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Surgical Innovations Lung Health 161 Cheshire Lane Suite 100 Plymouth, MN 55441 USA www.medtronic.com
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Study: NAVABLATE Official Title: Clinical description of a bronchoscopic approach to ablate lung nodules using the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology ClinicalTrials.gov ID: NCT03569111 Document Type: Study Protocol Document Date: 26-SEP-2019 (Version 4.0)
navablate clinical investigation plan
document cover page

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| Clinical Investigation Plan                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                     |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Clinical Investigation Plan/Study                                                                                                                                                                                                        | Clinical description of a bronchoscopic approach to ablate                                                                                                                                                                                                                          |
| Title                                                                                                                                                                                                                                    | lung nodules using the Emprint™ Ablation Catheter Kit with  Thermosphere™ Technology                                                                                                                                                                                                |
| Clinical Investigation Plan Identifier                                                                                                                                                                                                   | MDT18010ILSBA                                                                                                                                                                                                                                                                       |
| Study Product Name                                                                                                                                                                                                                       | Emprint™ Ablation Catheter Kit with Thermosphere™  Technology                                                                                                                                                                                                                       |
| Sponsor/Local Sponsor                                                                                                                                                                                                                    | Medtronic  Minimally Invasive Therapies Group Surgical Innovations, Lung Health 161 Cheshire Lane, Suite 100 Plymouth, MN 55441 Covidien Services Europe  (an indirect, wholly owned subsidiary of Medtronic plc) Block 3090-3094 Lake Drive Citywest Business Park Dublin, Ireland |
| Document Version                                                                                                                                                                                                                         | Version 4.0, 26-SEP-2019                                                                                                                                                                                                                                                            |
| Lead Principal Investigators                                                                                                                                                                                                             | Kelvin K.W. Lau, MA, DPhil, FRCS(CTh) St Bartholomew's Hospital West Smithfield, London EC1A 7BE Calvin Ng, BSc MB BS MRCS FRCSEd MD FCSHK FHKAM FCCP Prince of Wales Hospital 30-32 Ngan Shing St, Sha Tin Hong Kong                                                               |
| 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 llc is an indirect wholly owned subsidiary of Medtronic plc. |                                                                                                                                                                                                                                                                                     |  
  
  
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1. investigator statement

| Study Product Name                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Emprint™ Ablation Catheter Kit with Thermosphere™  Technology                                                                                                                                                                                                                      |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Sponsor/Local Sponsor                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Medtronic  Minimally Invasive Therapies Group Surgical Innovations, Lung Health 161 Cheshire Lane, Suite 100 Plymouth, MN 55441 Covidien Services Europe (an indirect, wholly owned subsidiary of Medtronic plc) Block 3090-3094 Lake Drive Citywest Business Park Dublin, Ireland |
| Clinical Investigation Plan Identifier                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | MDT18010ILSBA                                                                                                                                                                                                                                                                      |
| Version Number/Date                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Version 4.0, 26-SEP-2019                                                                                                                                                                                                                                                           |
| 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 ISO 14155:2011 (Clinical Investigation of Medical Devices for Human Subjects -  Good Clinical Practice), the European Union Medical Device Regulation, and the International  Conference on Harmonisation (ICH) of Technical Requirements For Registration of Pharmaceuticals  For Human Use, ICH Harmonised Tripartite Guideline for Good Clinical Practice E6 (R1). 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: |                                                                                                                                                                                                                                                                                    |  
| MDT18010ILSBA                                                                                                                                       | Version 4.0                                                                                                                                                     | 26-SEP-2019   | Page 3 of 50   | Medtronic   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|----------------|-------------|
| Table of Contents                                                                                                                                   |                                                                                                                                                                 |               |                |             |
| Investigator Statement                                                                                                                              |                                                                                                                                                                 |               |                |             |
| 1.                                                                                                                                                  |                                                                                                                                                                 |               |                |             |
| 2.                                                                                                                                                  | GIOSSARY                                                                                                                                                        |               |                |             |
| 2.1. Terms .                                                                                                                                        |                                                                                                                                                                 |               |                |             |
| 2. Definitions .                                                                                                                                    |                                                                                                                                                                 |               |                |             |
| 3.                                                                                                                                                  | Synopsis .................................................................................................................................................... 9 |               |                |             |
| 4.                                                                                                                                                  | Introduction .                                                                                                                                                  |               |                |             |
| 4.1.  Background .                                                                                                                                  |                                                                                                                                                                 |               |                |             |
| 4.2. Purpose                                                                                                                                        |                                                                                                                                                                 |               |                |             |
| Objectives and Endpoints                                                                                                                            |                                                                                                                                                                 |               |                |             |
| 5.                                                                                                                                                  |                                                                                                                                                                 |               |                |             |
| 5.1.  Objectives .                                                                                                                                  |                                                                                                                                                                 |               |                |             |
| 5.1.1.                                                                                                                                              | Primary Objective                                                                                                                                               |               |                |             |
| 5.1.2.                                                                                                                                              | Secondary Objectives                                                                                                                                            |               |                |             |
| 6.                                                                                                                                                  | Study Design .                                                                                                                                                  |               |                |             |
| 6.1. Duration                                                                                                                                       |                                                                                                                                                                 |               |                |             |
| 6.2. Rationale                                                                                                                                      |                                                                                                                                                                 |               |                |             |
| 7.                                                                                                                                                  | Product Description                                                                                                                                             |               |                |             |
| 7.1. General .                                                                                                                                      |                                                                                                                                                                 |               |                |             |
| 7.2.  Dosage Form and Route of Administration ...................................................................................................18 |                                                                                                                                                                 |               |                |             |
| 7.3. Manufacturer                                                                                                                                   |                                                                                                                                                                 |               |                |             |
| 7.4. Packaging                                                                                                                                      |                                                                                                                                                                 |               |                |             |
| 7.5.  Intended Use and Population                                                                                                                   |                                                                                                                                                                 |               |                |             |
| 7.6. Equipment                                                                                                                                      |                                                                                                                                                                 |               |                |             |
| 7. Product Use                                                                                                                                      |                                                                                                                                                                 |               |                |             |
| 7.8.  Product Training Requirements                                                                                                                 |                                                                                                                                                                 |               |                |             |
| 7.9.  Product Receipt, Tracking, Storage, Return, and Accountability............................................................20                  |                                                                                                                                                                 |               |                |             |
| Intended Claims                                                                                                                                     |                                                                                                                                                                 |               |                |             |
| 7.10.                                                                                                                                               |                                                                                                                                                                 |               |                |             |
| Selection of Subjects                                                                                                                               |                                                                                                                                                                 |               |                |             |
| 8.                                                                                                                                                  |                                                                                                                                                                 |               |                |             |
| 8.1.  Study Population                                                                                                                              |                                                                                                                                                                 |               |                |             |
| 8.2.  Subject Enrollment                                                                                                                            |                                                                                                                                                                 |               |                |             |
| 8.3.  Inclusion Criteria                                                                                                                            |                                                                                                                                                                 |               |                |             |
| 8.4.  Exclusion Criteria .                                                                                                                          |                                                                                                                                                                 |               |                |             |
| Medtronic Confidential                                                                                                                              |                                                                                                                                                                 |               |                |             |
| 056-F275, v A Clinical Investigation Plan Template                                                                                                  |                                                                                                                                                                 |               |                |             |
| This document is electronically controlled                                                                                                          |                                                                                                                                                                 |               |                |             |
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navablate clinical investigation plan

