A Prospective Single-center Pilot Study Evaluating the Technical Feasibility of Mucosal Staining During Colon Capsule Endoscopy (CCE) Procedure in Colorectal Cancer (CRC) High Risk Population, When Using MB-MMX (SPICE Study)
Phase: NA
Conditions: Colorectal Cancer, Polyp, Colonic
Sponsor: Medtronic - MITG

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APPROVALS
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DOCUMENT/RECORD 
 
 
This document/record is electronically controlled; printed copies are considered uncontrolled. 
System of Record: Regulatory Affairs Domain 
 
Document Name
RAD Version
Title
Monitor
Regulatory
Medical Advisor
Clinical Study Manager (CSM)
Schwartz, Naama
06/16/2022 20:48:54
4.0
Clinical Quality/Compliance
Clinical Leadership
Safety
06/16/2022 15:33:41
06/21/2022 10:35:47
Bergwerk, Ari
06/20/2022 12:45:22
CIP SPICE V4.0, 2022 06 16
Document Author
Fox, Roslana
06/20/2022 11:11:08
McManus, Heather
Leppens, Jan
Mamadou, Norbert
06/16/2022 16:17:18
06/20/2022 07:40:07
Eyal, Inbal
06/16/2022 15:20:27
Klozman Katz, Ira
Gielkens, Manon
Medical Writer
Monitor
Klozman Katz, Ira
06/16/2022 15:33:41
06/20/2022 12:36:25
Fox, Roslana
06/16/2022 16:16:52
Fox, Roslana
Fox, Roslana
06/16/2022 15:33:40
06/16/2022 15:33:40
Therapy SME
06/17/2022 13:57:59
Clinical Quality/Compliance
Wetzels, Iris
Clinical Leadership
CIP SPICE
Biostatistician

MDT20062 SPICE Clinical Investigation Plan 
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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  A prospective single-center pilot study evaluating the 
technical feasibility of mucosal staining during Colon 
Capsule Endoscopy (CCE) procedure in Colorectal Cancer 
(CRC) high risk population, when using MB-MMX  (SPICE 
study) 
Clinical Investigation Plan Identifier MDT20062 
Study Product Name PillCam™ COLON2 Capsule Endoscopy System 
Sponsor/Local Sponsor Given Imaging Ltd., an indirect wholly owned subsidiary 
of Medtronic plc. (“Medtronic”) 
2 Hacarmel St. New Industrial Park, P.O. Box 258 
Yokneam 2066724, Phone: +972 (4) 909-7700 
Local Sponsor (EU legal representative) 
Covidien Services Europe Ltd, an indirect wholly owned 
subsidiary of Medtronic plc. 
Block 3090-3094, Lake Drive Citywest Business Campus, 
Dublin D24 Xn47 Ireland 
Document Version Ver.4.0 
Version Date 16-Jun-2022 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic. Any 
distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly 
prohibited. Persons to whom the information is disclosed must know that it is confidential and that it may 
not be further disclosed by them. 
 
 
 

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1. Investigator Agreement and Signature Page 
Study product Name 
PillCam™ COLON2 Capsule Endoscopy System 
Sponsor 
Given Imaging Ltd., an indirect wholly owned 
subsidiary of Medtronic plc. (“Medtronic”) 
2 Hacarmel St. New Industrial Park, P.O. Box 258 
Yokneam 2066724, Phone: +972 (4) 909-7700 
Clinical Investigation Plan Identifier 
MDT20062 
Version Number/Date  
Ver. 4.0/ 16-Jun-2022 
I have read the protocol, including all appendices, and I agree that it contains all necessary details 
for me and my staff to conduct this study as described. I will conduct this study as outlined herein 
and will make a reasonable effort to complete the study within the time designated. 
I agree to comply with International Conference on Harmonization Guidelines on Good Clinical 
Practice, Principles of Declaration of Helsinki (DoH), ISO 14155, Clinical investigation of medical 
devices for human subjects, 21 CFR Part 11 (Electronic Records, Electronic Signatures)- when 
applicable, 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), The Clinical Trials 
Agreement (CTA), The procedures described within this Clinical Investigation Plan, and any local 
regulations. I agree to ensure that the confidential information contained in this document will 
not be used for any purpose other than the evaluation and conduct of the clinical investigation 
without the prior written consent of Medtronic. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Medtronic. I will discuss this material with them to ensure that they are 
fully informed about the products and the study. 
Investigator’s Signature: 
 
Investigator’s Name: 
 
Institution: 
 
Date: 
 
 
 
 
 

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Table of Contents 
1. 
Investigator Statement .................................................................................................................. 2 
Table of Contents ................................................................................................................................... 3 
2. 
Glossary .......................................................................................................................................... 7 
3. 
Synopsis .......................................................................................................................................... 9 
4. 
Introduction .................................................................................................................................. 14 
4.1. 
Background ........................................................................................................................... 14 
PillCam™ Capsule Endoscopy ....................................................................................................... 14 
The PillCam™ COLON capsule ...................................................................................................... 14 
Per-oral Methylene Blue Formulation (MB-MMX): .................................................................... 15 
4.2. 
Purpose ................................................................................................................................. 15 
5. 
Objectives and/or Endpoints ....................................................................................................... 15 
5.1. 
Objectives ............................................................................................................................. 15 
5.1.1. 
Primary Objective and Endpoints ................................................................................ 15 
5.1.2. 
Secondary Objective and Endpoint .............................................................................. 16 
6. 
Study Design ................................................................................................................................. 16 
6.1. 
Duration ................................................................................................................................ 16 
6.2. 
Rationale ............................................................................................................................... 16 
6.3. 
Study Oversight .................................................................................................................... 17 
7. 
Product Description ...................................................................................................................... 17 
7.1. 
General ................................................................................................................................. 17 
7.1.1. 
The PillCam™ Capsule Endoscopy System ................................................................... 17 
7.1.2. 
The PillCam™ COLON 2 Capsule ................................................................................... 18 
7.1.2.1. 
Product Description .................................................................................................. 18 
7.1.2.2. 
Intended Use ............................................................................................................ 18 
7.1.2.3. 
Intended Population ................................................................................................ 18 
7.1.3. 
The PillCam™ Recorder ................................................................................................ 18 
7.1.3.1. 
Sensor Arrays & Sensor Belt .................................................................................... 19 
7.1.4. 
The PillCam™ Software ................................................................................................ 19 
7.1.5. 
The Workstation Unit ................................................................................................... 19 
7.2. 
Dosage Form and Route of Administration ......................................................................... 19 
7.3. 
Manufacturer........................................................................................................................ 20 
7.4. 
Packaging .............................................................................................................................. 20 

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7.5. 
Equipment ............................................................................................................................ 20 
7.6. 
Product Use .......................................................................................................................... 20 
7.7. 
Product Training Materials .................................................................................................. 20 
7.8. 
Product Receipt and Tracking .............................................................................................. 21 
7.9. 
Product Storage .................................................................................................................... 21 
7.10. 
Product Return ................................................................................................................. 21 
7.11. 
Product Accountability ..................................................................................................... 22 
8. 
Study Site Requirements .............................................................................................................. 22 
8.1. 
Investigator/Investigation Site Selection ............................................................................ 22 
8.2. 
Study Site Activation ............................................................................................................ 23 
8.3. 
Role of the Sponsor Representatives .................................................................................. 23 
9. 
Selection of Subjects .................................................................................................................... 24 
9.1. 
Study Population .................................................................................................................. 24 
9.2. 
Subject Enrollment ............................................................................................................... 24 
9.3. 
Inclusion Criteria .................................................................................................................. 24 
9.4. 
Exclusion Criteria .................................................................................................................. 24 
10. 
Study Procedures ..................................................................................................................... 27 
10.1. 
Schedule of Events & Data collection .............................................................................. 27 
10.2. 
Subject Screening (visit 1) ................................................................................................ 28 
10.3. 
PillCam™ Capsule pre-ingestion preparation procedure ................................................ 28 
10.4. 
PillCam™ CCE Procedure (visit 2) ..................................................................................... 28 
10.5. 
Phone Call Follow-up Visit (visit 3) .................................................................................. 29 
10.6. 
CCE Procedure Video ........................................................................................................ 29 
10.7. 
Medication Compliance ................................................................................................... 29 
10.8. 
Optional X-ray Procedure................................................................................................. 30 
10.9. 
Subject Consent ................................................................................................................ 30 
10.10. 
Enrollment ........................................................................................................................ 31 
10.11. 
Assessment of Efficacy ..................................................................................................... 31 
10.12. 
Assessment of Safety ....................................................................................................... 31 
10.13. 
Recording Data ................................................................................................................. 32 
10.14. 
Deviation Handling ........................................................................................................... 32 
10.15. 
Subject Exit, Withdrawal or Discontinuation .................................................................. 34 
10.16. 
Lost to Follow-up .............................................................................................................. 35 
11. 
Risks and Benefits..................................................................................................................... 35 

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11.1. 
Potential Risks .................................................................................................................. 35 
11.2. 
Risk Minimization ............................................................................................................. 36 
11.3. 
Potential Benefits ............................................................................................................. 37 
11.4. 
Risk-Benefit Rationale ...................................................................................................... 37 
12. 
Adverse Events and Device Deficiencies ................................................................................. 38 
12.1. 
Adverse Events ................................................................................................................. 38 
12.2. 
Device Deficiency (DD) ..................................................................................................... 38 
12.3. 
Processing Updates and Resolution ................................................................................ 39 
12.4. 
Definitions/Classifications ............................................................................................... 39 
12.5. 
Reporting of Adverse Events ............................................................................................ 41 
12.5.1. 
Adverse Event and Device Deficiency Classification ....................................................... 44 
12.5.2. 
Adverse Event and Device Deficiency Reporting Requirements .................................... 45 
12.6. 
Subject Death ................................................................................................................... 47 
12.7. 
Product Complaint Reporting .......................................................................................... 48 
13. 
Statistical Design and Methods ............................................................................................... 48 
13.1. 
General Aspects of Analysis ............................................................................................. 49 
13.2. 
Interim Analysis ................................................................................................................ 50 
13.3. 
Primary Objective(s) ......................................................................................................... 50 
13.4. 
Secondary Objective ......................................................................................................... 51 
13.5. 
Sample Size Determination .............................................................................................. 51 
14. 
Ethics ......................................................................................................................................... 51 
14.1. 
Statement(s) of Compliance ............................................................................................ 51 
15. 
Study Administration ............................................................................................................... 53 
15.1. 
Monitoring ........................................................................................................................ 53 
15.1.1. 
Monitoring Visits .............................................................................................................. 53 
15.2. 
Data Management ............................................................................................................ 54 
15.3. 
Direct Access to Source Data/Documents ....................................................................... 54 
15.4. 
Confidentiality .................................................................................................................. 54 
15.5. 
Liability/Warranty/Insurance Information ..................................................................... 55 
15.6. 
CIP Amendments .............................................................................................................. 55 
15.7. 
Record Retention .............................................................................................................. 55 
15.7.1. 
Investigator Records ......................................................................................................... 55 
15.7.2. 
Sponsor Records ............................................................................................................... 56 
15.8. 
Reporting Requirements .................................................................................................. 57 

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15.8.1. 
Investigator Reports ......................................................................................................... 57 
15.8.2. 
Sponsor Reports ............................................................................................................... 58 
15.9. 
Publication and Use of Information ................................................................................. 59 
15.9.1. 
Criteria for Determining Authorship ................................................................................ 59 
15.9.2. 
Transparency .................................................................................................................... 60 
15.10. 
Suspension or Early Termination ..................................................................................... 60 
15.10.1. 
Planned Study Closure ................................................................................................. 60 
15.10.2. 
Early Termination or Suspension ................................................................................. 60 
15.10.2.1.1. 
Study-wide termination or suspension ................................................................... 61 
15.10.2.2. 
Investigator/study site termination or suspension................................................. 61 
15.10.3. 
Procedures for Termination or Suspension ................................................................. 61 
15.10.3.1. 
Sponsor-initiated and regulatory authority-initiated ............................................. 61 
15.10.3.2. 
Investigator-initiated................................................................................................ 62 
15.10.3.3. 
Ethics Committee-initiated ...................................................................................... 62 
16. 
References ................................................................................................................................ 63 
17. 
Appendices ............................................................................................................................... 64 
18. 
Version History ......................................................................................................................... 74 
 
 
 

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2. Glossary 
Term 
Definition 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
CA 
Competent Authority 
CAPA 
Corrective and Preventive Action 
CCE 
Colon Capsule Endoscopy 
CIP 
Clinical Investigation Plan 
CRC 
Colorectal Cancer 
CTA 
Clinical Trial Agreement 
CV 
Curriculum Vitae 
DD 
Device Deficiency 
DoH 
Declaration of Helsinki 
DR 
Data Recorder 
eCRF 
Electronic Case Report Form 
EC 
Ethics Committee 
EU 
European Union 
FAP 
Familial Adenomatous Polyposis 
FD 
Financial Disclosure 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IC 
Informed Consent 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 

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Term 
Definition 
IFU 
Instructions for Use 
MDD 
Medical Device Directive 
MedDRA 
Medical Dictionary for Regulatory Activities 
PMDA 
Pharmaceuticals and Medical Devices Agency 
RA 
Regulatory Authority 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SID 
Subject Identification 
UM 
User Manual  
 
 

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3. Synopsis 
Title 
A prospective single-center pilot study evaluating the technical 
feasibility of mucosal staining during COLON2 Capsule Endoscopy 
(CCE) procedure in Colorectal Cancer (CRC) high risk population, 
when using MB-MMX (SPICE study) 
Clinical Study Type 
Prospective, single-arm, single-center, non-randomized pilot post-
market study 
Product Name 
PillCam™ COLON2 Capsule Endoscopy System 
Sponsor & the funding 
source 
Given Imaging Ltd., an indirect wholly owned subsidiary of 
Medtronic plc. (“Medtronic”) 2 Hacarmel St. New Industrial Park, 
P.O. Box 258 Yokneam 2066724, Phone: +972 (4) 909-7700 
Investigation Purpose 
To evaluate the technical feasibility of mucosal staining during CCE 
in CRC high risk population, when using MB-MMX as a contrast- 
enhancement technique. 
Product Status 
PillCam™ COLON2 Capsule Endoscopy System- CE marked since 
2009 
Primary Objective(s) and/or 
Endpoint(s)s 
Primary objective:  
To demonstrate an effective colonic polyp enhancement during CCE 
procedure, when using MB-MMX as a contrast- enhancement 
technique.  
Primary endpoints:   
• 
The percent of colonic polyps which have a visible contrast 
to the healthy colonic mucosa during CCE, as indicated by an 
experienced 
reader, 
using 
the 
subjective 
reader 
questionnaire (For each polyp – was there a contrast 
between the polyp and the healthy mucosa? Yes/No), out of 
the examined polyps (Appendix D).  
• 
The interference level of detrimental effects on the 
visualization of the colonic mucosa during CCE, due to use of 
MB-MMX per colonic segment. Detrimental effect will be 
considered as any observation, such as an excessive blue dye 
deposit, dark and dim appearance of the tissue, interfering 
with tissue visualization and will be evaluated on a scale 
from 1 (no interference) to 5 (high interference) to evaluate 
the level of interference, using a subjective reader 
questionnaire (Appendix D). 

