEs in the AE CRF. ADEs that only affect a user 
(non-patient) are recorded in the technical complaint form only. 
9.1.3  Serious Adverse Event (SAE) 
Any adverse event that: 
a. Led to a death.  
b. Led to a serious deterioration in health that either: 
i. 
Resulted in a life-threatening illness or injury, 
ii. 
Resulted in a permanent impairment of a body structure or a body function, 
iii. 
Required in-patient hospitalization or prolongation of existing hospitalization, 
iv. 
Resulted in medical or surgical intervention to prevent life threatening illness or 
injury or permanent impairment to a body structure or a body function. 
c. Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
This includes device deficiencies that might have led to a serious adverse event if suitable action 
had not been taken; intervention had not been made, or if circumstances had been less fortunate. 
These are handled as SAEs. A planned hospitalization for pre-existing condition, or a procedure 
required by the protocol, without a serious deterioration in heath, is not considered to be a serious 
adverse event. 
9.1.4 Unanticipated Adverse Device Effect (UADE) 
Any ADE that meets the following: 
 
By its nature, incidence, severity or outcome has not been identified in the current version of 
the PINPOINT (or SPY Elite if applicable) risk analysis report. 
 
On health or safety, any life-threatening problem or death caused by, or associated with a 
device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the application; or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects. 

 
 
 
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9.2 Adverse Event Descriptions 
9.2.1 
Intensity 
The intensity of AEs, including ADEs and surgical complications will be characterized as mild, 
moderate, or severe, as follows: 
Mild 
Usually transient, requiring no special treatment, and does not interfere 
with the subject’s daily activities. 
Moderate 
Introduces a low level of inconvenience or concern to the subject and may 
interfere with daily activities, but is usually ameliorated by simple 
therapeutic measures. 
Severe 
Significantly interferes with a subject’s usual daily activities and requires 
systemic drug therapy or other treatment, if available. 
9.2.2 
Relationship 
Suspected 
There is a reasonable possibility that the AE is associated with use of the 
study device, such as temporal relationship of the event to use. 
Not suspected 
A relationship between the AE and the study device can reasonably be 
ruled out based on lack of any temporal relationship of the event to use, or 
when the subject’s underlying condition, medical history, or other therapy 
provide sufficient explanation for the observed event.  
9.3 Reporting and Evaluation of Serious Adverse Events and Unanticipated Adverse 
Device Effects  
Any SAE or UADE occurring in this study must be reported immediately (within 24 hours of 
discovery) by email to the Novadaq contact listed below: 
Attention:  Alicia Wilton 
 
 Phone: 905-629-3822 x209Email : pillar3@novadaq.com 
SAEs and UADEs will be reported to the Institutional Review Board (IRB)/Ethics Committee (EC) 
according to the institution’s policies, but within 10 days of occurrence.  
The Sponsor will provide documentation of reportable events to the Investigator, as specified in 
Section 13.1.4.  
The Investigator will ensure that the subject receives appropriate medical treatment and that the 
subject is followed up until the SAE or UADE resolves or becomes chronic, as defined in Section 
9.5.  
9.4 Surgical Complications: Special Instructions 
Anastomotic leaks, and strictures or abscesses that require intervention should be reported and 
followed as SAEs for this study.  

 
 
 
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Subjects who present with a clinical suspicion of anastomotic leak during the study will have a 
computerized tomography (CT) scan to confirm unless the patient’s condition warrants urgent 
operative intervention. A leak is considered confirmed if endoluminal contents (air, gastro-
intestinal contents or contrast material) through the anastomosis occur. The presence of infection 
or abscess thought to be related to the anastomosis may be classified as an anastomotic leak at 
the surgeon’s discretion even if it cannot be definitively identified as visualized during an operation 
or by contrast extravasation. An abscess adjacent to the anastomosis containing air will be 
classified as a leak. All Anastomotic leaks will be followed until resolution. 
Specific post-operative complications are defined as follows for this study and should be reported 
as surgical complications and SAEs if they meet SAE criteria at the time of the event: 
 
Prolonged post-operative NPO or nasogastric tube (NGT) use is defined as prolonged NPO 
status or NGT use for more than 3 post-operative days (POD4 or later), or the return to NPO 
status or insertion(or presence) of NGT anytime POD4 or later within 30 days.  
 