| MDT18010ILSBA                                                                                                                                                | Version 4.0                                                                                                                                                  | 26-SEP-2019   | Page 4 of 50   | Medtronic   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|----------------|-------------|
| 9.                                                                                                                                                           | Study Procedures .                                                                                                                                           |               |                |             |
| 9.1.  Schedule of Events                                                                                                                                     |                                                                                                                                                              |               |                |             |
| 9.2.  Subject Screening                                                                                                                                      |                                                                                                                                                              |               |                |             |
| 9.3.  Prior and Concomitant Medications ..................................................................................................................24 |                                                                                                                                                              |               |                |             |
| 9.4.  Subject Consent                                                                                                                                        |                                                                                                                                                              |               |                |             |
| 9.5.  Randomization and Treatment Assignment .                                                                                                               |                                                                                                                                                              |               |                |             |
| 9.6.  Medication Compliance                                                                                                                                  |                                                                                                                                                              |               |                |             |
| 9.7.  Assessment of Efficacy .                                                                                                                               |                                                                                                                                                              |               |                |             |
| 9.8.  Assessment of Safety .                                                                                                                                 |                                                                                                                                                              |               |                |             |
| Screening / Baseline Visit .                                                                                                                                 |                                                                                                                                                              |               |                |             |
| 9.8.1.                                                                                                                                                       |                                                                                                                                                              |               |                |             |
| 9.8.2.                                                                                                                                                       | Baseline Imaging .                                                                                                                                           |               |                |             |
| 9.8.3.                                                                                                                                                       | Nodule Characteristics .                                                                                                                                     |               |                |             |
| Index Procedure                                                                                                                                              |                                                                                                                                                              |               |                |             |
| 9.8.4.                                                                                                                                                       |                                                                                                                                                              |               |                |             |
| 9.8.5.                                                                                                                                                       | Safety Endpoints .                                                                                                                                           |               |                |             |
| 9.8.6.                                                                                                                                                       | 1-Month Follow-Up                                                                                                                                            |               |                |             |
| 9.8.7.                                                                                                                                                       | Study Completion .                                                                                                                                           |               |                |             |
| 9.9. Recording Data                                                                                                                                          |                                                                                                                                                              |               |                |             |
| D DEVIATION HANDLING                                                                                                                                         |                                                                                                                                                              |               |                |             |
| 9.10.                                                                                                                                                        | Subject Withdrawal or Discontinuation                                                                                                                        |               |                |             |
| 9.11.                                                                                                                                                        |                                                                                                                                                              |               |                |             |
| 10. Risks and Benefits                                                                                                                                       |                                                                                                                                                              |               |                |             |
| 10.1.                                                                                                                                                        | Potential Risks                                                                                                                                              |               |                |             |
| 10.1.1.                                                                                                                                                      | Summary of Risk Management Report ....................................................................................................30                     |               |                |             |
| 10.1.2.                                                                                                                                                      | Summary of Clinical Evaluation Report ...................................................................................................31                  |               |                |             |
| Radiation Exposure                                                                                                                                           |                                                                                                                                                              |               |                |             |
| 10.1.3.                                                                                                                                                      |                                                                                                                                                              |               |                |             |
| 10.2.                                                                                                                                                        | Potential Benefits .......................................................................................................................................32 |               |                |             |
| 10.3.                                                                                                                                                        | Risk-Benefit Rationale                                                                                                                                       |               |                |             |
| 1.  Adverse Events and Device Deficiencies .                                                                                                                 |                                                                                                                                                              |               |                |             |
| Definitions/Classifications                                                                                                                                  |                                                                                                                                                              |               |                |             |
| 1.1.                                                                                                                                                         | Adverse Event (AE) .                                                                                                                                         |               |                |             |
| 1.1.1.                                                                                                                                                       |                                                                                                                                                              |               |                |             |
| 1.1.2.                                                                                                                                                       | Serious Adverse Event (SAE)                                                                                                                                  |               |                |             |
| Adverse Device Effect (ADE)                                                                                                                                  |                                                                                                                                                              |               |                |             |
| 1.1.3.                                                                                                                                                       |                                                                                                                                                              |               |                |             |
| Medtronic Confidential                                                                                                                                       |                                                                                                                                                              |               |                |             |
| This document is electronically controlled                                                                                                                   | 056-F275, v A Clinical Investigation Plan Template                                                                                                           |               |                |             |  
| MDT18010ILSBA                                                                                                                                    | Version 4.0                                                                                                                                          | 26-SEP-2019   | Page 5 of 50   | Medtronic   |
|--------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|----------------|-------------|
| 1.1.4.                                                                                                                                           | Serious Adverse Device Effect (SADE) .                                                                                                               |               |                |             |
| 1.1.5.                                                                                                                                           | Unanticipated Serious Adverse Device Effect (USADE) ...................................................................34                            |               |                |             |
| 11.1.6.                                                                                                                                          | Device Deficiency                                                                                                                                    |               |                |             |
| 1.1.7.                                                                                                                                           | Adverse Event Relationship Classification ..........................................................................................35               |               |                |             |
| Adverse Event Outcome Classification ...............................................................................................36           |                                                                                                                                                      |               |                |             |
| 11.1.8.                                                                                                                                          |                                                                                                                                                      |               |                |             |
| 11.2.                                                                                                                                            | Reporting of Adverse Events ...........................................................................................................37            |               |                |             |
| 1.2.1.                                                                                                                                           | Notification to Authorities                                                                                                                          |               |                |             |
| 12.  Data Review Committees                                                                                                                      |                                                                                                                                                      |               |                |             |
| 13.  Statistical Design and Methods                                                                                                              |                                                                                                                                                      |               |                |             |
| 14.  Ethics                                                                                                                                      |                                                                                                                                                      |               |                |             |
| Statement(s) of Compliance                                                                                                                       |                                                                                                                                                      |               |                |             |
| 14.1.                                                                                                                                            |                                                                                                                                                      |               |                |             |
| 15.  Study Administration                                                                                                                        |                                                                                                                                                      |               |                |             |
| Monitoring ...................................................................................................................................40 |                                                                                                                                                      |               |                |             |
| 15.1.                                                                                                                                            | DATA Management                                                                                                                                      |               |                |             |
| 15.2.                                                                                                                                            | Direct Access to Source Data/Documents                                                                                                               |               |                |             |
| 15.3.                                                                                                                                            | Confidentiality ..................................................................................................................................41 |               |                |             |
| 15.4.                                                                                                                                            | Liability                                                                                                                                            |               |                |             |
| 15.5.                                                                                                                                            |                                                                                                                                                      |               |                |             |
| 15.6.                                                                                                                                            | CIP Amendments ..........................................................................................................................42          |               |                |             |
| 15.7.                                                                                                                                            | Record Retention ...........................................................................................................................42       |               |                |             |
| 15.8.                                                                                                                                            | Publication and Use of Information                                                                                                                   |               |                |             |
| 15.9.                                                                                                                                            | Suspension or Early Termination ....................................................................................................43               |               |                |             |
| 15.10.                                                                                                                                           | Study Contact Information ....................................................................................................................44     |               |                |             |
| 15.11.                                                                                                                                           | Financial Information                                                                                                                                |               |                |             |
| 16. References .                                                                                                                                 |                                                                                                                                                      |               |                |             |
| 17.  Appendices                                                                                                                                  |                                                                                                                                                      |               |                |             |
| User Manual..............................................................................................................................47      |                                                                                                                                                      |               |                |             |
| 17.1.                                                                                                                                            |                                                                                                                                                      |               |                |             |
| 17.2.                                                                                                                                            | Product Label                                                                                                                                        |               |                |             |
| 17.3.                                                                                                                                            | Bronchoscopic Ablation Patient Satisfaction and Pain Survey .....................................................47                                  |               |                |             |
| Quality of Life Questionnaire .......................................................................................................47          |                                                                                                                                                      |               |                |             |
| 17.4.                                                                                                                                            | NAVABLATE Adverse Event Reference List .................................................................................47                           |               |                |             |
| 17.5.                                                                                                                                            | Sample Informed Consent Form                                                                                                                         |               |                |             |
| 17.6.                                                                                                                                            |                                                                                                                                                      |               |                |             |
| 18.  Version History                                                                                                                             |                                                                                                                                                      |               |                |             |
|                                                                                                                                                  |                                                                                                                                                      |               |                |             |
| Medtronic Confidential                                                                                                                           |                                                                                                                                                      |               |                |             |
| This document is electronically controlled                                                                                                       | 056-F275, v A Clinical Investigation Plan Template                                                                                                   |               |                |             |  
NAVABLATE Clinical Investigation Plan  
  