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Secondary Objective(s) 
and/or Endpoint(s) 
Secondary objective:  
To evaluate the safety of CCE procedure while using MB-MMX. 
Secondary endpoint:  
All AEs will be reported by number, type, relatedness 
(device/procedure), seriousness, severity and duration. All AEs will 
be captured, regardless of severity. 
Study Design 
Single-center, prospective, non-randomized clinical trial designed to 
evaluate the technical feasibility during CCE procedure, when using 
MB-MMX as a contrast- enhancement technique of mucosal staining 
in CRC high risk population. 
Subjects will undergo a bowel preparation (single dose, 4L PEG), 
including 200 mg Methylthioninium chloride, corresponding to eight 
25 mg MB-MMX tablets.  An experienced Gastroenterologist will 
read the CCE procedure and complete a subjective questionnaire, to 
evaluate mucosal enhancement during a CCE procedure, when using 
MB-MMX as a contrast-enhancement technique. 
Sample Size 
Up to 15 subjects will be enrolled in 1 site in Spain. 
This is a pilot study where sample size will not be calculated. 
Inclusion/Exclusion Criteria 
Inclusion Criteria: 
1. Male or female adults ages 45-75 years  
2. Subject is classified as being at high risk for CRC due to one 
(or more) of the following risk factors: 
• A personal history of colorectal polyps  
• A first-degree family history of colorectal cancer 
• Family/personal inherited syndrome (Lynch syndrome, 
Familial adenomatous polyposis {FAP}, other inherited 
syndromes linked to colorectal cancer) 
• Subject with currently suspected or diagnosed rectal 
bleeding, including positive FIT or positive fecal DNA 
test 
• Subjects under surveillance for CRC (last OC≥1.5 years)   
3. Subject is willing and able to participate in study 
procedures, understand and sign the informed consent  
 
 
 
Exclusion Criteria: 
1. Subject has a previous history or suspicion of inflammatory 
bowel or Crohn’s disease, ulcerative Colitis or 
indeterminant Colitis 

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2. Subject has congestive heart failure or recent myocardial 
infarction (<3month) 
3. Subject with moderate/severe renal disease and/ or severe 
hepatic impairment  
4. Subject has uncontrolled diabetes 
5. Subject has a severe, life-threatening disease 
6. Subject with known gastrointestinal motility disorders 
7. Subject has known delayed gastric emptying 
8. Subject has undergone surgery of the luminal 
gastrointestinal (GI) tract, from esophagus to the rectum, 
other than uncomplicated appendectomy or 
cholecystectomy.   
9. Subject with any current condition believed to have an 
increased risk of capsule retention such as suspected or 
known bowel obstruction or pseudo-obstruction, stricture, 
or fistula (symptoms such as severe abdominal pain with 
accompanying nausea or vomiting) 
10. Subject with dysphagia, any swallowing disorder, or any 
major gastrointestinal motility disorder 
11. Subject has a history of inadequate bowel preparation for 
colon imaging with colonoscopy, CTC, CCE, or DCBE (self-
reporting) 
12. Subject with known or suspected constipation history as 
defined by the following:  as needing the use of medication 
(prescription or OTC) for management of constipation, or 
fewer than 3 BM/week regardless of medication use   
13. Subject with a cardiac pacemaker or other implanted 
electromedical device 
14. Subject with planned MRI examination within 7 days after 
ingestion of the capsule  
15. The subject is taking antidepressant medicine or a 
medicine for psychiatric illness, such as:  
o selective serotonin reuptake inhibitor (SSRI)- as 
fluoxetine, fluvoxamine, paroxetine, sertraline, 
citalopram, escitalopram and zimeldine; 
bupropion, venlafaxine, mirtazapine, 
clomipramine, buspirone  
o medicines classified as Monamine Oxidase 
Inhibitors (often used for treating depression). 
16. Subject has glucose-6-phosphate dehydrogenase (G6PD) 
deficiency and/or allergic to peanut/soya 

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17. Subject consumes any of the medicinal products which 
interacts with MB-MMX, as per MB-MMX label and 
Investigator’s discretion  
18. Subject with allergies or known contraindication to the 
device, medications or preparation agents used in the 
procedure as described in the relevant instructions for 
use/package inserts. 
19. Subject use of opioid medication on a regular basis and 
requires medication to treat opioid induced constipation  
20. Subject currently participating in another gastrointestinal 
clinical study (investigational drug or device) that might 
interfere with results of study 
21. Females who are pregnant or breastfeeding at time of 
bowel prep  
22. Any condition which precludes compliance with study 
and/or device instructions based on the clinical judgment 
of the investigator 
23. Subject who is considered to be part of a vulnerable 
population (e.g. prisoners or those without sufficient 
mental capacity) 
24. Medtronic employees 
Study Procedures and 
Assessments 
 Day -30 to (-3)- Screening visit: 
• 
Obtain written informed consent 
• 
Confirm inclusion/exclusion 
• 
Medical history+ concomitant medication+ demographics 
• 
Vital signs 
• 
Urine Pregnancy test (when applicable) 
• 
Provide study bowel preparation martials & MB-MMX 
tablets 
 
Day (-3) - (-2)- low fiber diet  
Day -1:  
• 
Clear liquid diet  
• 
Urine Pregnancy test (when applicable) 
• 
Bowel prep- 4L PEG+ MB-MMX (in accordance to the MB-
MMX IFU): 
o The first dose of 3 MB-MMX tablets should be 
taken after drinking at least 1 L of PEG; 
o The second dose of 3 MB-MMX tablets should be 
taken 1 hour after the first dose; 

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o The last dose of 2 MB-MMX tablets should be 
taken 1 hour after the second dose.  
Day 0:  
• 
Clear liquid diet 
• 
Vital signs 
• 
1 tablet of prucalopride 1mg 
 
• 
CE procedure, including boosts intake. 
 
Day 5-9: 
Follow-up phone call  
Safety Assessments 
Subjects will be asked at each visit, during the PillCam™ CCE 
procedure and during the follow-up phone call, about changes in 
their medical condition. All Adverse events and Device Deficiencies 
(DDs) will be recorded throughout the study period (starting at day 
-1 prior to the CCE procedure until the follow-up visit). 
 Statistics 
This is a pilot study where no formal sample sizing will be 
calculated. Up to 15 patients are planned to be enrolled to this 
study. 
Demographic and other characteristics will be provided. 
Summary statistics (arithmetic mean, standard deviation, and 
range for quantitative variables) will be presented for the total 
study population. Frequency tables for qualitative data will be 
provided. 
For the primary endpoint polyps contrast visibility, - the percent of 
polyps with visible contrast will be presented with 95%CI. 
For the primary endpoint of determinantal effects evaluation, the 
level of interference will be presented as mean, standard deviation, 
median and range (scale of 1-5; 1 = no interference and 5 = high 
interference). 
The percent of cases with at least one AE out of the total cases, will 
be presented with 95%CI. 
Any deviation from specified statistical plan will be in addition to 
“per protocol” analysis and will be reported as such. Post-hoc 
analysis will be conducted according to the existing data gathered, 
if necessary. 

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4. Introduction 
4.1. Background 
Colorectal Cancer 
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with an estimated 
1.8 million new cases in 20181. The incidence of colon cancer has been decreasing steadily since 2001; 
most recently, incidence declined an average of 3.1% per year between 2005 and 20142, 3. Mortality 
from colon and rectal cancers also has been declining for the past several decades, with the most rapid 
declines in the early 2000’s, which is likely due to screening 3. Screening can prevent CRC through the 
removal of precancerous adenomatous polyps and reduce deaths through early detection and 
treatment of cancer4. However, despite interventions for prevention, early detection and treatment, 
CRC still remains the third most common cause of cancer death among men and women in the United 
States and worldwide.5,6 
PillCam™ Capsule Endoscopy 
Capsule Endoscopy (CE) has evolved in recent years and became a first-line, noninvasive diagnostic 
technique for the small bowel. CE is now being utilized worldwide to assess patients for obscure 
gastrointestinal bleeding, possible Crohn’s disease and small bowel tumors. Alterations and 
improvements in the CE have led to the development of additional CE systems, namely the PillCam™ 
UGI, PillCam™ Colon and PillCam™ Crohn’s. 
The first PillCam™ endoscopy system indicated for the small bowel (SB) was cleared by the US Food 
and Drug Administration (FDA) in May 2001. Since then, more than 4,000,000 PillCam™ capsules have 
been sold worldwide in hospitals, outpatient clinics, and physician offices as an ambulatory procedure. 
After the capsule is ingested, the patient is not restricted to a medical environment. 
The PillCam™ COLON capsule 
The PillCam™ COLON system received CE mark on October 2006 and was cleared for marketing in the 
European Union (EU). The advanced generation of the system, the PillCam™ COLON 2 system, received 
CE mark in the EU on September 2009 and FDA clearance in the US on February 2014, Pharmaceuticals 
and Medical Devices Agency (PMDA) Japan in July 2013, and TGA approval in Australia in April 2013.  
Several thousand PillCam™ COLON2 capsules were safely ingested with numerous published clinical 
studies (please refer to Appendix C for list of clinical studies). 
Clinical literature on PillCam™ COLON2 capsule has demonstrated that the device and procedure are 
safe with very low occurance of adverse events. PillCam™ COLON2 has been clinically proven to serve 
as an effective alternative diagnostic modality when colonoscopy is incomplete or cannot be 
performed, and also shows to be preferred in patients who decline a colonoscopy procedure, making 
another option available to patients who are recommended to undergo a diagnostic evaluation of the 
colon (EU indication). The general conclusion confirms that the CCE procedure is safe, feasible, has 
acceptable accuracy rates, provides encouraging data for proposing PillCam™ COLON2 in the 
armamentarium of tools available for visualization the colon, and offers a more convenient and less 
risky procedure than other invasive colon exams.  

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Per-oral Methylene Blue Formulation (MB-MMX):  
Widespread application of blue dye to the mucosal surface of the colon has been shown to increase 
detection of colorectal neoplasia in patients at average or increased risk of CRC due to selective 
staining of subtle and nonpolypoid lesions (slightly elevated, flat, slightly depressed), both adenomas 
and sessile serrated adenomas (SSA). COSMO pharmaceuticals have combined methylene blue (MB) 
with a per-oral, colon-release, pH and time-dependent multimatrix structure (MB-MMX), able to 
directly deliver the agent in the colon lumen. When orally administered with bowel preparation, MB-
MMX tablets may increase the Adenoma Detection Rate (ADR) by staining and contrast-enhancement 
of the colorectal mucosa7. The MB-MMX formulation has been approved for use in EU in August 2020 
for the indication- diagnostic agent enhancing visualization of colorectal lesions in adult patients 
undergoing screening or surveillance colonoscopy. For additional information please refer to the MB-
MMX user manual. 
MB-MMX has been demonstrated as an efficient agent for polyp enhancement and increased polyp 
detection rate during Colonoscopy. Further evaluation of its' effect in CCE should be investigated.   
4.2. Purpose 
Given Imaging Ltd. (an indirect wholly owned subsidiary of Medtronic plc.) is sponsoring the SPICE 
study, a prospective single-center open-label pilot clinical study. The purpose of this study is to 
evaluate the technical feasibility of mucosal staining during capsule endoscopy (PillCam™ COLON2) 
procedure when using MB-MMX as mucosal enhancement technique. The study will be conducted in 
population with high risk for CRC.  
5. Objectives and/or Endpoints 
5.1. Objectives 
5.1.1. 
Primary Objective and Endpoints 
Primary objective:  
To demonstrate an effective polyp enhancement during a Colon Capsule Endoscopy procedure when 
using MB-MMX as a contrast- enhancement technique.  
Primary endpoints:  
• 
 The percent of colonic polyps which have a visible contrast to the healthy colonic mucosa 
during CCE, as indicated by an experienced reader, using the subjective reader questionnaire 
(For each polyp – was there a contrast between the polyp and the healthy mucosa? Yes/No), 
out of the examined polyps (Appendix D) 
• 
 The interference level of detrimental effects on the visualization of the colonic mucosa 
during CCE, due to use of MB-MMX per colonic segment. Detrimental effect will be 
considered as any observation, such as an excessive blue dye deposit, dark and dim 
appearance of the tissue, interfering with tissue visualization and will be evaluated on a 

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scale from 1 (no interference) to 5 (high interference) to evaluate the level of interference, 
using a subjective reader questionnaire (Appendix D) 
5.1.2. 
Secondary Objective and Endpoint 
Secondary objective:  
To evaluate the safety of CCE procedure while using MB-MMX. 
Secondary endpoint:  
All AEs will be reported by number, type, relatedness (device/procedure) seriousness, severity and 
duration. All AEs will be captured, regardless of severity. 
6. Study Design 
This is a single-center, prospective, pilot, non-randomized, open label post-market clinical trial, 
designed to evaluate the technical feasibility during CCE procedure, when using MB-MMX as a 
contrast- enhancement technique of mucosal staining in CRC high risk population. 
Up to 15 subjects, 45-75 years old, classified as being at high risk for CRC, will be enrolled in 1 site in 
Spain.  
Subjects will undergo a standard bowel preparation (single dose, 4L PEG), including 200 mg 
Methylthioninium chloride, corresponding to 8 tablets of 25 mg MB-MMX (per product's instructions 
for use) and will undergo a CCE procedure. An experienced Gastroenterologist will read the CCE 
procedure and complete a subjective questionnaire, to evaluate mucosal enhancement during a CCE 
procedure, when using MB-MMX as a contrast-enhancement technique. 
6.1. Duration 
The expected study duration is up to 13 months from EC/ Competent Authority (CA) approval (the 
latest). The duration of an individual subject participation will vary based on their enrollment; 
however, at a minimum, participation of an individual subject can vary for up to 39 days to include all 
study procedures (up to 30 days from screening to capsule ingestion and additional 5-9 days for the 
follow up call). 
6.2. Rationale 
This is a pilot, prospective, single center, open label, non-randomized, uncontrolled clinical study, to 
evaluate the technical feasibility of mucosal staining during CCE procedure, when using MB-MMX. 
MB-MMX oral formulation has been approved for use in EU and been evaluated during colonoscopy 
procedures. It has been established as an effective technique for colonic contrast enhancement.  In 
this study, this contrast enhancement technique will be evaluated for CCE procedure. 
MB-MMX intake in this study is considered a preceding investigational procedure, which is additional 
for this study and therefore outside standard of care.  

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The study design is based on clinical review (please refer to Appendix C: List of PillCam™ Colon Clinical 
Studies) and aligned with risk assessment results, as the product used in the study (PillCam COLON2) 
is a released CE marked product, which does not require additional risk evaluation, other than the 
standard risk evaluation process. 
The CCE procedure in the study, is the standard procedure performed in conjunction with MB-MMX 
standard regimen, in subjects at high risk for presence of colonic polyps during the CCE procedure. 
The study population was set to allow visualization of colonic polyps, under the assumption that the 
chance of observing colonic polyps in this population is higher comparing to CRC average risk 
population. 
The CCE results will be evaluated by an experience Gastroenterologist for the mucosal stanning 
outcomes. To evaluate safety, procedure and device-related adverse events will be captured and 
evaluated. 
This is an initial pilot study to generally evaluate polyp visualization during CCE, when using MB-MMX. 
In case of favorable results, a larger scale study, with a Colonoscopy procedure that follows the CCE, 
may be considered.   
6.3. Study Oversight 
No steering committee will be used in this study, due to the nature of this pilot study. 
7. Product Description 
7.1. General  
7.1.1. 
The PillCam™ Capsule Endoscopy System  
The PillCam™ capsule endoscopy system is comprised of four main subunits: 
(1)   The ingestible PillCam™ Capsule - a single-use ingestible video capsule designed to acquire 
images during natural propulsion through the digestive system. In general, the PillCam™ 
capsule is designed to withstand the mechanical forces and chemical environment of the 
digestive system.  
 (2)  The PillCam™ Recorder - an external, portable receiving/recording unit that receives and 
stores the acquired images from the capsule via sensors. 
(3) The PillCam™ Software – a proprietary software that supports the capsule endoscopy 
examination in all of its phases. 
(4)  The Workstation - a standard personal computer that is the operational platform for the 
PillCam™ software.    

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Figure 1: Data flow of the PillCam™ Colon Capsule Endoscopy System 
In general, the PillCam™ capsule has one or two optical heads and acquires images of different parts 
of the Gastrointestinal (GI) Tract (Esophagus, stomach, duodenum, Small bowel and Colon) during 
natural propulsion through the digestive system. The Capsule transmits the acquired images via digital 
radio frequency communication channel and antennas of the Sensor to the PillCam™ Recorder, both 
located outside the body, which is later downloaded to the workstation that utilizes the PillCam™ 
software to output an image of the examined gastrointestinal tract (Figure 1, for illustration only). 
For model numbers details refer to Appendix F. 
 The CE marked device PillCam COLON2 system will be used in accordance with the intended purpose 
as described in the approved IFU for which CE mark has been obtained. Thus, the study is classified as 
a post market study. Note that MB-MMX is used within the intended purpose described in the drug 
labeling as approved for use in EU.  
7.1.2. 
The PillCam™ COLON 2 Capsule   
7.1.2.1. Product Description  
The PillCam™ COLON2 capsule is a single-use capsule that has two optical heads (miniature color 
cameras with a flash), batteries, transmitter, and an antenna to transmit the acquired images. All of 
these are encapsulated in an ingestible capsule made of biocompatible plastic with a length of up to 
32.8 mm and diameter of 11.6 mm.      
7.1.2.2.      Intended Use  
The PillCam™ Capsule Endoscopy System with the PillCam™ COLON2 capsules is intended for the 
visualization of the colon for diagnosis of colonic disorders. 
7.1.2.3.      Intended Population  
The PillCam™ COLON2 capsule is intended for use in adults and children from 8 years of age.   
7.1.3. 
The PillCam™ Recorder  
The PillCam™ Recorder is a portable, external compact battery-operated receiving/recording unit that 
receives and stores the acquired images from the capsule.  

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The PillCam™ Recorder is capable of controlling the PillCam™ parameters such as frame rate, light 
pulse, power and incorporates an integrated LCD screen that supports real time display of images. It 
receives and stores the image data transmitted by the PillCam™ capsule. Currently PillCam™ recorder 
DR3 is the standard model commercially available.  
The PillCam™ Recorder set consists an antenna array or sensor belt carried in proximity to the body, 
a receiver, and memory for accumulation of the data during the examination.  
The PillCam™ recorder is supplied with a pouch to wear over the shoulder and with an adjustable strap 
to secure to the waist and worn by the patient during the procedure. 
7.1.3.1. Sensor Arrays & Sensor Belt   
The PillCam™ sensors are physical receptors that receive data transmission from the PillCam™ capsule 
and transfer it to the PillCam™ recorder. These sensors are placed on the patient as a sensor belt or a 
sensor array (in this study sensor belt will be used): 
• 
PillCam™ sensor belt: The sensor belt is worn around the patient’s waist over a thin shirt.  
• 
PillCam™ sensor array: The sensors of the sensor array are attached to the patient's skin. 
The sensor locations depend on the procedure type. Each sensor consists of a flexible 
printed circuit board (PCB) and is attached with a disposable, medical adhesive sleeve. 
7.1.4. 
 The PillCam™ Software 
The PillCam™ software program (v.9), supports the PillCam™ capsule endoscopy procedure by 
providing access to the different steps in the PillCam™ capsule endoscopy procedure. The software 
program, used for video creation and interpretation, has several useful incorporated features that aid 
the physician during diagnosis. For detailed description please refer to PillCam™ Endoscopy System 
user manual (UM). 
7.1.5. 
The Workstation Unit 
The workstation is a standard stand-alone personal computer dedicated workstation that cannot be 
connected to a network environment. The workstation supports multi-user configuration and 
intended for use during the interpretation and analysis of the acquired data and for generating 
PillCam™ reports.  
7.2. Dosage Form and Route of Administration 
The PillCam™ capsules are administered orally, following a pre-ingestion preparation procedure (see 
section 10.3) and are swallowed as any other pill with drinking a glass of water. Each subject will ingest 
one capsule. 

