A Prospective, Multi-center, Single Arm Non-comparative Pilot Study of BiZact™ on Adults Undergoing Tonsillectomy
Phase: NA
Conditions: Tonsillectomy
Sponsor: Medtronic - MITG

BiZact™ Adult Clinical Study Protocol and SAP 
This document is electronically controlled
 Cover/Title Page 
Clinical Investigation Plan Title 
A prospective, multi-center, single arm non-
comparative pilot study of BiZact™ on adults 
undergoing tonsillectomy. 
Clinical Investigation Plan Identifier 
COVBZTS0562 
Study Product 
BiZact™ (BZ4112) 
ClinicalTrials.gov Identifier 
NCT02876575 
Sponsor/Local Sponsor 
Covidien-Medtronic 
Minimally Invasive Therapies Group 
Surgical Innovations 
5920 Longbow Dr. 
Boulder, CO 80301 
Covidien Services Europe  
(an indirect, wholly owned subsidiary of 
Medtronic plc.) 
Block G, Ground Floor  
Cherrywood Business Park 
Loughlinstown, Dublin 18, Ireland 
Key Entities 
Ron J Karni, University of Texas Health 
Science Center at Houston 
Luciano Mazzaro, Clinical Study Manager, 
MITG 
Sylvain Anselme, Biostatistics, MITG 

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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  A prospective, multi-center, single arm non-
comparative pilot study of BiZact™ on adults 
undergoing tonsillectomy. 
Clinical Investigation Plan Identifier COVBZTS0562  
Study Product Name BiZact™ (BZ4112) 
Sponsor/Local Authorized Representative Covidien-Medtronic 
Minimally Invasive Therapies Group 
Surgical Innovations 
5920 Longbow Dr. 
Boulder, CO 80301 
 
Covidien Services Europe  
(an indirect, wholly owned subsidiary of 
Medtronic plc.) 
Medtronic plc., 
Block 3090-3094, Lake Drive 
Citywest Business Campus 
Co. Dublin, D24 XN47 
Ireland 
Document Version 4.0 Final dated 20-Mar-2018 
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. 
Covidien LP is an indirect wholly owned subsidiary of Medtronic plc. 
 
 

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1. Investigator Statement 
Study product Name 
BiZact™ (BZ4112) 
Sponsor/Local Authorized Representative 
Covidien-Medtronic 
Minimally Invasive Therapies Group 
Surgical Innovations 
5920 Longbow Dr. 
Boulder, CO 80301, USA 
 
Covidien Services Europe  
(an indirect, wholly owned subsidiary of Medtronic plc.) 
Medtronic plc., 
Block 3090-3094, Lake Drive 
Citywest Business Campus 
Co. Dublin, D24 XN47 
Ireland 
Clinical Investigation Plan Identifier 
COVBZTS0562  
Version Number/Date  
Version 4.0 dated 20-Mar-2018 
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 United States Food and Drug Administration regulations (US) or ISO 
14155:2011 (EU) and any regional or national regulations, as appropriate.  I agree to comply with the 
ethical principles that have their origin in the Declaration of Helsinki 2013 and the clinical trial 
agreement.  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 ................................................................................................................................................ 12 
4.1. Background ..................................................................................................................................................... 12 
4.2. Purpose ........................................................................................................................................................... 13 
4.3. Report of Prior Investigations ......................................................................................................................... 13 
4.3.1. 
Biocompatibility Evaluation ................................................................................................................. 13 
4.3.2. 
Animal Evaluations .............................................................................................................................. 13 
5. 
Objectives and Endpoints ............................................................................................................................ 16 
5.1. Objectives ....................................................................................................................................................... 16 
5.1.1. 
Primary Objective(s) ............................................................................................................................ 16 
5.1.2. 
Secondary Objective(s) ........................................................................................................................ 16 
5.2. Endpoints ........................................................................................................................................................ 16 
5.2.1. 
Primary Endpoint ................................................................................................................................. 16 
5.2.2. 
Secondary Endpoint(s) ......................................................................................................................... 17 
5.2.3. 
Safety Endpoints .................................................................................................................................. 17 
6. 
Study Design ................................................................................................................................................ 17 
6.1. Duration .......................................................................................................................................................... 17 
6.2. Rationale ......................................................................................................................................................... 17 
7. 
Product Description ..................................................................................................................................... 18 
7.1. General ........................................................................................................................................................... 18 
7.2. Dosage Form and Route of Administration .................................................................................................... 19 
7.3. Manufacturer ................................................................................................................................................. 19 
7.4. Packaging ........................................................................................................................................................ 19 
7.5. Intended Population ....................................................................................................................................... 19 
7.6. Equipment ...................................................................................................................................................... 19 

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7.7. Product Use .................................................................................................................................................... 19 
7.8. Product Training Requirements ...................................................................................................................... 20 
7.9. Product Receipt and Tracking ......................................................................................................................... 20 
7.10. Product Storage .............................................................................................................................................. 20 
7.11. Product Return ............................................................................................................................................... 20 
7.12. Product Accountability ................................................................................................................................... 20 
8. 
Selection of Subjects ................................................................................................................................... 20 
8.1. Study Population ............................................................................................................................................ 20 
8.2. Subject Enrollment ......................................................................................................................................... 21 
8.3. Inclusion Criteria ............................................................................................................................................. 21 
8.4. Exclusion Criteria ............................................................................................................................................ 21 
9. 
Study Procedures ........................................................................................................................................ 22 
9.1. Schedule of Events ......................................................................................................................................... 22 
9.1.1. 
Study Schematic ................................................................................................................................... 22 
9.1.2. 
Screening / Baseline Visit ..................................................................................................................... 23 
9.1.3. 
Surgical Procedure (Day 0) ................................................................................................................... 24 
9.1.4. 
Post-Operative Follow-up: Days 1 through 7, Day 10 and Day 14 ....................................................... 25 
9.2. Prior and Concomitant Medications ............................................................................................................... 26 
9.3. Subject Consent .............................................................................................................................................. 26 
9.4. Randomization and Treatment Assignment ................................................................................................... 27 
9.5. Medication Compliance .................................................................................................................................. 27 
9.6. Assessment of Efficacy ................................................................................................................................... 27 
9.7. Assessment of Safety ...................................................................................................................................... 27 
9.8. Recording Data ............................................................................................................................................... 27 
9.9. Deviation Handling ......................................................................................................................................... 27 
9.10. Screen Failure ................................................................................................................................................. 28 
9.11. Subject Withdrawal or Discontinuation ......................................................................................................... 28 
9.12. Selection of Investigators ............................................................................................................................... 29 
10. 
Risks and Benefits .................................................................................................................................... 29 
10.1. Potential Risks ................................................................................................................................................ 29 
10.2. Potential Benefits ........................................................................................................................................... 30 

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10.3. Risk-Benefit Rationale .................................................................................................................................... 30 
11. 
Adverse Events and Device Deficiencies ................................................................................................... 30 
11.1. Definitions/Classifications .............................................................................................................................. 30 
11.1.1. 
Adverse Event (AE) ........................................................................................................................... 30 
11.1.2. 
Serious Adverse Event (SAE) ............................................................................................................ 31 
11.1.3. 
Adverse Device Effect (ADE) ............................................................................................................ 32 
11.1.4. 
Serious Adverse Device Effect (SADE) .............................................................................................. 32 
11.1.5. 
Unanticipated Serious Adverse Device Effect (USADE) ................................................................... 32 
11.1.6. 
Adverse Event Severity Classification .............................................................................................. 33 
11.1.7. 
Adverse Event Relationship Classification ....................................................................................... 33 
11.1.8. 
Adverse Event Outcome Classification ............................................................................................ 35 
11.2. Reporting of Adverse Events .......................................................................................................................... 35 
11.3. Adverse Event Recording ................................................................................................................................ 36 
11.4. Study Contact Information ............................................................................................................................. 37 
11.5. Device Deficiencies ......................................................................................................................................... 37 
12. 
Data Review Committees ......................................................................................................................... 37 
13. 
Statistical Design and Methods ................................................................................................................ 38 
13.1. Statistical Test Methods ................................................................................................................................. 38 
13.2. Sample Size Determination ............................................................................................................................ 38 
13.3. Analysis Populations ....................................................................................................................................... 38 
13.4. Statistical Analysis of Endpoints ..................................................................................................................... 38 
13.4.1. 
Primary Endpoint ............................................................................................................................. 38 
13.4.2. 
Secondary Endpoints ....................................................................................................................... 38 
13.5. Statistical Analyses of Safety Endpoints ......................................................................................................... 39 
13.6. Handling of Missing Data ................................................................................................................................ 39 
13.7. Interim Analysis .............................................................................................................................................. 39 
14. 
Ethics ........................................................................................................................................................ 39 
14.1. Statement(s) of Compliance ........................................................................................................................... 39 
15. 
Study Administration ............................................................................................................................... 39 
15.1. Monitoring ...................................................................................................................................................... 39 
15.2. Data Management .......................................................................................................................................... 40 

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15.3. Direct Access to Source Data/Documents ...................................................................................................... 41 
15.4. Confidentiality ................................................................................................................................................ 41 
15.5. Liability ........................................................................................................................................................... 41 
15.6. CIP Amendments ............................................................................................................................................ 41 
15.7. Record Retention ............................................................................................................................................ 42 
15.8. Publication and Use of Information................................................................................................................ 42 
15.9. Suspension or Early Termination .................................................................................................................... 43 
15.10. 
Safety Committees................................................................................................................................... 43 
15.10.1. 
Independent Medical Monitor ........................................................................................................ 43 
15.10.2. 
Steering Committee ......................................................................................................................... 43 
16. 
References ............................................................................................................................................... 44 
17. 
Appendices ............................................................................................................................................... 45 
17.1. APPENDIX A: Post-operative home survey forms ........................................................................................... 45 
17.1.1. 
EORTC QLQ-H&N35 (English) ........................................................................................................... 46 
17.1.2. 
EORTC QLQ-H&N35 (Spanish) .......................................................................................................... 48 
17.1.3. 
EORTC QLQ-H&N35 (Swedish) ......................................................................................................... 50 
17.2. APPENDIX B: Visual Analogue Scale (VAS) ...................................................................................................... 52 
17.3. APPENDIX C: List of Investigators and Institutions ......................................................................................... 53 
18. 
Version History ......................................................................................................................................... 54 
 
 
 

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2. Glossary 
Term 
Definition 
ADE 
Adverse device effect 
ADL 
Activities of daily living 
AE 
Adverse event 
CIP 
Clinical Investigation Plan 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
ENT 
Ear, nose and throat 
EORTC 
European Organisation for Research and Treatment of Cancer 
FAS 
Full Analysis Set 
Focal infection 
Infection confined to a single organ or tissue; certain focal 
infections, as in tonsillar crypts or periodontal tissues, are a source 
of systemic disease as a result of blood-stream dissemination of 
the offending pathogen according to Dorland’s Illustrated Medical 
Dictionary 1976. 
GCP 
Good Clinical Practice 
Hemostasis 
The arrest of bleeding, whether it be by normal vasoconstriction 
(the vessel walls closing temporarily), by an abnormal obstruction 
(such as a plaque) or by coagulation or surgical means (such as 
ligation).  
ICMJE 
International Committee of Medical Journal Editors 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
MedDRA 
Medical Dictionary for Regulatory Activities 
PETG 
Polyethylene terepthalate glycol 

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Term 
Definition 
QOL 
Quality of Life (survey) 
RDC 
Remote Data Capture 
RF 
Radiofrequency 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
WHO 
World Health Organization 
 
 

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3. Synopsis 
Title 
A prospective, multi-center, single arm non-comparative pilot study of 
BiZact™ on adults undergoing tonsillectomy. 
Clinical Study Type 
Post-market interventional, prospective, multi-center, single arm, 
non-comparative pilot 
Product Name 
BiZact™ (BZ4112) 
Sponsor  
Covidien-Medtronic 
Minimally Invasive Therapies Group 
Surgical Innovations 
5920 Longbow Dr. 
Boulder, CO 80301, USA 
Local Authorized 
Representative 
Covidien Services Europe  
(an indirect, wholly owned subsidiary of Medtronic plc.) 
Medtronic plc., 
Block 3090-3094, Lake Drive 
Citywest Business Campus 
Co. Dublin, D24 XN47 
Ireland 
Indication under 
investigation  
Adult tonsillectomy 
Investigation Purpose 
The purpose of this study is to assess the severity of post-operative 
pain following the use of the BiZact™ device in adult (≥22 years of age 
in United States and ≥18 years of age in Europe) tonsillectomy 
procedures. 
Product Status 
Food and Drug Administration (FDA) 510(k) clearance and Conformité 
Européene (CE) Mark clearance  
Primary Objective(s) 
The primary objective of this study is to assess the severity of post-
operative pain following the use of the BiZact™ device in adult (≥22 
years of age in United States and ≥18 years of age in Europe) 
tonsillectomy procedures using the Visual Analogue Scale (VAS) at 
days 1 through 7, 10 and 14. 
Secondary Objective(s) 
The secondary objective of this study is to assess bleeding, and post-
operative ability to return to normal diet and activity up to 14 days.  
Study Design 
Prospective, multi-center, single-arm non-comparative pilot study to 
assess the severity of post-operative pain with the use of BiZact™ for 
tonsillectomy. 

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Sample Size 
A minimum of 48 subjects may be enrolled at up to 3 sites in the 
United States and Europe with competitive enrollment not to exceed 
24 subjects per site.  
Inclusion/Exclusion Criteria 
Subjects are eligible to be enrolled in the study only if they meet all 
of the following criteria:  
Inclusion Criteria: 
1. Adults (male or female) ≥22 years of age in United States and 
≥18 years of age in Europe 
2. Scheduled to undergo tonsillectomy  
3. Signed informed consent by subject  
 
Subjects will be excluded from the study if they meet any of the 
following criteria:  
Exclusion Criteria  
1. Subjects undergoing:  
a. Simultaneous adenoidectomy 
b. Tonsillectomy as a result of cancer 
c. Unilateral tonsillectomy 
d. Current participation in other clinical trials 
2. Subjects with: 
a. Current tobacco use  
b. Known bleeding disorders 
c. History of peritonsillar abscess 
d. Craniofacial disorders 
e. Down syndrome (Trisomy 21) 
f. Cerebral palsy  
g. Major heart disease (including but not limited to; right-
sided heart failure, left-sided heart failure, congestive 
heart failure, coronary artery disease, arrhythmias, 
chronic heart failure, acute heart failure, etc.) 
h. Subjects unable to comply with the required study 
follow-up visits 
i. 
Pregnancy 
3. The subject has comorbidities which, in the opinion of the 
investigator, will not be appropriate for the study or the 
subject has an estimated life expectancy of less than 6 
months 

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4. Any subject who is considered to be part of a vulnerable 
population (e.g. prisoners or those without sufficient mental 
capacity) 
5. The subject has participated in any drug or device research 
study within 30 days of enrollment 
Study Procedures and 
Assessments 
Pre-operative & Operative Assessments: 
• 
Histories: Medical, Surgical, Medication 
• 
Urine Pregnancy test for females of child bearing potential (US 
only) 
• 
Intra-operative bleeding volume-volume of stomach juices 
and blood should be measured prior to stomach draining 
• 
Irrigant volume – volume to be recorded of operative field 
irrigant used during procedure 
• 
Operative time-time from the first incision to complete 
hemostasis of the tonsillar bed (excluding closing time) 
• 
Subjects will be followed for 2 weeks post tonsillectomy 
procedure.  
 