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2. **Glossary**
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2.1. terms

| 2.1.                                       | Terms                                                             |
|--------------------------------------------|-------------------------------------------------------------------|
| Acronym / Term                             | Definition                                                        |
| ADE                                        | adverse device effect                                             |
| ADL                                        | activities of daily living                                        |
| AE                                         | adverse event                                                     |
| CBCT                                       | cone-beam computed tomography                                     |
| CIP                                        | clinical investigation plan                                       |
| CRF                                        | case report form                                                  |
| CT                                         | computed tomography                                               |
| CTCAE                                      | Common Terminology Criteria for Adverse Events                    |
| EC                                         | ethics committee                                                  |
| ENB                                        | electromagnetic navigation bronchoscopy                           |
| EU MDR                                     | European Union Medical Device Regulation                          |
| EWC                                        | extended working channel                                          |
| GCP                                        | good clinical practice                                            |
| GOLD                                       | Global Initiative for Chronic Obstructive Lung Disease            |
| ICF                                        | informed consent form                                             |
| ICH                                        | International Conference on Harmonisation                         |
| IFU                                        | Instructions for Use                                              |
| IRB                                        | institutional review board                                        |
| ISO                                        | International Organization for Standardization                    |
| IV                                         | intravenous                                                       |
| MHLW                                       | Ministry of Health, Labour, and Welfare                           |
| PMV                                        | post-market vigilance                                             |
| RDC                                        | remote data capture                                               |
| SADE                                       | serious adverse device effect                                     |
| SAE                                        | serious adverse event                                             |
| SAP                                        | statistical analysis plan                                         |
| SBRT                                       | stereotactic body radiation therapy                               |
| USADE                                      | unanticipated serious adverse device effectMedtronic Confidential |
| This document is electronically controlled | 056-F275, v A Clinical Investigation Plan Template                |  
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2.2. definitions

Refer to the NAVABLATE Adverse Event Reference List (Appendix 17.5) for additional definitions.  
Adverse Event See Section 11.1.1.  
Adverse Device Effect See Section 11.1.3.
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common terminology criteria for adverse

A set of criteria for the standardized classification of adverse effects of drugs used in cancer therapy.  
The CTCAE system is a product of the US National Cancer Institute Cancer Therapy Evaluation Program.1 This study will use Version 5.0 (published 27-NOV-2017), available at https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_50https://ctep.canc er.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_50
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instrumental activities of daily living

For the purpose of defining CTCAE grade, instrumental activities of daily living (ADL) refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
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investigational medical device

For the purpose of this clinical investigation plan, an Investigational Medical Device is defined as, "A
device, including a transitional device, which is the object of an investigation." The Investigational Medical Device being evaluated in this study is the Emprint™ Ablation Catheter Kit with Thermosphere™
Technology which has received the CE-Mark.
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investigational medical device

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Serious Adverse Device Effect See Section 11.1.4.  
Serious Adverse Event See Section 11.1.2.
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self-care activities of daily living

For the purpose of defining CTCAE grade, self-care activities of daily living (ADL) refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.1
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technical success

An evaluation of whether the lung nodule was treated according to the study protocol as determined at the immediate post-procedural timepoint. This is in contrast to procedures in which the protocol could not be executed completely, either for technical reasons or for reasons related to comorbid disease.2
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technique efficacy

An evaluation of whether the lung nodule was effectively ablated. Evaluates whether complete ablation of the nodule was achieved as evidenced by imaging follow-up 1-month post-procedure (including a window of 20-40 days post-procedure).2 Unanticipated Serious Adverse Device Effect See Section 11.1.5.  
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| 3. Synopsis Title                                      | Clinical description of a bronchoscopic approach to ablate lung  nodules using the Emprint™ Ablation Catheter Kit with  Thermosphere™ Technology                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
|--------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Clinical Study Type                                    | Prospective, single-arm, multicenter, non-randomized                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| Study Phase                                            | Post-market                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| Product Name                                           | Emprint™ Ablation Catheter Kit with Thermosphere™ Technology                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| Sponsor/Local Sponsor                                  | Medtronic  Minimally Invasive Therapies Group Surgical Innovations, Lung Health 161 Cheshire Lane, Suite 100 Plymouth, MN 55441 Covidien Services Europe (an indirect, wholly owned subsidiary of Medtronic plc) Block 3090-3094 Lake Drive Citywest Business Park Dublin, Ireland                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| Indications for  Use/Intended Use Under  Investigation | Indications for Use: The Emprint™ Ablation System with  Thermosphere™ Technology is intended for use in percutaneous,  laparoscopic, endoscopic, and intraoperative coagulation (ablation) of  soft tissue, including partial or complete ablation of non-resectable  liver tumors. The Emprint™ Ablation System with Thermosphere™ Technology is  not intended for use in cardiac procedures. Intended Use: The Emprint™ Ablation Catheter Kit with  Thermosphere™ Technology is designed for use with the Emprint™  Ablation System and is compatible with superDimension™ Navigation  System's Extended Working Channel (EWC) and Edge™ Bronchoscope  Adapter.  In this study, the flexible Emprint™ Ablation Catheter will be deployed  bronchoscopically using the superDimension™ Navigation System's  EWC in order to ablate lung nodules. |
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technique efficacy