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7.3. Manufacturer 
The PillCam™ Colon Capsule Endoscopy system is manufactured by Given Imaging Ltd., an indirect 
wholly owned subsidiary of Medtronic plc. (“Medtronic”). 
7.4. Packaging 
The PillCam™ COLON2 Capsules will be packaged in an appropriate Jewel style package box, using a 
controlled process that ensures the capsule is activated only when needed.  
Each PillCam™ capsule will be packed in a separate Jewel box with an embedded magnet that prevents 
it from activating when it is handled in the box prior to ingestion.  
Standard labeling will reflect the specifications of each PillCam™ capsule, as well as serial number, 
Lot number tracking, expiration date and will comply with the EU regulatory requirements for study 
product labeling. The CE-marked devices will be provided with the approved CE-mark labeling. A 
sticker will be added to the label with the statement "exclusively for clinical investigations" in local 
language. 
7.5. Equipment 
Devices under this study do not require any specialized or dedicated maintenance or calibration for 
the study, hence calibration and maintenance activities will not be documented. 
Every equipment used for the study will be tracked to assure it is used as intended. 
The following equipment might be used, per investigator's or designee's discretion: 
• 
Abdominal X-ray (will be performed in case of suspected capsule retention)  
7.6. Product Use 
The PillCam™ COLON2 capsule is dispensed to the subject by the investigator/study coordinator and 
administered orally, following a pre-ingestion bowel preparation procedure and ingested by the 
patient as any other pill with drinking a glass of water. 
The PillCam™ COLON2 capsule is moving through the patient’s GI tract, propelled by natural peristalsis 
until it is excreted. The procedure involves intake of bowel preparation and prokinetic agents, in order 
to propel the capsule agents, and MB-MMX tablets administration, in order to enhance colonic polyp 
visualization.  
The PillCam™ sensor belt that receives data transmission from the PillCam™ COLON2 capsule and 
transfer it to the PillCam™ recorder, is worn around the patient’s waist over a thin shirt. 
For further information, refer to the PillCam™ UM.  
7.7. Product Training Materials 
All investigators and clinical team personnel involved in conducting the PillCam™ endoscopy 
procedures throughout the study period, are knowledgeable with the PillCam™ endoscopy system and 
procedures and are well trained on performing the study procedures.  

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All the investigators and clinical team personnel will further be instructed and trained by the sponsor 
(or designee) on all relevant Clinical Investigation Plan (CIP) specific aspects and related documents, 
to a level that enables them to perform their delegated tasks appropriately, according to the study 
specific training plan and their training will be documented. Per ISO14155, the training/experience 
should be based on the risk assessment. 
Only trained team members with a signed training record and proper documented delegation, will be 
allowed to perform their delegated tasks as part of this study.  
7.8. Product Receipt and Tracking 
The sponsor will initiate product(s) shipment from the sponsor to the site upon obtaining CA and EC 
approval for study conduct and fully executed Clinical Trial Agreement (CTA). Both sponsor and site 
will maintain all shipment documentation and tracking, which will include dates, quantities received, 
lot/serial numbers and expiration dates, as applicable. Prior to any shipment, the site will be informed 
by the sponsor regarding the upcoming shipment, expected arrival date and content of the shipment. 
All products shipments will be supported by delivery and return notes.  
 “Product Accountability Log” will be managed and maintained by the site, filed in the Investigator Site 
File (ISF) at the site and monitored by the study Monitor(s). Products receipt & return processes, as 
well as products' identifying information will be documented in the log.  
For each dispensed capsule, the following information should be recorded, at minimum: subject’s ID, 
date dispensed, capsule ID number. At the termination of the study, all unused study material must 
be returned with the corresponding documentation as directed by the Sponsor. 
7.9. Product Storage 
The supplied PillCam™ COLON2 capsules will be stored in a locked, secured area with limited access 
only to approved study staff. The capsules should be stored in a dry place, at a temperature below 
25°C (77°F) and away from any magnetic source. To prevent capsule activation, the PillCam™ capsules 
will be kept in their original containers until use. Even when stored in their original containers and 
according to recommendations, the PillCam™ COLON2 capsules can be kept for a limited period, only 
as indicated by the expiration date of the container label.  
Minimum/ Maximum temperature log will be maintained on site to ensure that the PillCam™ COLON2 
capsules are stored at the correct temperature.  
It is the responsibility of the investigator to correctly handle, store, and track the study products 
maintained at the study site and the study products will be used only in the clinical study according to 
the CIP. 
7.10. 
Product Return 
Subjects are not required to return the PillCam™ COLON2 capsules following capsule excretion. At the 
end of the study, all unused study material must be returned with the corresponding documentation 
as directed by the Sponsor. Any capsule that reaches its expiration date before it has been dispensed 
should be returned to the Sponsor or destroyed on site; with proper documentation in either scenario.      

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7.11. 
Product Accountability 
The study site team is responsible for maintaining tracking of the PillCam™ system and components 
during the study. In order to maintain current and accurate inventory records for documentation of 
the receipt, dispensing and safe return (when applicable) of study product, 2 device accountability 
logs will be used- 1 for non-disposable PillCam™ system components (i.e. workstation, DRs) and 1 for 
disposable PillCam components (i.e. capsules). The logs will be monitored by the study Monitor, 
assigned by the Sponsor. For each dispensed capsule, the following information should be recorded: 
The subject study ID, capsule's serial number/ lot number, expiration date, received date, the date 
dispensed and the initials of the person dispensing the capsule, date/reason for return or disposal 
(when applicable).  
If upon arrival of the product at site, the product supply appears to be damaged, the investigator 
and/or the study coordinator will report this to the study Monitor immediately and follow the 
instructions provided.  
The product will be kept under the recommended storage conditions until administered to the subject 
and only authorized study personnel will have access to the study product. 
The Bowel preparation agents , as well as the MB-MMX tablets required for the capsule pre-ingestion 
preparation, will be provided to enrolled subjects by the site study team during the screening visit. 
Prucalopride & Prokinetic agents will be provided to enrolled subjects by the site study team during 
the CCE procedure visit. 
At the termination of the study, all unused study materials must be safely returned/destroyed per 
local regulations. Accountability log will be updated accordingly and reviewed by the Sponsor. 
The investigator shall make sure that all study products will be stored in such a manner as to be easily 
identifiable. If the study device cannot be identified, the device shall not be used. 
8. Study Site Requirements 
8.1. Investigator/Investigation Site Selection 
The role of the principal investigator is to implement and manage the day-to-day conduct of the 
clinical investigation, as well as ensure data integrity and the rights, safety and well-being of the 
subjects involved in the clinical investigation. 
The principal investigator shall: 
• 
Be qualified by education, training, and experience to assume responsibility for the proper 
conduct of the clinical investigation. 
• 
Be a qualified practitioner (experienced gastroenterologist) and experienced in the field 
of application and trained in the use of PillCam™ CE System. 
• 
Disclose potential conflicts of interest, including financial, that interfere with the conduct 
of the clinical investigation or interpretation of results. 

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• 
Be able to demonstrate that the proposed investigational study site: 
▪ 
Has the required number of eligible subjects needed within the recruitment 
period. 
▪ 
Has one or more qualified investigators, a qualified investigational study site team 
and adequate facilities for the foreseen duration of the clinical investigation. 
Study site personnel training will be completed and documented prior to participation in this study. 
8.2. Study Site Activation 
During the activation process (prior to subject enrollment), the Sponsor will train study site personnel 
on the clinical investigation plan, on relevant standards and regulations, informed consent, and on 
data collection and reporting tools. If new members join the study site team, they will receive training 
on the applicable study requirements relevant to their role before contributing to the study. 
Prior to performing study related activities, all regulatory requirements shall be fulfilled, including, 
but not limited to the following:  
• 
EC approval (and voting list, as required by local law) of the current version of the CIP 
and Informed Consent (IC).  
• 
CA approval or notification (as required per local law)  
• 
Fully executed CTA  
• 
Financial disclosure  
• 
CV of investigators and key members of the investigation study site team (as required). 
The signature on the CV must be dated within 3 years prior to the date of activation of 
the study site.   
• 
Documentation of delegated tasks 
• 
Documentation of study training 
• 
Additional requirements imposed by local regulations, the EC and CA shall be followed, if 
appropriate.  
In addition, all participating study site staff must be trained on the current version of the CIP as well 
as on the applicable study requirements depending on their role and must be delegated by the 
principal investigator to perform study related activities.   
The Sponsor will provide the study site with documentation of study site/investigator readiness- a 
site activation letter; this letter must be received prior to performing any study related activities. 
8.3. Role of the Sponsor Representatives 
In addition to performing monitoring and auditing activities, Sponsor representatives may provide 
support to the study site, as required for the study, under the supervision of the Principal Investigator, 
including but not limited to: 
• 
Provide study training relevant and pertinent to the involvement of personnel conducting 
study activities and investigator responsibilities 

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9. Selection of Subjects 
9.1. Study Population 
Up to 15 subjects at high risk for CRC (as defined by inclusion criterion #2) will be enrolled to this 
study.  
9.2. Subject Enrollment 
Written ICF will be obtained from each subject prior to performing any screening assessments. Once 
ICF is obtained, subjects will be screened to ensure they meet all of eligibility criteria prior to study 
enrollment. A subject is considered enrolled in the study once the ICF is signed and it is determined 
that all eligibility criteria are met. 
9.3. Inclusion Criteria 
1. Male or female adults ages 45-75 years  
2. Subject is classified as being at high risk for CRC due to one (or more) of the following risk 
factors: 
• 
A personal history of colorectal polyps  
• 
A first-degree family history of colorectal cancer  
• 
Family/personal inherited syndrome (Lynch syndrome, Familial adenomatous 
polyposis {FAP}, other inherited syndromes linked to colorectal cancer) 
• 
Subject with currently suspected or diagnosed rectal bleeding, including positive FIT 
or positive fecal DNA test 
• 
Subjects under surveillance for CRC (last OC≥1.5 years)    
3. Subject is willing and able to participate in study procedures, understand and sign the 
informed consent  
9.4. Exclusion Criteria 
1. Subject has a previous history or suspicion of inflammatory bowel or Crohn’s disease, 
ulcerative Colitis or indeterminant Colitis 
2. Subject has congestive heart failure or recent myocardial infarction (<3month) 
3. Subject with moderate/severe renal disease and/ or severe hepatic impairment  
4. Subject has uncontrolled diabetes 
5. Subject has a severe, life-threatening disease 
6. Subject with known gastrointestinal motility disorders 
7. Subject has known delayed gastric emptying 

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8. Subject has undergone surgery of the luminal gastrointestinal (GI) tract, from esophagus to 
the rectum, other than uncomplicated appendectomy or cholecystectomy.   
9. Subject with any current condition believed to have an increased risk of capsule retention 
such as suspected or known bowel obstruction or pseudo-obstruction, stricture, or fistula 
(symptoms such as severe abdominal pain with accompanying nausea or vomiting) 
10. Subject with dysphagia, any swallowing disorder, or any major gastrointestinal motility 
disorder 
11. Subject has a history of inadequate bowel preparation for colon imaging with colonoscopy, 
CTC, CCE, or DCBE (self-reporting) 
12. Subject with known or suspected constipation history as defined by the following:  as 
needing the use of medication (prescription or OTC) for management of constipation, or 
fewer than 3 BM/week regardless of medication use   
13. Subject with a cardiac pacemaker or other implanted electromedical device 
14. Subject with planned MRI examination within 7 days after ingestion of the capsule  
15. The subject is taking antidepressant medicine or a medicine for psychiatric illness, such as:  
o selective serotonin reuptake inhibitor (SSRI)- as fluoxetine, fluvoxamine, paroxetine, 
sertraline, citalopram, escitalopram and zimeldine; - bupropion, venlafaxine, 
mirtazapine, clomipramine, buspirone; -  
o medicines classified as Monamine Oxidase Inhibitors (often used for treating 
depression). 
16. Subject has glucose-6-phosphate dehydrogenase (G6PD) deficiency and/or allergic to 
peanut/soya 
17. Subject consumes any of the medicinal products which interacts with MB-MMX, as per MB-
MMX label and Investigator’s discretion  
18. Subject with allergies or known contraindication to the device, medications or preparation 
agents used in the procedure as described in the relevant instructions for use/ package 
inserts 
19. Subject use of opioid medication on a regular basis and requires medication to treat opioid 
induced constipation  
20. Subject currently participating in another gastrointestinal clinical study (investigational drug 
or device) that might interfere with results of study 
21. Females who are pregnant or breastfeeding at time of bowel prep  

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22. Any condition which precludes compliance with study and/or device instructions based on 
the clinical judgment of the investigator 
23. Subject who is considered to be part of a vulnerable population (e.g. prisoners or those 
without sufficient mental capacity) 
24. Medtronic employees 
 

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10. Study Procedures 
The study consists of a screening – enrollment phase, bowel preparation phase, including MB-MMX 
tablets administration, followed by the PillCam™ Colon endoscopy procedure visit and a post 
procedure telephone follow up visit, as described in Table 1- Schedule of events and data collection:.   
10.1. Schedule of Events & Data collection 
The study assessment in table 1 indicates the observations/ assessments/ data collection to be 
conducted throughout the study period. 
Table 1- Schedule of events and data collection: 
1 Screening/enrollment process may start 3-30 days prior to visit 2. 
2Preparation starts 3 days prior to visit 2 
3 Urine Pregnancy test must be performed at day (-1) prior to the bowel prep/MB-MMX intake (when applicable).  
4 MB-MMX is administrated at day (-1). 
  
Follow Up Visit 
Procedure Visit 
Preparation 
Screening/ 
Enrollment 
 
V3 
V2 
 
V1 
 Procedure            Visit 
 
7±2 
0 
(-3)-02 
(-30)-(-3)1 
 Time Schedule (Days)
 
 
 
X
 
Inform consent 
 
 
 
X
 
Eligibility criteria 
 
 
 
X
 
Demographic data 
 
 
 
X
 
Medical History 
 
X
 
 
X
 
Concomitant medication  
 
X
 
 
X
 
Vital Signs and height/weight 
measurements 
 
 
3
X
 
X
 
Urine Pregnancy test (when 
applicable) 
 
 
 
X
 
Provide Preparation materials 
(including MB-MMX) and subject 
instructions form  
 
 
X
 
 
Low Fiber Diet 
 
 
X
 
 
Bowel Preparation intake  
 
 
4
X
 
 
MB-MMX intake 
 
X
 
 
 
Bowel preparation and MB-MMX 
compliance verification 
 
X
 
 
 
Prucalopride administration 
 
X
 
 
 
CCE administration 
X
 
X
 
 
 
Device Deficiencies 
X
 
X
 
X
 
X
 
Study Deviations 
X
 
X
 
X
 
 
AEs collection 
X
 
 
 
 
Study exit 

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10.2. Subject Screening (visit 1) 
All subjects that are considered for the study should be included on the study screening log. The 
reason for non-eligibility, as determined by the Investigator, should be recorded on the study 
screening log. The screening log serves as a method for the Sponsor to assess selection bias in the 
trial. 
During the screening visit, the investigator will obtain patient’s written informed consent, after the 
subject had an ample time and opportunity to read and understand the ICF, verify that the subject 
does not have any contraindications for the PillCam™ Capsule Endoscopy procedure, and assess each 
subject for eligibility based on the inclusion/exclusion criteria.  
To determine subject eligibility, baseline information will be collected as outlined in Table 1- Schedule 
of events and data collection:. Informed consent, vital signs, medical history, concomitant 
medications, urine pregnancy test (performed in women with childbearing potential) and 
demographic information will be collected during the visit. Study medications required for the pre-
ingestion procedure will be provided to eligible subjects during this visit.  
Data of screen failure subjects will not be captured within the Electronic Case Report Form (eCRF). 
Their signed ICF and Inclusion-Exclusion criteria evaluation will be kept on site. 
10.3. PillCam™ Capsule pre-ingestion preparation procedure 
The pre-ingestion preparation procedure is similar to colonoscopy or capsule endoscopy standard 
preparation and is performed in accordance to the labeling of the agents which are being used. In this 
study MB-MMX tablets will be also administrated to evaluate colonic polyps staining during the CCE 
procedure. Use of MB-MMX will be according to the product's label. 
The preparation procedure will begin with a low fiber diet at days (-3)- (-2) before the CCE, followed 
by a clear liquid diet, starting from the day before capsule ingestion. At day (-1) prior to the CCE, a 
urine pregnancy test will be performed (as applicable and prior to prep/MB-MMX administration) and 
bowel preparation agent will be administrated (single dose) as well as administration of MB-MMX 
tablets (in accordance to the product's IFU). At the day of CCE procedure, 1 tablet of prucalopride (i.e. 
Resolor) 1mg  will be administrated Prior to the CCE procedure. The subject will be required to 
consume additional bowel preparation & prokinetic agents during the CCE procedure.  
Prior to the CCE procedure, the subjects will be given detailed instructions regarding the preparation 
regimen, as specified in the subject instructions form that will be provided to the subject during the 
screening visit. 
10.4. PillCam™ CCE Procedure (visit 2) 
On the morning of the scheduled CCE procedure, the subject will be requested to arrive to the site. 
Compliance to the bowel prep and MB-MMX intake will be recorded, vital signs will be taken and 
prucalopride tablet will be consumed. The subjects will then undergo the PillCam™ CCE procedure 
within defined timelines. During the CCE procedure subjects will comply with the prokinetic agents & 
bowel preparation regimen as described in Appendix A- SPICE Study- Bowel Preparation/MB-MMX 