Follow-up Assessments (Form filled out by subject on post-operative 
days 1-7, 10 and 14): 
• 
Pain level   
• 
Analgesic consumption 
• 
Ability to return to normal diet  
• 
Ability to return to normal activity 
• 
Incidence of post-operative hemorrhage - any primary (≤24 
hrs) and secondary (>24hrs) bleeding 
• 
Incidence of post-operative readmission  
Safety Assessments 
• 
Adverse events (AEs), Serious Adverse Events (SAEs), Adverse 
device effects (ADE) and Unanticipated serious adverse device 
effects (USADE)  
• 
Device deficiencies 
• 
Focal Infection  
 Statistics 
• 
Pain levels will be captured at post-operative days 1-7, 10, and 
14 for each subject. Paired tests may be used to test whether 
there is a mean change along the follow-up.  
• 
For operative time and intra-operative bleeding volume a 
sample value will be calculated. Incidence of post-operative 

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hemorrhage and post-operative readmission will be 
summarized using frequency and percentages. 
This study does not have a statistically powered hypothesis.  There will 
be no sample size calculations since the study is not hypothesis-driven.  
The number of enrolled subjects is pre-defined, and all the results will 
be summarized in a descriptive manner which will be further defined 
in the statistical analysis plan with the following measures utilized: 
• 
Mean, standard deviations, medians, minimum and 
maximum for quantitative variables. 
• 
Numbers and percentages for qualitative variables. 
The following aspects will be used to assess safety: 
• 
Adverse events (AEs), Serious Adverse Events (SAEs), 
Adverse device effects (ADE) and Unanticipated serious 
adverse device effects (USADE)  
• 
Device deficiencies 
• 
Focal Infection  
4. Introduction  
4.1. Background  
Tonsillectomy is one of the most frequently performed otorhinolaryngologic procedures with more than 
4.5 million procedures performed annually. Aside from the conventional technique of cold steel and 
electrocautery dissection, the introduction of numerous energy based tools and techniques allow for the 
simultaneous dissection and sealing of vessels, significantly improving safety and reducing the 
complications of the procedure (1-3). Generally thought of as safe and effective, energy based devices 
such as laser, Shaw scalpel, electrosurgical devices (needle, scissor, or knife), radiofrequency needle 
ablation device, thermal welding, and Coblator, use heat energy to denature protein, leading to vascular 
tamponade and hemostasis. Unfortunately, a byproduct of using this energy during surgery is the lateral 
heating of the surgical area, which can damage adjacent structures, delay wound healing, increase post-
operative pain, and increase the subject’s time to return to normal diet and activity (4).  
In order to address these concerns, Covidien (Covidien LP is an indirect wholly owned subsidiary of 
Medtronic plc.) has developed BiZact™, a bipolar electrosurgical instrument intended for use in open 
surgical procedures, such as tonsillectomies, where ligation and division of vessels, tissue bundles and 
lymphatics is desired. BiZact™ is designed as a pistol grip radiofrequency (RF) sealer/dissector for use with 
vessels up to and including 3mm. Compatible with the already in use Valleylab™ (LS10) energy platform, 
BiZact™ employs bipolar electrosurgical RF energy and pressure to ligate vessels interposed between its 
jaws which can then be transected using the built in knife deployed by the device trigger. Based off 

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Ligasure™ technology, bipolar electrosurgical devices have been shown to be safe and effective for 
tonsillectomy procedures, providing adequate hemostasis while minimizing postoperative pain (5, 6).  
In summary, biocompatibility testing and animal model studies have found BiZact™ to be safe and 
effective in achieving hemostasis and reducing lateral thermal spread potentially resulting in reduced 
post-operative pain. Full details of biocompatibility testing and prior investigations can be found in Section 
4.3.  
The primary objective of this study is to assess the severity of post-operative pain and return to normal 
diet and activity for up to 14 days following the use of the BiZact™ device in adult (≥22 years of age in 
United States and ≥18 years of age in Europe) tonsillectomy procedures. At the conclusion of this study, 
data will be used for publication.  
4.2. Purpose 
The purpose of this study is to assess the severity of post-operative pain following the use of the BiZact™ 
device in adult (≥22 years of age in United States and ≥18 years of age in Europe) tonsillectomy 
procedures.  
The results of this study will be offered for publication at the conclusion of the study, if participating 
investigators believe the data warrants publication in an appropriate journal. 
4.3. Report of Prior Investigations 
4.3.1. 
Biocompatibility Evaluation  
Biocompatibility testing for a device having tissue/bone/blood contact was conducted per ISO 10993: 
Biological evaluation of medical devices and met the necessary requirements.  This testing was performed 
utilizing BiZact™ (BZ4112) and included cytotoxicity, sensitization and irritation, toxicity (acute) and hemo-
compatibility testing.  
4.3.2. 
Animal Evaluations  
Table 1. Animal Trial Schematics 
Study 
Type and Number of 
Animals/ 
Study 
Duration 
Methods/Summary 
Endpoints 
Results 
Verification of the 
BiZact™ (BZ4112) 
Devices in an Acute 
1 pig 
 
204 seals total 
One (1) female 
porcine underwent 
various procedures to 
assess acute sealing 
• 
Intraoperative 
hemostasis  
• 
The mean lateral 
thermal spread 
from the BiZact™ 
(BZ4112) device 

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Table 1. Animal Trial Schematics 
Study 
Type and Number of 
Animals/ 
Study 
Duration 
Methods/Summary 
Endpoints 
Results 
Hemostasis Porcine 
Study 
(RE00033410) 
• 
102 seals – 
BiZact™ 
(BZ4112) 
• 
102 seals – 
LF1212 
 
Duration 
• 
1-day  
performance by the 
BiZact™ (BZ4112) 
device as well as the 
LF1212 control device. 
 
Efficacy was defined 
by:  
• 
Mean lateral 
thermal spread 
• 
Time to 
hemostasis (TTH) 
 
Evaluations and 
records: 
• 
Clinical 
observations 
• 
Clinical pathology 
parameters 
• 
Body weight 
• 
Seal Evaluation  
• 
Histopathology / 
Thermal spread 
analysis 
• 
Histopathology / 
Thermal spread 
analysis 
was statistically 
lower than the 
predicate LF1212 
device.  
• 
There was no 
statistical 
difference 
between the rate 
of hemostatic 
seals between 
BiZact™ (BZ4112) 
and the 
predicate LF1212 
device.   
 

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Table 1. Animal Trial Schematics 
Study 
Type and Number of 
Animals/ 
Study 
Duration 
Methods/Summary 
Endpoints 
Results 
Verification of the 
BiZact™ (BZ4112) 
Devices in a Chronic 
Hemostasis Porcine 
Study 
(RE00030667) 
6 pigs 
 
245 seals total using 
BiZact™ (BZ4112) 
 
Duration 
21-days 
Six (6) female porcine 
underwent a 
total 
ovariohysterectomy 
and splenectomy in 
which as many 
appropriately sized 
vessels (4.0 mm 
and smaller) as 
possible were sealed. 
 
Efficacy was defined 
by:  
• 
Long term seal 
quality over 21 
days 
 
Evaluations and 
records: 
• 
Clinical 
observations 
• 
Clinical pathology 
parameters 
• 
Body weight 
• 
Gross 
observation of 
seal at time of 
necropsy 
• 
Gross 
observation of 
seal at time of 
necropsy 
• 
At necropsy 
chronic 
hemostasis was 
confirmed and 
there was no 
evidence of post-
operative 
bleeding, 
peritoneal cavity 
hematoma 
formation, or 
free 
intraperitoneal 
blood in any of 
the six animals. 
Verification of the 
BiZact™ (BZ4112) 
Devices in a Fresh 
Renal Burst Pressure 
Study 
(RE00031977) 
118 porcine renal 
artery seals 
60 seals - BiZact™ 
(BZ4112)  
58 seals – LF1212 
Freshly excised renal 
arteries underwent 
ligation and resection 
with either BiZact™ 
(BZ4112) or the 
control LF1212. Burst 
pressure (mmHg) was 
then monitored 
 
Efficacy was defined 
by:  
• 
Number of bursts 
• 
Burst Pressure 
• 
Number of bursts 
• 
Burst Pressure 
 
• 
There was no 
statistical 
difference in 
sealing 
performance 
between BiZact™ 
(BZ4112) and the 
control LF1212.  
• 
BiZact™ (BZ4112) 
had a statistically 
significant faster 
renal activation 
time than the 

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Table 1. Animal Trial Schematics 
Study 
Type and Number of 
Animals/ 
Study 
Duration 
Methods/Summary 
Endpoints 
Results 
Evaluations and 
records: 
• 
Vessel size 
• 
Total Bursts 
• 
Burst pressure 
(mmHg)  
LF1212 control 
device.  
5. Objectives and Endpoints 
5.1. Objectives 
5.1.1. 
Primary Objective(s) 
The primary objective of this study is to assess the severity of post-operative pain following the use of the 
BiZact™ device in adult (≥22 years of age in United States and ≥18 years of age in Europe) tonsillectomy 
procedures using the Visual Analogue Scale (VAS) at days 1 through 7, 10 and 14. 
5.1.2. 
Secondary Objective(s)  
The secondary objective of this study is to assess intra-operative bleeding volume, and ability to return to 
normal diet and activity up to 14 days post-operative.   
5.2. Endpoints 
5.2.1. 
Primary Endpoint 
The primary endpoint will be post-operative pain level measured using the VAS at days 1 through 7, 10 
and 14.  

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5.2.2. 
Secondary Endpoint(s) 
• 
Analgesic consumption 
• 
Ability to return to normal diet (days 1-7, 10, 14) 
• 
Ability to return to normal activity (days 1-7, 10, 14) 
• 
Incidence of post-operative hemorrhage 
• 
Primary (≤24 hrs) bleeding and  
• 
Secondary (>24hrs) bleeding 
• 
Incidence of post-operative readmission  
• 
Intra-operative bleeding volume- volume of stomach juices and blood should be measured prior 
to stomach draining 
• 
Irrigant volume – volume to be recorded of operative field irrigant used during procedure 
• 
Operative time - time from the first incision to complete hemostasis of the tonsillar bed 
5.2.3. 
Safety Endpoints 
• 
Adverse events (AEs), Serious Adverse Events (SAEs), Adverse device effects (ADE) and 
Unanticipated serious adverse device effects (USADE)  
• 
Device deficiencies 
• 
Focal Infection  
 
6. Study Design  
6.1. Duration 
Including enrollment and follow up time, the current study is estimated to progress for up to 1 year. During 
this time subjects will be pre-screened for the study up to 30 days prior to the procedure. Post-procedure, 
subjects will be assessed for pain and their ability to return to normal diet and activity via Visual Analog 
Scale (VAS) and Quality of Life (QoL) questionnaire (EORTC QLQ – H&N35) at days 1 through 7, 10 and 14.  
These materials can be found in Appendices A and B. 
6.2. Rationale  
In order to demonstrate the clinical use of BiZact™ (BZ4112) effects post-operative pain and return to 
normal diet and activity after standard tonsillectomy procedure, Medtronic is performing a prospective, 
multi-center, single arm non-comparative pilot study of BiZact™ on adults (≥22 years of age in United 
States and ≥18 years of age in Europe) undergoing tonsillectomy. Post-operative pain, and other quality 
of life aspects will be collected via questionnaire for up to 14 days following the procedure. As a study 
with no comparator this study does not utilize any randomization or blinding. The BiZact™ device will only 
be used during the course of the tonsillectomy procedure and subjects will be followed for up to 14 days 
to monitor bleeding, pain and return to normal diet and activity. Currently there are no known factors 

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that may compromise study outcomes or the interpretation of results (e.g., baseline characteristics, 
concomitant medications, the use of other study products, or subject-related factors such as age, gender 
or lifestyle). If any adverse occurrences are identified they will be assessed, reported and documented. 
7. Product Description 
7.1. General 
The BiZact™ (BZ4112) is a single use bipolar electrosurgical instrument intended for use with the 
Valleylab™ (LS10 with V1.1 or V1.2 software) energy platform in general open surgical procedures.  It is 
also indicated for adult ENT procedures, including tonsillectomy, for the ligation and division of vessels, 
tissue bundles and lymphatics 2-3 mm away from unintended thermally sensitive structures. This 
instrument creates tissue fusion by application of bipolar electrosurgical RF energy and pressure to 
vessels/tissue interposed between the jaws of the instrument. The tissue fusion can then be transected 
using the built in cutting mechanism.  The instrument can be used for vessels and lymphatic tissue up to 
and including 3mm in diameter and tissue bundles. The instrument also incorporates inline RF activation, 
features for grasping and tips for dissection. The instrument is intended primarily for surgeons performing 
tonsillectomies. It is also indicated for adult ear, nose and throat (ENT) procedures, including 
tonsillectomy, for the ligation and division of vessels, tissue bundles and lymphatics 2-3 mm away from 
unintended thermally sensitive structures.  
See Instructions for Use for additional information.  
 
 
Figure 1: BiZact™ (BZ4112) schematic diagram (left), and device photo (right) 
 
BiZact™ is a pistol grip RF-based sealer/dissectors similar (design, technology and materials) to current 
Ligasure™ devices. Similar to its predicate device LF1212 (Ligasure™ small jaw), BiZact™ includes a jaw, a 
deploying knife, a lever to open and close the jaws, and a trigger to deploy the knife and inline activation 

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of bipolar energy. The device does not include a rotation knob for rotating the jaws, but the device does 
allow surgeons to perform procedures by switching hands. BiZact™ is compatible with the Valleylab™ 
(LS10 with V1.1 or V1.2 software) energy platform, which is able to recognize the device utilizing RFID 
identification capabilities. In total, 96 BiZact™ units will be assigned to this study to account for any 
situations in which more than one device is needed.  
7.2. Dosage Form and Route of Administration 
Not applicable. 
7.3. Manufacturer 
BiZact™ is manufactured by Covidien (Covidien LP is an indirect wholly owned subsidiary of Medtronic 
plc.). 
7.4. Packaging 
Each instrument is individually packaged in a single-use polyethylene terephthalate glycol (PETG) tray and 
sealed with Tyvek lid. Six sealed trays are packaged in one shipper case. 
7.5. Intended Population 
The BiZact™ (BZ4112) device is indicated for use in general open surgical procedures. The device is also 
indicated for adult ENT procedures, including tonsillectomy, for the ligation and division of vessels, tissue 
bundles and lymphatics. 
7.6. Equipment 
BiZact™ devices are single-use disposable products. For this study, BiZact™ will be used in combination 
with a Valleylab™ (LS10 with V1.1 or V1.2 software) energy platform.  No maintenance or calibration of 
this equipment is required.  
7.7. Product Use 
The BiZact™ (BZ4112) is a single use bipolar electrosurgical instrument intended for use with the 
Valleylab™ (LS10 with V1.1 or V1.2 software) energy platform in general open surgical procedures.  It is 
also indicated for adult ENT procedures, including tonsillectomy, for the ligation and division of vessels, 
tissue bundles and lymphatics 2-3 mm away from unintended thermally sensitive structures.  
The BiZact™ device has not been shown to be effective for tubal sterilization or tubal coagulation for 
sterilization procedures and should not be used for these procedures. 

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7.8. Product Training Requirements 
Each Investigator participating in the clinical trial and the associated clinical study staff will receive training 
on the clinical protocol, as well as the BiZact™ device. Investigators will be trained on device 
characteristics, shelf life and storage requirements, device use, and warnings, precautions, 
contraindications, etc. 
7.9. Product Receipt and Tracking 
BiZact™ and a Valleylab™ (LS10 with V1.1 or V1.2 software) energy platform will be shipped to each site 
and each site will document the date received, quantity, expiration date, model number and lot number 
of each product upon receipt. For each procedure, the serial number of the device being used will be 
recorded in the eCRF as well as the date of use and date of disposal or return.  
7.10. Product Storage 
The devices will be labeled “Exclusively for Clinical Investigations” and should be stored in a secure 
(locked) area under the appropriate storage conditions (room temperature). Access should be limited to 
designated study staff only. 
7.11. Product Return 
It is the site’s responsibility to return the Valleylab™ (LS10) energy platform to Medtronic within 30 days 
of the End of Study as well as any unopened BiZact™ devices.  Date of return should be documented in 
the eCRFs. 
7.12. Product Accountability  
BiZact™ and a Valleylab™ (LS10 with V1.1 or V1.2 software) energy platform will be provided to each site 
upon Sponsor collection and approval of all required regulatory documentation.  Device accountability 
logs will be provided to the site. It is the site’s responsibility to document the receipt (maintain shipping 
logs), disposition of the product (per subject use, including amount used, amount remaining, etc.), 
transfer (if applicable) and return of all unopened study devices.  
8. Selection of Subjects 
8.1. Study Population 
A minimum of 48 adult subjects (males and females ≥22 years of age in United States and ≥18 years of 
age in Europe) undergoing tonsillectomy surgery will be enrolled in the study.  

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8.2. Subject Enrollment 
After being informed of the nature of the study, the subject will provide written informed consent that 
has been approved by the sponsor and the appropriate IRB/EC of the respective clinical site.  A minimum 
of 48 subjects will be enrolled in the study at up to 3 sites with competitive enrollment not to exceed 24 
subjects per site. Subjects’ participation in the study will last 14 days (+3) post procedure.  
 
A subject is considered enrolled in the study when ICF is signed, and must be followed for the full 14 days 
follow-up regardless of whether or not the subject received treatment with the study device.   
 
The procedure will be performed per the institution’s standard practice.  Subjects will be considered for 
the study if they meet specific preoperative and intraoperative inclusion/exclusion criteria.  The criteria 
for enrollment must be followed explicitly.  
8.3. Inclusion Criteria 
Subjects are eligible to be enrolled in the study only if they meet all of the following inclusion criteria: 
1. Adults (male or female) ≥22 in United States and ≥18 years of age in Europe years of age 
2. Scheduled to undergo tonsillectomy  
3. Signed informed consent by subject  
8.4. Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following exclusion criteria: 
• 
Subjects undergoing; 
• 
Simultaneous adenoidectomy 
• 
Tonsillectomy as a result of cancer 
• 
Unilateral tonsillectomy 
• 
Current participation in other clinical trials 
• 
Subjects with; 
• 
Current tobacco use 
• 
Known bleeding disorders 
• 
History of peritonsillar abscess 
• 
Craniofacial disorders 
• 
Down syndrome (Trisomy 21) 
• 
Cerebral palsy  
• 
Major heart disease  
• 
Subjects unable to comply with the required study follow-up visits 
• 
Pregnancy 
 

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• 
The subject has comorbidities which, in the opinion of the investigator, will not be appropriate 
for the study or the subject has an estimated life expectancy of less than 6 months 
• 
Any subject who is considered to be part of a vulnerable population (e.g. prisoners or those 
without sufficient mental capacity) 
• 
The subject has participated in any drug or device research study within 30 days of enrollment 
that would interfere with this study 
9. Study Procedures  
9.1. Schedule of Events 
9.1.1. 
Study Schematic  
Subjects who meet the eligibility criteria will be considered for study participation. The schematic of the 
trial is presented in the table below. 