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| Devices will be used within approved intended use as described in the  approved Instructions for Use (IFU) for which CE mark has been  obtained per country.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Investigation Purpose                                                                                                                                          | The purpose of this investigation is to characterize the safety and  performance of the Emprint™ Ablation Catheter Kit with  Thermosphere™ Technology in clinical use.                                                                                                                                                                                                                                                                                                                                                                                       |
| Product Status                                                                                                                                                 | The Emprint™ Ablation Catheter Kit with Thermosphere™ Technology  is CE marked and approved for use in each country.                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Primary Objective                                                                                                                                              | The primary objective of this prospective, single-arm, multicenter,  non-randomized study is to characterize the safety of the Emprint™  Ablation Catheter Kit with Thermosphere™ Technology device in  subjects undergoing lung ablation procedures.  The primary endpoint is the composite rate of adverse events related  to the Emprint™ Ablation Catheter Kit with Thermosphere™  Technology through 1-month follow-up.                                                                                                                                 |
| Secondary Objectives                                                                                                                                           | The following secondary endpoints will be evaluated:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| -                                                                                                                                                              | Composite rate of serious adverse events related to the Emprint™  Ablation Catheter Kit with Thermosphere™ Technology through 1- month follow-up.                                                                                                                                                                                                                                                                                                                                                                                                            |
| -                                                                                                                                                              | Composite rate of all adverse events related to the procedure or  study devices through 1-month follow-up.                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| -                                                                                                                                                              | Composite rate of all serious adverse events related to the  procedure or study devices through 1-month follow-up.                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| -                                                                                                                                                              | Patient satisfaction and pain (Bronchoscopic Ablation Patient Pain  and Satisfaction Survey)                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| -                                                                                                                                                              | Quality of life (EQ-5D Scale)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| -                                                                                                                                                              | Technical success                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| -                                                                                                                                                              | Technique efficacy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| Safety Assessments                                                                                                                                             | For safety reporting, only adverse events related to the Emprint™  Ablation Catheter Kit with Thermosphere™ Technology, accessory  devices, or study procedures will be captured and reported until the  subject exits the study. Adverse events will be summarized as event  counts and percentages that occurred during the ablation procedure  or were detected after the procedure. For the primary endpoint,  relationship specifically to the Emprint™ Ablation Catheter with  Thermosphere™ Technology device will be assessed.Medtronic Confidential |  
Medtronic Confidential  
This document is electronically controlled 056-F275, v A Clinical Investigation Plan Template  
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| All adverse events related to the Emprint™ Ablation Catheter with  Thermosphere™ Technology will be graded for severity based on the  Common Terminology Criteria for Adverse Events.1   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Study Design                                                                                                                                                                             | This is a prospective, single-arm, multicenter, non-randomized study.  Up to 3 sites in up to 3 countries will enroll up to 30 subjects in total.  The study is designed to characterize the safety and performance of  the bronchoscopic ablation procedure using the Emprint™ Ablation  Catheter Kit with Thermosphere™ Technology.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Randomization                                                                                                                                                                            | This study is not randomized.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| Sample Size                                                                                                                                                                              | Up to 30 subjects will be enrolled at up to 3 sites in up to 3 countries.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Inclusion/Exclusion Criteria                                                                                                                                                             | Inclusion Criteria: 1. Subject is ≥ 18 years of age 2. Subject has provided informed consent  3. Subject is able and willing to comply with the study follow-up  schedule 4. Subject has a definitive diagnosis of cancer in the lung  5. Target nodule is ≤ 30mm in maximum diameter  6. There is ≥ 5mm of nodule-free lung parenchyma between  target nodule and pleura or fissure 7. Subject is a candidate for an elective electromagnetic  navigation bronchoscopy (ENB) procedure 8. Subject is a candidate for an elective lung ablation procedure according to standard of care and product Instructions for  Use  9. Subject is not a candidate for lung surgery or refuses lung  surgery 10. Subject is not a candidate for stereotactic body radiation  therapy (SBRT) or refuses SBRT Exclusion Criteria: 1. Target nodule is abutting main stem bronchus, main  pulmonary vasculature, esophagus and/or trachea 2. Patients currently diagnosed with Global Initiative for Chronic  Obstructive Lung Disease (GOLD) Stage IV emphysema 3. Female subjects who are pregnant or nursing as determined Medtronic Confidential |
| This document is electronically controlled                                                                                                                                               | 056-F275, v A Clinical Investigation Plan Template                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |  
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| by standard site practices   |                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                          |
|------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 4.                           | Subject has participated in an investigational drug or device  research study within 30 days of enrollment that would  interfere with this study                                                                                                                                                                                                                                                  |                                                                                                                                                                          |
| 5.                           | The investigator determines that participation in the study  may jeopardize the safety or welfare of the subject                                                                                                                                                                                                                                                                                  |                                                                                                                                                                          |
| Study Procedures and         | Subjects will be evaluated at:                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                          |
| Assessments                  | -                                                                                                                                                                                                                                                                                                                                                                                                 | Baseline: To determine study eligibility and collect baseline  information (demographics, medications, medical history, etc.),  Quality of Life Evaluation (EQ-5D scale) |
| -                            | Procedure: To re-confirm nodule eligibility criteria, and collect  nodule characteristics, medication changes, procedure plan and  procedure information, standard imaging, immediate postprocedure evaluation, adverse event evaluation                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                          |
| -                            | 1-month follow-up (20-40 days post-procedure): Standard imaging,  follow-up evaluation, medication changes, adverse event  evaluation, Bronchoscopic Ablation Patient Satisfaction and Pain  Survey, Quality of Life Evaluation (EQ-5D scale)                                                                                                                                                     |                                                                                                                                                                          |
| Statistics                   | No formal sample size estimates were conducted. Based on the  design and purpose of the study, there is no required number of  subjects to prove study claims or objectives. The study is predefined  to include up to 30 subjects with 20 being the approximate minimum.  Study data will be summarized as descriptive statistics (frequencies  and percentages) and will inform future studies. |                                                                                                                                                                          |
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4. introduction 4.1. background

While surgical resection remains the gold standard for the treatment of localized well-defined lung tumors, many patients are medically inoperable due to existing comorbidities. For this reason, alternative modalities are needed as an option for inoperable subjects.  
Image-guided thermal ablation is a minimally invasive option that is becoming increasingly accepted for solitary lung tumors or selected metastatic tumors in patients who are medically inoperable.3 Approaches include radiofrequency ablation, microwave ablation, cryoablation, and laser ablation.  
4, 5 Radiofrequency ablation has been the most well-characterized thermal ablation method to date.  
Radiofrequency ablation uses electromagnetic energy to induce local tissue heating and cell death by coagulation necrosis.  
6, 7 Radiofrequency ablation has been recommended for peripheral tumors < 3 cm in inoperable patients.  
8 While effective, use of radiofrequency ablation is limited by high rates of incomplete ablation and local recurrence, particularly in large tumors.  
9, 10 Microwave ablation involves placement and activation of an antenna directly into the target tissue. The system generates an alternating electric field which radiates microwave energy into target tissue. This causes rotation of water molecules, leading to friction, and resulting in thermal necrosis of the tissue.  
Advantages of microwave ablation over radiofrequency ablation include faster treatment of a larger tissue volume, and the minimization of the heat sink effect, in which local recurrence is increased in perivascular regions when heat is drawn away from the ablation zone by flowing blood faster than can be generated by the ablation device. Faster, hotter, and larger ablation zones also reduce the number of antenna placements required.  
4, 5, 11 However, previously available microwave ablation systems were still challenged by variations in the anatomical environment (e.g., proximity to large vessels, size of tumor, tissue type, tissue hydration), particularly in the lung. These factors influence the predictability of ablation zone size and shape, preventing complete ablation of diseased tissue and ultimately resulting in local recurrence. The Emprint™ Ablation Catheter Kit with Thermosphere™ Technology is a novel thermal ablation device that uses wavelength-controlled, field-based energy to deliver adequate energy to create a large, spherical active zone regardless of tissue environment.  
12-14 This resilience to anatomical distortion minimizes reliance on passive heating and reduces the number of overlapping ablations required to achieve a desired ablative effect. The safety and performance data currently available for use of the Emprint™ Ablation System in the lung include a published study15 and an unpublished sponsored study (Clinicaltrials.gov identifier NCT02323854) describing use of the Emprint™ Ablation System using a percutaneous approach. These studies demonstrate that the Emprint™ Ablation System performed as expected in the lung with a safety Medtronic Confidential This document is electronically controlled 056-F275, v A Clinical Investigation Plan Template  
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profile consistent with the known safety profile for ablation in the lung. Additionally, an external research project has been initiated which will report on a retrospective analysis of use of the Emprint™ Ablation System in lung malignancies using a percutaneous approach.  
The safety of image-guided bronchoscopic access of lung nodules using the superDimension™ navigation system has been established. In a meta-analysis of 15 published studies, pneumothorax occurred in 3.1% of patients (1.6% with intervention) and minor/moderate bleeding in 0.9%.16 This is lower than the pooled complication rates of computed tomography (CT)-guided transthoracic core biopsy and fineneedle aspiration across 32 publications: 18.8%-25.3% pneumothorax, 4.3%-5.6% pneumothorax with intervention, 6.4%-18.0% pulmonary hemorrhage, and 1.7%-4.1% hemoptysis.17 The Emprint™ Ablation Catheter with Thermosphere™ Technology was introduced as part of the Emprint™ Ablation System to provide a bronchoscopic approach using the superDimension™ navigation system. The current clinical study will be conducted to characterize the safety and performance of the Emprint™ Ablation Catheter with Thermosphere™ Technology for bronchoscopic thermal ablation in the lung.
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4.2. purpose

The purpose of this investigation is to characterize the safety and performance of the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology in clinical use.
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5. objectives and endpoints 5.1.