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administration Schedule. Subjects will be allowed to drink clear liquids and eat upon clinical team 
instructions. 
Following capsule ingestion and intake of the 2nd bowel preparation boost, the subjects might be 
dismissed to continue the procedure at home, upon physician decision. In such case, the data recorder 
and sensor belt will be removed according to the clinical team instructions and up to 12 hours from 
ingestion.     
Prior to discharge, the subject will be instructed to contact the study physician/ team in any case of 
an adverse event. In case a subject didn't excrete the capsule during the CCE procedure, he/she will 
be instructed to attempt to verify that the capsule exited the body and to inform the study team on 
the exit time, if possible.  
10.5. Phone Call Follow-up Visit (visit 3) 
5 to 9 days after the CCE procedure (after visit 2), each subject will be contacted by the study team 
over the phone, to verify that there have been no changes in their well-being following the procedure. 
In addition, capsule excretion will be verified.  
An acceptable indication for safe excretion of the PillCam™ is capsule entry to the colon as visualized 
in the CCE video. The risk for retention may be considered null when the capsule enters the colon. 
 Subjects who didn’t report capsule excretion until the phone call follow up visit, and the capsule didn’t 
reach the Colon during the CCE procedure, as observed in the CCE video, will be evaluated for a need 
to perform abdominal x-ray to verify capsule exit, based on the investigator’s judgment.  
Should a subject miss a visit or the visit fall outside the pre-specified window of 5-9 days following the 
CE procedure, a study deviation must be reported. A subject will be considered as lost to follow-up if 
at least three attempts to contact the subject are unsuccessful. The method of attempt will be 
documented in subject’s records. 
10.6. CCE Procedure Video 
The nature and purpose of this pilot study is an initial assessment and not medical evaluation. The raw 
data from the CCE procedure will be sent to the Sponsor for customized video compilation, which will 
allow reading of the CCE procedure in conjunction with the MB-MMX. All of the videos are read and 
analyzed by an experienced gastroenterologist. In cases the video is eligible for reading and allows 
assessment, a report will be generated and provided to the subject.   
10.7. Medication Compliance 
All enrolled subjects will receive detailed bowel preparation/MB-MMX administration instructions for 
the CCE procedure. Compliance to the bowel preparation/MB-MMX intake will be captured and 
documented on a dedicated subject instructions form. 

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10.8. Optional X-ray Procedure  
If needed, the progress/excretion of the capsule may need to be verified by an abdominal x-ray. 
The expected radiation exposure from an abdominal x ray is approximately 0.7mSV.  This may be 
compared to the annual exposure of an individual of 3mSV in background radiation or a chest 
radiograph of 0.4 mSV.  
10.9. Subject Consent 
Informed consent is defined as a legally effective documented confirmation of a subject’s voluntary 
agreement to participate in a particular study, after information has been given and explained to the 
subject on all aspects of the study that are relevant to the subject’s decision to participate. This 
process includes obtaining an IC form that has been approved by the study site’s EC and signed and 
dated by the subject and investigator.  
Prior to enrolling subjects, the ICF must be approved by the EC. The ICF must be controlled (i.e. 
versioned and dated) to ensure it is clear which version was approved by the EC. Any adaptation of 
the sample ICF must be reviewed and approved by the Sponsor and the EC reviewing the application 
prior to enrolling subjects.  
The investigator must notify the subject of any significant new findings about the study that become 
available during the course of the study, which are pertinent to the safety and well-being of the 
subject, as this could impact a subject’s willingness to participate in the study. If relevant, re-consent 
may be requested from subjects to confirm their continued participation. 
Prior to initiation of any study-specific procedures, IC must be obtained from the subject. The IC 
process must be conducted by the principal investigator or an authorized designee, and the IC Form 
must be given to the subject in a language he/she is able to read and understand. The process of IC 
must be conducted without using coercion or undue improper influence on or inducement of the 
subject to participate by the investigator or other study site personnel. The IC process shall not waive 
or appear to waive subject’s legal right. The language used shall be as non-technical as possible and 
must be understandable to the subject and the impartial witness, where applicable.  
The subject must have ample time and opportunity to read and understand the IC form, to inquire 
about details of the study, and to decide whether or not to participate in the study. All questions about 
the study should be answered to the satisfaction of the subject. 
When the subject decides to participate in the study, the ICF must be signed and personally dated by 
the subject and investigator or authorized designee, as required, and ensured by the principal 
investigator or his/her authorized designee.  
A copy of the ICF, signed and dated as required by law, must be provided to the subject. 
Per ISO14155, in the event the subject cannot read and/or write, the IC process shall be obtained 
through a supervised oral process. An independent and impartial witness must be present during this 
process. The ICF and any other information must be read aloud to the prospective subject. Whenever 
possible, the subject shall sign and personally date the informed consent form. The witness signs and 
personally dates the IC attesting that the information was accurately explained and that informed 
consent was freely given. 

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The original of the signed ICF must be filed on site with the subject’s study documents.  
The ICF (and any subsequent version) will be submitted for ECs/ CA approval, as required per local 
regulations.  
The IC must be available for monitoring and auditing and the study monitor must be able to review 
the subject’s signed and dated ICF and verify its completeness.  
Consistent with the Declaration of Helsinki (DoH), vulnerable adults (i.e. those subjects mentally 
incapable of giving consent) are excluded from this protocol.  Any subjects with mental incompetence 
(e.g. Alzheimer’s, dementia, psychiatric disorders, developmental disorders) should be assessed for 
vulnerable status. If the ICF is signed by an individual other than the subject, the monitor may discuss 
whether the Investigator believes the subject meets the definition of a vulnerable adult.  This protocol 
defines vulnerable adult as those subjects mentally incapable of giving consent, in the Investigator’s 
opinion. The Investigator should consider the definition of vulnerable adult per ISO 14155, which 
defines vulnerable adults as: “individuals who are unable to fully understand all aspects of the 
investigation that are relevant to the decision to participate, or who could be manipulated or unduly 
influenced as a result of a compromised position, expectation of benefits or fear of a retaliatory 
response". For example, this could include Individuals with loss of autonomy due to immaturity or 
through mental disability, persons in nursing homes, children, impoverished persons, subjects in 
emergency situations, ethnic minority groups, homeless persons, nomads, refugees, and those 
incapable of giving IC. Other vulnerable subjects could include, for example, members of a group with 
a hierarchical structure such as university students, subordinate hospital and laboratory personnel, 
employees of the sponsor, members of the armed forces, and persons kept in detention. 
10.10. Enrollment 
Written ICF will be obtained from each subject prior to performing any screening assessments. Once 
ICF is obtained, subjects will be screened to ensure they meet all of eligibility criteria prior to study 
enrollment. A subject is considered enrolled in the study once the ICF is signed and it is determined 
that all eligibility criteria are met. A log of all subjects enrolled in the study will be maintained and the 
date the subject signed the ICF will be documented in the subject’s medical records.  
10.11. Assessment of Efficacy 
Please refer to Section 13- Statistical Design and Methods for further information regarding 
assessment of efficacy. 
10.12. Assessment of Safety 
AEs information is collected in this study.  
To monitor safety in this study, subjects will be asked at each visit about any changes in their medical 
condition/well-being. All adverse events will be recorded throughout the study, from start of Bowel 
preparation (1 day prior to the CCE procedure) until the end of the follow up call. AEs should be 
assessed in terms of their seriousness, type, relatedness (device/procedure), severity and duration. 
All anticipated adverse events will be collected. Subjects will be able to contact the investigator at any 
time during the study, if they notice any change in their medical condition/well-being. 

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The data regarding severity, seriousness, timing, relatedness (device/procedure), duration and type 
of procedure as well as AE outcome will be observed and documented. See Section 12 for further 
information on the collection of AEs and safety information. 
10.13. Recording Data 
This study will utilize an electronic eCRF database. All data requested on the eCRF are considered 
required. All entries made in the eCRF must be verified against source documents. For each complete 
case, the Principal Investigator or designee must ensure the accuracy and completeness of the 
recorded data and then provide an electronic signature on the appropriate eCRFs. The Investigator’s 
electronic signature for specific eCRFs will be documented in compliance with local regulations. 
The source documents must be made available for monitoring or auditing by Sponsor's representative 
or representatives of the CA and other applicable regulatory agencies. 
Visual and/or computer data review will be performed to identify possible data discrepancies. Manual 
and/or automatic queries will be created in the Oracle remote RDC system and will be issued to the 
site for appropriate response.  
eCRFs are recommended to be entered into the electronic system within no later than 10 days of the 
completion of the protocol-specified visit, or sooner, as required by the CIP and local regulations. 
Data points not collected and/or recorded will be considered deviations unless otherwise specified. 
Procedures used for data review, database cleaning, and issuing/resolving data queries will be 
included in the Data Management Plan. 
The study eCRF is an FDA CFR title 21 Part 11 compliant electronic data capture system.  
The investigator must ensure the availability of source documents from which the information on the 
eCRFs was derived. The type and location of source documents should be documented. Where 
printouts of electronic medical records, are provided as source documents, or where copies of source 
documents are retained as source documents, those should be certified. Certification must contain 
(1) the signature of the individual making the copy, (2) the date the copy was made and (3) a statement 
attesting to the accuracy and completeness of the copy.  
Data generated from using the device will be stored on an external hard drive provided by the 
Sponsor in accordance to local data protection laws. This data will remain confidential and identified 
only by subject’s code. The data will be available to the monitor and will be considered as source 
data. De-identified videos and raw data from the CCE procedure will be sent to the Sponsor for 
analysis using an encrypted device. Additional data collection may apply. In case that following the 
CCE procedure, the subject is referred to a colonoscopy procedure, de-identified colonoscopy report 
and images/videos may be collected.  All data sent to the Sponsor will not include any subject 
identifying information.    
10.14. Deviation Handling 
A study deviation is defined as an event within a study that did not occur according to the CIP or the 
CTA. Use of waivers from the CIP is prohibited. 
Prior written approval by the Sponsor is expected in situations where the investigator anticipates, 
contemplates, or makes a conscious decision to deviate. Prior approval is not required when a 

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deviation is necessary to protect the safety, rights or well-being of a subject in an emergency or in 
unforeseen situations beyond the investigator’s control (e.g. subject failure to attend scheduled 
follow-up visits, inadvertent loss of data due to computer malfunction, inability to perform required 
procedures due to subject illness). 
For medically justifiable conditions which preempt a subject’s ability to complete a study-required 
procedure, it may be permitted to report only one deviation which will apply to all visits going forward. 
This may also apply for other unforeseen situations (e.g. the subject permanently refuses to complete 
a study required procedure and the data will not contribute to the primary end point analysis). 
However, prior approval from the Sponsor is required for such situations.  
All study deviations must be reported on the eCRF regardless of whether medically justifiable, pre-
approved by the Sponsor, an inadvertent occurrence, or taken to protect the subject in an emergency. 
Multiple deviations of the same type at the same visit may be reported on one case report form. 
In the event the deviation involves a failure to obtain a subject’s consent, or is made to protect the 
life or physical well-being of a subject in an emergency, the deviation must be reported to the EC as 
well as the Sponsor within 5 working days.  
Reporting of all other study deviations should comply with EC policies and/or local laws and must be 
reported to the Sponsor as soon as possible upon the study site becoming aware of the deviation. 
Reporting of deviations must comply with EC policies, local laws, and/or CA requirements.  Refer to 
Investigator Reports, Table 7: Investigator reports for geography-specific deviation reporting 
requirements and timeframes for reporting to the Sponsor and/or RAs.  
Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions (e.g. amend the CIP, conduct additional training, 
terminate the investigation). Repetitive or serious investigator compliance issues may result in 
initiation of a corrective action plan with the investigator and study site, and in some cases, may 
necessitate suspending enrollment until the problem is resolved or ultimately terminating the 
investigator's participation in the study. If further escalation is needed, it may result in Corrective and 
Preventive Action (CAPA), suspension, or termination. If it is determined that there is investigator 
fraud, or strong evidence of fraud, the course of action may include, but is not limited to: potential 
exclusion from analyses, site closure, notification of the responsible EC of the actions to be taken, 
notification of key stakeholders and/or study team of the actions to be taken, notification of 
appropriate CA and/or restrictions on future participation in clinical studies. The Sponsor will provide 
reports to investigator summarizing information on deviations that occurred at the investigational 
study site on a periodic basis.  
Major deviations are defined as deviations with respect to: 
• 
Failure to obtain proper IC  
• 
Subject's eligibility criteria not met 
Bowel preparation related deviations are common and expected. Deviations related to bowel 
preparation consumption/MB-MMX intake will be specifically defined for the study and captured 
accordingly in the eCRF. For further details please refer to Appendix B: Bowel Preparation/MB-MMX 
administration Deviations. 

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10.15. Subject Exit, Withdrawal or Discontinuation 
A study exit eCRF is required for all subjects. The reason for study exit, including screen failure, will be 
documented on the applicable eCRF and in the subject file. The Sponsor must be informed of each 
withdrawal case. Prior to exiting a subject from the study, it is recommended to follow the subject 
until all ongoing device and/or procedure related AEs are resolved or unresolved with no further 
actions planned. At the completion of the follow-up visit, the subject will be exited from the study. A 
follow-up eCRF and a Study Exit eCRF will to be completed. Upon exiting from the study, no further 
study data will be collected, or study visits will occur for the subject, unless the subject has been 
referred to a colonoscopy procedure post the CCE procedure (de-identified colonoscopy report and 
images/videos may be collected) and/or AE follow up is required.   
Subjects will be informed that they have the right to withdraw from the study at any time, without 
prejudice to their medical care, and are not obliged to state their reasons.  
If the subject wishes to exit from the study (i.e. the subject revokes consent), the study site is required 
to document the reason for exit on the Exit eCRF. In addition, study site shall follow the regulations 
set forth by the governing EC. Per ISO14155 guidance, permission may be requested to follow up with 
the subject outside of the study, due to withdrawal based on issues related to the investigational 
feature safety or performance. 
The investigator may withdraw a subject from the assigned study at any time if any of the following 
situations arise: 
1. 
Subject did not provide consent/ withdrawal of informed consent by the subject 
2. 
The Principal Investigator deems that it is in the subject’s best interest to withdraw from the study 
for subject's safety.  
3. 
Subject's death 
4. 
Occurrence of a Serious Adverse Device Effect (SADE), or severe side effects 
5. 
Presence or appearance of any of the exclusion criteria/inclusion criteria not met 
6. 
A significant CIP violation, as determined either by the sponsor or the investigator  
7. 
Subject noncompliant with study procedures/visits 
Every effort will be made to determine the reason for the subject dropping out of the study. Any 
withdrawal must be fully documented and recorded including the reason for withdrawal on the study 
termination page on the study eCRF and in the subject file.  
Subjects removed from the study because of a Serious Adverse Device Event or Serious Adverse Event 
will be followed-up until the adverse event has resolved or study closure, whichever occurs first.  
The eCRF will be completed for withdrawn subjects and will include all available information including:  
Demographics, medical information, all parts of the procedures that were performed, safety 
information, reason for end of study etc. 

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10.16. Lost to Follow-up 
A subject is considered to be lost to follow-up if at least three attempts to contact the subject are 
unsuccessful. The method of attempt (e.g., three phone calls) must be documented in the subject’s 
medical record. In addition, regulation set forth by the governing EC must be followed, if any.  Subjects 
replacement will not be performed in this study. 
11. Risks and Benefits 
11.1. Potential Risks 
Device related risks: 
The Sponsor follows rigorous Quality Assurance and Control procedures throughout the life of a 
product, from the business analysis phase through development, market release, and post-market 
surveillance. Per ISO 14155, the risk analysis process for the SPICE Study, product- PillCam™ COLON2, 
is being performed in accordance with ISO 14971, and will ensure that the level of risk is acceptable 
prior to starting the study. 
Based on the literature evaluation, clinical trials, PillCam User Manual, the risk assessment reports, 
and post market vigilance, potential adverse events associated with the use of PillCam™ capsules may 
include: Adverse events associated with difficulty and/or inability to swallow the capsule (i.e. choking), 
Symptomatic/asymptomatic capsule retention (including delayed excretion of the capsule), aspiration 
(extremely rare risk), obstruction, perforation, and mucosal injury or bleeding. In some instances, 
intervention was required to remove the capsule. 
The clinical investigation has been designed to involve as little pain, discomfort, fear and any other 
foreseeable risk as possible for the subjects, and both the risk threshold and the degree of distress are 
specifically defined in the clinical investigation plan and constantly monitored. 
For complete risk assessment and further information (i.e. foreseeable AEs), please refer to the 
PillCam COLON risk file and the PillCam system manual. 
 