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Table 1: Study Schematic 
 
Screening 
/ Baseline 
Day -30 to 
0 
Surgery 
(Day 0) 
Post-Op 
Follow-Up 
Day 1 – Day 7 
(Home) 
Post-Op 
Follow-Up 
Day 10 
(Home) 
Post-Op 
Follow-Up 
Day 14 
(+3 days) 
Informed Consent Form1 
X 
x 
 
 
x 
Eligibility Criteria 
x 
x 
 
 
 
Urine pregnancy test (female Pts; US 
only)2 
x 
x 
 
 
 
Demographic data 
x 
 
 
 
 
Medical history 
x 
 
 
 
 
Surgical history 
x 
 
 
 
 
Medication history 
x 
 
 
 
 
Concomitant medications 
 
x 
x 
x 
X 
Type of admission 
 
x 
 
 
 
Physical Examination  
 
x 
 
 
 
Intra-operative bleeding volume 
 
x 
 
 
 
Tonsil measurement 
 
x 
 
 
 
Surgical technique 
 
x 
 
 
 
Operation time 
 
x 
 
 
 
Device ease of use 
 
x 
 
 
 
Dissection assessment 
 
x 
 
 
 
Alternate device used (if any) 
 
x 
 
 
 
Post-operative bleeding 
 
 
x 
x 
x 
AE, SAE, ADE, USADE Assessment & 
Device Deficiencies3 
 
x 
x 
x 
x 
Readmission 
 
 
x 
x 
x 
QOL Home survey (EORTC QLQ – 
H&N35)  
• 
Ability to return to normal diet 
• 
Ability to return to normal 
activity 
 
 
x 
x 
x 
Pain via VAS scale (Appendix B) 
 
 
x 
x 
x 
Return to clinic follow-up visit 
 
 
 
 
x 
Return VAS and QoL questionnaire 
 
 
 
 
x 
Device accountability 
 
x 
 
 
 
Protocol deviation collection 
x 
x 
 
 
x 
1 No study procedures will be performed until informed consent form has been completed.  
2Urine pregnancy test (US only): unless female subject is surgically sterile or postmenopausal for at least 2 years. 
Confirmed by PI judgment and subject signature and noted in medical history and eCRF.  
3AEs/SAEs must be followed to resolution or 30 days post EOS, whichever is first. 
9.1.2. 
Screening / Baseline Visit 
A screening/baseline visit will be performed within 30 days up to/on the day of the scheduled procedure. 
Subjects will be consented prior to enrollment in the study before any procedures specific to the study 
are undertaken. The purpose and all aspects of the study will be explained to the subject. Subjects who 

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agree to study participation must sign and personally date the sponsor and an IRB/EC-approved informed 
consent form prior to participating in any study activities.   
Once informed consent has been signed and eligibility is confirmed, the subject’s demographics and 
medical history will be assessed to include: age, gender and weight. 
• 
Relevant medical history will be assessed based on clinical condition categorized by category 
codes specified in the electronic case report form (eCRF). 
• 
Female subjects will be assessed for childbearing potential, and if they do have childbearing 
potential, they will undergo a urine pregnancy test (US only). If the test is positive, they will be 
withdrawn from the study. If the pregnancy test is negative, these subjects should practice 
contraceptive methods through the course of the study. Additional urine pregnancy test will be 
performed on the day of surgery (US only). In Europe female subjects of childbearing potential 
will be asked pregnancy status. Women who respond as pregnant will not be included. 
 
The following assessments will be performed within 30 days prior to the scheduled surgical procedure and 
the results recorded on the appropriate subject eCRFs: 
• 
Verification of preoperative eligibility criteria 
• 
Verification of surgical candidacy 
• 
Demographic data 
• 
Medical history, including concomitant medications and comorbidities 
• 
Surgical history 
• 
Medication history 
• 
Pregnancy test, if applicable (US only) 
• 
Concomitant medication(s) 
Note: All medications will be coded using the World Health Organization (WHO) drug coding 
dictionary. 
9.1.3. 
Surgical Procedure (Day 0)  
The Study Investigator should perform the surgical procedure according to the appropriate standard 
procedures and practices at his/her institution using BiZact™.  BiZact™, in conjunction with other non-
energy surgical tools (e.g. Allis clamp), should be used to complete the entire procedure unless it is 
medically necessary to use another device. Additionally, the following procedures and assessments will 
be performed:  
• 
Type of admission 
• 
AE/SAE assessment 
• 
Pre-operative procedure specific physical examination 
o Including assessment of heart/lungs, neurological, ENT, immune system and vital signs 
(blood pressure, respiration rate, heart rate, temperature) 

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• 
Pregnancy test, if applicable (US only) 
• 
Intra-operative bleeding volume  
o Record volume of any irrigant used 
o Record presence of gastric fluids 
o Record amount of fluid in suction container prior to stomach drainage 
• 
Surgical performance parameters 
o Surgical technique 
o Operation time 
o Device ease of use 
o Dissection assessment 
o Other non-study device alternative procedural devices used (if any),  
 
Operation time used 
 
Tonsil location (Left/Right) 
 
Reason for use  
o Tonsil size measurement (Measured via water displacement) 
 
Using a graduated container that has 1mL markings, fill container to half full with 
water note mL level. Put the first tonsil into the water and record the mL level. 
The difference equals the volume of the first tonsil. Remove the first tonsil and 
note water level. Put the second tonsil into the water and record how much the 
water level rises. The difference equals the volume of the second tonsil.  
• 
Device accountability 
• 
Concomitant medications  
Note: All medications will be coded using the World Health Organization (WHO) drug coding 
dictionary.  
9.1.4. 
Post-Operative Follow-up: Days 1 through 7, Day 10 and Day 14 
Post-operative hospital stay and AE/SAE assessment will take place by delegated study personnel. 
Additionally, during post-operative days 1 through 7, day 10 and day 14 the following will be assessed via 
an at home survey form (EORTC QLQ – H&N35, Appendix A):  
• 
Pain assessment   
o VAS (see Appendix B) 
o Consumption of recommended standard of care analgesic pain regimen; 
 
10 mg dose dexamethasone intra-operative 
 
Ibuprofen 800 mg q8hrs 
 
Hydrocodone/acetaminophen 10/325 mg q4 hrs PRN 
 
Any modifications to recommended pain regimen will be noted in the eCRF 
• 
Postoperative AEs and SAEs 

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• 
Readmission  
• 
Ability to return to normal diet  
• 
Ability to return to normal activity  
• 
Day 14 (+3) days clinical visit for follow-up and to return VAS and QoL questionnaires 
• 
Concomitant medications 
• 
Post-operative bleeding – Any bleeding that occurs, from the presence of blood in saliva to 
bleeding that requires re-operation 
9.2. Prior and Concomitant Medications 
All concomitant medications will be managed by the investigator per their standard of care and will be 
recorded on the appropriate eCRFs from Screening/Baseline through end of study. 
Consumption of recommended standard of care analgesic pain regimen post-procedure is as follows; 
• 
10 mg dose dexamethasone intra-operative 
• 
Ibuprofen 800 mg q8hrs 
• 
Hydrocodone/acetaminophen 10/325 mg q4 hrs PRN 
• 
Any modifications to recommended pain regimen will be noted in the eCRF 
9.3. Subject Consent 
Subjects will be consented prior to enrollment in the study before any procedures specific to the study 
are undertaken.  The principal investigator or his/her authorized designee will provide the subjects with 
a description of the device and procedure; risks, benefits, and alternative procedures; length of 
participation required; method and amount of compensation, if applicable; and information regarding 
injury and confidentiality with ample time given to consider their participation in the clinical study. 
Subjects will be informed that their participation in this study is voluntary and they may refuse to 
participate or discontinue from the study at any time. Subjects will be given the opportunity to ask the 
investigator questions so that they are adequately informed about the research. The informed consent 
form must be in a native non-technical language and must be personally signed and dated by subject and 
investigator at time of consent. The principal investigator or his/her authorized designee shall avoid any 
coercion or undue improper influence on, or inducement of, the subject to participate.  The informed 
consent process will be documented in the source records and a copy of the consent will be provided to 
the subject. 
If new information becomes available that may affect a subject’s decision to continue to take part in the 
study, this information will be discussed with the subject by the investigator and new consent will be 
obtained in writing. A revised consent will be first reviewed and approved by Medtronic and the IRB/EC. 
The informed consent form must be personally signed and dated by subject and investigator at time of 

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consent. The informed consent process will be documented in the source records and a copy of the 
consent will be provided to the subject. 
9.4. Randomization and Treatment Assignment 
No randomization will occur during the course of the study. 
9.5. Medication Compliance 
A recommended standard of care analgesic pain regimen is listed in section (9.2). Compliance to this 
regimen will be monitored via the at home survey (EORTC QLQ – H&N35, Appendix A).   
9.6. Assessment of Efficacy 
Procedure time, pain relief, bleeding details patient outcomes and QOL will be recorded in the eCRF and 
used to assess efficacy of the BiZact™ device.  
9.7. Assessment of Safety 
Safety will be assessed by monitoring the occurrence of adverse events (AEs), serious adverse events 
(SAEs), death, adverse device effects (ADE), unanticipated serious adverse device effects (USADE), device 
deficiencies or the presence of focal infection. Assessments will take place during the procedure through 
post-operative day 14 and will be recorded in the eCRF.    
9.8. Recording Data 
This study will utilize an electronic database and eCRF. All data requested on the eCRF are considered 
required. Data points not collected and/or recorded will be considered deviations unless otherwise 
specified. The Principal Investigator or authorized designee(s) must ensure the accuracy and 
completeness of the recorded data and then provide his/her electronic signature on the appropriate 
eCRFs.  The Investigator’s electronic signature for specific eCRFs will be documented in compliance with 
local regulations.  Changes to data previously submitted to the sponsor will require a new electronic 
signature by the Investigator to acknowledge/approve the changes. 
9.9. Deviation Handling 
A study deviation is an event where the Investigator or site personnel did not conduct the clinical study 
according to the Clinical Investigational Plan or Clinical Investigation Agreement. The Investigator is not 
allowed to deviate from the above-mentioned documents except under emergency circumstances to 
protect the rights, safety and well-being of human subjects.  No changes to the protocol will be permitted 
without the written approval from Medtronic, the IRB/EC and Competent Authority. The investigator must 

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notify Medtronic and the reviewing IRB/EC of any deviation, which will be recorded in the eCRF, from the 
Investigational Plan when specific to the protection of the life or physical well-being of a subject in an 
emergency. Such notice must be given as soon as possible, but in no event later than 5 working days after 
the emergency has occurred. Except in such an emergency, prior written approval by Medtronic is 
required for changes in or deviations from the Investigational Plan. If these changes or deviations affect 
the scientific soundness of the Investigational Plan or the rights, safety, or welfare of human subjects the 
IRB/EC will also be notified. All other deviations will be reported per the site’s IRB/EC deviation policy. 
Should any deviations from the Investigational Plan occur, these will be reviewed by Medtronic for their 
clinical significance and identifying any additional corrective and/or preventive actions (e.g. amend the 
CIP, additional training, terminate the study, etc.). Repetitive or serious investigator compliance issues 
may result in the need to initiate a corrective action plan, and in some cases, freeze enrolment or 
ultimately terminate the Investigator’s participation in the clinical study. 
9.10. Screen Failure 
A subject is considered enrolled in the study when ICF is signed, and must be followed regardless of 
whether or not the subject received treatment with the study device unless considered a screen failure 
or withdrawn due to physician decision. Subjects who provide study consent, but then are determined to 
be ineligible prior to study procedure will be considered a screen failure and will not require additional 
study follow-up visits. The reason for the screening failure will be clearly delineated on the applicable 
eCRFs.   
Subjects in whom the procedure is begun but not completed will be considered “discontinued” and will 
be followed until discharge. These subjects will only contribute AE data intraoperatively until discharge 
(no additional follow-up).  
9.11. Subject Withdrawal or Discontinuation  
The reason for study exit, including screen failure, will be documented on the applicable electronic case 
report form (eCRF).  In the event the subject withdraws consent during the study, the date of withdrawal 
will be documented.  If the Study Investigator voluntarily removes a subject from further study 
participation, supporting documentation must be in place for the rationale and date of removal. Follow 
up to subjects withdrawn or discontinued will be deemed by the standard of care for a standard 
tonsillectomy procedure. Every attempt will be made to contact subjects that are noncompliant with study 
procedures.  Subjects will be considered lost to follow-up once the following steps have been taken: 
• 
Two phone calls should be made to the subject.  Each attempt should be clearly documented in 
the source documents and the response or lack thereof should be captured.   

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• 
If there is no response to the phone calls, then an official, certified letter should be written to 
the subject.  A copy of the letter and return or delivery receipts should be retained in the 
subject’s source document. 
• 
Additionally, the site should attempt to reach out to the primary care practitioner to determine 
the status of the subject. 
• 
When all due diligence attempts to contact have been made, after a period of two (2) weeks, 
the subject will be considered Lost to Follow-up.  The Sponsor should be notified and the End of 
Study (EOS) form should be completed.   
9.12. Selection of Investigators  
Surgeons who are qualified by training (board certified in otolaryngology in accordance with US/European 
and hospital guidelines), education, and relevant experience appropriate to the use of the product and 
associated procedures will be considered for participation as investigators in this study. Investigators/sites 
must have adequate time and resources to conduct the study throughout the duration of the study and 
have access to an adequate number of eligible subjects. Investigators/sites must be able to comply with 
applicable Institutional Review Board (IRB)/Ethics Committee (EC) and regulatory requirements. 
Investigator is not debarred, disqualified, or working under sanctions in applicable regions. Qualifications 
are verified through valid CV and current licensing and maintained with study documentation.   
10. Risks and Benefits 
10.1. Potential Risks 
The potential risks associated with the standard tonsillectomy procedure include but are not limited to: 
reaction to anesthesia, swelling, bleeding, infection and pain.  
The potential risks associated with BiZact™ include, but are not limited to: unintended cutting or bruising, 
arcing, pinching, tearing of tissue, inadequate/no seal, pain, bleeding, nausea, vomiting, and headache. 
Results from preclinical testing and the instructions for use (IFU) will be used to mitigate risk.    
Reproductive and developmental toxicology studies in animals to evaluate the potential for AEs on 
reproductive ability and effects on the embryo/fetus have not been conducted.  As with any device, there 
is always a risk of a rare or previously unknown side effect developing from the treatment. 
The risk analysis assumes the system is operated by properly trained personnel.  The overall residual risk 
after design risk mitigation strategies and/or design control was deemed acceptable in the Risk 
Management Report for the BiZact™ system.  

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10.2. Potential Benefits 
The potential benefits associated with BiZact™ device usage include, but are not limited to: reduction in 
pain and decreased time to return to normal diet and activity post tonsillectomy procedure. 
10.3. Risk-Benefit Rationale 
Post-operative pain and delayed time to normal diet and activity are common challenges after 
tonsillectomy procedures. Aside from conventional cold steel and electrocautery dissection, the 
introduction of numerous energy based tools and techniques allow for the simultaneous dissection and 
sealing of vessels significantly improving safety and reducing the complications of the procedure. In 
most cases however, these energy based devices use heat to establish hemostasis, which can lead to 
lateral heating and damage to adjacent structures delaying wound healing and increasing post-operative 
pain.  
A positive risk/benefit ratio has been demonstrated with BiZact™ as evidenced by preclinical and 
biocompatibility testing. BiZact™ was safely tolerated in animals and there were no apparent adverse 
systemic or local effects in any of the preclinical studies. BiZact™ is also based off Ligasure™ technology 
which historically has been shown to be safe and effective for tonsillectomy procedures providing 
adequate hemostasis while minimizing postoperative pain. 
The product design, as well as the results of these studies, shows that BiZact™ is a promising class 2 FDA 
and CE-mark approved product. Consequently, with respect to performance and safety, BiZact™ 
presents a favorable risk/benefit ratio to the subject. Results from preclinical testing, the device 
instructions for use (IFU) and experienced surgeons will be used to mitigate risk. There are currently no 
known interactions between the BiZact™ device and concurrent medical interventions.  
11. Adverse Events and Device Deficiencies 
Adverse event (AE) definitions used in this study are based on ISO 14155:2011 (Clinical Investigation of 
Medical Devices for Human Subjects -- Good Clinical Practice).  
11.1. Definitions/Classifications 
11.1.1. 
Adverse Event (AE) 
In alignment with ISO 14155:2011 (Section 3.2), an Adverse Event is any 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.  

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This definition includes events related to the investigational medical device and the procedures involved. 
For users or other persons, this definition is restricted to events related to investigational medical devices. 
For study purposes, the following occurrences are considered to be expected observations and will not 
be considered reportable Adverse Events, as long as the event is not associated with significant sequelae, 
does not prolong hospitalization and responds to standard medical therapy: 
• 
Postoperative transient nausea determined to be procedure and/or medication related. 
• 
Postoperative transient emesis determined to be procedure and/or medication related. 
• 
Postoperative inflammation determined to be a part of every healing process. 
• 
Postoperative headaches determined to be procedure and/or medication related. 
• 
Postoperative constipation determined to be procedure and/or medication related. 
• 
Postoperative pain that the Investigator considers common and within normal limits for the 
procedure and is well-managed with medication. 
o Pain that the investigator considers outside normal, or is not well-managed with 
medication, as well as pain that is severe (score 7 or higher on the VAS) and ongoing at 
the end of study will be reported as an AE in the eCRFs. 
 
AEs will be collected and documented at baseline and 0 to 14 days follow-up. 
11.1.2. 
Serious Adverse Event (SAE) 
In alignment with ISO 14155:2011 (Section 3.37), a serious adverse event (SAE) is any AE that has: 
• 
led to death, 
• 
led to serious deterioration in the health of the subject that either resulted in 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient or prolonged hospitalization, or 
o medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function, or 
• 
led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
NOTE: Planned hospitalization for a pre-existing condition or a procedure required by the clinical 
investigational plan, without serious deterioration in health, is not considered an SAE. 
SAEs will be collected and documented at baseline and 0 to 14 days follow-up. 

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11.1.3. 
Adverse Device Effect (ADE) 
In alignment with ISO 14155:2011 (Section 3.1), an Adverse Device Effect is an adverse event related to 
the use of an investigational medical device.  
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical 
device. 
This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device. 
Adverse Device Effects will be reported by the Investigator(s). If escalation is required, ADEs will be 
reviewed by medical affairs as part of Medtronic’s Post-Market Vigilance program. Both confirmed and 
possible device related events will be included in the study report. 
Examples of adverse device effects include but are not limited to: unintended cutting, unintended 
electrical path, fire or explosion, or arching.  
ADEs will be collected and documented at baseline and 0 to 14 days follow-up. 
11.1.4. 
Serious Adverse Device Effect (SADE) 
In alignment with ISO 14155:2011 (Section 3.36), a Serious Adverse Device Effect is an adverse device 
effect that has resulted in any of the consequences characteristic of a serious adverse event. 
SADEs will be collected and documented at baseline and 0 to 14 days follow-up. 
11.1.5. 
Unanticipated Serious Adverse Device Effect (USADE) 
In alignment with ISO 14155:2011 (Section 3.42), an Unanticipated Serious Adverse Device Effect is a 
serious adverse device effect which by its nature, incidence, severity, or outcome has not been identified 
in the current version of the risk analysis report.  
NOTE: Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
USADEs will be collected and documented at baseline and 0 to 14 days follow-up. 