Post-operative ileus is defined as insertion or reinsertion of a NGT after surgery or a return to 
NPO status for nausea and/or vomiting with failure of passage of flatus and/or stool.  
 
A small bowel obstruction is defined as radiologic or operative evidence of an obstruction.  
All adverse events and post-operative complications occurring during the study period will be 
graded according to the following Clavien-Dindo classification system20 as shown in Table 2. 
Grades will be recorded on the CRF. 
TABLE 2.  Classification of Surgical Complications 
Grade 
Definition 
Clinical Example of 
Complication Grade 
Grade I 
Any deviation from the normal post-operative course without 
the need for pharmacological treatment or surgical, 
endoscopic, and radiological interventions 
Non-infectious diarrhea 
Grade II 
Requiring pharmacological treatment with drugs other than 
such allowed for grade I complications. Blood transfusions and 
total parenteral nutrition are also included. 
Infectious diarrhea requiring 
antibiotics 
Grade IIIa 
Requiring surgical, endoscopic or radiological intervention not 
under general anesthesia 
Radiologic or endoscopic 
intervention of an anastomotic leak 
that is taken care of outside of the 
operating room 
Grade IIIb 
Requiring surgical, endoscopic or radiological intervention 
under general anesthesia 
Surgical intervention of an 
anastomotic leak that is taken care 
of in the operating room 
Grade IVa 
Life-threatening complication (including CNS complications)a 
requiring IC/ICU management with single organ dysfunction 
(including dialysis) 
Necrotizing pancreatitis 
Grade IVb 
Life-threatening complication (including CNS complications)a 
requiring IC/ICU management  with multi organ dysfunction 
Necrotizing pancreatitis with 
hemodynamic instability 
Grade V 
Death of a patient 
Organ failure after surgical 
intervention- 
Suffix “d” 
If the patient suffers from a complication at the time of 
discharge, the suffix “d” (for disability) is added to the 
respective grade of complication. This label indicates the need 
for a follow-up to fully evaluate the complication. 
 
a 
Brain hemorrhage, ischemic stroke, subarachnoidal bleeding, but excluding transient ischemic attacks 

 
 
 
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9.5 Follow-up for Adverse Events and Adverse Device Effects 
Throughout the study to the final study visit contact, ADEs will be followed until they resolve or 
become chronic. All AEs will be followed throughout the study until the Week 8 visit. All AEs 
related to the PINPOINT, SPY Elite or the surgical procedures, as determined by the Investigator, 
will be followed until resolution or deemed chronic. 
At the final study visit, new AEs, as well as follow-up information for continuing AEs, will be 
recorded in the CRF and source document. If an SAE or UADE is unresolved at the final study 
visit, it will be followed by the Investigator until it resolves or becomes chronic (as judged by the 
Investigator). Follow-up data for such SAEs will be recorded in the source document and reported 
to the safety contacts. Non-serious ongoing AEs will be followed beyond the final study visit at 
the discretion of the Investigator. 
9.6 Reporting of Technical Complaints/Device Deficiencies 
9.6.1 Definitions 
Device Complaint: A quality complaint received in writing, electronically, or orally that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a device product. (In this definition, "effectiveness" refers to the actual function of 
the device, not to how the subject responds to the action of the device. Also in this definition, 
"device product" refers only to devices provided by the Sponsor for clinical studies and to 
investigational devices.) 
In this definition, safety includes the safety of a subject, user, or other person associated with the 
use of a medical device. 
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 labeling. 
9.6.2 Reporting Procedures 
Any technical complaint/device deficiency should be reported to the Sponsor. Technical 
Complaints occurring in this study must be reported immediately (within 24 hours) by fax or email 
to the appropriate Novadaq representative or to Novadaq Quality (quality@novadaq.com).  
Any complaint about a device must be reported regardless of whether the defect or deficiency 
had any effect on a subject or on study personnel. 
9.7 ADEs, Technical Complaints/Device Deficiencies that are UADEs 
Novadaq will evaluate all ADE reports and technical complaints/device deficiencies to determine 
if the report meets the definition of an unanticipated adverse device effect. If Novadaq determines 
that it does meet the definition, an investigation will be begun immediately. Novadaq will inform 
the Investigator of any additional reporting requirements beyond those stated in Sections 9.3 and 
9.7 as applicable. 