The primary objective of this prospective, single-arm, multicenter, non-randomized study is to characterize the safety of the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology device in subjects undergoing lung ablation procedures. The primary endpoint is the composite rate of adverse events (AEs) related to the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology through 1-month follow-up.
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5.1.2. secondary objectives

The following secondary endpoints will be evaluated:
- Composite rate of serious AEs (SAEs) related to the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology through 1-month follow-up.  
- Composite rate of all AEs related to the procedure or study devices through 1-month follow-up.  
  
- Composite rate of all SAEs related to the procedure or study devices through 1-month follow-up.  
- Patient satisfaction and pain (Bronchoscopic Ablation Patient Pain and Satisfaction Survey)
- Quality of life evaluation (EQ-5D scale)
- Technical success: An evaluation of whether the lung nodule was treated according to the study protocol as determined at the immediate post-procedural timepoint. This is in contrast to procedures in which the protocol could not be executed completely, either for technical reasons or for reasons related to comorbid disease.2
- Technique efficacy: An evaluation of whether the lung nodule was effectively ablated. Evaluates whether complete ablation of the nodule was achieved as evidenced by imaging follow-up 1-month post-procedure (including a window of 20-40 days post-procedure).2
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6. study design

This is a prospective, single-arm, multicenter, non-randomized study. Up to 3 sites in up to 3 countries/regions will enroll up to 30 subjects in total. The study is designed to characterize the safety and performance of the bronchoscopic ablation procedure using the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology.
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6.1. duration

Assessments will occur at baseline, during and immediately post-procedure, and at 1-month follow-up. The expected duration of each subject's participation in the study from the baseline visit to the 1-month follow-up is up to approximately 2 months (based on a baseline visit a maximum of 30 days preprocedure and a follow-up window up to 40 days post-procedure).  
Based on the expected enrollment rate of 1 subject per site per month, the total duration of the study from first subject enrollment to last subject follow-up is expected to be approximately 18 months.
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6.2. rationale

This study is a prospective, single-arm, multicenter, non-randomized study. Up to 3 sites in up to 3 countries will enroll up to 30 subjects in total. The study is designed to characterize the safety and performance of the bronchoscopic ablation procedure using the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology.  
This study is single-arm and is not statistically powered. A maximum number of sites and subjects is proposed in order to provide a multicenter evaluation while minimizing risk to subjects. Enrollment of subjects who are not candidates for lung surgical resection or SBRT (or who refuse surgical resection or SBRT) will minimize exposure to only those with limited clinically viable options. Restricting nodules to those with ≥5mm of nodule-free lung parenchyma between the target nodule and pleura or fissure and excluding target nodules abutting the main stem bronchus, main pulmonary vasculature, esophagus  
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and/or trachea will minimize exposure and risk to the vasculature and surrounding tissue. While these inclusion/exclusion criteria are designed to minimize risk to subjects, results may not be generalizable to other populations of patients not evaluated as part of this study protocol. In addition, the results of this study will represent the outcomes in a small number of centers with experienced users and may not be generalizable across all institutions. If the study results support further clinical research, additional studies will examine a broader patient population across more diverse clinical sites.  
Prior bench, preclinical, and clinical testing to justify the current clinical evaluation of the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology have been described in the Clinical Evaluation Report for the Covidien Emprint™ Ablation System and Accessories and are summarized briefly below.  
Design verification and validation test results provide reasonable assurance that the device conforms to the requirements for its indications for use and intended use. Extensive bench verification was performed to confirm the catheter's compatibility with the system generator, demonstrate its robustness to mechanical stresses, and establish its reliability, after conditions of misuse. Tissue-based testing was conducted using an ex-vivo soft tissue model (bovine liver) to confirm functionality. The catheter passed all verification tests, meeting all of the associated design requirements. The verification tests were designed to be clinically relevant and their successful completion supports the readiness of the device for clinical use. All reported deviations were minor in nature and did not impact the overall test result.  
Biocompatibility evaluations and appropriate testing were performed on the patient contact components of the Emprint™ Ablation System. Arnitel EM740 (Trans Grey 431 C) is the only patientcontacting material in the ablation catheter (all other materials are considered non-patient contacting).  
The catheter passed all ISO and MHLW cytotoxicity, sensitization, and hemolysis tests as well as ISO systemic injection testing, ISO intracutaneous testing, and physiochemical testing.  
A Covidien-sponsored chronic in vivo study examined use of the Emprint™ Ablation Catheter in 6 domestic male swine undergoing lung bronchoscopic ablation in a survival study. All ablations were performed using the Emprint™ Ablation Catheter with the Emprint™ Ablation System. Safety endpoints included incidence/severity assessment of pneumothorax, intra-operative bleeding assessment after device use, macroscopic/microscopic evaluation of representative tissues, and overall animal health.  
Observations did not raise a safety concern regarding use of the ablation catheter or microwave ablation procedure in the lung and were consistent with known clinical findings in humans. Most findings were considered common observations in laboratory animals following an anesthetic and surgical procedure and no abnormalities were attributed to the catheter device. Eight published clinical studies evaluated the safety and performance of the Emprint™ ablation system for primary or metastatic cancer. Six studies were conducted in the liver,18-23 1 in the pancreas,24 and 1 in the lung.  
15 Ierardi 2017 evaluated 19 patients with 31 primary or metastatic lung tumors (28 microwave ablation procedures) undergoing percutaneous lung ablation with the Emprint™ ablation system.15 Only  
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1 major complication occurred: pneumothorax. Minor complications included self-resolving pneumothorax (14 of 28 sessions) and perilesional hemorrhagic effusion (13 of 28 sessions), as well as hospitalization-related lower urinary tract infection in 3 of 28 sessions.15 An additional unpublished sponsored study (NCT02323854) also describes use of the Emprint™ Ablation System in the lung using a percutaneous approach in 15 subjects. All 15 subjects underwent ablation followed by planned surgical resection. Complete ablation was detected in 54.4% (6/11), incomplete ablation in 36.4% (4/11), and delayed necrosis in 9.1% (1/11). There were no device-related AEs reported. A total of 5 SAEs occurred in 3 subjects (20%). SAEs included acute respiratory failure, pulmonary air leakage, prolonged air leak, Guillain-Barre Syndrome, and respiratory arrest, which resolved after the procedure. All 5 SAEs were either not related or unlikely to be related to the procedure. Twelve AEs were related to the ablation procedure, including bleeding, pneumothorax (Grade 1, n=4), hemoptysis (Grade 1, n=1), hemothorax (Grade 2, n=2), and vasovagal syncope (Grade 1, n=1). These studies demonstrate that the Emprint™
Ablation System performed as expected with a safety profile consistent with the known safety profile for lung ablation. The Emprint™ Ablation Catheter was introduced as part of the Emprint™ Ablation System in 2016. Its CE
mark was based on equivalence to the percutaneous antenna utilizing the same Thermosphere™ technology. Therefore, the proposed clinical study will be conducted specifically to characterize the safety and performance of the catheter device in the lung with a bronchoscopic approach.
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7. product description 7.1. general

The device under study is the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology
(CA108L1), an endoscopic ablation accessory for use with the Emprint™ Ablation System. The Emprint™
Ablation Catheter Kit with Thermosphere™ Technology is for use with the Emprint™ Ablation System with Thermosphere™ Technology for the ablation of lung tissue.  
Microwave-based soft tissue ablation uses microwave energy to increase target tissue temperature resulting in thermocoagulation and cellular death. Microwave energy is supplied by a generator and emits from the exposed portion of an antenna. The Evident™ Microwave Ablation System was designed to provide microwave power for ablation of soft tissue during medical procedures. It received the CE
mark in 2007 and 510k clearance in 2008. The Emprint™ Ablation System is an evolution of the technology within the Evident™ Microwave Ablation System, which received both CE mark and 510k clearance in 2014. The Emprint™ system utilizes higher power, a more efficient cable and antenna design, and an antenna designed to create a more spherical field pattern (Thermosphere™ technology). An ablation catheter has been added as an accessory to the Emprint™ system- to be used in a bronchoscopic approach for lung ablation.  
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The shelf life of the product is intended to be expanded to 24 months which may occur during the course of the study. No other changes to the product are anticipated.
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7.2. dosage form and route