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11.1.6. 
Adverse Event Severity Classification 
Severity will be defined according to the following criteria: 
Mild 
Awareness of event, but easily tolerated 
Moderate 
Discomfort enough to cause some interference with activities of daily living (ADL) 
Severe 
Incapacitating, with an inability to perform ADL 
Death 
Death related to AE 
An AE can be classified as severe and not deemed an SAE. Similarly, an SAE is not automatically severe 
in nature. 
11.1.7. 
Adverse Event Relationship Classification 
Causality assessments define the relationship between the use of the medical device (including the 
medical-surgical procedure) and the occurrence of each adverse event, according to MEDDEV (Guidelines 
on Medical Devices, Clinical Investigations: Serious Adverse Event Reporting). The presence of 
confounding factors, such as concomitant medication/treatment, the natural history of the underlying 
disease, other concurrent illness or risk factors shall also be considered. 
Each SAE will be classified according to five different levels of causality. The sponsor and the investigators 
will use the following definitions to assess the relationship of the serious adverse event to the 
investigational medical device or procedures: 
Not related:  relationship to the device or procedures can be excluded when: 
1. the event is not a known side effect of the product category the device belongs to or of similar 
devices and procedures 
2. the event has no temporal relationship with the use of the device or the procedures; 
3. the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 
4. the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or increase of the 
level of activation/exposure), do not impact on the serious event; 
5. the event involves a body-site or an organ not expected to be affected by the device or 
procedure; 
6. the serious event can be attributed to another cause (e.g. an underlying or concurrent illness/ 
clinical condition, an effect of another device, drug, treatment or other risk factors); 
7. the event does not depend on a false result given by the device used for diagnosis, when 
applicable; 
8. harms to the subject are not clearly due to use error; 

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9. In order to establish the non-relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
Unlikely: the relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
Possible:  the relationship with the use of the device is weak but cannot be ruled out completely. 
Alternative causes are also possible (e.g. an underlying or concurrent illness/ clinical condition or/and an 
effect of another device, drug or treatment). Cases were relatedness cannot be assessed or no 
information has been obtained should also be classified as possible. 
Probable:  the relationship with the use of the device seems relevant and/or the event cannot 
reasonably explained by another cause, but additional information may be obtained. 
Causal relationship: the serious event is associated with the device or with procedures beyond 
reasonable doubt when: 
1. the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
2. the event has a temporal relationship with device use/application or procedures; 
3. the event involves a body-site or organ that 
a. the device or procedures are applied to; 
b. the device or procedures have an effect on; 
4. the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known); 
5. the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
6. 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; 
7. harm to the subject is due to error in use; 
8. the event depends on a false result given by the device used for diagnosis, when applicable; 
9. In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event. 
The Sponsor and the Investigators will distinguish between the serious adverse events related to the 
device and those related to the procedures (any procedure specific to the clinical investigation). An 
adverse event can be related both to procedures and the device. Complications of procedures are 
considered not related if the said procedures would have been applied to the subjects also in the absence 
of device use/application. 

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In some particular cases the event may be not adequately assessed because information is insufficient or 
contradictory and/or the data cannot be verified or supplemented. The sponsor and the Investigators will 
make the maximum effort to define and categorize the event and avoid these situations. Where the 
sponsor remains uncertain about classifying the serious event, it should not exclude the relatedness and 
classify the event as “possible”.  
Particular attention shall be given to the causality evaluation of unanticipated serious adverse (device) 
events. The occurrence of unanticipated events related to the use of the device (USADE) could suggest 
that the clinical investigation places subjects at increased risk of harm than was to be expected 
beforehand. 
11.1.8. 
Adverse Event Outcome Classification  
Outcome of the event will be defined according to the following: 
• 
Fatal: This event is determined to be the cause of death.  
• 
Not Recovering/Not Resolved: The event has retained pathological conditions resulting from the 
prior disease or injury. 
• 
Recovered/Resolved: The event has fully resolved at the end of the study. 
• 
Recovering/Resolving: The event is ongoing at the end of the study. 
• 
Unknown: The event has been unclassified at the end of the study. 
11.2. Reporting of Adverse Events 
The following events are generally considered reportable during the course of this study and should be 
reported in a timely manner to the sponsor: 
• 
any ADE, SADE, SAE, or USADE 
• 
any Device Deficiency that might have led to an SADE if  
• 
suitable action had not been taken or  
• 
intervention had not been made or  
• 
if circumstances had been less fortunate  
• 
new findings/updates in relation to already reported events 
 
Events will be reviewed by the sponsor to determine any reporting obligations to National Competent 
Authorities and IRBs/ECs.  
SAEs need to be reported to the sponsor within 24 hours of becoming aware. 

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11.3. Adverse Event Recording  
Assessment of the occurrence of an AE will be based on changes in the subject’s physical examination, 
laboratory results and/or signs and symptoms. Adverse events will be monitored until a subject completes 
the study unless the Investigator determines the event is related to the device, in which case they will be 
monitored until resolution if possible. Medical care will be provided, as defined in the informed consent, 
for any AE related to study participation. Adverse events will be collected on an AE eCRF and applicable 
source documentation. To the extent possible, the event to be recorded and reported is the event 
diagnosis as opposed to event symptoms (e.g., fever, chills, nausea and vomiting in the presence of a 
clinically diagnosed infection is to be reported as infection only). For the purposes of this protocol, AEs 
will collected and documented in a timely manner at baseline and 0 to 14 days follow-up. 
The following should not be considered an AE: 
• 
A condition requiring a preplanned procedure unless the condition worsened since screening 
• 
A preexisting condition found as a result of screening, unless the condition has worsened since 
enrollment. 
All responses to the above events that require treatment beyond the institution’s standard procedures 
will be reported as AEs. 
All AEs observed during the course of this study, regardless of severity or relationship to the device will 
be recorded on the appropriate eCRF except for what is noted in Section 11.1.1. 

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11.4. Study Contact Information 
Questions regarding safety or medical procedures should be directed to Medtronic MITG Medical Affairs. 
All other questions should be directed to Medtronic MITG Surgical Innovations, Clinical Research. 
Clinical Research 
Medical Affairs 
Kelley Kennedy 
Director, Clinical Research 
Medtronic 
MITG Surgical Innovations 
555 Long Wharf Drive 
New Haven, CT 06511 USA 
Phone: (001 if Ex-US) 203-821-4743 
Kelley.e.Kennedy@Medtronic.com 
Matthew Savary, MD 
Associate Director of Medical Affairs  
Medtronic 
MITG Surgical Innovations 
5920 Longbow Dr.  
Boulder, CO 80301 USA 
Phone: (001 if Ex-US) 203-530-1395 
Matthew.Savary@medtronic.com 
11.5. Device Deficiencies 
In alignment with ISO14155:2011 (Section 3.15), a Device deficiency is an inadequacy of a medical device 
related to its identity, quality, durability, reliability, safety or performance, such as malfunction, misuse or 
use error and inadequate labeling. 
All BiZact™ device deficiencies will be documented on the appropriate Device malfunction eCRF and the 
device should be returned to Medtronic for analysis, if possible.  Instructions for returning the device will 
be provided.  Device deficiencies should also be documented in the subject’s medical record. 
Device deficiencies are NOT to be reported as AEs.  However, if there is an AE that results from a device 
deficiency, that specific event would be recorded on the appropriate eCRF. 
12. Data Review Committees  
There will be no use of data review committees in this study.  Instead, a steering committee and an 
internal safety review committee will monitor the trial’s progress including trends of data over time and 
scientific relevance of the data collected. Please see section 15.10 on the review of data for this study. 
These groups will provide oversight in terms of scientific validity and the safe conduct of the study.  
By nature, this study’s focus is about the level of post-operative pain.  Additionally, this is a study of two 
sites with forty-eight subjects, with no planned interim analysis, and as such, has a less burden in terms 
of severity of implications, and degree of data review and analysis compared to a larger study with 
interim data review needs or a study focusing on severe complications or mortality. Per FDA guidance 
(OMB Control No 0910-0581 “The Establishment and Operation of Clinical Trial Data Monitoring 
Committees for Clinical Trial Sponsors” Data Monitoring Committees (DMCs) are “generally 

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recommended for any controlled trial of any size that will compare rates of mortality or major morbidity 
but a DMC is not required or recommended for most clinical studies.” The guidance goes on to list 
conditions wherein a DMC may offer additional protections to study participants. This study does not 
meet any of the criteria listed wherein a DMC would provide added benefit.  
13. Statistical Design and Methods 
13.1. Statistical Test Methods 
Continuous variables will be summarized using counts, means, standard deviations, medians, minimum 
and maximum. Categorical variables will be summarized using frequencies and percentages. Changes to 
the planned statistical analysis as defined in the protocol will be documented in the statistical analysis 
plan and clinical study report. 
13.2. Sample Size Determination 
This study does not have a statistically powered hypothesis. There will be no sample size calculations 
since the study is not hypothesis-driven. The number of enrolled subjects is pre-defined at a minimum 
of 48, which is adequate to reflect the study purposes. All the results will be summarized in a descriptive 
manner which will be further defined in the statistical analysis plan with the following measures utilized: 
• 
Mean, standard deviations, medians, minimum and maximum for quantitative variables. 
• 
Numbers and percentages for qualitative variables. 
13.3. Analysis Populations 
The analyses will be done based on the subjects who are enrolled and have the intended procedure. 
13.4. Statistical Analysis of Endpoints 
13.4.1. 
Primary Endpoint 
To assess pain, pain levels will be captured at post-operative days 1-7, 10, and 14 for each subject using 
the VAS. For each defined post-operative time point, paired tests will be used to test whether there is a 
mean change along the follow-up.  
13.4.2. 
Secondary Endpoints 
To assess procedure details, operative time and intra-operative bleeding volume a sample value and 
margin of error (95% confidence level) will be calculated.  

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Incidence of post-operative hemorrhage, and post-operative readmission will be summarized using 
frequency and percentages. 
13.5. Statistical Analyses of Safety Endpoints 
• 
Focal Infection 
• 
Other intra/post-operative complications (complications related to device deficiency) 
• 
Incidence and severity of adverse events 
13.6. Handling of Missing Data 
No data imputation will be performed for missing data.  All practical monitoring and follow-up steps will 
be taken to ensure complete and accurate data collection. Since endpoints are assessed intra-operatively, 
it is anticipated that there will be minimal missing data for these endpoints.  
13.7. Interim Analysis 
Currently no interim analysis is planned for this study however this is subject to change. 
14. Ethics 
14.1. Statement(s) of Compliance  
This clinical investigation will be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki 2013, the clinical trial agreement and any regional or national regulations 
such as FDA regulations (US) or ISO 14155:2011 (EU), as appropriate. All principles of the Declaration of 
Helsinki have been implemented in this clinical study by means of the patient informed consent process, 
IRB/EC approval, clinical study training, clinical study registration, publication policy.  
The clinical investigation will not begin until all necessary approvals/favorable opinions are obtained from 
the appropriate IRB/EC or regulatory authority, as appropriate.  Should an IRB/EC or regulatory authority 
impose any additional requirements, they will be followed.  Information regarding the study and study 
data will be made available via publication on clintrials.gov.   
15. Study Administration 
15.1. Monitoring  
Site visits will be conducted by an authorized Medtronic representative to monitor study data, subjects’ 
medical records, and eCRFs in accordance with current applicable regulations and standards and the 

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respective local and national regulations and guidelines (if applicable). The Study Investigator and the 
investigating site will permit authorized clinical research personnel and clinical monitors employed by 
Medtronic to review completed eCRFs, IRB/EC decisions, and Investigator and clinical site records at 
regular intervals throughout the study as well as permit study-related monitoring, audits, IRB/EC review, 
and regulatory inspection(s) by providing direct access to source data/documents. Additionally, subject 
charts and clinical records will be requested and reviewed so that protocol adherence and source 
documentation can be verified. In instances where data protection regulations prohibit the direct 
examination of hospital records by the study Sponsor or designee(s), the Investigator will cooperate in a 
system of source data verification with the Sponsor.  Monitoring, including site initiation visits, interim 
monitoring visits, and closeout visits may be performed with in person visits or remotely, when applicable. 
To ensure the rights, safety, and welfare of study subjects are being maintained, the monitor will maintain 
assurance that all study staff are trained on the study protocol and use of the study devices.  If the monitor 
discovers that an investigator is not complying with the signed Investigator Agreement, the Investigational 
Plan, applicable laws, or any conditions of approval imposed by the reviewing IRB/EC, the monitor will 
report to the Sponsor and take such steps necessary to promptly secure compliance.  If compliance cannot 
be secured, device shipments to the investigator may be discontinued and the investigator’s participation 
in the investigation terminated. The monitor shall also require such an investigator to dispose of or return 
the device, unless this action would jeopardize the rights, safety, or welfare of a subject. 
15.2. Data Management 
Visual and/or computer data review will be performed to identify possible data discrepancies.  The 
investigator will clearly mark clinical record to indicate that the subject is enrolled in this clinical 
investigation (in regions where applicable). Where copies of the original source document as well as print 
outs of original electronic source documents are retained, these shall be signed and dated by a member 
of the investigation site team with a statement that it is a true reproduction of the original source 
document.  Manual and/or automatic queries will be created in the Oracle remote data capture (RDC) 
system and will be issued to the site for appropriate response.  The site staff will be responsible for 
resolving all queries in the database. Medications will be coded under the WHO dictionary while Medical 
History, Surgical History and/or Adverse Events will be coded in Medical Dictionary for Regulatory 
Activities (MedDRA). 
This study will be using a 21 CFR Part 11 compliant electronic data capture system. All system level 
validation documentation is retained within the Information Systems group. 

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15.3. Direct Access to Source Data/Documents  
Investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/EC review, and regulatory 
inspection(s), and provide direct access to source data/documents as per local policies and regulations.  
15.4. Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the applicable 
laws and/or regulations, will not be made publicly available.  
Subject names will be kept confidential. Only the subject number will be recorded in the eCRF, and if the 
subject name appears on any other document, it must be obliterated. In cases were the local law does 
not allow using the subject initials, an identifying number will be assigned. Study findings stored on a 
computer will be stored in accordance with local data protection laws. The subjects will be informed in 
writing that representatives of the sponsor, IRBs/ECs, or Regulatory Authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for inspection 
will be handled in strictest confidence and in accordance with local data protection laws. Subjects will also 
be informed that information regarding the study that does not include subject identifiers will be posted 
on clinicaltrials.gov. 
If the results of the trial are published, the subject’s identity will remain confidential.  
The investigator will maintain a master list to enable subjects’ records to be identified. 
15.5. Liability 
Medtronic 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 study insurance statement/certificate will be provided to the EC.  
Covidien Services Europe 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 study insurance statement/certificate will be provided to the EC. 
15.6. CIP Amendments 
A CIP amendment will be prepared when there are revisions that are significant changes or corrections, 
or modifications that impact subject safety, ethical conduct, data integrity or trial design. CIP amendments 
must undergo review and approval by the sponsor, IRB/EC and any appropriate regulatory authority, and 
will be logged in the document version history (Section 18). IRB/EC approval, regulatory authority 

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approval, site training and a new Acknowledgement form will be signed and returned before any new 
procedures take place. 
15.7. Record Retention 
The investigator and the sponsor will maintain the records of the study including all pertinent 
correspondence, the study protocol with any/all amendments, all correspondence with and approval from 
the IRB/EC, the clinical trial agreement, the Investigator Agreement, device accountability records, 
individual subject records, and signed informed consent forms. Subject files, other source data and 
essential documentation kept in the Investigator study files, must be kept for a period of not less than 2 
years after the latter of the following two dates:  the date on which this investigation is terminated or 
completed, or the date that the records are no longer required for purposes of supporting a premarket 
application. Records may need to be maintained by the Principal Investigator for a longer duration if 
national regulations require or if agreed to in writing with Medtronic. All data and documents should be 
made available if requested by relevant authorities. 
15.8. Publication and Use of Information 
The Medtronic Publication and Authorship Policy is aligned with the International Committee of Medical 
Journal Editors (ICMJE) recommendations (www.icmje.org). Medtronic will seek to publish, in appropriate 
peer-reviewed journals and scientific conferences, results of clinical studies where human subjects are 
involved, regardless of outcome. While study results are owned by Medtronic, all data on which a 
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 provided that 
such publication or use is in accordance with this this protocol, the Medtronic Publication and Authorship 
Policy, and the Clinical Investigation Agreement. Investigators must submit a copy of all manuscripts 
and/or abstracts to Medtronic for review and comment 30 days prior to planned submission. Medtronic 
acknowledges that its right to review and comment shall relate solely to the proprietary, licensing, and/or 
confidential rights Medtronic may have in such proposed publication, rather than whether such results 
and/or opinions are favorable to Medtronic. 
The publication of post-hoc analyses, regional results, or single-center experiences based on multicenter 
clinical studies should not precede that of the primary multicenter publication, and should cite the primary 
publication whenever possible, as required by specific journal and scientific meeting guidelines.  
Medtronic 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 International Committee of Medical Journal Editors. Authors must ensure that an 