 
 
 
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Novadaq will report the UADE and the results of any investigations to the FDA. All participating 
Investigator(s) will submit the required reports to their IRBs within 10 working days after Novadaq 
first received notice of the effect. 
10 STATISTICAL CONSIDERATIONS 
10.1 Primary Objective  
To demonstrate an improvement in post-operative anastomotic leak rate in low anterior resection 
procedures where colon and rectal tissue perfusion is evaluated using PINPOINT or SPY Elite 
near infrared fluorescence imaging as an adjunct to standard surgical practice compared to 
surgical procedures performed according to standard surgical practice alone. 
10.2 Hypotheses 
H0: 
pt = pc 
H1: 
pt < pc 
 
Where pt and pc represent the expected population incidences of post-operative anastomotic 
leaks in the treatment (PERFUSION) and control groups, respectively. Within their respective 
treatment groups, pt and pc will be estimated as the number of subjects who experience a post-
operative anastomotic leak according to the definition in Section 3.1, divided by the number of 
subjects who either are included in the numerator or are known to be free of such leaks as of the 
8 weeks visit.  Subjects without a known anastomotic leak but with less than 6 weeks of follow-up 
(i.e., insufficient follow-up to declare them "leak-free") will not be included in these estimates.  
  
10.3 Statistical Analysis 
Analysis of these hypotheses will be conducted using a z-test (i.e., normal approximation to the 
binomial distribution, using a pooled variance estimate and without continuity correction), using a 
(one-sided) significance level of 0.025.  
10.4 Adaptive Design and Sample Size Considerations 
Available literature does not provide a precise estimate of the expected anastomotic leak rate in 
the control group or in the treatment group. As previously described, anastomotic leak is reported 
to occur in a wide range of 3-20% of the time in colorectal surgery6-10 and the risk increases for 
lower anastomoses. In the limited prior experience with the PINPOINT PILLAR II study (n=139 
subjects) the anastomotic leak rate was 1.4%. 
Given the limited knowledge of control incidence and the treatment effect size, the PILLAR III 
study will employ an adaptive design with a mid-trial sample size re-assessment.  The planned 
sample size is N = 800, with possible early stopping for efficacy or futility at an interim analysis at 
N = 450.  The planned total of 800 subjects will provide >80% power to test the one-sided 
hypothesis of superiority for treatment over control in leak rate at the 0.025 significance level if 
the true leak rates pc and pt are 12.5% and 6.25% (a 50% relative reduction), assuming a two-
look group sequential analysis plan (with Pocock alpha-spending bounds and analyses at 450 
and 800). If the trial does not stop at N = 450, sample size will be assessed at that time and 
possibly increased up to a maximum of 1000 subjects, using the method of Chen et al.23and 
described in Mehta and Pocock22 . 

 
 