Procedure related risks: 
Bowel preparation risks: 
As the study procedure involves bowel preparation, additional risks are anticipated.   
Some bowel-cleansing preparation agents may involve risks of dehydration (loss of body water) and/or 
imbalance in the levels of salts in the bloodstream. These risks may be further avoided by strictly 
following the instructions, such as carefully drinking the amounts of fluids required before and during 
the capsule preparation procedure. 
Due to bowel preparation the subject might experience abdominal pain, headache, vomiting, nausea, 
gagging, bloating, significant anal burning/irritation, hemorrhoids bleeding, dizziness, fatigue, which 
are anticipated symptoms, mostly mild, that could be related to the bowel preparation procedure. 
Another risk is possible allergic reaction to bowel preparation agents. 

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For further information and complete list of adverse events, please refer to the bowel preparation 
agents' leaflets/manuals for use. 
 
MB-MMX related AEs: 
The most common reported adverse events related to the MB-MMX intake include Chromaturia and 
discolored feces. These are temporary events, mostly mild in nature which are related to the presence 
of a vital dye in the drug formulation. For the complete list of AEs, please refer to MB-MMX UM.  
There are no known incremental risks introduced to the subject as a result of participation in this 
study. 
For possible interaction with concomitant medical treatments, complete list of adverse events and 
additional information, please refer to the PillCam™ Endoscopy system UM, Bowel Preparation 
materials leaflets and MB-MMX UM. 
11.2. Risk Minimization 
The potential risks associated with the CCE were identified and have been successfully mitigated, as 
described in the PillCam COLON2 risk assessment file/documents. The overall residual risk has been 
determined to be acceptable. Any potential risks associated with this study are further minimized by 
selecting qualified and experienced investigators and training study personnel on the CIP.  
In addition, investigators will be actively involved in the follow-up of the subjects undergoing the CCE 
procedure. Risks will be minimized by careful assessment of each subject prior to, during, and after 
the procedure.  
The Sponsor has further minimized the possibility of risks by providing guidelines for subject selection 
and evaluation and providing adequate instructions and labeling.  
The risks for CCE procedure, as noted, will be minimized by excluding subjects who have evidence of 
complicated medical or surgical histories that would otherwise preclude them from participating. In 
addition, subjects with sensitivity to substances used during the preparation for the CCE procedure will be 
excluded. Furthermore, training on the CIP screening, procedures, and follow-up will be given to all 
investigators and personnel included in the study. 
Retention of the CCE capsule will be minimized since capsule will be administered only to those subjects 
who have no prior history of strictures, GI surgeries/diseases or major motility disorders. In addition, 
subjects with swallowing disorders are excluded to avoid the risk of capsule aspiration or inability to 
swallow the capsule. 
 
 

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Table 2- Potential risks and risk minimization for study subjects 
Potential risk  
Risk Minimization 
Capsule retention/bowel 
obstruction 
Capsule retention is a known complication of CE. Physicians are 
trained to identify those patients who may be at increased risk 
for retention, including some who may be covered by the 
contraindication for CCE with suspected or known bowel 
obstruction. All subjects with prior GI histories, including 
surgeries, strictures, prior obstructions, or who are otherwise at 
risk or contraindicated for CCE will be excluded per the 
exclusion criteria.   
Capsule aspirated instead of 
swallowed 
Aspiration of the capsule has been reported as rare 
complication of CE. This risk is mitigated by the contraindication 
to use of the device with any patient with a swallowing 
disorder. In addition, ingestion of the capsule is usually 
performed under medical supervision. 
11.3. Potential Benefits 
The study participation may offer no direct benefit, as this is a pilot study, which does not include 
medical evaluation. Subject would be contributing to future knowledge and potential improvement in 
colonic polyp identification in the future during CCE procedure. 
For the specific type of population included in the study (high risk for CRC), there might be a benefit 
related to the frequency of their standard of care CRC surveillance. The CCE procedure in between 
their surveillance Colonoscopy procedures, may offer additional information such as visualization of 
lesions which were missed during Colonoscopy and/or visualization of small lesions which might have 
malignancy potential. This is a non-invasive procedure which does not involve sedation nor bowel 
insufflation.       
Due to the use of MB-MMX in conjunction with the CCE procedure, an additional benefit to the 
subject could be considered, as the MB-MMX has been found potentially effective in colonic polyp 
enhancement.    
11.4. Risk-Benefit Rationale 
CCE procedure is considered as a safe, feasible, procedure for visualization of the colon, and offers a 
more convenient with relatively low risks than other invasive colon exams. 
PillCam™ capsule and the corresponding endoscopy systems, have been cleared for marketing in many 
countries world-wide, including USA, EU, Canada, Japan and Australia. All capsules are considered as 
class IIa devices in Europe. Risk assessment has been performed and no major or intolerable risks were 
found.  
All the mitigations as biocompatibility test, electrical safety and electromagnetic safety were 
documented according to ISO 14971. In addition, sponsor facilities have been certified to relevant 
medical device quality system requirements. The risk management summary demonstrates that the 

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risks associated with the tested device are well mitigated and the residual risks are as low as 
reasonably practicable as defined by the applicable standards. 
To conclude, the risks to subjects participating in this study would be similar to the expected risks for 
CRC surveillance subjects in standard medical practice, while the subjects can potentially benefit from 
better colonic polyps enhancement and the data gathered from this study could  contribute to future 
knowledge and potential improvement in colonic polyps identification in future  CCE procedures. 
12. Adverse Events and Device Deficiencies 
12.1. Adverse Events 
AEs definitions are provided in Table 3- Adverse Event and Device Deficiency Definitions.  
Adverse Events will be collected for all enrolled subjects at the start of the bowel preparation, at day 
(-1), until the follow-up phone call (visit 3). Medical care will be provided, as defined in the informed 
consent, for any AE related to study participation, if needed.  
Reporting of these events to the Sponsor will occur on an AE Form. Each event must be reported 
separately. Documented pre-existing conditions are not considered AEs unless the nature or severity 
of the condition has worsened.  Also, Diarrhea<24h after the CCE and mild anal burning/irritation are 
considered as the expected outcome of the bowel preparation process and shall not be recorded as 
Adverse Events, as long as the event does not require any medical intervention. Incidental findings 
observed during CCE video analysis will not be considered as AEs and will not be reported as such. In 
addition, in case of discovering a pregnancy during the course of the study, it will not be considered 
as an AE and will not be reported as such. 
 Per ISO14155:2020, it is required to collect all AEs and DDs. Non-subject AEs are not expected in this 
study, thus are not collected. 
For AEs that require immediate reporting, initial reporting may be done by phone, fax, or on the eCRF 
completing as much information as possible. The completed AE eCRF must be submitted to the 
Sponsor as soon as possible.   
Any medication/treatment associated with the treatment of an AE must be reported. 
Subject deaths are also required to be reported. Refer to Section 12.6 for Subject Death collection and 
reporting requirements. 
12.2. Device Deficiency (DD) 
The DD definition is provided in Table 3. DD information will be collected throughout the study and 
reported to Medtronic. Note that DD that result in an AE to the subject should be captured as an AE 
only. 
DD that did not lead to an AE but could have led to a SADE (i.e., if suitable action had not been 
taken, if intervention had not been made, or if the circumstances had been less fortunate) require 
immediate reporting ( 
 

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Table 6: Reporting Requirements). 
12.3. Processing Updates and Resolution 
For any changes in status of a previously reported adverse event or DD (i.e. change in actions taken, 
change in outcome, change in relatedness), information needs to be updated on, or added to the 
original AE or DD form. All AEs must be followed until the AE has been resolved, is unresolved with no 
further actions planned, the subject dies or exits the study, or until study closure, whichever occurs 
first.  
If the subject is exited from the  study prior to study completion, all efforts should be made to continue 
following the subject until all unresolved device or procedure related AEs, as classified by the 
investigator, are resolved, unresolved with no further actions planned, or study closure, whichever 
occurs first.  
At the time of study exit, all collected adverse events that are unresolved must be reviewed and an 
update to the original AE must be reported. 
12.4. Definitions/Classifications 
For the list of anticipated adverse events and anticipated adverse device effects, please refer to 
section 11. 
Table 3- Adverse Event and Device Deficiency Definitions 
General 
Adverse Event (AE) 
Untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or 
other persons, whether or not related to the investigational medical 
device and whether anticipated or unanticipated 
NOTE 1: This definition includes events related to the investigational 
medical device or the comparator. 
NOTE 2: This definition includes events related to the procedures 
involved. 
NOTE 3: For users or other persons, this definition is restricted to events 
related to the use of investigational medical devices or comparators. 
(ISO 14155:2020, 3.2) 
Adverse Device 
Effect (ADE) 
AE related to the use of an investigational medical device 
NOTE 1: This definition includes AEs resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, 
or operation, or any malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or 
from intentional misuse of the investigational medical device.  
NOTE 3: this includes ‘comparator’ if the comparator is a medical device. 
(ISO 14155:2020, 3.1) 
 

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Device Deficiency 
(DD) 
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, usability, safety or performance.  
NOTE 1: DD include malfunctions, use errors and inadequacy in the 
information supplied by the manufacturer including labeling.  
NOTE2: This definition includes device deficiencies related to the 
investigational medical device or the comparator. (ISO 14155:2020, 3.19) 
Relatedness 
Device Related 
 
 
An AE that results from the presence or performance of any component 
of the device. 
Device-related: An AE that results from the presence or performance 
(intended or otherwise) of the device.  
Procedure Related 
An AE that occurs due to any procedure related to the CCE procedure 
(other than device). The preparation procedure for the CCE procedure in 
the study includes consumption of bowel preparation materials and MB-
MMX tablets (non-MDT products). 
Seriousness 
Serious Adverse 
Event (SAE) 
 
AE that led to any of the following 
a) death, 
b) serious deterioration in the health of the subject, users or other 
persons as defined by one or more of the following:  
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body 
function, including chronic disease, or 
3) in-patient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening 
illness or injury, or permanent impairment to a body structure or 
a body function, 
c) foetal distress, foetal death, a congenital abnormality, or birth defect 
including physical or mental impairment 
NOTE 1: Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in health, is 
not considered an SAE. 
(ISO 14155:2020, 3.45)  
Serious Adverse 
Device Effect (SADE)  
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
(ISO 14155:2020, 3.44)  

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Serious Health 
Threat 
Signal from any adverse event or device deficiency that indicates an 
imminent risk of death or a serious deterioration in the health in subjects, 
users or other persons, and that requires prompt remedial action for 
other subjects, users or other persons 
NOTE 1: This would include events that are of significant and unexpected 
nature such that they become alarming as a potential serious health 
hazard or possibility of multiple deaths occurring at short intervals.  
(ISO 14155:2020, 3.46) 
12.5. Reporting of Adverse Events 
Please refer to below for a list of the minimum AE reporting requirements for Investigators.  If local 
regulations or EC require faster reporting, then the Investigator will adhere to those requirements. 
Reporting of all safety events to the Sponsor will be completed through Investigator submission of the 
AE eCRF in the remote data capture system.  
Events will be reviewed by the Sponsor to determine any reporting obligations to the CA. Reporting 
will occur within the timelines per local regulations and requirements. The Principal Investigator is 
responsible to report the events to the EC. 
Event’s relatedness to the study device and procedure will be assessed according to the following 
levels of causality: 
Causal relationship- the serious adverse event is associated with the investigational device, 
comparator or with procedures beyond reasonable doubt when: 
- the event is a known side effect of the product category the device belongs to or of similar devices 
and procedures; 
- the event has a temporal relationship with investigational device use/application or procedures; 
- the event involves a body-site or organ that- 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
- the serious adverse event follows a known response pattern to the medical device (if the response 
pattern is previously known); 
- the discontinuation of medical device application (or reduction of the level of activation/exposure) 
and reintroduction of its use (or increase of the level of activation/exposure), impact on the serious 
adverse event (when clinically feasible); 
- other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and an effect of 
another device, drug or treatment) have been adequately ruled out; 
- harm to the subject is due to error in use; 
- the event depends on a false result given by the investigational device used for diagnosis, when 
applicable; 
In order to establish the relatedness, not all the criteria listed above might be met at the same time, 
depending on the type of device/procedures and the serious adverse event. 

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Probable- The relationship with the use of the investigational device or comparator, or the 
relationship with procedures, seems relevant and/or the event cannot be reasonably explained by 
another cause. 
Possible- The relationship with the use of the investigational device or comparator, or the relationship 
with procedures, is weak but cannot be ruled out completely. Alternative causes are also possible (e.g. 
an underlying or concurrent illness/ clinical condition or/and an effect of another device, drug or 
treatment). Cases where relatedness cannot be assessed, or no information has been obtained should 
also be classified as possible. 
Not related- Relationship to the device, comparator or procedures can be excluded when: 
- the event has no temporal relationship with the use of the investigational device, or the procedures 
related to application of the investigational device; 
- the serious adverse event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 
- the discontinuation of medical device application or the reduction of the level of activation/exposure 
when clinically feasible and reintroduction of its use (or increase of the level of activation/exposure), 
do not impact on the serious adverse event; 
- the event involves a body-site or an organ that cannot be affected by the device or procedure; 
- the serious adverse event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk factors); 
- the event does not depend on a false result given by the investigational device used for diagnosis, 
when applicable; 
In order to establish the non-relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious adverse event. 
Event's Severity will be defined according to the following criteria: 
Mild 
Event results in mild or transient discomfort, not requiring intervention or treatment; 
does not limit or interfere with daily activities (e.g., insomnia, mild headache).  
Moderate 
Event is sufficiently discomforting so as to limit or interfere with daily activities; may 
require interventional treatment (e.g., fever requiring antipyretic medication).  
Severe 
Event results in significant symptoms that prevents normal daily activities may require 
hospitalization or invasive intervention (e.g., anemia resulting in blood transfusion).  
An AE can be classified as severe and not deemed an SAE. Similarly, an SAE is not automatically severe 
in nature. Severity will be assessed by the Investigator. 
Regardless of severity, all AEs occurring during the study must be recorded in the subject’s eCRF.  The 
following information and assessments should be documented:   
• 
Type of event (AE term) 
• 
Subject number 
• 
Date of AE onset 

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• 
Date of resolution 
• 
Seriousness  
• 
Severity degree: mild / moderate / severe  
• 
Relationship to study device and procedure: causal relationship/ probable/ possible/ 
not related  
• 
Measures taken 
• 
Outcome of event:  
▪ 
not recovered/ not resolved 
▪ 
recovered/resolved 
▪ 
recovered/ resolved with sequelae 
▪ 
recovering/ resolving 
▪ 
unknown 
▪ 
fatal 
The sponsor shall immediately conduct an evaluation of any unanticipated events if determined that 
the events presents an unreasonable risk to subjects and report the results of such evaluation per the 
local requirements. 
In case of SAEs and SADEs, the following emergency contact may be approached: 
Table 4: Emergency contacts 
Clinical Affaires 
Medical Affairs 
Inbal Eyal 
Senior Manager, Clinical Affairs 
Medtronic, GI Solutions  
POB 258, 20692 Yoqneam, Israel 2 Hacarmel St. 
New Industrial Park POB 258 20692 Yoqneam, 
Phone: +972 (4) 909-7774 Mobile: 
 
 Fax: +972 (73) 250-1533  
Email: inbal.eyal@medtronic.com 
 
Roslana Fox 
Clinical Trials Leader 
Medtronic, GI Solutions  
POB 258, 20692 Yoqneam, Israel 2 Hacarmel St. 
New Industrial Park POB 258 20692 Yoqneam, 
Phone: +972 (73) 250-1552 
Mobile: 
  
Email: roslana.fox@medtronic.com  
 
Ari Bergwerk MD  
Medical Advisor, Medical Affairs  
Medtronic, GI Solutions  
New Industrial Park  
POB 298, 20698 Yoqneam, Israel  
Phone +972 (4) 909-7822  
Mobile 
  
Fax +972 (73) 250-1537  
Email: Ari.Bergwerk@medtronic.com  
Regulatory reporting of Subject Deaths will be completed according to local regulatory requirements. 

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12.5.1. Adverse Event and Device Deficiency Classification 
All AE and DD will be reviewed by a Sponsor representative. AEs will be classified according to the 
definitions provided.  
Upon receipt of AE at the Sponsor, a representative will review the AE/DD for completeness and 
accuracy and when necessary will request clarification and/or additional information from the 
Investigator. The Sponsor will utilize MedDRA, to assign a MedDRA term for each AE based on the 
information provided by the investigator.  
Regulatory reporting of AEs and DDs will be completed according to local regulatory requirements. 
Refer to  
 

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Table 6 for a list of required investigator and Sponsor reporting requirements and timeframes. It is the 
responsibility of both investigators and Sponsor, to abide by any additional AE reporting requirements 
stipulated by the EC responsible for oversight of the study. 
For emergency contact regarding SAE and/or SADE, contact a study representative immediately (refer 
to the study contact list provided in the study site’s study documents binder/investigator site file or 
refer to the Sponsor contact information provided on the title page). 
AEs and Deaths will be classified according to the standard definitions as outlined below. 
Table 5:Adverse Event Classification Responsibilities 
What is classified?  
Who classifies? 
Classification Parameters 
Relatedness 
Investigator 
Device, Procedure  
Sponsor 
Device, Procedure  
Seriousness 
Investigator 
SAE, DD with SADE potential 
Sponsor 
SAE, DD with SADE potential  
Diagnosis 
Investigator 
Based on presenting signs and symptoms and other 
supporting data 
Sponsor 
MedDRA term assigned based on the data provided by 
Investigator 
12.5.2. Adverse Event and Device Deficiency Reporting Requirements 
Regulatory reporting of AEs and DDs will be recorded and reported according to local regulatory 
requirements. It is the responsibility of the Investigator and the sponsor to abide by the AE reporting 
requirements stipulated by local law and the study site’s EC.  
 