The Emprint™ Ablation Catheter Kit with Thermosphere™ Technology is deployed endoscopically (bronchoscopically) and will be used to conduct bronchoscopic ablations in the lung using the superDimension™ navigation system.
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7.3. manufacturer

The Emprint™ Ablation Catheter Kit with Thermosphere™ Technology is manufactured by Covidien llc, an indirect wholly owned subsidiary of Medtronic plc.
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7.4. packaging

The Emprint™ Ablation Catheter will be provided to health care providers as part of a kit (Catalog No.  
CA108L1). In addition to the catheter, the kit includes a stabilizing rail that is attached to the Edge Bronchoscope Adapter and a locking clip. Products used in this study that are commercially available are packaged and labelled accordingly. Labeling of devices will be provided in accordance with local language requirements.  
  
Figure 1. The Emprint™ Ablation Catheter, rail, and clip. (1) Intravenous IV Bag Spike; (2) Drip Chamber;
(3) Pump Tubing; (4) Generator Connector; (5) Ablation Catheter Handle; (6) Top Groove, (7) Control Ring,
(8) Radiating Section; (9) Clip; (10) Rail
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7.5. intended use and population

The Emprint™ Ablation System with Thermosphere™ Technology is intended for use in percutaneous, laparoscopic, endoscopic, and intraoperative coagulation (ablation) of soft tissue, including partial or complete ablation of non-resectable liver tumors.  
The Emprint™ Ablation System with Thermosphere™ Technology is not intended for use in cardiac procedures.  
This study will evaluate the population of patients where the use of the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology is conducted via a bronchoscope for ablation of malignant nodules in the lung.
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7.6. equipment

The Emprint™ Ablation Catheter is designed for use with the Emprint™ system components (Figure 1 above) and is compatible with the Covidien Edge™ or Edge™ Firm Tip Extended Working Channel (EWC)  
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and Edge Bronchoscope Adapter. The system's reusable cable (connects the percutaneous antenna to the microwave generator) is not used with the flexible catheter, as the catheter is designed to connect to the generator directly. Sites must have access to the superDimension™ navigation system utilizing either software version 6 or higher at the time of study initiation for each site, with potential for upgrade to the most recent software release throughout the duration of the study. Sites must also have a procedure room equipped with a cone-beam computed tomography (CBCT) imaging system. Sites may also use the CrossCountry™ Transbronchial Access Tool to obtain access.
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7.7. product use

For the purpose of this post-market clinical study, the Emprint™ ablation catheter and Emprint™ Ablation Catheter Kit with Thermosphere™ Technology should be used according to manufacturer's Instructions for Use and standard-of-care. Typically, one ablation catheter is used per procedure but more than one may be used at the investigator's discretion.
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7.8. product training requirements

Physicians must have documented completion of the manufacturer's bronchoscopic ablation training program and sufficient experience conducting ENB procedures and in using CBCT, the CrossCountry™ Access Tool, and the Emprint™ ablation system. Documented completion will be recorded on the Study Enrollment Eligibility Form.
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7.9. product receipt tracking storage

The study devices provided by the Sponsor will be recorded on the study specific Product Accountability Log. Information to be recorded will include, but is not limited to, date of receipt, and the date used or date of return to the Sponsor. The study-specific devices shall be kept in a locked room. The study devices provided by the Sponsor will be labeled with a study-specific label indicating that it is only to be used for study subjects.
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7.10. intended claims

The purpose of this investigation is to characterize the safety and performance of the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology in clinical use. This study does not specifically evaluate efficacy claims.  
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8. selection of subjects 8.1.

The study population will consist of consented adults undergoing bronchoscopic lung ablation procedures using electromagnetic navigation bronchoscopy (ENB). Additional inclusion and exclusion criteria are listed below.
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8.2. subject enrollment

Up to 30 subjects will be enrolled at up to 3 sites in up to 3 regions. The minimum and maximum number of subjects to be included at each site are not prespecified since the study is not statistically powered.  
For the purpose of this clinical study investigational plan, the point of enrollment is defined as the insertion of the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology into the EWC.  
Subjects will be approached to obtain written informed consent prior to any institution non-standard-ofcare assessments or study-specific data being collected. During the index procedure imaging, nodule eligibility criteria will be re-confirmed. Any patients with nodules no longer meeting eligibility criteria will not be enrolled. Subjects who provide study consent but then are determined to be ineligible prior to the insertion of the ablation catheter will be considered screen failures and documented as such in the database.
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8.3. inclusion criteria

1. Subject is ≥ 18 years of age 2. Subject has provided informed consent 3. Subject is able and willing to comply with the study follow-up schedule 4. Subject has a definitive diagnosis of cancer in the lung 5. Target nodule is ≤ 30mm in maximum diameter 6. There is ≥ 5mm of nodule-free lung parenchyma between target nodule and pleura or fissure 7. Subject is a candidate for an elective ENB procedure 8. Subject is a candidate for an elective lung ablation procedure according to standard of care and product Instructions for Use 9. Subject is not a candidate for lung surgery or refuses lung surgery 10. Subject is not a candidate for stereotactic body radiation therapy (SBRT) or refuses SBRT
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8.4. exclusion criteria

1. Target nodule is abutting main stem bronchus, main pulmonary vasculature, esophagus and/or  
  
trachea 2. Patients currently diagnosed with Global Initiative for Chronic Obstructive Lung Disease (GOLD)
Stage IV emphysema 3. Female subjects who are pregnant or nursing as determined by standard site practices 4. Subject has participated in an investigational drug or device research study within 30 days of enrollment that would interfere with this study 5. The investigator determines that participation in the study may jeopardize the safety or welfare of the subject
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9. study procedures

Following confirmation of eligibility and informed consent, subjects with inoperable lung nodules will undergo an ablation procedure using a bronchoscopic approach. A target nodule will be identified on a pre-procedure CBCT scan. Nodule localization will be aided by ENB using the superDimension™ navigation system. Once localized, if no suitable bronchus sign leads to the proposed area to ablate, access to the region may be obtained using the CrossCountry™ Transbronchial Access Tool. Once ablation region access has been achieved, the ablation catheter will be placed inside the EWC and will be unsheathed inside the target nodule. Correct positioning will be verified using CBCT and the nodule will then be ablated. AEs related to Emprint™ Ablation Catheter Kit with Thermosphere™ Technology, accessory devices, or study procedures will be captured and reported until the 1-month follow-up visit.
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9.1. schedule of events

Variables to be collected (following confirmation of eligibility and written informed consent), follow-up visit schedule, and tests to be performed at each visit are described in **Table 1** below.
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9.1. schedule of events

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| Table 1. Schedule of Events.                                                             | During the   |    |    |
|------------------------------------------------------------------------------------------|--------------|----|----|
| Procedure and                                                                            |              |    |    |
| Immediately PostProcedure                                                                                          | 1-Month Follow-up  (20 to 40 Days PostProcedure)              |    |    |
| Baseline                                                                                 |              |    |    |
| (Day -30 to Day 0)                                                                       |              |    |    |
| Subject demographics                                                                     | X            |    |    |
| Medical history (Lung  Diagnoses, Previous Lung  procedures, Lung function  tests, etc.) | X            |    |    |
| Eligibility assessment                                                                   | X            | X  |    |
| Nodule characteristics                                                                   | X            |    |    |
| Procedural information                                                                   | X            |    |    |
| Adverse event assessment                                                                 | X            | X  |    |
| Imaging                                                                                  | X*           | X  | X  |
| Concomitant medications                                                                  | X            | X  | X  |
| Quality of life survey (EQ-5D)                                                           | X            | X  |    |
| Bronchoscopic Ablation  Patient Pain and Satisfaction                                    | X            |    |    |
| Survey                                                                                   |              |    |    |
| *Standard-of-care CT scan performed prior to consent.                                    |              |    |    |
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9.2. subject screening