 
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For the primary objective, the following analysis plan will be used After N = 450 subjects have 
been enrolled, randomized and treated and the primary outcomes observed. The primary 
objective null hypothesis will be tested against the one-sided alternative hypothesis above.  If p < 
0.0169 (as determined by the Pocock alpha spending function),  the null hypothesis will be 
rejected, whereas if p ≥ 0.4, the trial will be considered futile However, if 0.0169 ≤ p < 0.4an 
assessment of whether to increase the sample size above the planned 800 subjects will be made 
in accordance with the “promising zone” method of Mehta and Pocock. If the conditional power 
(CP) at N =800 subjects based on the available data at the time of the interim analysis is less than 
0.5 or at least 0.8, enrollment will continue to 800 subjects and the final analysis will be conducted.  
Alternatively, if 0.5 ≤ CP < 0.8, the sample size will be re-estimated in accordance with the Mehta 
and Pocock method for sample size re-estimation up to a maximum of 1000 subjects. (The re-
calculated sample size cannot be less than 800 subjects based on the interim analysis.)  The final 
sample size is calculated by determining the added sample size needed to achieve the target 
conditional power of 80% given the data at the time of the interim analysis, subject to a maximum 
of 1000 subjects.  This method guarantees control of the type I error while still allowing standard 
inferential methods of analysis. 
10.5 The  planned sample size 800 . is based on the following rationale: If the true leak 
rates pc and pt are 12.5% and 6.25% (a 50% relative reduction), respectively,then 
PASS 13 24 indicates that , a two-look group sequential analysis plan (with Pocock 
alpha-spending bounds and analyses at 450 and 800) achieves 81.6% power to reject 
the null hypothesis at a one-sided significance level of 0.025. Study Populations for 
Analysis 
10.5.1 Modified Intent-to-Treat (mITT)   
The mITT analysis population includes all randomized subjects in whom a low anterior resection 
surgical procedure is initiated or at least one injection with ICG was performed. All subjects 
meeting these criteria are included in the mITT population, regardless of whether or not they 
received the planned open, or minimally invasive surgical intervention or NIR fluorescence 
imaging assessment using the PINPOINT or SPY Elite device.  Subjects who have the surgical 
resection procedure aborted due to circumstances such as a higher stage cancer than initially 
anticipated will not be included in the mITT population. Subjects will be analyzed according to 
their randomized group assignment. The mITT population is the analysis population for both the 
primary and secondary endpoints. 
10.5.2 As-Treated (AT) 
The As-Treated (AT) analysis population includes all randomized subjects in whom the intended 
open, or minimally invasive low anterior resection surgical procedure and, if assigned to the 
PERFUSION arm, PINPOINT or SPY Elite NIR fluorescence imaging with at least one perfusion 
assessment using ICG was successfully performed. Subjects in whom the intended surgical 
procedure is not performed or imaging with PINPOINT or SPY Elite was not successful are 
excluded from the AT population. mITT subjects not included in the AT population will be followed 
in the same manner as mITT subjects who do meet AT population inclusion criteria. Subjects will 
be analyzed according to the treatment actually received.   
The AT population will be used for a secondary analysis of the primary endpoint. 

 
 
 
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10.5.3 Per-protocol (PP) 
The Per-protocol (PP) population will consist of all AT subjects that: [1] meet critical study eligibility 
criteria; [2] have no significant protocol deviations; and [3] have evaluable assessment for the 
primary study endpoint.   
The PP population will be used for subset analysis of the primary endpoints. 
10.6 Safety (S)  
The safety analysis population includes all randomized subjects. Secondary safety endpoints 
including the summary of adverse events in the trial will be analyzed using this analysis 
population, divided into groups according to actual use or non-use of PINPOINT and SPY Elite.   
10.7 Secondary Objectives 
The planned secondary objectives are listed below; they will be formally analyzed only once (at 
the interim analysis if the primary objective is passed at that time, or at the final analysis if the 
primary objective is not passed at the interim analysis).    Data from these secondary objectives 
will not be included in the sample size re-assessment that occurs at the time of the interim 
analysis.The following objectives are intended to support product labeling. They will be tested in 
sequential fashion. I.e., if and only if the primary objective passes according to the criteria in 
Section 10.5 (which has a type I error rate of 2.5%), testing will proceed to the first secondary 
objective below (proportion of PERFUSION arm subjects in whom the PINPOINT or SPY Elite 
system provided sufficient visualization for assessment of blood flow and related tissue perfusion 
during the procedure).  If and only if that objective passes, testing will proceed to the second 
secondary objective (incidence of abscess requiring surgical management). The standard for 
“passing” the secondary objectives will be a p-value less than 0.025 one sided. 
To evaluate the ability of the PINPOINT or SPY Elite system to provide sufficient visualization for 
assessment of blood flow and related tissue perfusion during the procedure. 
The statistical threshold for study success will be sufficient visualization for assessment of blood 
flow and related tissue perfusion in greater than 90% of subjects. Letting pt represent the 
PERFUSION-group proportion of subjects for whom there was sufficient visualization for 
assessment of blood flow and related tissue perfusion, the following hypotheses will be tested: 
H0:  pt ≤ 0.9 
H1:  pt > 0.9 
The statistical test will be a one-sided exact binomial test of proportions. Descriptive statistics and 
95% confidence intervals will be calculated for pt. 
To evaluate the effectiveness of assessing perfusion of colon and rectal tissue using PINPOINT 
or SPY Elite in reducing the incidence of post-operative abscess requiring surgical management. 
Letting pt and pc respectively represent the treatment-group and control-group incidence of post-
operative abscess requiring surgical management, the following hypotheses will be tested: 