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acknowledgement/disclosure statement is included in the body of the manuscript for Medtronic 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. 
To enable health care providers, payers, and subjects access to the wealth of Medtronic’s research, 
Medtronic will report its scientific data in accordance with the principles outlined in the Guidance 
Document on Registration and Reporting Results of Company-Sponsored Clinical Trials Under FDAAA 2007 
(Title VIII).  
15.9. Suspension or Early Termination 
Medtronic or appropriate regulatory authorities reserve the right to suspend or discontinue the study at 
any stage, with written notice to all investigators, all institutions, all reviewing IRBs (US), any 
investigator(s) in communication with the EC (EU), all subjects and subjects’ personal physicians and any 
applicable regulatory agencies. Similarly, investigators may withdraw from the study at any time, subject 
to providing written notification to Medtronic 30 days prior to the date they intend to withdraw. However, 
Medtronic 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 protocol, and 
information obtained during subject follow-up shall be reported to Medtronic on the appropriate eCRF. 
15.10. Safety Committees 
The Sponsor will employ a comprehensive safety plan for this study comprised of the following 
components: Independent Medical Monitor and Steering Committee. 
15.10.1. Independent Medical Monitor 
The Sponsor will utilize an Independent Medical Monitor to provide an independent medical review and 
adjudication of pre-specified adverse events in support of protocol defined endpoint data. The 
Independent Medical Monitor will be a qualified, board-certified otolaryngology surgeon that is not 
affiliated with an investigative center.  
During the review of adverse events, the Independent Medical Monitor will be blinded to the treatment 
and investigational site. 
15.10.2. Steering Committee  
The Steering Committee will consist of Investigators participating in this study, as well as relevant 
members of Medtronic Clinical and Medical Affairs. The role of the Steering Committee is to make 
recommendations on the design and conduct of the study, the analysis of data, and the communication 

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of results in alignment with the Medtronic Publication and Authorship Policy. The Steering Committee will 
also review aggregate adverse event data on an as needed basis, as described in the Steering Committee 
Charter. 
16. References 
1. 
Younis RT, Lazar RH. History and current practice of tonsillectomy. Laryngoscope. 2002;112(8 Pt 
2 Suppl 100):3-5. doi: 10.1002/lary.5541121403. PubMed PMID: 12172228. 
2. 
Timms MS, Temple RH. Coblation tonsillectomy: a double blind randomized controlled study. J 
Laryngol Otol. 2002;116(6):450-2. doi: 10.1258/0022215021911031. PubMed PMID: 12385358. 
3. 
Karatzias GT, Lachanas VA, Sandris VG. Thermal welding versus bipolar tonsillectomy: a 
comparative study. Otolaryngol Head Neck Surg. 2006;134(6):975-8. doi: 10.1016/j.otohns.2006.03.003. 
PubMed PMID: 16730541. 
4. 
Sinha UK, Gallagher LA. Effects of steel scalpel, ultrasonic scalpel, CO2 laser, and monopolar and 
bipolar electrosurgery on wound healing in guinea pig oral mucosa. Laryngoscope. 2003;113(2):228-36. 
doi: 10.1097/00005537-200302000-00007. PubMed PMID: 12567074. 
5. 
Prokopakis EP, Lachanas VA, Benakis AA, Helidonis ES, Velegrakis GA. Tonsillectomy using the 
Ligasure vessel sealing system. A preliminary report. Int J Pediatr Otorhinolaryngol. 2005;69(9):1183-6. 
doi: 10.1016/j.ijporl.2005.03.042. PubMed PMID: 15961165. 
6. 
Lachanas VA, Prokopakis EP, Bourolias CA, Karatzanis AD, Malandrakis SG, Helidonis ES, et al. 
Ligasure 
versus 
cold 
knife 
tonsillectomy. 
Laryngoscope. 
2005;115(9):1591-4. 
doi: 
10.1097/01.mlg.0000172044.57285.b6. PubMed PMID: 16148700. 
 

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17. Appendices  
17.1. APPENDIX A: Post-operative home survey forms  
Subjects will receive a minimum of 9 copies of the following survey, and be asked to fill out the survey on 
post-operative days 1-7, 10 and 14 to assess their return to normal diet and activity. All surveys will be 
returned during their 14 day post-operative follow-up visit.  

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17.1.1. 
EORTC QLQ-H&N35 (English) 
 

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17.1.2. 
EORTC QLQ-H&N35 (Spanish) 
 

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17.1.3. 
EORTC QLQ-H&N35 (Swedish) 
 
 
 

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17.2. APPENDIX B: Visual Analogue Scale (VAS) 
Subjects will receive at least nine copies of the VAS scale (below) where the lines are printed exactly 10cm 
in length. Prior to the subject receiving the scale, the subject ID will be written on the pages. On post-
operative days 1 through 7, 10 and 14, each day the subjects will be instructed to place a vertical mark on 
the line, along with the date and time, to indicate their degree of pain. Rulers will be provided to each site 
and after their return on post-operative day 14 (+3), the vertical marks will be rounded to the nearest 
whole centimeter and entered into the eCRF. Marks which fall directly between two whole numbers will 
be rounded to the larger number; i.e. 3.5 would be rounded to 4.      
 
 
 
 

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17.3. APPENDIX C: List of Investigators and Institutions 
Investigator 
Institution Address 
Dr. Ron Karni, MD 
University of Texas Health Science Center – Houston 
Memorial Hermann 
6400 Fannin Street #2700 
Houston, TX  77030 
USA 
 
Dr. Per Attner, MD, PhD 
Sophiahemmet Hospital 
ENT Department 
Valhallavägen 91 
11486, Stockholm 
Sweden 
 

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18. Version History 
Version 
Summary of Changes 
Author(s)/Title 
1.0 
• 
New Document 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Sections reordered per CIP template 056-F275 
(Table of Contents) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
 
• 
Local Sponsor for EU CAE added and Coordinating 
Investigator removed from Clinical Investigation 
Plan cover page   
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Added ISO 14155:2011 and location specificity to 
Investigator Statement (Section 2)  
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Updated Primary Objective and added Post-
market interventional to Clinical Study Type, 
Primary Endpoint, Secondary Endpoints and 
Secondary   Objectives to Synopsis (Section 4).  
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Sample size revised to “a minimum of 48” 
throughout document  
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Updated the definition of Hemostasis in the 
Glossary (Section 3) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Deleted “or the legally authorized representative” 
from Inclusion Criteria (Sections 4 and 9.3)  
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Additional detail regarding justification, rationale 
and summary of clinical evaluation added to 
Background (5.1)  
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Secondary Objectives added to Section 6.1.2 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Additional details were added to Rationale 
(Section 7.2) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
V1.2 software was added to LS10 description in 
General Product Description (Section 8.1) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 

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1.1 
• 
“lot number” changed to “serial number” in 
Product Receipt and Tracking (Section 8.7) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Added 
“(room 
temperature)” 
to 
Product 
Accountability (Section 8.8) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Added “the sponsor and” , “(+3)”, and “for the full 
14  days follow-up” to Subject Enrollment (Section 
9.2) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
‘Device Accountability’ removed from Study 
Schematic (Section 10.1.1) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
QOL 
home 
survey 
removed 
from 
Screening/Baseline in Study Schematic (Section 
10.1.1) and Screening/Baseline Visit section 
(10.1.2) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
 “Return to clinic follow-up visit” added to ‘14 
days’ in study schematic (Section 10.1.1) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Added “Protocol deviation collection” to Study 
Schematic (Table 1, Section 10.1.1) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Screening/Baseline Visit (Section 10.1.2) was 
edited for clarity and consistency 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
“(+3) days” and “Post-operative bleeding – Any 
bleeding that occurs, from the presence of blood 
in saliva to bleeding that requires re-operation” 
added to Post-Operative Follow-up: Days 1 
through 7, Day 10 and Day 14 (Section 10.1.4) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Subject Consent (Section 10.2) was updated for 
clarity and consistency 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Details of Assessment of Efficacy (Section 10.4) 
were added 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Medication Compliance section was added 
(Section 10.3) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Assessment of Safety section was added (Section 
10.5) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 

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1.1 
• 
“or authorized designee(s)” was added to 
Recording Data (Section 10.6) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Deviation Handling section edited for clarity 
(Section 10.7) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Additional 
detail 
added 
to 
Selection 
of 
Investigators (Section 10.10) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Risks of tonsillectomy procedure added to 
Potential Risks (Section 11.1) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Potential Benefits section added (Section 11.2) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Additional details added to Risk-Benefit Rationale 
(Section 11.3) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
“which is aligned with MEDDEV 2.7/3 Revision 3, 
May 2015 (Guidelines on Medical Devices, Clinical 
Investigations: Serious Adverse Event Reporting).” 
was removed from Adverse Event Assessments 
(Section 12) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
References to ISO 14155:2011 added to Adverse 
Event Assessment definitions (Sections 12.1.1 to 
12.1.5 and 12.5 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Removed “During causality assessment activity, 
clinical judgment shall be used and the relevant 
documents, such as the Clinical Evaluation Report 
and the Risk Management Report shall be 
consulted, as all the foreseeable serious adverse 
events and the potential risks are listed and 
assessed there.“ from Adverse Event Relationship 
Classification (Section 12.1.7) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Removed “Reporting to National Competent 
Authorities will occur within the timelines 
described in the study Safety Plan.” And added 
“SAEs need to be reported to the sponsor within 
24 hours of becoming aware.” to Reporting of 
Adverse Events (Section 12.2) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Sample size Determination (Section 14.2) edited 
for clarity and consistency 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 

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1.1 
• 
Added Interim Analysis (Section 14.7) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
“Changes to the planned statistical analysis as 
defined in the protocol will be documented in the 
statistical analysis plan and clinical study report.” 
Added to Statistical Test Methods (Section 14.1) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Statistical Primary and Secondary Endpoint 
sections were edited for clarity (14.4.1-2) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Interim Analysis edited for clarity in Synopsis and 
Interim Analysis (Sections 4 and 14.7) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Statements of Compliance (Section 15.1) edited 
for clarity  
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Protocol Compliance (Section 15.2) edited for 
clarity  
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Added “Medtronic 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 
study 
insurance 
statement/certificate will be provided to the EC.” 
to Liability (Section 15.3) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
“Site visits will be conducted by an authorized 
Medtronic representative to inspect study data, 
subjects’ 
medical 
records, 
and 
eCRFs 
in 
accordance with current ICH GCPs and the 
respective 
local 
and 
national 
government 
regulations and guidelines (if applicable).” and “as 
well as permit study-related monitoring, audits, 
MEC/IRB review, and regulatory inspection(s) by 
providing 
direct 
access 
to 
source 
data/documents.” Added to Statement(s) of 
Compliance (Section 16.1)  
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
“and initials” was deleted from Confidentiality 
(Section 16.4) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
CIP Amendments edited for clarity (Section 16.5) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 

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1.1 
• 
Record Retention (Section 16.6) edited for clarity 
and additional detail  
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Publication and Use of Information edited for 
clarity (Section 16.7) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Suspension or Early Termination edited for clarity 
and updated for suspension of study (Section 16.8) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Safety Committees (Section 16.9) edited for clarity Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Steering Committee (Section 16.9.2) was edited 
for clarity 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Removed “Subjects will also be asked to complete 
the form prior to the procedure on Day 0)” 
(Section 18.1) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
“subject’s name” replaced with “subject ID” and 
“(+3)” in Appendix B (Section 18.2) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
EORTC QLQ H&N35 (Spanish) added to Section 
18.1.2 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
1.1 
• 
Added “List of Investigators and Institutions” 
section (Section 18.3) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
2.0 
• 
Updated Study Schematic Screening/Baseline Days 
(Section 10.1.1) and Screening/Baseline Visit 
(Section 10.1.2) to allow for screening to take 
place on the procedure day 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
2.0 
• 
Pre-operative 
procedure 
specific 
physical 
examination moved from Screening/Baseline Visit 
(Section 10.1.2.) to Surgical Procedure (Section 
10.1.3) and added to Study Schematic (Section 
10.1.1) 
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
2.0 
• 
Visual Analog Scale (VAS) image replaced and text 
updated (Section 18.2)  
Nicholas Paquette, Ph.D. 
Senior Medical Writer, Scientific 
Communications 
3.0 
• 
Clarify age of adult in the US (≥22) and Europe 
(≥18) (Section 5.1, 5.2, 6.1.1, 7.2, 9.1, 9.3, 10.1.1 
and Synopsis) 
Caitlin Gibbons, Clinical Study 
Manager 

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3.0 
• 
Remove 
“non-elective” 
under 
tonsillectomy 
inclusion criteria (Section 9.1, 9.3 and Synopsis) 
Caitlin Gibbons, Clinical Study 
Manager 
3.0 
• 
Remove Elective Tonsillectomy exclusion criteria 
(Section 9.4 and Synopsis) 
Caitlin Gibbons, Clinical Study 
Manager 
3.0 
• 
Clarify urine pregnancy tests are only for females 
in the United States (Section 10.1.1. 10.1.2, Study 
Schematic and Synopsis) 
Caitlin Gibbons, Clinical Study 
Manager 
4.0 
• 
Transferred to 056-F275 Clinical Investigation Plan 
Template 
v3.0 
and 
updated 
all 
revised 
Section/Appendix references throughout the 
document (Summary of Changes moved to end of 
document, Additional headings in Sections 7 & 9) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Corrected 
Local 
Sponsor/Authorized 
Representative Address (Cover Page, Section 1, 3 
and 15.5) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Compliance Statement revised (Section 1 and 
14.1) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Clarified Statistical Tests (Section 3 and 13.4.1) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Clarified Device Deficiencies (Section 3, 5.2.3, and 
9.7) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Aligned purpose with Synopsis and described 
publication intent (Section 4.2) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Clarified timeline of Primary Endpoint (Section 
5.2.1) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Modified Reference to VAS and QoL (Section 6.1, 
9.1.4, and 9.5) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Added device deficiencies to Table 1 (Section 9.1.) Luciano Mazzaro, Clinical Study 
Manager & 

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Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Added additional ISO14155 elements to subject 
consent (Section 9.3) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Added Deviation definition and escalation of 
repetitive non-compliance (Section 9.9) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Clarified when to follow subjects (Section 9.10) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Add AE Reporting guidelines (Section 11.1.1) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0  
• 
Clarified Adverse Event Recording (Section 11.3)  
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Revised Clinical Research point of contact (Section 
11.4) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Clarified phone number for ex-US callers (Section 
11.4) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Added rationale for not using a Data Review 
Committee (Section 12) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Removed Protocol Compliance section (Section 
14.2) as it is duplicated in Section 9.9 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Clarifications made to Monitoring responsibilities 
(Section 15.1) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 

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4.0 
• 
Clarified documentation in clinical records and use 
of original electronic records as source (Section 
15.2) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Added Covidien Services Europe Liability language 
(Section 15.5) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Added Swedish EORTC QLQ-H&N35 (Section 
17.1.3) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
4.0 
• 
Added List of Investigators and Institutions 
(Section 17.3) 
Luciano Mazzaro, Clinical Study 
Manager & 
Nicole Brini, Clinical Research 
Specialist 
 

This document is electronically controlled. Printed copies are considered uncontrolled. 
Confidential 
Page 1 of 20 
 
 
 
  
Statistical Analysis Plan 
Clinical Investigation Plan Title 
A prospective, multi-center, single arm non-
comparative pilot study of BiZact™ on adults 
undergoing tonsillectomy. 
Clinical Investigation Plan Identifier COVBZTS0562 
Clinical Investigation Plan Version CIP_V4.0 Final 13MAR2018 
Sponsor/Local Sponsor Medtronic 
Minimally Invasive 
Therapies Group 
5920 Longbow Dr. 
Boulder, CO 80301 
Document Version SAP v3.0 Final 
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.  