A baseline visit will be performed within 30 days prior to the scheduled procedure to assess study eligibility. During the index procedure imaging, nodule eligibility criteria will be re-confirmed. Consented subjects will be considered for the study if they meet specified inclusion criteria and none of the exclusion criteria. The criteria for enrollment must be followed explicitly. Subjects who provide study consent, but then are determined to be ineligible prior to the start of the ablation portion of the procedure will be considered screen failures and will not require additional study follow-up visits. The reason for the Screen Failure will be clearly documented on the applicable electronic case report forms (eCRFs). Screen failures will not be counted towards the number of study subjects.
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9.3. prior and concomitant medications

All prior and concomitant medications should be managed according to standard-of-care.
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9.4. subject consent

Subjects will be approached to obtain written informed consent prior to any institution non-standard-ofcare assessments or study-specific data being collected. The purpose of the study and the benefits and risks of participating in the study will be explained to the subject and the consent process must be documented accordingly.  
Subjects will be informed that their participation in this study is voluntary and that they may refuse to participate or discontinue from the study at any time. Additionally, subjects will be informed that despite signing informed consent, the screening assessments may demonstrate the subject is not a suitable candidate for the study or the ablation procedure and may be withdrawn. Subjects will be given the opportunity to ask the investigator questions so that they are adequately informed about the research.  
After being informed of the nature of the study, subjects who agree to study participation must sign a written informed consent form (ICF) that has been approved by the appropriate Ethics Committee (EC)
or Institutional Review Board (IRB) and Regulatory Authority if required per country, of the respective clinical site. A copy of the signed ICF must be provided to the subject. For this study, the subject must sign and date the ICF personally. *The use of Legally Authorized* Representatives, Healthcare Proxies or any other means of representation will not be permitted. All procedures evaluated in this study are considered elective; no emergency procedures or circumstances where the subject is unable to give consent will be permitted according to the study inclusion criteria. 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. The principal investigator or his/her authorized designee must conduct the informed consent process.
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9.5. randomization and treatment assignment

Not applicable. There are no treatment arms or randomizations required for this study.
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9.6. medication compliance

Not applicable. There are no required medications or medication protocols for this study.
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9.7. assessment of efficacy

The following efficacy endpoints will be evaluated:
- Technical Success: An evaluation of whether the lung nodule was treated according to the study protocol as determined at the immediate post-procedural timepoint. This is in contrast to procedures in which the protocol could not be executed completely, either for technical reasons or for reasons related to comorbid disease.2
- Technique Efficacy: An evaluation of whether the lung nodule was effectively ablated. Evaluates whether complete ablation of the nodule was achieved as evidenced by imaging follow-up 1-month post-procedure (including a window of 20-40 days post-procedure).2 Full procedures for study visits and the index ablation procedure are described in the section
"Assessment of Safety" below.
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9.8. assessment of safety 9.8.1.

A screening/baseline visit will be performed within 30 days prior to the ablation procedure to assess eligibility. The following assessments will be performed and the results recorded on the appropriate subject eCRFs:
- Verification of eligibility criteria
- Subject demographics (e.g.,. subject age, sex, ethnicity, race)
- Subject medical history (e.g., COPD, asthma, emphysema, tobacco history, cancer diagnosis) - History of prior invasive lung procedures
- Medication use (e.g., immunotherapy, chemotherapy, targeted antineoplastic therapy, prescription antithrombotics)
- Pulmonary function testing (if available per standard of care)
- Quality of Life Survey (EQ-5D)
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9.8.2. baseline imaging

In accordance with inclusion criteria, nodules ≤ 30mm in maximum diameter with ≥ 5mm of nodule-free lung parenchyma between target nodule and pleura or fissure are eligible to be considered target nodules for the study analysis. This will be based on standard-of-care (SOC) baseline imaging. One target nodule per subject will be identified on a SOC baseline CT prior to patient consent. If the study subject has more than one nodule meeting the above criteria, the most easily accessible nodule, as determined by the physician investigator, will be targeted for the study.
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9.8.3. nodule characteristics

Nodule characteristics (e.g., size, location, morphology) will be captured at procedure.
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9.8.4. index procedure

The index procedure workflow is shown in Figure 2. The EWC will be inserted and navigation to the target will be conducted according to the manufacturer's Instructions for Use. CBCT will be used to confirm target nodule localization using fluoroscopy overlay. If CT indicates the absence of a bronchus sign leading to the center of the target nodule, access to the nodule may be obtained using the CrossCountry™ Transbronchial Access Tool under CBCT guidance. During the index procedure imaging, nodule eligibility criteria will be re-confirmed. Any patients with nodules no longer meeting eligibility criteria will not be enrolled. For the purpose of this clinical study investigational plan, the point of enrollment is defined as the insertion of the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology into the EWC. A high-level procedure workflow is shown below. Investigators will refer to the manufacturer's instructional documents for additional detail.  
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Figure 2. Index procedure workflow
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9.8.5. safety endpoints

The primary objective of this prospective, single-arm, multicenter, non-randomized study is to characterize the safety of the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology device in subjects undergoing lung ablation procedures. The primary endpoint is the composite rate of AEs related to the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology through 1-month follow-up. In addition, the following secondary safety endpoints will be evaluated:
- Composite rate of SAEs related to the Emprint™ Ablation Catheter Kit with Thermosphere™
Technology through 1-month follow-up.  
- Composite rate of all AEs related to the procedure or study devices through 1-month follow-up.  
- Composite rate of all SAEs related to the procedure or study devices through 1-month follow-up.  
All AEs related to the Emprint™ Ablation Catheter with Thermosphere™ Technology will be graded for severity based on the Common Terminology Criteria for Adverse Events.1  
  
  
  
For safety reporting, only AEs related to the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology, accessory devices, or study procedures will be captured and reported until the subject exits the study (refer to Section 11.1 for additional details). Related AEs will be summarized as the event counts and percentage which occurred during the ablation procedure or detected after the procedure within the 1-month reporting timeframe. For the primary endpoint, relationship specifically to the Emprint™ Ablation Catheter with Thermosphere™ Technology device will be assessed.
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9.8.6. 1-month follow-up

The study subject will complete the study at the conclusion of the 1-month follow-up visit, conducted per standard local practice, but within the window of 20-40 days after the study index procedure. The following assessments will be performed and the results recorded on the appropriate subject eCRFs:
- Medication use (e.g., immunotherapy, chemotherapy, targeted antineoplastic therapy, prescription antithrombotics)
- A follow-up CT scan at this timepoint will be used for the evaluation of Technique Efficacy
- AE assessment (AEs related to the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology, accessory devices, or study procedures)
- Quality of life survey (EQ-5D)
- Bronchoscopic Ablation Patient Pain and Satisfaction Survey
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9.8.7. study completion

Subjects will complete the study at the completion of the 1-month post-procedure visit. No additional study-specific care will be provided to study subjects after completion of the study. Standard of care should continue. The reporting window for the 1-month follow-up is 20-40 days.
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9.9. recording data

This study will utilize an eCRF. The eCRF will be used to capture the required data elements. Medical and study records, rather than eCRFs, will serve as the source documentation.
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9.10. deviation handling