 
 
 
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H0:  pt = pc 
H1:  pt < pc 
The statistical test will be a z-test using pooled variance estimate and no continuity correction.  In 
the case of small counts, an exact procedure will be used.  Descriptive statistics and 95% 
confidence intervals will be calculated for pt, pc, and (pt – pc). 
10.8 Handling of Missing Data 
Reasonable efforts will be made to obtain complete data for all patients; however, missing 
observations will inevitably occur due to patients lost to follow-up or noncompliance with required 
assessments. The reasons for missing data will be documented and evaluated (e.g. patient is 
deceased, lost to follow up, missed visit, etc.). In addition, the distribution of prognostic factors 
between patients with data and those without data will be examined to evaluate any potential 
sources of bias.  Any missing observations will be described in detail and evaluated for 
assessment of possible bias. The planned sensitivity analyses for the primary outcome in the 
primary analysis population (including a tipping point analysis which addresses the worst case 
scenario in which treatment group subjects with missing observations are considered failures and 
control group subjects with missing observations are considered successful) is described in 
further detail in the Statistical Analysis Plan (SAP).    
10.9 Pooling of Site Data 
The homogeneity of safety and effectiveness results across study sites will be examined and if 
no significant heterogeneity is found, the results will be pooled.  The justification for pooling is that 
all study sites will follow one Protocol, use the same device system (PINPOINT or SPY Elite), 
follow the same Instructions for Use and perform surgery in accordance with surgical guidelines 
from ASCRS. Additionally, frequent contact and monitoring of the sites will be performed to ensure 
that all Study sites are evaluating participants and recording Study results in a reliable and 
reproducible manner. It is not anticipated that any individual Study site will dominate the Study 
results. Therefore, it is believed that these procedures will help to ensure that the data from these 
Study sites can be combined and analyzed as if generated at a single site.  Further explanation 
on poolability analyses, including testing baseline factors and the handling of significant site 
interactions, is described in the SAP. 
11 ESTIMATED DURATION OF THE STUDY 
The expected study duration is approximately 2.5 years. The study is expected to start in the first 
half of 2015 and take approximately 24 months to complete enrollment.  
12 STUDY ETHICAL CONSIDERATIONS 
12.1 Ethical Conduct of the Study 
The study will be conducted in accordance with US 21 CFR Part 812 and US 21 CFR Parts 50, 
54, and 56. Any additional requirements imposed by the local Institutional Review Board/Ethics 
Committee/Research Ethics Board or regulatory agency will be followed as necessary. 

 
 
 
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12.2 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. 
12.3 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. 
13 ADMINISTRATIVE PROCEDURES 
13.1 Sponsor's Responsibilities 
13.1.1 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 where the study is 
conducted. This includes but is not limited to the US National Institute of Health 
(www.clinicaltrials.gov). The Sponsor will update the information, including any changes to the 
study or recruitment status throughout the study. 
13.1.2  Study Supplies 
The Sponsor will provide the PINPOINT Endoscopic Fluorescence Imaging System and if 
requested, the SPY Elite Intraoperative Imaging System along with sufficient quantities of 
PINPOINT Procedure Kits with Introducer and SPY PAQs.  
13.1.3 Investigator Training 
13.1.3.1 Study Initiation Visit 
Study centers will have a study initiation meeting to ensure the research personnel understand 
the protocol, study requirements, and data capture processes. This training will take place prior 
to enrollment of the first subject at each study center.  