This document is electronically controlled. Printed copies are considered uncontrolled. 
Confidential 
Page 2 of 20 
 
 
 
Table of Contents 
 
 
1. 
Version History .......................................................................................................................................... 4 
2. 
List of Abbreviations and Definitions of Terms .......................................................................................... 5 
3. 
Introduction ............................................................................................................................................... 5 
4. 
Study Objectives ........................................................................................................................................ 6 
5. 
Investigation Plan....................................................................................................................................... 7 
 
Inclusion criteria ............................................................................................................................... 7 
 
Exclusion criteria ............................................................................................................................... 7 
6 
Determination of Sample Size .................................................................................................................... 8 
7 
Statistical Methods .................................................................................................................................... 8 
 
Study Subjects ................................................................................................................................... 8 
7.1.1 
Disposition of Subjects .................................................................................................................. 8 
7.1.2 
Clinical Investigation Plan (CIP) Deviations ................................................................................... 8 
7.1.3 
Analysis Sets .................................................................................................................................. 9 
 
General Methodology ....................................................................................................................... 9 
 
Center Pooling................................................................................................................................... 9 
 
Handling of Missing Data and Dropouts ......................................................................................... 10 
 
Adjustments for Multiple Comparisons .......................................................................................... 10 
 
Demographic and Other Baseline Characteristics ........................................................................... 10 
 
Treatment Characteristics ............................................................................................................... 10 
 
Interim Analyses ............................................................................................................................. 12 
 
Evaluation of Objectives ................................................................................................................. 12 
7.9.1 
Primary objective ........................................................................................................................ 12 
7.9.2 
Secondary objectives .................................................................................................................. 12 
 
Safety Evaluation ............................................................................................................................ 15 
7.10.1 
Serious Adverse Event ............................................................................................................ 15 
7.10.2 
Adverse Device Effect ............................................................................................................. 15 
7.10.3 
Serious Adverse Device Effect ................................................................................................ 16 
7.10.4 
Unanticipated Serious Adverse Device Effect ......................................................................... 16 
7.10.5 
Adverse Event Severity Classification ..................................................................................... 16 
7.10.6 
Adverse Event Relationship Classification .............................................................................. 17 

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7.10.7 
Adverse Event Outcome Classification ................................................................................... 18 
7.10.8 
Device Deficiency .................................................................................................................... 19 
 
Health Outcomes Analyses ............................................................................................................. 19 
 
Changes to Planned Analysis .......................................................................................................... 19 
8 
Validation Requirements ......................................................................................................................... 19 
9 
References ............................................................................................................................................... 20 
10 
Statistical Appendices ......................................................................................................................... 20 
 
 
 
 
 

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1. Version History 
 
Version 
Summary of Changes 
Author(s)/Title 
1 
          First version 
Sylvain Anselme, Sr. Biostatistician 
2 
·         Definition of primary/secondary bleeding 
Sylvain Anselme, Sr. Biostatistician 
·         Update Subjects’ participation in the study 
will last 14 days 14 (+3) post-procedure 
·         Process of primary endpoint revised 
3 
·         Section 3: biocompatibility testing and 
animal model studies conclusion developed 
Sylvain Anselme, Sr. Biostatistician 
 
·         Add of 95% Agresti-Coull Confidence 
Intervals 
 
·         Center pooling section updated 
·         Adjustments for Multiple Comparisons 
updated 
·         Demographic, treatment characteristics, 
safety evaluation updated 
·         References updated 
·         Changes to planned analysis updated 
·         Validation Requirement Level I added 
 
 
 
 
 
 

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2. List of Abbreviations and Definitions of Terms 
 
Abbreviation 
Definition 
AE 
Adverse Event 
ADE 
Adverse Device Effect 
ADL 
Activity of Daily Living 
CIP 
Clinical Investigational Plan 
eCRF 
Electronic Case Report Form 
EORTC QLQ-H&N35 European Organization for Research and Treatment of Cancer 
Quality of Life Head & Neck cancer module 
FAS 
Full Analysis Set 
ITT 
Intent-to-treat 
PPAS 
Per-Protocol Analysis Set 
RF 
Radiofrequency 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
USADE 
Unanticipated Adverse Device Effect 
VAS 
Visual Analogue Scale 
3. Introduction 
 
Tonsillectomy is one of the most frequently performed otorhinolaryngologic procedures with more than 4.5 
million procedures performed annually. The introduction of numerous energy based tools and techniques 
allow for the simultaneous dissection and sealing of vessels, significantly improving safety and reducing the 
complications of the procedure. Generally thought of as safe and effective, energy based devices such as 
laser, Shaw scalpel, electrosurgical devices (needle, scissor, or knife), radiofrequency needle ablation 
device, thermal welding, and Coblator, use heat energy to denature protein, leading to vascular tamponade 
and hemostasis. Unfortunately, a byproduct of using this energy during surgery is the lateral heating of the 
surgical area, which can damage adjacent structures, delay wound healing, increase post-operative pain, 
and increase the subject’s time to return to normal diet and activity. In order to address these concerns, 
Medtronic (formerly Covidien) has developed BiZact™, a bipolar instrument intended for use in open 
surgical procedures, such as tonsillectomies, where ligation and division of vessels, tissue bundles and 
lymphatics is desired. BiZact™ is designed as a pistol grip radiofrequency (RF) sealer/dissector for use with 
vessels up to and including 3mm. Compatible with the already in use Valleylab (LS10) energy platform, 
BiZact™ employs bipolar electrosurgical RF energy and pressure to ligate vessels interposed between its 
jaws which can then be transected using the built in knife deployed by the device trigger. Based off 
LigaSure technology, bipolar electrosurgical devices have been shown to be safe and effective for 
tonsillectomy procedures, providing adequate hemostasis while minimizing postoperative pain.  
In summary, biocompatibility testing and animal model studies have found BiZact™ to be safe and 
effective in achieving hemostasis and reducing lateral thermal spread potentially resulting in reduced 
post‐operative pain. 

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4. Study Objectives 
 
  
The study population consists of patients being treated with BiZact™ device for tonsillectomy. 
 
4.1. Primary objective 
 
The primary objective of this study is to assess the severity of post-operative pain following the use of the 
BiZact™ device in adult tonsillectomy procedures using the Visual Analogue Scale (VAS) at days 1 through 
7, 10 and 14. 
 
 
4.2. Secondary objectives 
 
Several secondary hypotheses will be analyzed: 
• 
To assess the incidence of patients with post-operative analgesic consumption 
• 
To assess the ability to return to normal diet and normal activity after operation: 
o 
Time between dates of operation and return to a normal situation 
o 
Incidence of patients returning to a normal situation 
 
• 
To assess the incidence of patients with of post-operative hemorrhage 
o 
Incidence of patients with primary bleeding, occurring at the latest 24 hours after 
operation. 
o 
Incidence of patients with secondary bleeding, occurring more than 24 hours after 
operation. 
 
• 
To assess the incidence of patients with post-operative readmission 
 
• 
To assess the quantity of intra-operative bleeding volume 
 
• 
To assess the quantity of intra-operative irrigant volume 
 
• 
To assess the operative time from the first incision to complete hemostasis of the tonsillar bed 
(procedure duration and device use duration) 
 
 
 

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5. Investigation Plan 
 
 
This is a Prospective, multi-center, single-arm non-comparative pilot study to assess the severity of post-
operative pain with the use of BiZact™ for tonsillectomy. 
A minimum of 48 subjects being treated with BiZact™ for tonsillectomy may be enrolled at up to 3 sites 
in the United States and Europe with competitive enrollment not to exceed 24 subjects per site. 
 
Subjects’ participation in the study will last 14 days 14 (+3) post-procedure. Assessments of pain, quality 
of life, safety, readmission, concomitant medications, ability to return to normal diet and activity will be 
performed. An at home survey form during post-operative days 1 through 7 and day 10 will be used. At 
day 14 (+3) these parameters will be evaluated via a clinical follow-up visit in the sites. 
 
 
 Inclusion criteria 
Subjects are eligible to be enrolled in the study only if they meet all of the following inclusion criteria: 
1. Adults (male or female) ≥22 years of age in United States and ≥18 years of age in Europe  
2. Scheduled to undergo non-elective tonsillectomy  
3. Signed informed consent by subject or the legally authorized representative 
 
 Exclusion criteria 
Subjects will be excluded from the study if they meet any of the following exclusion criteria: 
Subjects undergoing; 
a. Simultaneous adenoidectomy 
b. Tonsillectomy as a result of cancer 
c. Unilateral tonsillectomy 
d. Current participation in other clinical trials 
Subjects with; 
e. Current tobacco use 
f. 
Known bleeding disorders 
g. History of peritonsillar abscess 
h. Craniofacial disorders 
i. 
Down syndrome (Trisomy 21) 
j. 
Cerebral palsy  
k. Major heart disease  
l. 
Subjects unable to comply with the required study follow-up visits 
m. Pregnancy 

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The subject has comorbidities which, in the opinion of the investigator, will not be appropriate for the 
study or the subject has an estimated life expectancy of less than 6 months 
Any subject who is considered to be part of a vulnerable population (e.g. prisoners or those without 
sufficient mental capacity) 
The subject has participated in any drug or device research study within 30 days of enrollment that 
would interfere with this study 
 
6 Determination of Sample Size 
 
This study does not have a statistically powered hypothesis. There will be no sample size calculations 
since the study is not hypothesis-driven. The number of enrolled subjects is pre-defined and all the 
results will be summarized in a descriptive manner.  
 
 
 
7 Statistical Methods 
 
 
 Study Subjects 
 
7.1.1 Disposition of Subjects 
 
Screen, consented, eligible, intent-to-treat patients (ITT), operated patients (Full Analysis Set - FAS) and 
per-protocol patients (PP) will be summarized by frequency, as well as patients early withdrawn. 
Early withdrawal reasons will be presented by related reason and listed. Protocol deviations, post-operative 
assessment completions and length of follow-up will be reported (frequency and percentage from Full 
Analysis Set population). 
 
Subjects who provide study consent, but then are determined to be ineligible prior to study procedure will be 
considered a screen failure and will not require additional study follow-up visits as well as subjects withdrawn 
due to physician decision. The reason for the screening failure will be clearly delineated.   
Subjects in whom the procedure is begun but not completed will be considered “discontinued” and will be 
followed until discharge. These subjects will only contribute to Adverse Event data intraoperatively until 
discharge (no additional follow-up). They will only be part of the ITT analysis set. 
 
 
7.1.2 Clinical Investigation Plan (CIP) Deviations 
 
 
Full-list of protocol deviations will be reported and major violations to be excluded from Per-Protocol 
Analysis Set (PPAS) will be reviewed and discussed with the study team prior to run statistical analysis. 

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7.1.3 Analysis Sets 
 
 
Three analysis sets will be created for study purpose: 
1. Intent-To-Treat. ITT includes all subjects: 
o 
who signed the informed consent 
o 
who satisfied the eligibility criteria 
o 
who began the procedure 
Subjects in whom the procedure is begun but not completed will be considered “discontinued” and will be 
followed until discharge. These subjects will only contribute AE data intraoperatively until discharge (no 
additional follow-up). 
 
2. Full Analysis Set. FAS is a subset of the ITT, restricted to subjects: 
o 
who signed the informed consent 
o 
who satisfied the eligibility criteria 
o 
who were operated with BiZact™ procedure successfully completed 
 
 
3. Per Protocol Analysis Set. PPAS is a subset of the FAS, restricted to subjects who adhere 
to the protocol and do not have major protocol violation. 
 
 
 
 General Methodology 
 
Continuous variables will be summarized using counts, means, 95% Agresti-Coull Confidence Intervals, 
standard deviations, medians, minimum and maximum. 
Categorical variables will be summarized using frequencies and percentages. 
 
 
 Center Pooling 
 
Subgroup analyses for primary and secondary endpoints will be presented by clinical center.  
 
 

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 Handling of Missing Data and Dropouts 
 
No method of imputation will be used for missing data.  A summary of missing data will be provided 
according to the number of subjects, the time points where the data are missing and clinical center. For 
each clinical center, number and percent of subjects with no missing data will be presented in tabular 
form.  
 
 Adjustments for Multiple Comparisons 
 
Only one analysis will be performed then no adjustment for multiple comparison will be performed. 
 
 
 
 Demographic and Other Baseline Characteristics 
 
 
Patient’s characteristics and other baseline data will be summarized for the FAS and reported using 
statistical methods described above (see section 7.2 General Methodology).  
 
 
 Treatment Characteristics 
 
 
 
The Study Investigator should perform the surgical procedure according to the appropriate standard 
procedures and practices at his/her institution using BiZact™. Additionally, the following procedures and 
assessments will be performed:  
• 
Type of admission 
• 
Adverse Events/Serious Adverse Events assessment 
• 
Intra-operative bleeding volume  
o 
Record volume of any irrigant used 
o 
Record presence of gastric fluids 
o 
Record amount of fluid in suction container prior to stomach drainage 
• 
Surgical performance parameters 
o 
Surgical technique 
o 
Operation time 
o 
Device ease of use 
o 
Dissection assessment 
o 
Other alternative devices used (if any) 
 
Operation time used 
 
Side 
 
Reason for use 
o 
Tonsil size measurement (Measured via water displacement) 
 
Using a graduated container that has 1mL markings, fill container to half full with 
water note mL level. Put the first tonsil into the water and record the mL level. The 
difference equals the volume of the first tonsil. Remove the first tonsil and note 

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water level. Put the second tonsil into the water and record how much the water 
level rises. The difference equals the volume of the second tonsil.  
• 
Concomitant medications - medications used during procedure, used for Averse Events and used for 
the treatment of pain (including but not limited to analgesics, anti-inflammatories, etc.) 
 
 
Surgical procedure data will be summarized on the FAS and reported using statistical methods described 
above (see section 7.2 General Methodology). 
 
 
 
 
 
 
 
 
 

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 Interim Analyses 
 
No interim analysis is planned. 
 
 
 Evaluation of Objectives 
 
7.9.1 Primary objective 
 
The severity of pain will be analyzed at each post-operative assessment: at days 1 through 7, 10 and 
14. This pain score will be assessed quantitatively using the VAS scale and qualitatively using the 
below subgroups: 
• 
No Pain: VAS= 0 
• 
Mild Pain: VAS > 0 and < 4 
• 
Moderate: VAS ≥ 4 and < 7 
• 
Severe: VAS ≥ 7 
 
 
Friedman’s test will be performed so as to assess the distribution of the VAS along the follow-up and testing 
whether the VAS per visits are from a same population: 
• 
H0: M1 = M2 = M3 = M4 = M5 = M6 = M7 = M10 = M14 (the distribution of the VAS is the same in 
all timepoints) 
• 
Ha: There is at least one paire (i,j) such as Mi ≠ Mj. 
 
 
Subgroup analyses will be performed according to the use of pain killers. 
 
Primary objective analysis will be run on both FAS and PPAS. 
 
7.9.2 Secondary objectives 
 
 
• 
The incidence of patients with analgesic consumption will be assessed at each timepoint and 
globally using frequency and percentages. On the whole follow-up the total consumption of 
analgesics (narcotics and non-narcotics analgesics) will be assessed. Patients with analgesics will be 
identified based on dosing diary. 
 
• 
Ability to return to normal diet and normal activity and patients quality of life after operation will be 
presented: 
 
o 
Calculating the time (counts, means, standard deviations, medians, minimum and 
maximum) between the operation and the return to normal diet or activity dates. 
o 
Calculating the incidence of patients being returned to normal diet or activity after 
operation. 
 
o 
Using the EORTC QLQ-H&N35 questionnaire: 
 
The head & neck cancer module is meant for use among a wide range of patients with head & neck cancer, 
varying in disease stage and treatment modality (i.e. surgery, radiotherapy and chemotherapy) (Bjordal and 
Kaasa, 1992; Bjordal et al., 1994, 1999, 2000) (1-3). The module comprises 35 questions assessing 
symptoms and side effects of treatment, social function and body image/sexuality. The module has been 

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developed according to the guidelines, and pretested on patients from Norway, Sweden, Denmark, the UK 
and French-speaking Belgium. It has been field tested in Norway, Sweden and The Netherlands, and in a 
large cross-cultural study involving more than ten countries (EORTC Protocol 15941). 
 
Scoring of the head & neck cancer module 
The head & neck cancer module incorporates seven multi-item scales that assess pain, swallowing, senses 
(taste and smell), speech, social eating, social contact and sexuality. There are also eleven single items. For 
all items and scales, high scores indicate more problems (i.e. there are no function scales in which 
high scores would mean better functioning). 
Friedman’s test will be applied to assess the distribution of the scores along the follow-up timepoint: 
o 
H0: M1 = M2 = M3 = M4 = M5 = M6 = M7 = M10 = M14 (The distribution of the Symptom 
score is the same in all timepoints) 
o 
Ha: There is at least one paire (i,j) such as Mi ≠ Mj . 
Scale name 
Scale 
Number 
of items 
Item 
range* 
QLQ-H&N35 Item 
numbers 
Symptom scales / items 
  
Pain 
HNPA 
4 
3 
1-4 
Swallowing 
HNSW 
4 
3 
5-8 
Senses problems 
HNSE 
2 
3 
13, 14 
Speech problems 
HNSP 
3 
3 
16, 23, 24 
Trouble with social eating 
HNSO 
4 
3 
19-22 
Trouble with social contact 
HNSC 
5 
3 
18, 25-28 
Less sexuality 
HNSX 
2 
3 
29,30 
Teeth 
HNTE 
1 
3 
9 
Opening mouth 
HNOM 
1 
3 
10 
Dry mouth 
HNDR 
1 
3 
11 
Sticky saliva 
HNSS 
1 
3 
12 
Coughing 
HNCO 
1 
3 
15 
Felt ill 
HNFI 
1 
3 
17 
Pain killers 
HNPK 
1 
1 
31 
Nutritional supplements 
HNNU 
1 
1 
32 
Feeding tube 
HNFE 
1 
1 
33 
Weight loss 
HNWL 
1 
1 
34 
Weight gain 
HNWG 
1 
1 
35 
 * Item range is the difference between the possible maximum and the minimum response to individual 
items. 
Example: 
Pain 
RawScore = (Q1 + Q2 + Q3 + Q4)/4 
Pain Score = {(RawScore-1)/Item range}*100 
Questions scores 
Not at all = 1 
No = 1 
A little = 2 
Yes = 2 
Quite a bit = 3 
Very much = 4 

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• 
The incidence of patients having a post-operative hemorrhage, primary and secondary bleeding, 
and post-operative readmission along the follow-up will be assessed. 
• 
Intra-operative bleeding, irrigant volumes and operative time will be calculated (counts, means, 
standard deviations, medians, minimum and maximum). 
 
Secondary objectives will be run on both FAS and PPAS. 
 

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 Safety Evaluation 
 
An Adverse Event (AE) is any 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.  
This definition includes events related to the investigational medical device and the procedures involved. For 
users or other persons, this definition is restricted to events related to investigational medical devices. 
Adverse Events may include but are not limited to pain, bleeding, nausea, vomiting, and headache. 
AEs will be reported by frequencies and percentages of subjects by categories of AEs and by count of each 
AE. A listing will also be provided. 
 
AEs will be collected and documented at baseline and 0 to 14 days follow-up. AEs will be presented 
globally and based on their occurrence periods: PRE-PROCEDURE, DURING PROCEDURE and POST-
PROCEDURE. The MedDRA coding system will be used so as to report the AEs in the statistical tables.  
 
Safety analysis will be run on the whole ITT population and on the FAS. 
 
7.10.1 Serious Adverse Event 
 
 
A serious adverse event (SAE) is any AE that has: 
• 
led to death, 
• 
led to serious deterioration in the health of the subject that either resulted in 
o 
a life-threatening illness or injury, or 
o 
a permanent impairment of a body structure or a body function, or 
o 
in-patient or prolonged hospitalization, or 
o 
medical or surgical intervention to prevent life threatening illness or injury or permanent 
impairment to a body structure or a body function, or 
• 
led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
NOTE: Planned hospitalization for a pre-existing condition or a procedure required by the clinical 
investigational plan, without serious deterioration in health, is not considered an SAE. 
SAEs will be collected and documented at baseline and 0 to 14 days follow-up. 
 