 

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Table 6: Reporting Requirements 
SAEs 
Investigator shall submit to: 
Sponsor 
Report to the sponsor, immediately, all serious adverse events and no later than 3 
calendar days after investigator first learns of the event. 
CA 
Submit to CA per local reporting requirement. 
EC 
Submit to EC per local reporting requirement. 
Sponsor shall submit to: 
CA 
Submit to CA per local reporting requirement. 
EC 
Submit to EC per local reporting requirement. 
ADEs 
Investigator shall submit to: 
Sponsor 
Submit without unjustified delay, after the investigator first learns of the effect. 
CA 
Submit to CA per local reporting requirement. 
EC 
Submit to EC per local reporting requirement. 
Sponsor shall submit to: 
CA 
Submit to CA per local reporting requirement. 
EC 
Submit to EC per local reporting requirement. 
SADEs  
Investigator shall submit to: 
Sponsor 
Submit immediately after the investigator learns of the event or of new information 
in relation to an already reported event, and no later than 3 calendar days after the 
investigator first learns of the effect. 
CA 
Submit to CA per local reporting requirement 
EC 
Submit to EC per local reporting requirement. 
Sponsor shall submit to: 
CA 
 Submit to CA per local reporting requirement. 
EC 
 Submit to EC per local reporting requirement. 
Investigators  Submit per local reporting requirement. 
 

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All other reportable AEs  
Investigator shall submit to: 
Sponsor 
 Submit without unjustified delay after the investigator first learns of the event. 
CA 
 Submit to CA per local reporting requirement. 
EC 
 Submit to EC per local reporting requirement. 
DDs with SADE potential 
Investigator shall submit to: 
Sponsor 
 Submit immediately, and no later than 3 calendar days after the investigator first 
learns of the effect. 
CA 
 Submit to CA per local reporting requirement. 
EC 
 Submit to EC per local reporting requirement. 
Sponsor shall submit to: 
CA 
 Submit to CA per local reporting requirement. 
EC 
 Submit to EC per local reporting requirement. 
All other Device Deficiencies 
Investigator shall submit to: 
Medtronic 
 Submit without unjustified delay after the investigator first learns of the deficiency. 
CA 
 Submit to CA per local reporting requirement. 
EC 
 Submit to EC per local reporting requirement. 
12.6. Subject Death 
All subject deaths must be reported by the investigator to Medtronic on an AE form (AE with outcome 
of fatal) as soon as possible after the investigator first learns of the death. In case of death, there 
should be one AE with the outcome of fatal.  
Local laws and procedures must be followed where applicable. If any system component is returned 
to the Sponsor, internal return product reporting systems may be used to gather additional 
information about the returned device/component. 
A copy of the death certificate, if available and allowed by state/local law, should be sent to the 
Sponsor clinical study team. When a death occurs in a hospital, a copy of the death summary report 
and all relevant hospital records, if available should be sent to the Sponsor clinical study team. If an 
autopsy is conducted, a copy of the autopsy report should also be sent to the Sponsor clinical study 
team if available and allowed by state/local law. When the death occurs at a remote study site, it is 
the investigative study site’s responsibility to attempt retrieval of information about the death. 
Additionally, device disposition information should be updated.  

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In summary, the following data will be collected: 
• 
Date of death 
• 
Detailed description of death 
• 
Cause of death  
• 
Relatedness to device and procedure 
• 
Device disposition information 
• 
Death summary/hospital records (if available and allowed by state/local law) 
• 
Autopsy report (if available and allowed by state/local law) 
• 
Death certificate (if available and allowed by state/local law) 
12.7. Product Complaint Reporting 
It is the responsibility of the investigator to report all product complaint(s) associated with a medical 
device distributed by the Sponsor, regardless whether they are related to intended use, misuse or 
abuse of the product. Reporting must be done immediately and via the regular channels for market-
released products. The reporting of product complaints by the clinical team must be done according 
to the local Standard Operating Procedures. The Sponsor will notify the RAs (e.g. CA) as applicable for 
the following incidents immediately upon learning of them and is not limited to AEs and DDs only: 
• 
Any malfunction or deterioration in the characteristics and/or performance of a 
device, as well as any inadequacy in the labeling or instructions for use which led or 
might have led to the death or serious deterioration in the state of health of a patient, 
user, or other person. 
• 
Any technical or medical reason resulting in withdrawal of a device from the market 
by the manufacturer. 
• 
Any serious deterioration in the state of health, including: 
▪ 
Life-threatening illness or injury 
▪ 
Permanent impairment of a body function or permanent damage to a body 
structure 
▪ 
A condition necessitating medical or surgical intervention to prevent 
permanent impairment of a body function or permanent damage to a body 
structure 
13. Statistical Design and Methods 
This is a single-center, prospective, non-randomized clinical trial designed to evaluate the technical 
feasibility (descriptive) of mucosal staining during CCE procedure, using MB-MMX, in CRC high risk 
population. As a result, no formal sample size was calculated and up to 15 patients are planned to be 
enrolled to this study. No interim analysis is planned. 

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As a result, the methods for analysis will be descriptive in nature (frequency and percent as well as 
distribution measures such as: mean, standard deviation, median and range). 95% confidence 
intervals will be presented as well. 
Primary objective:  
To demonstrate effective polyp enhancement during a COLON2 Capsule Endoscopy procedure when 
using MB-MMX as a contrast- enhancement technique.  
Primary endpoints:  
• 
The percent of colonic polyps which have a visible contrast to the healthy colonic mucosa 
during CCE, as indicated by an experienced reader, using the subjective reader questionnaire 
(For each polyp – was there a contrast between the polyp and the healthy mucosa? Yes/No), 
out of the examined polyps  
• 
The interference level of detrimental effects on the visualization of the colonic mucosa during 
CCE, due to use of MB-MMX per colonic segment  
Detrimental effect will be considered as any observation, such as an excessive blue dye deposit, dark 
and dim appearance of the tissue, interfering with tissue visualization and will be evaluated on a scale 
from 1 (no interference) to 5 (high interference) to evaluate the level of interference, using a 
subjective reader questionnaire. 
Secondary objective:  
To evaluate the safety of CCE procedure while using MB-MMX. 
Secondary endpoint:  
All AEs will be reported by number, type, relatedness (device/procedure) seriousness, severity and 
duration. All AEs will be captured, regardless of severity. 
This section presents statistical considerations for the study design and provides a high-level 
description of planned analysis and reporting. More details will be given in a separate Statistical 
Analysis Plan (SAP) that will be approved before data freeze or lock. Any deviation to the pre-specified 
statistical analyses will be noted in the study report.  
13.1. General Aspects of Analysis 
Data analysis will be performed by the sponsor and/or designee.  
The analysis will include all of the available information. Demographic and other characteristics will 
be provided. Summary statistics (arithmetic mean, standard deviation, and range for quantitative 
variables) will be presented for the total study population. Frequency tables for qualitative data will 
be provided. All confidence intervals will be presented as 95% confidence intervals unless otherwise 
stated. For each of the objectives the available data will be summarized, and missing data will be 
discussed. The main analysis of the study objectives will be based on available data and missing data 
will not be imputed.  
Two analysis sets will be used for the statistical analysis. The definition of each is defined below: 
Full Analysis Set (FAS). FAS includes all enrolled subjects:  

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• 
Who signed the informed consent and 
• 
Who satisfied the eligibility criteria 
• 
Ingested the PillCam™ COLON2 capsule 
 
FAS will be used for subject disposition, population and procedures description, for performance and 
for Safety analyses.  
 
Per Protocol Analysis Set (PPAS): PPAS is a subset of the FAS, which includes only subject who have 
demonstrated all of the following: 
- Subjects' compliance to the bowel prep regimen/MB-MMX administration is ≥75% according to 
each of the following criteria: 
o 
Total volume of bowel prep material (PEG) consumed is ≥3L (out of 4L in total) 
o 
Intake of ≥6 MB-MMX tablets (out of total of 8 tablets) 
- No major deviations related to Eligibility Criteria and/or Informed Consent   
- The capsule reached the colon during the procedure 
- Raw data has been generated for the CE procedure  
Any deviation from specified statistical plan will be in addition to “per protocol” analysis and will be 
reported as such. Post-hoc analysis will be conducted according to the existing data gathered, if 
necessary. 
13.2. Interim Analysis 
No interim analyses are planned for this study. 
13.3. Primary Objective(s) 
Primary Objective - to demonstrate effective polyp enhancement during a Colon Capsule Endoscopy 
procedure when using MB-MMX as a contrast- enhancement technique. 
As this is a descriptive pilot study, no formal hypothesis was formulated. In any case of post hoc 
analysis which will include statistical testing, P-value<0.05 will be considered significant. 
The primary objective will be measured via a subjective questionnaire, at the polyp level and at the 
case level: 
Primary endpoint at the polyp level – the reader will answer for each polyp the following question: " 
was there a contrast between the polyp and the healthy mucosa? Yes/No". The endpoint refers to the 
percent of colonic polyps which have a visible contrast to the healthy colonic mucosa during CCE, as 
indicated by the reader (i.e. the reader marked "Yes"), out of the examined polyps. the percent of 
polyps with visible contrast will be presented with 95% confidence level (95%CI) 
Primary endpoint at the case level – for each case the reader will be asked to mark the level of 
interference form a 5-point scale (1 =no interference to 5= high interference). The level of interference 
refers to the detrimental effects on the visualization of the colonic mucosa during CCE, due to use of 

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MB-MMX per colonic segment (detrimental effect will be considered as any observation, such as an 
excessive blue dye deposit, dark and dim appearance of the tissue, interfering with tissue 
visualization). Analysis of this endpoint will include summary statistics (arithmetic mean, standard 
deviation, median and range) as well as frequency and percent of each scale level. 
All of the available information will be analyzed according to the CIP criteria (inclusion, exclusion, 
deviations etc.). 
13.4. Secondary Objective 
Secondary Objective - To evaluate the safety of CCE procedure while using MB-MMX. 
As this is a descriptive pilot study, no formal hypothesis was formulated. 
All AEs will be reported by number, type, relatedness (device/procedure), seriousness, severity and 
duration. All AEs will be captured, regardless of severity. 
The percent of cases with at least one AE out of the total cases, will be presented with 95%CI. 
All of the available information will be analyzed according to the CIP criteria (inclusion, exclusion, 
deviations etc.). 
13.5. Sample Size Determination 
This is a pilot study where no formal sample size will be calculated.  
As this is the first time that MB-MMX is being used during a CCE procedure, the chosen sample size 
includes small number of subjects, which allows visualization of colonic polyps and evaluation of their 
contrast to the healthy mucosa, under the assumption that not all subjects will have colonic polyps 
presence during the CCE procedure. Up to 15 patients are planned to be enrolled to this study. 
14. Ethics 
14.1. Statement(s) of Compliance 
• 
The study shall be conducted in accordance with the protocol and ethical principles that 
have their origin in the DoH. All principles of the Declaration of Helsinki have been 
implemented in this clinical study by means of the patient informed consent process, EC 
approval, clinical study training, clinical study registration, publication policy. 
• 
The study will be conducted in compliance with the protocol, International Conference on 
Harmonization Guidelines on Good Clinical Practice (GCP), EU MDR 2017/745 as of Date 
of Application (where applicable), Medical Device Directive (MDD) 93/42/EEC and ISO 
14155:2020. 
• 
The clinical study will not begin until the EC and regulatory authority approvals/ 
notification, as required by the local regulations, are received. This also applies to the 
continuing review of an ongoing study, and approval of any subject facing materials, 
including the ICF. Approval of the CIP and CIP amendments is required from the following 
entities prior to any study procedures at a study site: 

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▪ 
Medtronic 
▪ 
Principal Investigator (where required by local law/regulations) 
▪ 
Geography-specific regulatory authorities (if regulatory approval is required) 
▪ 
An independent EC 
• 
Similarly, approval of subsequent revisions to the CIP is required at the study site from the 
above-mentioned entities prior to implementation of the revised CIP at the study site. 
• 
The SPICE study was designed to reflect the GCP principles outlined in ISO 14155:2020 
and other international clinical requirements outlined below. These include the 
protection of the rights, safety and well-being of human subjects, controls to ensure the 
scientific conduct and credibility of the clinical investigation and the definition of 
responsibilities of the sponsor and investigators. In accordance with ISO 14155, the 
sponsor shall avoid improper influence on, or inducement of, the subject, monitor, any 
investigator(s) or other parties participating in, or contributing to, the clinical 
investigation. All investigators shall avoid improper influence on or inducement of the 
subject, sponsor, monitor, other investigator(s) or other parties participating in or 
contributing to the clinical investigation. AE and DD handling in the SPICE study is ISO 
14155:2020 compliant, other than collection of Non-subject AEs, which are not expected 
in this study, thus are not collected. As this is a post-market study, USADE will also not be 
collected.   
• 
The study is sponsored by All Given Imaging, an indirect wholly owned subsidiary by 
Medtronic plc and all financial aspects are outlined in the clinical investigation site 
agreement (CTA). 
• 
Written informed consent is mandatory and must be obtained from each subject prior to 
his/her participation in this trial and screening procedures are initiated. Any additional 
requirements imposed by the EC or regulatory authority will be followed.  
• 
By signing the ICF, the subjects will acknowledge that the video originated from the CCE 
procedure may be of a poor quality, or otherwise unsuitable for examination or 
interpretation. Subjects shall be further advised that the CCE report provided for the CCE 
procedure may be incomplete or inaccurate and may not identify the actual condition of 
the subject’s digestive tract. Subjects will acknowledge that the procedure and any results 
stemming therefrom, including any reports provided with respect thereto, are not 
substitute for a medical exam and must not be relied upon. 
• 
The PillCam™ endoscopy capsules and the other parts of the PillCam™ Endoscopy system 
does not incorporate any medicinal product, human blood derivative or tissues of animal 
origin. 
• 
All Given Imaging, an indirect wholly owned subsidiary by Medtronic plc. products fully 
comply with all safety and radio standards worldwide. 
• 
Given Imaging Ltd, is a wholly owned subsidiary of Medtronic, which as the parent 
company of such entity maintains appropriate clinical study liability insurance coverage 
as required under applicable laws and regulations and will comply with applicable local 

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law and custom concerning specific insurance coverage. If required, a clinical study 
insurance statement/certificate will be provided to the EC. All subjects participating in the 
study will have insurance coverage by the sponsor, which is in line with the applicable 
laws and/or local regulations for Clinical Trials.  
• 
The study will be publicly registered prior to in accordance with the 2007 FDA act and DoH 
on http://clinicaltrials.gov (PL 110-85, section 810(a)). In addition, the study may be 
registered in local regulatory databases where required by local law.  
• 
The study will also comply (when applicable) with 21 CFR Part 11 for use of electronic 
Records and electronic Signatures and 21 CFR Part 54 for collection and handling of 
Financial Disclosure by Clinical Investigators. 
15. Study Administration 
15.1. Monitoring 
It is the responsibility of the sponsor to ensure proper monitoring of this study.   
Trained sponsor personnel or delegates appointed by the Sponsor may perform study monitoring at 
the study site in order to ensure that the study is conducted in accordance with the CIP, the CTA, and 
the applicable regulatory and local requirements. Sponsor, or delegates, must therefore be allowed 
direct access to the subjects’ case histories (clinic and hospital records, and other source 
data/documentation) upon request as per the IC and CTA.  The principal investigator or designee 
should also be available during monitoring visits.   
15.1.1. Monitoring Visits 
Frequency of monitoring visits may be based upon subject enrollment, study compliance, number of 
adverse events, number of deviations, observations from previous monitoring visits and any suspected 
inconsistency in data that requires investigation. Regulatory documents will be reviewed at each study 
site. Monitoring for the study, including site qualification visits (if applicable), site initiation visits, 
interim monitoring visits, and closeout visits, will be done in accordance to the study-specific 
monitoring plan. 
Monitoring visits may be conducted periodically to assess study site progress, the investigator’s 
adherence to the CIP, regulatory compliance including but not limited to EC approval and review of 
the study, maintenance of records and reports, and review of source documents against subject eCRFs 
in accordance to the study-specific monitoring plan. Monitors review study site regulatory and study 
compliance by identifying observations of non-compliance and communicating those observations 
along with recommendations for preventative/corrective actions to study site personnel. Monitors 
may work with study personnel to determine appropriate corrective action recommendations and to 
identify trends within the study or at a particular study site. 