 
 
 
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13.1.3.2 PINPOINT and SPY Elite System 
Appropriate personnel at the study centers shall be required to participate in training on the 
procedural use of PINPOINT and SPY Elite as it relates to the conduct of this study (refer to 
Section 6.1 and Section 6.2).  
 
13.1.4 Ongoing Communication of Safety Information During the Study 
The Sponsor will provide the Investigator with documentation of UADEs and reportable 
events/effects, from all study centers, reported to regulatory authorities during the conduct of the 
study. The Investigator must forward this documentation to the IRB, as described in Section 9.3. 
The Sponsor will also notify the Investigator about any other safety findings that could affect the 
safety of subjects, affect the conduct of the study, or alter the IRB's opinion about continuation of 
the study. 
13.1.5 Study Monitoring 
The conduct of the study will be monitored by representatives of the Sponsor to ensure 
compliance with the protocol, GCP and applicable regulations. A separate study specific 
Monitoring Plan will outline the monitoring procedures to be followed, the required access to 
source data and the extent of source verification planned.  
13.1.6 Records Retention 
The Sponsor must retain all documentation pertaining to the study according to Novadaq standard 
operating procedures. 
13.2 Investigator's Responsibilities 
13.2.1 Reporting and Recording of Study Data 
Data will be captured and compiled using procedures developed by the Sponsor or their 
representatives. All requested study data must be recorded clearly on the CRF and other study 
forms as required. An explanation should be provided for all missing data. Only individuals who 
are identified on the Study Signature and Delegation Log may enter or correct data in the CRF. 
Incomplete or inconsistent data on the CRFs will result in data queries that require resolution by 
the Investigator. 
The protocol, informed consent form, protocol amendments, safety information, and other 
required documents must be submitted to the IRB in a timely manner, as described in Section 
12.3. 
13.2.2 Source Documentation 
The Investigator must maintain adequate and accurate source documents upon which CRFs for 
each subject are based. They are to be separate and distinct from CRFs, except for cases in 
which the Sponsor has predetermined that direct data entry into specified pages of the subject's 
CRF is appropriate. These records should include detailed notes on: 

 
 
 
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 
The oral and written communication with the subject regarding the study treatment (including 
the risks and benefits of the study). The date of informed consent must be recorded in the 
source documentation. 
 
The subject's basic identifying information, such as demographics, that links the subject's 
source documents with the CRFs. 
 
All relevant observations and data on the condition of the subject throughout the study. 
 
The subject's exposure to PINPOINT and SPY Elite. 
 
All adverse events. 
 
13.2.3 Study Devices 
The Investigator is responsible for ensuring the PINPOINT system and SPY Elite system, 
including imaging agent, is controlled and is used or dispensed only to subjects enrolled in the 
study. Only Investigators identified on the Signature and Delegation Log may use PINPOINT and 
SPY Elite for the purposes of this study.   
The Investigator shall keep records documenting the receipt, use, return and disposal of the study 
device and components.  
The Investigator will ensure that PINPOINT and SPY Elite is returned and that any other study 
material will be returned to the Sponsor or disposed of according to the Sponsor’s instructions on 
completion of the study. 
13.2.4 Records Retention  
The Investigator must ensure that clinical study records are retained according to national 
regulations, as documented in the clinical trial agreement entered into with the Sponsor in 
connection with this study.  
Subject files and other source data must be kept for the maximum period of time permitted by the 
hospital, institution, or private practice. The Investigator must inform the Sponsor immediately if 
any documents are to be destroyed, to be transferred to a different facility, or to be transferred to 
a different owner. 
13.3 Data and Safety Review 
A Data and Safety Monitoring Committee (DSMC) has been established by the Study Sponsor 
to oversee the safety and other aspects of the study. The DSMC will also be responsible for 
reviewing the interim analysis conducted by an independent statistician in conjunction with the 
Study Sponsor and/or the Sponsor’s Delegates and advising the Study Sponsor on determining 
the sample size of Stage 2. The DSMC consists of two independent board certified colorectal 
surgeons and an independent biostatistician. Ad-Hoc members may be appointed if specific 
expertise is needed. The role of the DSMC is to provide independent oversight and ensure that 
the study is conducted according to currently established safety and ethical standards. The 
Sponsor will oversee the provision of data to the DSMC. In general, it is anticipated that the 
DSMC meets twice a year. The DSMC reviews and evaluates all SAEs, UADEs and outcome 
measures and also receives a summary report for all ADEs and non-serious AEs. Unless 
specific action is required, the results of the analyses reviewed by the DSMC will not be shared 