7.10.2 Adverse Device Effect 
 
 
An Adverse Device Effect (ADE) is an adverse event related to the use of an investigational medical device.  
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. 

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This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device. 
Adverse Device Effects will be reported by the Investigator(s). If escalation is required, ADEs will be reviewed 
by medical affairs as part of Medtronic’s Post-Market Vigilance program. Both confirmed and possible device 
related events will be included in the study report. 
 
7.10.3 Serious Adverse Device Effect 
 
A Serious Adverse Device Effect (SADE) is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
SADEs will be collected and documented at baseline and 0 to 14 days follow-up. 
 
 
7.10.4 Unanticipated Serious Adverse Device Effect 
 
An Unanticipated Serious Adverse Device Effect (USADE) is a serious adverse device effect which by its nature, 
incidence, severity, or outcome has not been identified in the current version of the risk analysis report.  
USADEs will be collected and documented at baseline and 0 to 14 days follow-up. 
 
 
7.10.5 Adverse Event Severity Classification 
 
 
Severity will be defined according to the following criteria: 
Mild 
Awareness of event, but easily tolerated 
Moderate 
Discomfort enough to cause some interference with activities of daily living (ADL) 
Severe 
Incapacitating, with an inability to perform ADL 
Death 
Death related to AE 
 
An AE can be classified as severe and not deemed an SAE. Similarly, an SAE is not automatically 
severe in nature. 
In this study, the incidence of patients by AEs category will be summarized by worst severity. 
 
 

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7.10.6 Adverse Event Relationship Classification 
 
Causality assessments define the relationship between the use of the medical device (including the medical-
surgical procedure) and the occurrence of each adverse event, according to MEDDEV 2.7/3 Revision 3, May 
2015 (Guidelines on Medical Devices, Clinical Investigations: Serious Adverse Event Reporting). During 
causality assessment activity, clinical judgment shall be used and the relevant documents, such as the Clinical 
Evaluation Report and the Risk Management Report shall be consulted, as all the foreseeable serious adverse 
events and the potential risks are listed and assessed there. The presence of confounding factors, such as 
concomitant medication/treatment, the natural history of the underlying disease, other concurrent illness or 
risk factors shall also be considered. 
Each SAE will be classified according to five different levels of causality. The sponsor and the investigators 
will use the following definitions to assess the relationship of the serious adverse event to the investigational 
medical device or procedures: 
Not related:  relationship to the device or procedures can be excluded when: 
1. the event is not a known side effect of the product category the device belongs to or of similar 
devices and procedures 
2. the event has no temporal relationship with the use of the device or the procedures; 
3. the serious event does not follow a known response pattern to the medical device (if the response 
pattern is previously known) and is biologically implausible; 
4. the discontinuation of medical device application or the reduction of the level of activation/exposure 
- when clinically feasible – and reintroduction of its use (or increase of the level of 
activation/exposure), do not impact on the serious event; 
5. the event involves a body-site or an organ not expected to be affected by the device or procedure; 
6. the serious event can be attributed to another cause (e.g. an underlying or concurrent illness/ 
clinical condition, an effect of another device, drug, treatment or other risk factors); 
7. the event does not depend on a false result given by the device used for diagnosis, when 
applicable; 
8. harms to the subject are not clearly due to use error; 
9. In order to establish the non-relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event. 
Unlikely: the relationship with the use of the device seems not relevant and/or the event can be reasonably 
explained by another cause, but additional information may be obtained. 
Possible:  the relationship with the use of the device is weak but cannot be ruled out completely. Alternative 
causes are also possible (e.g. an underlying or concurrent illness/ clinical condition or/and an effect of 
another device, drug or treatment). Cases were relatedness cannot be assessed or no information has been 
obtained should also be classified as possible. 
Probable:  the relationship with the use of the device seems relevant and/or the event cannot reasonably 
explained by another cause, but additional information may be obtained. 
Causal relationship: the serious event is associated with the device or with procedures beyond reasonable 
doubt when: 

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1. the event is a known side effect of the product category the device belongs to or of similar devices 
and procedures; 
2. the event has a temporal relationship with device use/application or procedures; 
3. the event involves a body-site or organ that 
a. the device or procedures are applied to; 
b. the device or procedures have an effect on; 
4. the serious event follows a known response pattern to the medical device (if the response pattern is 
previously known); 
5. the discontinuation of medical device application (or reduction of the level of activation/exposure) 
and reintroduction of its use (or increase of the level of activation/exposure), impact on the serious 
event (when clinically feasible); 
6. 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; 
7. harm to the subject is due to error in use; 
8. the event depends on a false result given by the device used for diagnosis, when applicable; 
9. In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event. 
 
In this study, the incidence of patients with AEs related with study procedure or study device will be 
calculated. For each patients having at least one AE, their worst relationship will be identified. An AE 
will be considered as related when it is coded as: 
 
Relationship 
Study CRF 
Final code used (Not related/Related) 
NOT RELATED 
Not related 
UNLIKELY 
Related 
POSSIBLE 
Related 
PROBABLE 
Related 
CAUSAL RELATIONSHIP 
Related 
 
7.10.7 Adverse Event Outcome Classification 
 
Outcome of the event will be defined according to the following: 
• 
Fatal: This event is determined to be the cause of death.  
• 
Not Recovering/ Not Resolved: The event has retained pathological conditions resulting from the 
prior disease or injury. 
• 
Recovered/ Resolved: The event has fully resolved at the end of the study. 
• 
Recovering/ Resolving: The event is ongoing at the end of the study. 
• 
Unknown: The event has been unclassified at the end of the study. 
 
 

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7.10.8 Device Deficiency 
 
A Device deficiency is an inadequacy of a medical device related to its identity, quality, durability, reliability, 
safety or performance, such as malfunction, misuse or use error and inadequate labeling. 
All BiZact™ device deficiencies will be documented on the appropriate Device malfunction eCRF and the device 
should be returned to Medtronic for analysis, if possible.  Instructions for returning the device will be provided.  
Device deficiencies should also be documented in the subject’s medical record. 
Device deficiencies are NOT to be reported as AEs.  However, if there is an AE that results from a device 
deficiency, that specific event would be recorded on the appropriate eCRF. 
Device deficiencies will be reported by frequencies and percentages, and listing will also be provided. 
 
 
 
 Health Outcomes Analyses 
 
Health outcomes have been previously described. 
 
 
 Changes to Planned Analysis 
 
Analysis corresponds to the planned analysis in the CIP. Any deviations from this statistical plan will be 
justified in future revisions to this document or in the final report, as appropriate. 
 
 
8 Validation Requirements 
 
 
Level I validation will be performed for all the analysis output. Level I is defined as that the peer 
reviewer independently programs output and then compares the output with that generated by the 
original Statistical Programmer. 
 

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9 References 
 
 
1. 
Bjordal K., Kaasa S. Psychometric validation of the EORTC Core Quality of Life Questionnaire, 30-
item version and a diagnosis-specific module for head and neck cancer patients. Acta Oncol. 1992;31:311-
21. 
 
2. 
Bjordal K, Ahlner-Elmqvist M, Tolleson E, el al. Development of a European Organization for 
Research and Treatment of Cancer (EORTC) questionnaire module to be used in quality of life assessments 
in head and neck cancer patients. EORTC Quality of Life Study Group. Acta Oncol. 1994;33:879-85 
 
3. 
Bjorda K. Hammerlid E, Ahlner-Elmqvist M, et al. Quality of life in head and neck cancer patients: 
validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
H&N35. J Clin Oncol. 1999;17:1008-19. 
 
 
 
10 Statistical Appendices 
 
Appendix 1: Table shells (provided in a separated file) 
 
 

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Statistical Analysis Plan 
Clinical Investigation Plan Title 
A prospective, multi-center, single arm non-
comparative pilot study of BiZact™ on adults 
undergoing tonsillectomy. 
Clinical Investigation Plan Identifier COVBZTS0562 
Clinical Investigation Plan Version CIP_V4.0 Final 13MAR2018 
Sponsor/Local Sponsor Medtronic 
Minimally Invasive 
Therapies Group 
5920 Longbow Dr. 
Boulder, CO 80301 
Document Version SAP v3.0 Final 
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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Table of Contents 
 
 
1. 
Version History .......................................................................................................................................... 4 
2. 
List of Abbreviations and Definitions of Terms .......................................................................................... 5 
3. 
Introduction ............................................................................................................................................... 5 
4. 
Study Objectives ........................................................................................................................................ 6 
5. 
Investigation Plan....................................................................................................................................... 7 
 
Inclusion criteria ............................................................................................................................... 7 
 
Exclusion criteria ............................................................................................................................... 7 
6 
Determination of Sample Size .................................................................................................................... 8 
7 
Statistical Methods .................................................................................................................................... 8 
 
Study Subjects ................................................................................................................................... 8 
7.1.1 
Disposition of Subjects .................................................................................................................. 8 
7.1.2 
Clinical Investigation Plan (CIP) Deviations ................................................................................... 8 
7.1.3 
Analysis Sets .................................................................................................................................. 9 
 
General Methodology ....................................................................................................................... 9 
 
Center Pooling................................................................................................................................... 9 
 
Handling of Missing Data and Dropouts ......................................................................................... 10 
 
Adjustments for Multiple Comparisons .......................................................................................... 10 
 
Demographic and Other Baseline Characteristics ........................................................................... 10 
 
Treatment Characteristics ............................................................................................................... 10 
 
Interim Analyses ............................................................................................................................. 12 
 
Evaluation of Objectives ................................................................................................................. 12 
7.9.1 
Primary objective ........................................................................................................................ 12 
7.9.2 
Secondary objectives .................................................................................................................. 12 
 
Safety Evaluation ............................................................................................................................ 15 
7.10.1 
Serious Adverse Event ............................................................................................................ 15 
7.10.2 
Adverse Device Effect ............................................................................................................. 15 
7.10.3 
Serious Adverse Device Effect ................................................................................................ 16 
7.10.4 
Unanticipated Serious Adverse Device Effect ......................................................................... 16 
7.10.5 
Adverse Event Severity Classification ..................................................................................... 16 
7.10.6 
Adverse Event Relationship Classification .............................................................................. 17 

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7.10.7 
Adverse Event Outcome Classification ................................................................................... 18 
7.10.8 
Device Deficiency .................................................................................................................... 19 
 
Health Outcomes Analyses ............................................................................................................. 19 
 
Changes to Planned Analysis .......................................................................................................... 19 
8 
Validation Requirements ......................................................................................................................... 19 
9 
References ............................................................................................................................................... 20 
10 
Statistical Appendices ......................................................................................................................... 20 
 
 
 
 
 

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1. Version History 
 
Version 
Summary of Changes 
Author(s)/Title 
1 
          First version 
Sylvain Anselme, Sr. Biostatistician 
2 
·         Definition of primary/secondary bleeding 
Sylvain Anselme, Sr. Biostatistician 
·         Update Subjects’ participation in the study 
will last 14 days 14 (+3) post-procedure 
·         Process of primary endpoint revised 
3 
·         Section 3: biocompatibility testing and 
animal model studies conclusion developed 
Sylvain Anselme, Sr. Biostatistician 
 
·         Add of 95% Agresti-Coull Confidence 
Intervals 
 
·         Center pooling section updated 
·         Adjustments for Multiple Comparisons 
updated 
·         Demographic, treatment characteristics, 
safety evaluation updated 
·         References updated 
·         Changes to planned analysis updated 
·         Validation Requirement Level I added 
 
 
 
 
 
 

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2. List of Abbreviations and Definitions of Terms 
 
Abbreviation 
Definition 
AE 
Adverse Event 
ADE 
Adverse Device Effect 
ADL 
Activity of Daily Living 
CIP 
Clinical Investigational Plan 
eCRF 
Electronic Case Report Form 
EORTC QLQ-H&N35 European Organization for Research and Treatment of Cancer 
Quality of Life Head & Neck cancer module 
FAS 
Full Analysis Set 
ITT 
Intent-to-treat 
PPAS 
Per-Protocol Analysis Set 
RF 
Radiofrequency 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
USADE 
Unanticipated Adverse Device Effect 
VAS 
Visual Analogue Scale 
3. Introduction 
 
Tonsillectomy is one of the most frequently performed otorhinolaryngologic procedures with more than 4.5 
million procedures performed annually. The introduction of numerous energy based tools and techniques 
allow for the simultaneous dissection and sealing of vessels, significantly improving safety and reducing the 
complications of the procedure. Generally thought of as safe and effective, energy based devices such as 
laser, Shaw scalpel, electrosurgical devices (needle, scissor, or knife), radiofrequency needle ablation 
device, thermal welding, and Coblator, use heat energy to denature protein, leading to vascular tamponade 
and hemostasis. Unfortunately, a byproduct of using this energy during surgery is the lateral heating of the 
surgical area, which can damage adjacent structures, delay wound healing, increase post-operative pain, 
and increase the subject’s time to return to normal diet and activity. In order to address these concerns, 
Medtronic (formerly Covidien) has developed BiZact™, a bipolar instrument intended for use in open 
surgical procedures, such as tonsillectomies, where ligation and division of vessels, tissue bundles and 
lymphatics is desired. BiZact™ is designed as a pistol grip radiofrequency (RF) sealer/dissector for use with 
vessels up to and including 3mm. Compatible with the already in use Valleylab (LS10) energy platform, 
BiZact™ employs bipolar electrosurgical RF energy and pressure to ligate vessels interposed between its 
jaws which can then be transected using the built in knife deployed by the device trigger. Based off 
LigaSure technology, bipolar electrosurgical devices have been shown to be safe and effective for 
tonsillectomy procedures, providing adequate hemostasis while minimizing postoperative pain.  
In summary, biocompatibility testing and animal model studies have found BiZact™ to be safe and 
effective in achieving hemostasis and reducing lateral thermal spread potentially resulting in reduced 
post‐operative pain. 

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4. Study Objectives 
 
  
The study population consists of patients being treated with BiZact™ device for tonsillectomy. 
 
4.1. Primary objective 
 
The primary objective of this study is to assess the severity of post-operative pain following the use of the 
BiZact™ device in adult tonsillectomy procedures using the Visual Analogue Scale (VAS) at days 1 through 
7, 10 and 14. 
 
 
4.2. Secondary objectives 
 
Several secondary hypotheses will be analyzed: 
• 
To assess the incidence of patients with post-operative analgesic consumption 
• 
To assess the ability to return to normal diet and normal activity after operation: 
o 
Time between dates of operation and return to a normal situation 
o 
Incidence of patients returning to a normal situation 
 
• 
To assess the incidence of patients with of post-operative hemorrhage 
o 
Incidence of patients with primary bleeding, occurring at the latest 24 hours after 
operation. 
o 
Incidence of patients with secondary bleeding, occurring more than 24 hours after 
operation. 
 
• 
To assess the incidence of patients with post-operative readmission 
 
• 
To assess the quantity of intra-operative bleeding volume 
 
• 
To assess the quantity of intra-operative irrigant volume 
 
• 
To assess the operative time from the first incision to complete hemostasis of the tonsillar bed 
(procedure duration and device use duration) 
 
 
 

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5. Investigation Plan 
 
 
This is a Prospective, multi-center, single-arm non-comparative pilot study to assess the severity of post-
operative pain with the use of BiZact™ for tonsillectomy. 
A minimum of 48 subjects being treated with BiZact™ for tonsillectomy may be enrolled at up to 3 sites 
in the United States and Europe with competitive enrollment not to exceed 24 subjects per site. 
 
Subjects’ participation in the study will last 14 days 14 (+3) post-procedure. Assessments of pain, quality 
of life, safety, readmission, concomitant medications, ability to return to normal diet and activity will be 
performed. An at home survey form during post-operative days 1 through 7 and day 10 will be used. At 
day 14 (+3) these parameters will be evaluated via a clinical follow-up visit in the sites. 
 
 
 Inclusion criteria 
Subjects are eligible to be enrolled in the study only if they meet all of the following inclusion criteria: 
1. Adults (male or female) ≥22 years of age in United States and ≥18 years of age in Europe  
2. Scheduled to undergo non-elective tonsillectomy  
3. Signed informed consent by subject or the legally authorized representative 
 
 Exclusion criteria 
Subjects will be excluded from the study if they meet any of the following exclusion criteria: 
Subjects undergoing; 
a. Simultaneous adenoidectomy 
b. Tonsillectomy as a result of cancer 
c. Unilateral tonsillectomy 
d. Current participation in other clinical trials 
Subjects with; 
e. Current tobacco use 
f. 
Known bleeding disorders 
g. History of peritonsillar abscess 
h. Craniofacial disorders 
i. 
Down syndrome (Trisomy 21) 
j. 
Cerebral palsy  
k. Major heart disease  
l. 
Subjects unable to comply with the required study follow-up visits 
m. Pregnancy 

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The subject has comorbidities which, in the opinion of the investigator, will not be appropriate for the 
study or the subject has an estimated life expectancy of less than 6 months 
Any subject who is considered to be part of a vulnerable population (e.g. prisoners or those without 
sufficient mental capacity) 
The subject has participated in any drug or device research study within 30 days of enrollment that 
would interfere with this study 
 
6 Determination of Sample Size 
 
This study does not have a statistically powered hypothesis. There will be no sample size calculations 
since the study is not hypothesis-driven. The number of enrolled subjects is pre-defined and all the 
results will be summarized in a descriptive manner.  
 
 
 
7 Statistical Methods 
 
 
 Study Subjects 
 
7.1.1 Disposition of Subjects 
 
Screen, consented, eligible, intent-to-treat patients (ITT), operated patients (Full Analysis Set - FAS) and 
per-protocol patients (PP) will be summarized by frequency, as well as patients early withdrawn. 
Early withdrawal reasons will be presented by related reason and listed. Protocol deviations, post-operative 
assessment completions and length of follow-up will be reported (frequency and percentage from Full 
Analysis Set population). 
 