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15.2. Data Management 
Data will be collected using an electronic data management system. eCRF data will be stored in a 
secure, password-protected database which will be backed up nightly. Data will be reviewed using 
programmed and manual data checks. Data queries will be made available to study sites for resolution.  
Study management reports may be generated to monitor data quality and study progress.  At the end 
of the study, the data will be frozen and will be retained indefinitely by the Sponsor. 
All records and other information about subjects participating in this study will be treated as 
confidential. Data will be transferred and processed by the Sponsor or a third party designated by the 
Sponsor in a key coded form.  
Procedures in the CIP require source documentation. Source documentation will be maintained at the 
study site. Source documents, which may include worksheets, subject medical records, programmer 
printouts, and interrogation files, must be created and maintained by the investigational study site 
team.  
Per ISO14155, the investigator will clearly mark clinical records to indicate that the subject is enrolled 
in this clinical investigation.  
The data reported on the eCRFs shall be derived from source documents and be consistent with these 
source documents, and any discrepancies shall be explained in writing.  
Data generated from using the device will be stored on site on a dedicated secured storage device 
provided by the Sponsor in accordance to local data protection laws. This data will remain confidential 
and identified only by subject’s code. The data will be available to the monitor and will be considered 
as source data. De-identified videos and raw data from the CCE procedure will be sent to the Sponsor 
for analysis using an encrypted device. The data will not include any subject identifying information.    
15.3. Direct Access to Source Data/Documents 
The Sponsor may conduct audits at participating study sites. The purpose of an audit is to verify the 
performance of the monitoring process and the study conduct, independently of the personnel 
directly involved in the study. CAs/RAs, such as the FDA, may also perform inspections at participating 
study sites. The investigator and/or institution shall permit the Sponsor, ECs and RAs direct access to 
source data and documents during monitoring, audits and regulatory inspections. 
15.4. Confidentiality 
All information and data sent to parties involved in study conduct concerning subjects or their 
participation in this study will be considered confidential. Study sites will assign a unique study ID to 
each subject. Records of the subject/ Subject Identification (SID) relationship will be maintained by 
the study site. The SID number is to be recorded on all study documents to link them to the subject’s 
medical records at the study site. Confidentiality of data will be observed by all parties involved at all 
times throughout the clinical investigation. All data shall be secured against unauthorized access. The 
privacy of each subject and confidentiality of his/her information shall be preserved in reports and 
when publishing any data.  To maintain confidentiality, the subject’s name or any other identifying 
information should not be recorded on any study document other than the ICF and study identification 

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log. In the event a subject’s name is included for any reason, it will be blinded as applicable. In the 
event of inability to blind the identification (e.g., digital media), it will be handled in a confidential 
manner by the authorized personnel.  Data relating to the study might be made available to third 
parties (for example in case of an audit performed by CA/RA), provided the data are treated as 
confidential and that the subject’s privacy is guaranteed. No identifiable subject information will be 
published. 
15.5. Liability/Warranty/Insurance Information 
Given Imaging Ltd. is a wholly owned subsidiary of Medtronic, which as the parent company of such 
entity maintains appropriate clinical study liability insurance coverage as required under applicable 
laws and regulations and will comply with applicable local law and custom concerning specific 
insurance coverage. If required, a Clinical Trial insurance statement/certificate will be provided to the 
EC. 
15.6. CIP Amendments 
Any revisions or amendments to the CIP or ICF, along with a statement of justification for the changes, 
will be submitted to all affected CA and governing ECs, according to applicable regulations. All 
amendments to the CIP shall be agreed upon between the Sponsor and the principal investigator. 
Approval by regulatory agencies (when applicable) and EC must be obtained prior to implementing a 
CIP revision at the study site. 
15.7. Record Retention 
All study-related documents must be retained at the clinical investigation site for a period of at least 
25 years after completion or early termination of the clinical investigation. The Sponsor will inform 
the investigator/study site when these documents are no longer required to be retained. 
No study document or image will be destroyed without prior written agreement between the Sponsor 
and the investigator. The investigator should take measures to prevent accidental or premature 
destruction of documents. Should the investigator wish to assign the study records to another party 
or move them to another location, advance written notice must be given to Medtronic. 
The Sponsor will retain the study records according to Sponsor's corporate policy and record retention 
schedule. 
15.7.1. Investigator Records 
The investigator is responsible for the preparation and retention of the records cited below. All of the 
below records, with the exception of case history records and case report forms, should be kept in the 
Investigator Site File (i.e., the study binder provided to the investigator) or Subject Study Binder. eCRFs 
must be maintained and signed electronically within the electronic data capture system during the 
study. The following records are subject to inspection and must be retained for a period of two years 
(or longer as local law or hospital administration requires) after product approval or the date on which 
the investigation is terminated or the date that the records are no longer required for purposes of 
supporting a pre-market approval application. 

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• 
All essential correspondence between the EC, sponsor, monitor, CA and the 
investigator that pertains to the investigation, including required reports.  
• 
Subject’s case history records, including:  
▪ 
Signed and dated ICF (signed by subject and investigator)  
▪ 
Observations of AEs/ADEs/DDs 
▪ 
Medical history 
▪ 
Documentation of the dates and rationale for any deviation from the 
protocol 
• 
Financial Disclosure (FD) 
• 
Subject screening log & ID log  
• 
All approved versions of the CIP, ICF  
• 
Signed and dated CTA 
• 
CV (signed and dated) of principal investigators and key members of investigation 
study site team. 
• 
Documentation of delegated tasks.  
• 
EC approval documentation. Written information that the investigator or other 
study staff, when member of the EC, did not participate in the approval process. 
Approval documentation must include the ECs composition, where required per 
local law.   
• 
CA notification, correspondence and approval, where required per local law. 
• 
Study training records for study site staff.  
• 
Insurance certificate 
• 
Any other records that local regulatory agencies require to be maintained.  
• 
Final Study Report including the statistical analysis. 
15.7.2. Sponsor Records 
The sponsor shall maintain the following accurate, complete, and current records: 
• 
All correspondence which pertains to the investigation 
• 
Study device traceability record containing serial numbers/ID of devices, shipping 
date and name and address of person that received shipped device, location (if 
different than person shipped to), transfer and receipt by the Sponsor dates.  
• 
Sample of label attached to study device 
• 
Signed Investigator Trial Agreements, Financial Disclosure and current signed and 
dated CV of principal investigator and key members of the investigation study site 
team (as required by local law), delegated task list 
• 
All signed and dated case report forms submitted by investigator, including reports 
of AEs, ADEs and DDs  

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• 
All approved ICF templates, and other information provided to the subjects and 
advertisements, including translations 
• 
Copies of all EC approval letters and relevant EC correspondence and EC voting 
list/roster/letter of assurance 
• 
Names of the institutions in which the study will be conducted 
• 
CA correspondence, notification and approval as required by national legislation 
• 
Insurance certificates  
• 
Names/contact addresses of monitors 
• 
Monitoring visit reports 
• 
Statistical analyses and underlying supporting data 
• 
Final report of the study 
• 
The CIP, study related reports, and revisions 
• 
Study training records for study site personnel and Sponsor personnel involved in 
the study 
• 
Any other records that local regulatory agencies require to be maintained.  
The Sponsor records and reports will be maintained in a password-protected document management 
system, and paper documents (where applicable) will be stored in stored in secured file cabinets at 
the Sponsor during the course of this study.  
After closure of the study Medtronic will archive records and reports indefinitely. 
15.8. Reporting Requirements 
15.8.1. Investigator Reports 
The investigator is responsible for the preparation (review and signature) and submission to the 
sponsor of all case report forms, adverse events and adverse device effects (reported per the country-
specific collection requirements), device deficiencies, deaths, and any deviations from the clinical 
investigation plan.  If any action is taken by an EC with respect to this study, copies of all pertinent 
documentation must be forwarded to Medtronic in a timely manner. Reports are subject to inspection 
and to the retention requirements as described above for investigator records.  
Safety data investigator reporting requirements are listed in Section 12. The investigator shall prepare 
and submit in a complete, accurate and timely manner the reports listed in this section. 
Table 7: Investigator reports 
Report  
Submit to 
Description/Constraints 
Withdrawal of EC 
approval 
Sponsor and CA 
(when applicable) 
The investigator must report a withdrawal of approval by 
the reviewing EC of the investigator’s part of the 
investigation within 5 working days. 
Progress Report  
Sponsor and 
EC 
Provide if required by local law or EC.  
 

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Study Deviations  
Sponsor and 
when applicable 
to EC and CA 
Any deviation from the CIP shall be recorded together with 
an explanation for the deviation.  Deviations shall be 
reported to the sponsor who is responsible for analyzing 
them and assessing their significance. Notice of deviations 
from the CIP to protect the life or physical well-being of a 
subject in an emergency shall be given as soon as possible, 
but no later than 5 working days after the emergency 
occurred.  Except in such emergency, prior approval is 
required for changes in the plan or deviations.   
Per ISO 14155:2020- when relevant, ethics committee, or 
the appropriate RAs should be informed.  
Failure to obtain IC 
Sponsor and 
ECs 
ICF shall be obtained in writing and documented before a 
subject is enrolled into the clinical investigation.  (ISO 
14155:2020) 
15.8.2. Sponsor Reports 
The Sponsor shall prepare and submit the following complete, accurate, and timely reports listed in 
the tables below (by geography). In addition to the reports listed below, the Sponsor shall, upon 
request of the reviewing EC or CA, provide accurate, complete and current information about any 
aspect of the investigation. Safety data Sponsor reporting requirements are listed in section 12. 
Table 8: Sponsor reports  
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, 
EC and CA (when 
applicable) 
Provide prompt notification of termination or suspension 
and reason(s). (ISO 14155:2020) 
Withdrawal of EC 
approval 
Investigators, 
EC  and CA (when 
applicable) 
Investigators, ECs and CAs (when applicable) will be 
notified only if required by local laws or by the EC. 
Withdrawal of CA 
approval 
Investigators, 
EC and CA (when 
applicable) 
Investigators, ECs and CAs (when applicable) will be 
notified only if required by local laws or by the EC. 
Progress Reports 
EC and CA (when 
applicable) 
This will be submitted to the EC/CA only if required by the 
local regulations. 
Final report 
Investigators, CA 
and EC (when 
applicable) 
The final report shall be submitted within 12 months of 
study completion or termination. 
The investigator shall have the opportunity to review and 
comment on the final report and the signature of the 
principal Investigator will be obtained. 

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Report  
Submit to 
Description/Constraints 
Study deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with 
the appropriate clinical investigator(s), are reported on the 
eCRFs and the final report of the clinical investigation.  (ISO 
14155:2020) 
Study site specific study deviations will be submitted to 
investigators periodically.   
 
15.9. Publication and Use of Information 
Publications from the SPICE Study (if applicable) will be handled according to Standard Operating 
Procedures and as indicated in the CTA. 
The Sponsor Publication and Authorship Policy is aligned with the International Committee of Medical 
Journal Editors (ICMJE) recommendations (www.icmje.org). the Sponsor may seek to publish, in 
appropriate peer-reviewed journals and scientific conferences, results of clinical studies where human 
subjects are involved, regardless of outcome. Information regarding the study will be made available 
on clinicaltrials.gov. Additionally, the results of this study may be submitted for publication in an 
appropriate journal. While study results are owned by the Sponsor, all data on which a potential 
publication is based will be made available to all authors as required for their participation in the 
publication process.  
Furthermore, data may be published or used by study investigators, with written approval by the 
Sponsor, provided that such publication or use is in accordance with this this protocol, the Sponsor 
Publication and Authorship Policy, and the Clinical Investigation Agreement. Investigators must submit 
a copy of all manuscripts and/or abstracts to the Sponsor for review and comment 30 days prior to 
planned submission. The Sponsor acknowledges that its right to review and comment shall relate 
solely to the proprietary, licensing, and/or confidential rights The Sponsor may have in such proposed 
publication, rather than whether such results and/or opinions are favorable to the Sponsor.  
15.9.1. Criteria for Determining Authorship 
Publications will adhere to authorship criteria defined by the International Committee of Medical 
Journal Editors (ICMJE, Uniform requirements for manuscripts submitted to biomedical journals, 
www.icmje.org).  Individual authorship criteria defined by the target journal or conference will be 
followed when it differs from ICMJE criteria. 
Authors, including Sponsor personnel, must at a minimum meet all of the conditions below: 
• 
Substantial contributions to conception and design of the work, or the acquisition, 
analysis, or interpretation of data for the work; AND 
• 
Drafting the work or revising it critically for important intellectual content; AND 
• 
Final approval of the version to be published; AND 
• 
Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.  

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The Sponsor involvement in a publication (e.g., funding of the study; sponsor of the study; collection, 
analysis, and interpretation of data; professional writing assistance) must be disclosed according to 
journal-specific policies, submission requirements, and prevailing editorial standards, in addition to 
those specified by ICMJE. Authors must ensure that an acknowledgement/disclosure statement is 
included in the body of the manuscript for the Sponsor to review for accuracy. All authors must also 
disclose financial or personal affiliations that could be considered conflicts of interest as per 
journal/conference requirements. 
Decisions regarding authorship and contributor-ship will be made by the Sponsor. The selected 
authors will be responsible for drafting the publication. All selected authors must fulfill the authorship 
conditions stated above to be listed as authors, and all contributors who fulfill the conditions must be 
listed as authors. 
All investigators not listed as co-authors will be acknowledged as the “Sponsor SPICE Study 
Investigators” and will be individually listed according to the guidelines of the applicable scientific 
journal when possible and affiliation. Any other contributors will be acknowledged by name with their 
specific contribution indicated. 
15.9.2. Transparency 
Transparency of clinical study results will be maintained by the following means: 
• 
A final report, describing the results of all objectives and analysis, will be distributed 
to the investigator, ECs and CAs of participating countries when required.  
• 
Registering and posting the study results on a publicly accessible database, e.g., 
ClinicalTrials.gov based on the posting rules stipulated  
• 
Disclosing conflicts of interest (e.g., financial)  
15.10. Suspension or Early Termination 
15.10.1. Planned Study Closure 
Study Closure is a process initiated by distribution of a study closure letter. Study closure is defined as 
closure of a study that occurs when the Sponsor requirements have been satisfied per the CIP and/or 
by a decision by the Sponsor or CA), whichever occurs first. The study closure process is complete 
upon distribution of the Final Report or after final payments, whichever occurs last. Ongoing EC 
oversight is required until the overall study closure process is complete. Refer to section 10.14 for 
additional information regarding study exit procedures. 
15.10.2. Early Termination or Suspension 
Early Termination is the closure of a study that occurs prior to meeting defined endpoints. This is 
possible for the whole study or a single study site Suspension is a temporary postponement of study 
activities related to enrollment and distribution of the product. This is possible for the whole study or 
a single study site.  
The Sponsor reserves the right to discontinue the study at any stage, with suitable written notice to 
all investigators and reviewing ECs. The appropriate sites and ECs will be notified of discontinuation 

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of the study for any reason no later than 5 working days after the sponsor makes this determination.  
In addition, ECs can decide whether the study is to be terminated and will notify the Sponsor. 
Similarly, investigators may withdraw from the study at any time, subject to providing written 
notification to the Sponsor prior to the date they intend to withdraw, as described in the CTA. 
However, the Sponsor and investigators will be bound by their obligation to complete the follow-up 
of subjects already participating in the study. The subjects must be followed according to the clinical 
Investigation Plan, and information obtained during subject follow-up shall be reported to the Sponsor 
on the appropriate eCRF.  
15.10.2.1.1. 
Study-wide termination or suspension 
Possible reasons for considering study-wide suspension or termination of the study include but are 
not limited to: 
• 
AEs associated with the product under investigation which might endanger the safety 
or welfare of the subject 
• 
Observed/suspected performance different from the product’s design intent 
• 
Decision by the Sponsor or CA  
• 
Technical issues during the manufacturing process 
15.10.2.2. Investigator/study site termination or suspension 
Possible reasons for investigator or study site termination or suspension include but are not limited 
to: 
• 
Failure to obtain initial EC approval or annual renewal of the study 
• 
Persistent non-compliance to the clinical investigation (e.g. failure to adhere to 
inclusion/exclusion criteria, failure to follow subjects per scheduled follow-ups)  
• 
Lack of enrollment 
• 
Noncompliance to regulations and the terms of the CTA (e.g. failure to submit data in 
a timely manner, failure to follow-up on data queries and monitoring observations in 
a timely manner, etc.)  
• 
EC suspension of the study site 
• 
Fraud or fraudulent misconduct is discovered (as defined by local law and regulations)  
• 
Investigator request (e.g. no longer able to support the study) 
15.10.3. Procedures for Termination or Suspension 
15.10.3.1. Sponsor-initiated and regulatory authority-initiated 
• 
The Sponsor will promptly inform the clinical investigators of the termination or 
suspension and the reasons and inform the RAs where required 
• 
In the case of study termination or suspension for reasons other than a temporary EC 
approval lapse, the investigator will promptly inform the EC  

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• 
In the case of study termination, the investigator must inform the subjects and may 
inform the personal physician of the subjects to ensure appropriate care and follow-
up is provided 
• 
In the case of a study suspension, subject enrollment must stop until the suspension 
is lifted by the Sponsor 
• 
In the case of a study suspension, enrolled subjects should continue to be followed 
out of consideration of their safety, rights and welfare 
15.10.3.2. Investigator-initiated 
• 
The investigator will inform the Sponsor and provide a detailed written explanation 
of the termination or suspension 
• 
The investigator will promptly inform the institution (where required per regulatory 
requirements)  
• 
The investigator will promptly inform the EC 
• 
Per ISO1415, the investigator will promptly inform the regulatory authorities 
• 
The investigator will promptly inform the subjects and/or the personal physician of 
the subjects to ensure appropriate care and follow-up is provided 
• 
In the case of a study suspension, subjects enrolled should continue to be followed 
out of consideration of their safety, rights and welfare 
15.10.3.3. Ethics Committee-initiated 
• 
The investigator will inform the Sponsor and provide a detailed written explanation 
of the termination or suspension within 5 business days 
• 
Subject enrollment must stop until the suspension is lifted 
• 
Subjects already enrolled should continue to be followed in accordance with EC policy 
or its determination that an overriding safety concern or ethical issue is involved 
• 
The investigator will inform his/her institution (where required per local 
requirements)  
• 
The investigator will promptly inform the subjects and/or the personal physician of 
the subjects, with the rationale for the study termination or suspension 
• 
Per ISO14155, the investigator will promptly inform the CA 
 
 

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16. References 
1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of 
incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 
2018;68:394–424. 
 
2. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2012 Incidence and 
Mortality Web-based Report. Available from URL: www.cdc.gov/uscs. 
 
3. Howlader N, N A, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto 
A, Lewis DR, et al., editors. [accessed June 15, 2017];SEER Cancer Statistics Review, 1975-
2014. Available from URL: http://seer.cancer.gov/csr/1975_2013/ 
 
4. Theodore R. Levin, Douglas A. Corley, Christopher D. Jensen, Joanne E. Schottinger, Virginia P. 
Quinn, Ann G. Zauber, Jeffrey K. Lee, Wei K. Zhao, Natalia Udaltsova, Nirupa R. Ghai, Alexander 
T. Lee, Charles P. Quesenberry, Bruce H. Fireman, Chyke A. Doubeni, Effects of Organized 
Colorectal Cancer Screening on Cancer Incidence and Mortality in a Large Community-Based 
Population, Gastroenterology, Volume 155, Issue 5, 2018, Pages 1383-1391.e5, ISSN 0016-5085, 
https://doi.org/10.1053/j.gastro.2018.07.017. 
 
5. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 
2020;70(3):145-164. 
 
6. Wild C, Weiderpass E, Stewart B. World Cancer Report: Cancer Research for Cancer Prevention. 
Lyon,France: International Agency for Research on Cancer. . In:2020. 
 
7. Repici A, et al., Efficacy of Per-oral Methylene Blue Formulation for Screening Colonoscopy, 
Gastroenterology. 2019 Jun;156(8):2198-2207.e1. doi: 10.1053/j.gastro.2019.02.001. Epub 2019 
Feb 10. PMID: 30742834. 
 
8. ANNEX I- Summary of Product Characteristics, Methylthioninium Chloride Cosmo 25 mg 
prolonged-release tablets 
 
9. PillCam™ Capsule Endoscopy User Manual 
 
 

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17. Appendices 
Appendix A: SPICE Study- Bowel Preparation/MB-MMX administration Schedule 
PEG --> Citrafleet/Picosalax 
Time
Activity 
Day (-3) 
All day 
Low-fiber diet 
No nuts, seeds, granola, fruit with skin or seeds, any 
type of legume, whole grains, anything with red or 
purple dye, vegetables as Corn, potatoes with skin, 
tomatoes, cucumbers with seeds and peel, etc. 
Day (-2) 
 
Low-fiber diet 
All day 
Water 
At least 10 glasses 
Day (-1) 
All Day 
Clear liquid diet 
No solid food 
18:00-19:00 
Bowel prep 
1L of PEG solution (i.e. Solución evacuante) 
19:00-20:00 
Bowel prep 
1L of PEG solution 
20:00 
MB-MMX 1st dose 
3 MB-MMX tablets after drinking at least 1L of PEG 
20:00-21:00 
Bowel Prep 
1L of PEG solution 
21:00 
MB-MMX 2nd dose 
3 MB-MMX tablets 1h after the 1st dose 
21:00-22:00 
Bowel Prep 
1L of PEG solution 
22:00 
MB-MMX 3rd dose 
2 MB-MMX tablets 1h after the 2nd dose 
 
All day 
Clear liquid diet 
No solid food 
Day 0 
07:00- 
Tablet  
1 Prucalopride (i.e. Resolor) tablet of 1 mg  
08:00 
PillCam™ capsule 
45 – 90 min after Prucalopride consumption 
08:45 - 09:15 
DR alert #1 
Boost 1 (G2SB) * 
1 sachet of Citrafleet/Picosalax, diluted with water- 
150ml 
09:15 - 10:15 
 
Water 
1L water- through 1h duration after DR alert #1 
11:45-12:00  
DR alert #2 
Boost 2  
1 sachet of Citrafleet/Picosalax, diluted with water- 
150ml, 3h after alert #1 
12:00-13:00 
Water 
1L water- Through 1h duration after DR alert #2 
13:45 
DR alert #3  
Suppository  
Bisacodilo/ Contalax 10 mg (Bisacodyl)  
2h after alert #2 
15:45 
DR alert #4  
Meal 
Light meal 
2h after alert #3 
* Time of G2S is estimated.  10 mg Metoclopramide (i.e. Primperan/ Pramin will be administrated in 
case the capsule fails to enter SB within 1h from ingestion (alert 0) 
 
 

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Appendix B: Bowel Preparation/MB-MMX administration Deviations 
Activity 
Deviation specifications 
Diet 
restrictions 
Complete deviation if: 
• Low-fiber diet was not followed at day 2 and day 3 prior to CCE procedure 
• Clear liquid diet was not followed 24h prior to and during the CCE procedure 
Bowel prep & 
MB-MMX 
schedule and 
volume 
Complete deviation if: 
• MB-MMX intake is less than 8 tablets. If less than 6 tablets- Exclude from the 
analysis  
• MB-MMX is taken after less than 1L of PEG. 
• MB-MMX timing of intake for 2nd and 3rd doses is ±10 min from the allowed 
intervals (as described in Appendix A) 
• PEG volume consumed is less than 3.5L. 
• PEG volume consumed is less than 3L.: Exclude from the analysis.    
• PEG volume consumed is less than 2.5L: No ingestion 
• PEG consumed during more than 5h/ less than 2h.   
• Bowel prep consumed prior to Day (-1)– cancel/postpone the procedure. 
Prucalopride 
Intake  
Complete deviation if Prucalopride tablet was not administrated prior to capsule 
ingestion.  
Capsule 
ingestion  
Complete deviation if the capsule was ingested less than 45m or more than 90m 
from Prucalopride intake. 
Boosts 
schedule/ 
volume 
Complete deviation if: 
• Boost consumption started more than 15m from alert** 
• Complete deviation if less than entire volume was consumed*** 
* In case of a PEG volume deviation s, it should be reported as 1 deviation. 
**In case a boost consumption was not started within the regimen timelines and a capsule was 
excreted within 30 minutes from alert, it will not be considered as a deviation.  
***In case a capsule is excreted during boost consumption, partial volume of boost consumption 
will not be considered as a deviation. 

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Appendix C: List of PillCam™ COLON2 Clinical Studies 
Several Clinical investigations with the PillCam™ COLON2 capsule have been conducted in major 
academic and experienced clinical research centers and have established the safe use and 
performance capability of the PillCam™ COLON2 capsule endoscopy system. The main clinical studies 
for the PillCam™ COLON2 capsule endoscopy system sponsored by Medtronic are listed below: 
# 
NCT Number 
Title 
1 
NCT01372878 
Evaluation of Capsule Endoscopy with PillCam® COLON 2 in Visualization of 
the Colon 
2 
NCT01269372 
Evaluation of Capsule Endoscopy with PillCam® COLON2 in Visualization of 
the Colon 
3 
NCT01185002 
Evaluation of PillCam® COLON2Capsule Endoscopy Regimen 
4 
NCT01063231 
Evaluation of PillCam® COLON2 in Visualization of the Colon 
5 
NCT01087528 
Evaluation of PillCam® COLON2 in Visualization of the Colon 
6 
NCT02481219 
Optimization of the Bowel Preparation Regimen for the PillCam® COLON2 
Capsule Endoscopy Procedure 
7 
NCT01575093 
Safety Evaluation of Bowel Cleansing Regimen for PillCam® COLON2 Capsule 
Endoscopy 
8 
NCT01576120 
Evaluation of a PillCam Colon Bowel Preparation Regimen in Crohn's Disease 
Patients 
9 
NCT00884624 
Evaluation of the PillCam® COLON Capsule -2 System 
10 NCT01631435 
PillCam Platform with the PillCam Crohn's Disease Capsule 
11 NCT02754661 
Colon 
Capsule 
Endoscopy 
(CCE) 
Versus 
Computed 
Tomographic 
Colonography (CTC) in the Identification of Colonic Polyps in a Screening 
Population. (TOPAZ) 
 
 
 
 

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Appendix D: Subjective Assessment Questionnaire (filled by the CCE reading physician) 
 

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Appendix E: list of participating sites/investigators: 
Name of the site 
Hospital de Navarra, Department of Gastroenterology 
Address of the site 
Pamplona, Spain ZIP 31008 
PI's name 
Dr. Ignacio Fernandez-Urien 
PI's professional 
position 
Gastroenterologist 
Appendix F: System components' model numbers 
 
PillCam™ Recorder 
FGS-0347 
PillCam™ recorder, DR3 
PillCam™ Recorder accessories including Sensor Belt  
Sensor Belts 
FGS-0325 
PillCam™ sensor belt, DR2, SB 
FGS-0443 
PillCam™ sensor belt, DR3 C2 
FGS-0508 
PillCam™ sensor belt 2, DR3 SB3 
FGS-0568 
PillCam™ sensor belt 2T, DR3 SB3 
FGS-0590 
PillCam™ sensor belt, Small Bowel 
FGS-0605 
PillCam™ sensor belt, DR3 C2 Crohn’s 
FGS-0666 
PillCam™ Sensor Belt disp kit – 5pk 
Accessories 
FGS-0214 
PillCam™ recorder pouch, DR2C 
FGS-0355 
PillCam™ recorder cradle, DR3 
ASM-0355-01 
PillCam™ recorder accessories, DR3 
FGS-0362 
PillCam™ recorder accessories, DR3 

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Medtronic Business Restricted   056-F275, vE Clinical Investigation Plan 
 
FGS-0431 
PillCam™ sensor belt cover, DR3 
 
FGS-0448 
PillCam™ sensor belt, C2 sleeves 
FGS-0452 
PillCam™ sensor sleeves, 5-pack 
FGS-0453 
PillCam™ sensor sleeves,10-pack 
FGS-0496 
PillCam™ sensor belt cover, DR3, SB3 
FGS-0509 
PillCam™ sensor belt 2 cover, DR3, SB3 
FGS-0510 
PillCam™ sensor belt 2 disp kit, 5-pk 
FGS-0475 
PillCam sensor belt cover, DR3, C2 
FGS-0575 
Data Recorder 3 Software Upgrade v28D 
FGS-0619 
PillCam™ recorder DR3 SW upgrade 
FGS-0664 
PillCam™ Recorder DR3 SW upgrade 
FGS-0435 
SD Card for PillCam™ recorder DR3 
FGS-0581 
Velcro sleeve, downlink antenna 
FGS-0686 
DR3 Firmware upgrade for UGI 
RAPID®/PillCam™ Software workstations 
FGS-0595 
RAPID® WS, Dell T5810 V8.0 WW 
FGS-0480-01 
RAPID® SW kit, v8.0 SCA WS 
FGS-0598 
RAPID® WS, Dell T5810 V8.3 WW 
FGS-0594 
RAPID® WS, Dell T5810 V8.5 WW 
FGS-0533 
RAPID® SW kit, v8.5 WS OUS 
FGS-0616 
PillCam™ WS, Dell T5810 WW 
FGS-0673 
RAPID® WS, V8.3 WW 
FGS-0675 
PillCam™ WS, WW 
RAPID®/PillCam™ Software 
FGS-0396 
RAPID® Access SW kit, v7.0 
FGS-0399 
RAPID® SW upgrade, v7.0 

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FGS-0478-01 
RAPID® SW kit, v8.0 SCA 
 
FGS-0479-01 
RAPID® SW upgrade, v8.0 SCA 
FGS-0601 
RAPID® SW kit, v8.3 WW 
FGS-0603 
RAPID® SW kit, V8.3 WW WS 
FGS-0604 
RAPID® SW upgrade, v8.3 WW 
FGS-0531 
RAPID® SW kit, v8.5 OUS 
FGS-0532 
RAPID® SW upgrade, v8.5 OUS 
FGS-0614 
PillCam™ SW Kit, WW 
FGS-0615 
PillCam™ SW Upgrade Kit, WW 
FGS-0626 
PillCam™ Software v9.0, WW WS 
FGS-0676 
PillCam™ Software Kit V9.0E, WW 
FGS-0677 
PillCam™ Software upgrade kit V9.0E, WW 
RAPID®/PillCam™ Software (Web) 
FGS-0587 
PillCam™ Software V1, OUS 
FGS-0623 
PillCam™ Web Software v9.0, WW 
PillCam™ Software (Remote Reader) 
FGS-0665 
PillCam™ Remote Reading Software 
PillCam™ COLON2 Capsule 
FGS-0517 
PillCam™ COLON2 Capsule, 1-pack 
FGS-0518 
PillCam™ COLON2 Capsule, 5-pack 
FGS-0519 
PillCam™ COLON2 Capsule, 10-pack 
 
 

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18. Version History 
Version 
Summary of changes 
Justification of 
changes 
Potential impact 
of the change on 
performance, 
effectiveness, or 
safety or other 
endpoints 
Identification 
of the 
affected 
study 
documents 
Author(s)/ 
Title 
1.0 
Not Applicable- 
initial release 
 
 
 
Roslana Fox/ 
CSM 
2.0 
1. Throughout the 
document- updated 
study classification 
to post-market 
study, including 
replacing study 
classification as 
“feasibility study” to 
“pilot study” 
2. Study name- SPICE 
has been added to 
the title 
3. Sec. 6.1- “the 
latest” has been 
added 
4. Throughout the 
document- changes 
according to CIP 
template Ver. C. 
5. Throughout the 
document- 
information re 
USADE not being 
collected was 
updated 
6. Sec. 6.2 added 
“MB-MMX intake in 
this study is 
considered a 
preceding 
investigational 
procedure, which is 
additional for this 
study and therefore 
outside standard of 
care.   
1. Following 
AEMPS (Spanish 
RA) decision that 
the study is not 
classified as a pre-
market study  
2. N/A  
3. Clarification of 
the study expected 
duration  
4. for template C 
version adherence 
5. Update as 
USADEs are not 
collected in a post 
market study. 
6. to comply with 
MDR requirements  
1. N/A 
2. N/A 
3. N/A 
4. N/A 
5. N/A 
6. N/A 
1. ICF- 
language to 
be updated. 
2. N/A 
3. N/A 
4. N/A 
5. Safety plan 
6. N/A 
Roslana Fox/ 
CSM 

MDT20062 SPICE Clinical Investigation Plan 
Version 4.0 
Version Date: 16Jun2022 
Page 75 of 75 
 
 
Medtronic Business Restricted   056-F275, vE Clinical Investigation Plan 
 
Version 
Summary of changes 
Justification of 
changes 
Potential impact 
of the change on 
performance, 
effectiveness, or 
safety or other 
endpoints 
Identification 
of the 
affected 
study 
documents 
Author(s)/ 
Title 
3.0 
1. Part 11 compliant 
signature- added 
when applicable 
2. Throughout the 
document- morning 
bowel preparation 
was removed and 2L 
of PEG were moved 
to day -1.  
3. Prucalopride 
tablet was added to 
the regimen 
4.Exclusion criteria 
#17- added per 
Investigator’s 
discretion  
5. Appendix B: 
Deviations table was 
updated   
6. Appendix D: 
Subjective 
Assessment 
Questionnaire was 
updated  
7. Section 12 was 
updated  
1. Added to reflect 
that this regulation 
is not applicable in 
the study 
geography (EU) 
and the documents 
signed under the 
study are not  
submitted to the 
FDA  
2. This change 
reflects the change 
in bowel prep 
regimen- single 
PEG dose at day -1, 
instead of spit 
dose. 
3. Added as an 
agent to support to 
capsule movement 
in the colon. 
4. Added for 
clarification 
5. Was updated to 
reflect the current 
CIP deviations    
6. Appendix D: 
Subjective 
Assessment 
Questionnaire was 
updated to include 
more rows for 
polyps (up to 25) 
7. for better 
alignment with ISO 
14155:2020 
language 
1. N/A 
2. N/A 
3. N/A 
4. NA 
5. N/A 
6. N/A 
7. N/A 
1. N/A 
2. ICF 
3. ICF 
4. NA 
5. N/A 
6. N/A 
7. N/A 
Roslana Fox/ 
CSM 
4.0 
1. Section 6.1- study 
duration was 
extended to 13 
months 
1. Duration was 
extended to allow 
study procedures 
completion 
1. NA 
1. NA 
Roslana Fox/ 
CSM