 
 
 
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with site investigators. The DSMC will also develop rules for stopping the study. The Study 
Sponsor will distribute DSMC summary reports to collaborating clinical sites for submission to 
the sites’ IRB. A separate DSMC Charter will define monitoring procedures and stopping rules.  
13.4 Independent CT/Contrast Enema Scan Assessment 
An independent Radiologist will review CT/contrast enema scans for all subjects who present with 
a clinical suspicion of anastomotic leak during the study. The independent Radiologist’s 
assessment will be the final determination recorded for the study database. A separate IR Charter 
will define the image acquisition, data management and image analysis procedures. 
14 DATA MANAGEMENT 
Study data will be collected using paper and/or electronic case report forms (CRFs). Data will be 
entered into a study specific database in one of two ways or a combination of the following: 
 
Center research personnel will enter study data directly into an electronic case report form 
which functions as an electronic data capture screen for the study database. 
 
Center research personnel will enter study data onto paper CRFs, which will be submitted 
to the Sponsor or assigned designee.  
The Sponsor or designee will follow standardized procedures for data review, database cleaning 
and issuing/resolving queries. Procedures for data verification, validation, security and data 
retention will be followed in order that the study data reported are complete, accurate and 
consistent with source data. 
For the purpose of data analysis and presentation, the data of the original data set may be 
manipulated and additional variables calculated when necessary. Once the study data are 
completely entered, reviewed and checked, the study database will be locked and no further 
changes will be made.  
15 POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
The results of the study will be published by the PILLAR III Study Group (PSG). In addition to 
overall principal investigator, additional authors listed separately on the manuscript will be 
selected based on scientific input on the design of the study, interpretation of results, participation 
in manuscript preparation and on enrollment numbers. The final number of authors will depend 
on the journal’s publication guidelines. All participating centers will be acknowledged in the main 
study manuscript.  
The Sponsor also encourages the scientific publication of data from clinical research studies. 
However, Investigators may not present or publish partial or complete study results individually 
without participation of the study Principal Investigator as well as the Sponsor. The Principal 
Investigators and the Sponsor may propose appropriate scientific manuscripts or abstracts from 
the study data. All proposed publications must be reviewed and commented on by the Sponsor 
before submission for publication. The detailed procedures for the review of publications are set 
out in the clinical trial agreement entered into with the Sponsor in connection with this study. 
These procedures are in place to ensure coordination of study data publication and adequate 
review of data for publication against the validated study database for accuracy. Names of all 

 
 
 
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Investigators and Sponsor representatives responsible for designing the study and analyzing the 
results will be included in the publication(s). 

 
 
 
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Hyman N, Manchester TL, Osler T, et al. Anastomotic leaks after intestinal anastomosis: 
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Guillou PJ, Quirke P, Thorpe H, et al. Short-term endpoints of conventional versus 
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Sauer R, Fietkau R, Wittekind C, et al. Adjuvant vs. neoadjuvant radiochemotherapy for 
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Senagore A, Lane FR, Lee E, Wexner S, Dujovny N, Sklow B, et al. Bioabsorbable staple 
line reinforcement in restorative protectomy and anterior resection: A randomized study. 
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