Subjects who provide study consent, but then are determined to be ineligible prior to study procedure will be 
considered a screen failure and will not require additional study follow-up visits as well as subjects withdrawn 
due to physician decision. The reason for the screening failure will be clearly delineated.   
Subjects in whom the procedure is begun but not completed will be considered “discontinued” and will be 
followed until discharge. These subjects will only contribute to Adverse Event data intraoperatively until 
discharge (no additional follow-up). They will only be part of the ITT analysis set. 
 
 
7.1.2 Clinical Investigation Plan (CIP) Deviations 
 
 
Full-list of protocol deviations will be reported and major violations to be excluded from Per-Protocol 
Analysis Set (PPAS) will be reviewed and discussed with the study team prior to run statistical analysis. 

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7.1.3 Analysis Sets 
 
 
Three analysis sets will be created for study purpose: 
1. Intent-To-Treat. ITT includes all subjects: 
o 
who signed the informed consent 
o 
who satisfied the eligibility criteria 
o 
who began the procedure 
Subjects in whom the procedure is begun but not completed will be considered “discontinued” and will be 
followed until discharge. These subjects will only contribute AE data intraoperatively until discharge (no 
additional follow-up). 
 
2. Full Analysis Set. FAS is a subset of the ITT, restricted to subjects: 
o 
who signed the informed consent 
o 
who satisfied the eligibility criteria 
o 
who were operated with BiZact™ procedure successfully completed 
 
 
3. Per Protocol Analysis Set. PPAS is a subset of the FAS, restricted to subjects who adhere 
to the protocol and do not have major protocol violation. 
 
 
 
 General Methodology 
 
Continuous variables will be summarized using counts, means, 95% Agresti-Coull Confidence Intervals, 
standard deviations, medians, minimum and maximum. 
Categorical variables will be summarized using frequencies and percentages. 
 
 
 Center Pooling 
 
Subgroup analyses for primary and secondary endpoints will be presented by clinical center.  
 
 

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 Handling of Missing Data and Dropouts 
 
No method of imputation will be used for missing data.  A summary of missing data will be provided 
according to the number of subjects, the time points where the data are missing and clinical center. For 
each clinical center, number and percent of subjects with no missing data will be presented in tabular 
form.  
 
 Adjustments for Multiple Comparisons 
 
Only one analysis will be performed then no adjustment for multiple comparison will be performed. 
 
 
 
 Demographic and Other Baseline Characteristics 
 
 
Patient’s characteristics and other baseline data will be summarized for the FAS and reported using 
statistical methods described above (see section 7.2 General Methodology).  
 
 
 Treatment Characteristics 
 
 
 
The Study Investigator should perform the surgical procedure according to the appropriate standard 
procedures and practices at his/her institution using BiZact™. Additionally, the following procedures and 
assessments will be performed:  
• 
Type of admission 
• 
Adverse Events/Serious Adverse Events assessment 
• 
Intra-operative bleeding volume  
o 
Record volume of any irrigant used 
o 
Record presence of gastric fluids 
o 
Record amount of fluid in suction container prior to stomach drainage 
• 
Surgical performance parameters 
o 
Surgical technique 
o 
Operation time 
o 
Device ease of use 
o 
Dissection assessment 
o 
Other alternative devices used (if any) 
 
Operation time used 
 
Side 
 
Reason for use 
o 
Tonsil size measurement (Measured via water displacement) 
 
Using a graduated container that has 1mL markings, fill container to half full with 
water note mL level. Put the first tonsil into the water and record the mL level. The 
difference equals the volume of the first tonsil. Remove the first tonsil and note 

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water level. Put the second tonsil into the water and record how much the water 
level rises. The difference equals the volume of the second tonsil.  
• 
Concomitant medications - medications used during procedure, used for Averse Events and used for 
the treatment of pain (including but not limited to analgesics, anti-inflammatories, etc.) 
 
 
Surgical procedure data will be summarized on the FAS and reported using statistical methods described 
above (see section 7.2 General Methodology). 
 
 
 
 
 
 
 
 
 

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 Interim Analyses 
 
No interim analysis is planned. 
 
 
 Evaluation of Objectives 
 
7.9.1 Primary objective 
 
The severity of pain will be analyzed at each post-operative assessment: at days 1 through 7, 10 and 
14. This pain score will be assessed quantitatively using the VAS scale and qualitatively using the 
below subgroups: 
• 
No Pain: VAS= 0 
• 
Mild Pain: VAS > 0 and < 4 
• 
Moderate: VAS ≥ 4 and < 7 
• 
Severe: VAS ≥ 7 
 
 
Friedman’s test will be performed so as to assess the distribution of the VAS along the follow-up and testing 
whether the VAS per visits are from a same population: 
• 
H0: M1 = M2 = M3 = M4 = M5 = M6 = M7 = M10 = M14 (the distribution of the VAS is the same in 
all timepoints) 
• 
Ha: There is at least one paire (i,j) such as Mi ≠ Mj. 
 
 
Subgroup analyses will be performed according to the use of pain killers. 
 
Primary objective analysis will be run on both FAS and PPAS. 
 
7.9.2 Secondary objectives 
 
 
• 
The incidence of patients with analgesic consumption will be assessed at each timepoint and 
globally using frequency and percentages. On the whole follow-up the total consumption of 
analgesics (narcotics and non-narcotics analgesics) will be assessed. Patients with analgesics will be 
identified based on dosing diary. 
 
• 
Ability to return to normal diet and normal activity and patients quality of life after operation will be 
presented: 
 
o 
Calculating the time (counts, means, standard deviations, medians, minimum and 
maximum) between the operation and the return to normal diet or activity dates. 
o 
Calculating the incidence of patients being returned to normal diet or activity after 
operation. 
 
o 
Using the EORTC QLQ-H&N35 questionnaire: 
 
The head & neck cancer module is meant for use among a wide range of patients with head & neck cancer, 
varying in disease stage and treatment modality (i.e. surgery, radiotherapy and chemotherapy) (Bjordal and 
Kaasa, 1992; Bjordal et al., 1994, 1999, 2000) (1-3). The module comprises 35 questions assessing 
symptoms and side effects of treatment, social function and body image/sexuality. The module has been 

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developed according to the guidelines, and pretested on patients from Norway, Sweden, Denmark, the UK 
and French-speaking Belgium. It has been field tested in Norway, Sweden and The Netherlands, and in a 
large cross-cultural study involving more than ten countries (EORTC Protocol 15941). 
 
Scoring of the head & neck cancer module 
The head & neck cancer module incorporates seven multi-item scales that assess pain, swallowing, senses 
(taste and smell), speech, social eating, social contact and sexuality. There are also eleven single items. For 
all items and scales, high scores indicate more problems (i.e. there are no function scales in which 
high scores would mean better functioning). 
Friedman’s test will be applied to assess the distribution of the scores along the follow-up timepoint: 
o 
H0: M1 = M2 = M3 = M4 = M5 = M6 = M7 = M10 = M14 (The distribution of the Symptom 
score is the same in all timepoints) 
o 
Ha: There is at least one paire (i,j) such as Mi ≠ Mj . 
Scale name 
Scale 
Number 
of items 
Item 
range* 
QLQ-H&N35 Item 
numbers 
Symptom scales / items 
  
Pain 
HNPA 
4 
3 
1-4 
Swallowing 
HNSW 
4 
3 
5-8 
Senses problems 
HNSE 
2 
3 
13, 14 
Speech problems 
HNSP 
3 
3 
16, 23, 24 
Trouble with social eating 
HNSO 
4 
3 
19-22 
Trouble with social contact 
HNSC 
5 
3 
18, 25-28 
Less sexuality 
HNSX 
2 
3 
29,30 
Teeth 
HNTE 
1 
3 
9 
Opening mouth 
HNOM 
1 
3 
10 
Dry mouth 
HNDR 
1 
3 
11 
Sticky saliva 
HNSS 
1 
3 
12 
Coughing 
HNCO 
1 
3 
15 
Felt ill 
HNFI 
1 
3 
17 
Pain killers 
HNPK 
1 
1 
31 
Nutritional supplements 
HNNU 
1 
1 
32 
Feeding tube 
HNFE 
1 
1 
33 
Weight loss 
HNWL 
1 
1 
34 
Weight gain 
HNWG 
1 
1 
35 
 * Item range is the difference between the possible maximum and the minimum response to individual 
items. 
Example: 
Pain 
RawScore = (Q1 + Q2 + Q3 + Q4)/4 
Pain Score = {(RawScore-1)/Item range}*100 
Questions scores 
Not at all = 1 
No = 1 
A little = 2 
Yes = 2 
Quite a bit = 3 
Very much = 4 

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• 
The incidence of patients having a post-operative hemorrhage, primary and secondary bleeding, 
and post-operative readmission along the follow-up will be assessed. 
• 
Intra-operative bleeding, irrigant volumes and operative time will be calculated (counts, means, 
standard deviations, medians, minimum and maximum). 
 
Secondary objectives will be run on both FAS and PPAS. 
 

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 Safety Evaluation 
 
An Adverse Event (AE) is any 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.  
This definition includes events related to the investigational medical device and the procedures involved. For 
users or other persons, this definition is restricted to events related to investigational medical devices. 
Adverse Events may include but are not limited to pain, bleeding, nausea, vomiting, and headache. 
AEs will be reported by frequencies and percentages of subjects by categories of AEs and by count of each 
AE. A listing will also be provided. 
 
AEs will be collected and documented at baseline and 0 to 14 days follow-up. AEs will be presented 
globally and based on their occurrence periods: PRE-PROCEDURE, DURING PROCEDURE and POST-
PROCEDURE. The MedDRA coding system will be used so as to report the AEs in the statistical tables.  
 
Safety analysis will be run on the whole ITT population and on the FAS. 
 
7.10.1 Serious Adverse Event 
 
 
A serious adverse event (SAE) is any AE that has: 
• 
led to death, 
• 
led to serious deterioration in the health of the subject that either resulted in 
o 
a life-threatening illness or injury, or 
o 
a permanent impairment of a body structure or a body function, or 
o 
in-patient or prolonged hospitalization, or 
o 
medical or surgical intervention to prevent life threatening illness or injury or permanent 
impairment to a body structure or a body function, or 
• 
led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
NOTE: Planned hospitalization for a pre-existing condition or a procedure required by the clinical 
investigational plan, without serious deterioration in health, is not considered an SAE. 
SAEs will be collected and documented at baseline and 0 to 14 days follow-up. 
 
7.10.2 Adverse Device Effect 
 
 
An Adverse Device Effect (ADE) is an adverse event related to the use of an investigational medical device.  
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. 

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This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device. 
Adverse Device Effects will be reported by the Investigator(s). If escalation is required, ADEs will be reviewed 
by medical affairs as part of Medtronic’s Post-Market Vigilance program. Both confirmed and possible device 
related events will be included in the study report. 
 
7.10.3 Serious Adverse Device Effect 
 
A Serious Adverse Device Effect (SADE) is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
SADEs will be collected and documented at baseline and 0 to 14 days follow-up. 
 
 
7.10.4 Unanticipated Serious Adverse Device Effect 
 
An Unanticipated Serious Adverse Device Effect (USADE) is a serious adverse device effect which by its nature, 
incidence, severity, or outcome has not been identified in the current version of the risk analysis report.  
USADEs will be collected and documented at baseline and 0 to 14 days follow-up. 
 
 
7.10.5 Adverse Event Severity Classification 
 
 
Severity will be defined according to the following criteria: 
Mild 
Awareness of event, but easily tolerated 
Moderate 
Discomfort enough to cause some interference with activities of daily living (ADL) 
Severe 
Incapacitating, with an inability to perform ADL 
Death 
Death related to AE 
 
An AE can be classified as severe and not deemed an SAE. Similarly, an SAE is not automatically 
severe in nature. 
In this study, the incidence of patients by AEs category will be summarized by worst severity. 
 
 

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7.10.6 Adverse Event Relationship Classification 
 
Causality assessments define the relationship between the use of the medical device (including the medical-
surgical procedure) and the occurrence of each adverse event, according to MEDDEV 2.7/3 Revision 3, May 
2015 (Guidelines on Medical Devices, Clinical Investigations: Serious Adverse Event Reporting). During 
causality assessment activity, clinical judgment shall be used and the relevant documents, such as the Clinical 
Evaluation Report and the Risk Management Report shall be consulted, as all the foreseeable serious adverse 
events and the potential risks are listed and assessed there. The presence of confounding factors, such as 
concomitant medication/treatment, the natural history of the underlying disease, other concurrent illness or 
risk factors shall also be considered. 
Each SAE will be classified according to five different levels of causality. The sponsor and the investigators 
will use the following definitions to assess the relationship of the serious adverse event to the investigational 
medical device or procedures: 
Not related:  relationship to the device or procedures can be excluded when: 
1. the event is not a known side effect of the product category the device belongs to or of similar 
devices and procedures 
2. the event has no temporal relationship with the use of the device or the procedures; 
3. the serious event does not follow a known response pattern to the medical device (if the response 
pattern is previously known) and is biologically implausible; 
4. the discontinuation of medical device application or the reduction of the level of activation/exposure 
- when clinically feasible – and reintroduction of its use (or increase of the level of 
activation/exposure), do not impact on the serious event; 
5. the event involves a body-site or an organ not expected to be affected by the device or procedure; 
6. the serious event can be attributed to another cause (e.g. an underlying or concurrent illness/ 
clinical condition, an effect of another device, drug, treatment or other risk factors); 
7. the event does not depend on a false result given by the device used for diagnosis, when 
applicable; 
8. harms to the subject are not clearly due to use error; 
9. In order to establish the non-relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event. 
Unlikely: the relationship with the use of the device seems not relevant and/or the event can be reasonably 
explained by another cause, but additional information may be obtained. 
Possible:  the relationship with the use of the device is weak but cannot be ruled out completely. Alternative 
causes are also possible (e.g. an underlying or concurrent illness/ clinical condition or/and an effect of 
another device, drug or treatment). Cases were relatedness cannot be assessed or no information has been 
obtained should also be classified as possible. 
Probable:  the relationship with the use of the device seems relevant and/or the event cannot reasonably 
explained by another cause, but additional information may be obtained. 
Causal relationship: the serious event is associated with the device or with procedures beyond reasonable 
doubt when: 

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1. the event is a known side effect of the product category the device belongs to or of similar devices 
and procedures; 
2. the event has a temporal relationship with device use/application or procedures; 
3. the event involves a body-site or organ that 
a. the device or procedures are applied to; 
b. the device or procedures have an effect on; 
4. the serious event follows a known response pattern to the medical device (if the response pattern is 
previously known); 
5. the discontinuation of medical device application (or reduction of the level of activation/exposure) 
and reintroduction of its use (or increase of the level of activation/exposure), impact on the serious 
event (when clinically feasible); 
6. 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; 
7. harm to the subject is due to error in use; 
8. the event depends on a false result given by the device used for diagnosis, when applicable; 
9. In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event. 
 
In this study, the incidence of patients with AEs related with study procedure or study device will be 
calculated. For each patients having at least one AE, their worst relationship will be identified. An AE 
will be considered as related when it is coded as: 
 
Relationship 
Study CRF 
Final code used (Not related/Related) 
NOT RELATED 
Not related 
UNLIKELY 
Related 
POSSIBLE 
Related 
PROBABLE 
Related 
CAUSAL RELATIONSHIP 
Related 
 
7.10.7 Adverse Event Outcome Classification 
 
Outcome of the event will be defined according to the following: 
• 
Fatal: This event is determined to be the cause of death.  
• 
Not Recovering/ Not Resolved: The event has retained pathological conditions resulting from the 
prior disease or injury. 
• 
Recovered/ Resolved: The event has fully resolved at the end of the study. 
• 
Recovering/ Resolving: The event is ongoing at the end of the study. 
• 
Unknown: The event has been unclassified at the end of the study. 
 
 

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7.10.8 Device Deficiency 
 
A Device deficiency is an inadequacy of a medical device related to its identity, quality, durability, reliability, 
safety or performance, such as malfunction, misuse or use error and inadequate labeling. 
All BiZact™ device deficiencies will be documented on the appropriate Device malfunction eCRF and the device 
should be returned to Medtronic for analysis, if possible.  Instructions for returning the device will be provided.  
Device deficiencies should also be documented in the subject’s medical record. 
Device deficiencies are NOT to be reported as AEs.  However, if there is an AE that results from a device 
deficiency, that specific event would be recorded on the appropriate eCRF. 
Device deficiencies will be reported by frequencies and percentages, and listing will also be provided. 
 
 
 
 Health Outcomes Analyses 
 
Health outcomes have been previously described. 
 
 
 Changes to Planned Analysis 
 
Analysis corresponds to the planned analysis in the CIP. Any deviations from this statistical plan will be 
justified in future revisions to this document or in the final report, as appropriate. 
 
 
8 Validation Requirements 
 
 
Level I validation will be performed for all the analysis output. Level I is defined as that the peer 
reviewer independently programs output and then compares the output with that generated by the 
original Statistical Programmer. 
 

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9 References 
 
 
1. 
Bjordal K., Kaasa S. Psychometric validation of the EORTC Core Quality of Life Questionnaire, 30-
item version and a diagnosis-specific module for head and neck cancer patients. Acta Oncol. 1992;31:311-
21. 
 
2. 
Bjordal K, Ahlner-Elmqvist M, Tolleson E, el al. Development of a European Organization for 
Research and Treatment of Cancer (EORTC) questionnaire module to be used in quality of life assessments 
in head and neck cancer patients. EORTC Quality of Life Study Group. Acta Oncol. 1994;33:879-85 
 
3. 
Bjorda K. Hammerlid E, Ahlner-Elmqvist M, et al. Quality of life in head and neck cancer patients: 
validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
H&N35. J Clin Oncol. 1999;17:1008-19. 
 
 
 
10 Statistical Appendices 
 
Appendix 1: Table shells (provided in a separated file)