No written waivers from the CIP will be granted. The Principal Investigator must make every effort to follow the CIP, unless the deviation is necessary in an emergent situation to protect the rights, safety and/or well-being of the subject. Deviations from the CIP will be collected on a Protocol Deviation CRF
and reviewed with the Principal Investigator to ensure compliance. The investigator must notify Medtronic and the reviewing ethics committee (EC) / institutional review board (IRB) of any deviation from the Investigational Plan when specific to the protection of the life or  
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physical well-being of a subject in an emergency. Such notice must be given as soon as possible, but in no event later than five (5) working days after the emergency has occurred. All study deviations will be reported by Medtronic to the Regulatory Authority (if applicable) via either Final Clinical Study Report or separate notification in case of substantial CIP deviation, for which the Regulatory Authority approval is required before its implementation.  
If a pattern of non-compliance is noted, the study manager will determine the course of action to take, such as root cause, review relevant CIP procedures and as applicable retrain and verify understanding of the issue in question. This will be documented in the Study Master Files. In the case of repeated or serious non-compliance, the Sponsor reserves the right to disqualify the offending site.
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9.11. subject withdrawal or discontinuation

Subjects may voluntarily withdraw from the study if they no longer wish to have their study-related information used. Additionally, the Principal Investigators may withdraw or choose not to enroll subjects if they feel they do not meet the CIP defined inclusion and exclusion criteria or if it is in the best medical interest of the subjects in question.  
In cases of voluntary subject withdrawal, all data collected from the time of informed consent to the time of voluntary withdrawal may be used. The General Data Protection Regulation (GDPR) process will be followed as applicable per country regulations. Withdrawn subjects will not be replaced. Enrollment will continue as per CIP definitions up to the predefined maximum number of subjects. All subjects will be followed per institutional standard of care after any withdrawal, discontinuation, or completion of the study follow-ups.  
The reason for study exit of all enrolled subjects 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. Every attempt will be made to contact subjects who are noncompliant. Subjects will be considered lost to follow-up once the following steps have been taken:
- Three 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.  
- If there is no response to the phone calls, then a certified/registered letter should be written to the subject. A copy of the letter should be retained in the subject's source document.  
- After a period of one week following completion of the above actions, the subject will be considered lost to follow-up. The sponsor should be notified and the Study Exit form should be completed.  
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10. risks and benefits 10.1.

The potential risks of the Emprint™ Ablation System have been described in the Risk Management Report for the Emprint Ablation System with Ablation Catheter and the Clinical Evaluation Report for the Covidien Emprint™ Ablation System and Accessories and are summarized briefly below. The clinical investigation has been designed to involve as little pain, discomfort, fear, and any other foreseeable risk as possible for the subjects, and both the risk threshold. The degree of distress are specifically defined in the clinical investigation plan and constantly monitored.
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10.1.1. summary of risk management

A clinical risk/benefit analysis evaluated whether the Emprint™ Ablation System with Ablation Catheter is likely to provide more benefit than harm. Listed below are the high-risk residual risks from the risk analysis. All of the residual risks listed below have been described in the literature as known and/or experienced complications of ablation procedures. All patients who undergo an ablation procedure are consented for such risks. Benefit estimation describes the expected performance of the device, expected clinical outcome, and risks and benefits related to other procedural options. The risk/benefit comparison documents the judgments of whether the benefits exceed the residual risks.  
- Pleural effusion
- Intraparenchymal pulmonary hemorrhage / bronchopulmonary hemorrhage - Pain/shoulder pain
- Mortality
- Pyothorax - Atrial fibrillation
- Hemolysis
- Pulmonary/upper respiratory fistula
- Hemothorax
- Abscess
- Hematoma - Hemoptysis - Pneumonia
- Pulmonary edema
- Ventricular arrhythmia - Unintended microwave burn - unintended tissue ablation
- Unintended microwave burn - vessel thrombosis /thrombus /embolism  
  
  
- Unintended microwave burn - diaphragmatic paresis Expected AE rates are described in Section 10.1.2 below.  
In accordance with the safety assessments described in Section 9.8.5, risks will be continuously monitored, assessed and documented by the investigator.
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10.1.2. summary of clinical evaluation

A Clinical Evaluation Report (CER) for the Covidien Emprint™ Ablation System and Accessories was performed according to the provisions of the Medical Devices Directive 93/42/EEC (MDD), as amended by Directive 2007/47/EC. This report was prepared in accordance with the following Guidelines and Standard Operating Procedures (SOPs) to provide evidence of the medical safety and performance of the Emprint™ Ablation System and Accessories for its intended use: MEDDEV 2.7/1 rev. 4 (June 2016),
MEDDEV 2.12/2 rev. 2 (January 2012). The intent of this CER was to provide evidence that the Emprint™ Ablation System and Accessories are safe, effective, and state-of-the-art for the indications and intended use, through a critical review of product-related documents, testing, published clinical literature and post-market data. A brief summary of that report is included below.  
The safety of the Emprint™ Ablation System has been assessed in 8 clinical studies evaluating its use in the liver,18-23 pancreas, 24 and lung,15 as well as complaints and vigilance reports of 27,150 devices sold.  
All complications occurred in < 1% of patients each (total complication rate 4.7%). This is comparable to or better than the 10.3% complication rate in the liver for minor and major complications reported in the literature. The majority of complications reported with use of microwave ablation in the lung (such as pneumothorax and hemorrhagic effusion) were from one clinical publication and one clinical investigation and are either known complications of microwave ablation or were deemed to not be related to the device or the procedure. In one clinical publication of microwave ablation in the pancreas, pain was the only complication reported. Pain is a common complication, and often resolves spontaneously or with treatment. In the post-market complaints and vigilances report spanning a 5-year period, all confirmed injuries are known to occur with microwave ablation. In addition, 5 of 7 deaths reported occurred in patients with major comorbidities.  
All complications that occurred with use of the Emprint™ MWA ablation system in the liver, lung, and pancreas are either known to occur with microwave ablation or were deemed to be unrelated. In addition, complications in the liver and lung occurred at similar rates to other microwave ablation devices reported in the literature.
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10.1.3. radiation exposure

There are risks associated with the use of x-ray fluoroscopy, CBCT, and CT imaging for this study.
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10.1.3. radiation exposure

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The CT scan and the imaging that will be carried out as part of the ablation procedure are part of the patient's routine care. These procedures use ionizing radiation to form images of the body and provide the doctor with other clinical information. Ionizing radiation can cause cell damage that may, after many years or decades, turn cancerous. The chances of this happening are the same whether patients take part in this study or not. It should be noted that radiation dose will vary based on the type of imaging system used and the size of the patient.
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10.2. potential benefits

Benefit estimations of the general use of the Emprint™ Ablation Catheter with Thermosphere™ Technology are described in the Risk Management Report for the Emprint™ Ablation System with the Ablation Catheter. Microwave ablation is an alternative for patients with lung cancer who are either ineligible for or refuse other treatments such as surgical resection. Furthermore, bronchoscopic ablation may result in fewer complications than percutaneous ablation (see Section 4.1). For patients who are not candidates for alternative therapies, the benefits of microwave ablation outweigh the risks described above.  
The bronchoscopic ablation procedure described in this study is commercially available. Patients could receive these potential benefits without taking part in the study and may not gain any direct medical benefits compared to routine care. However, the data collected from this study will help characterize the safety and performance of the Emprint™ Ablation Catheter with Thermosphere™ Technology. If the results of this study support additional clinical research, further studies may be justified to evaluate the potential for improved standard-of-care using microwave ablation technology in lung nodules.
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10.3. risk-benefit rationale

As described in the Risk Management Report for the Emprint™ Ablation System with the Ablation Catheter, performing image-guided microwave ablation involves risk. Complications have been reported in the literature associated with thermal ablation of the lung. These complications are associated with both the intervention itself and patient comorbidity. For patients who are not candidates for alternative therapies, the benefits of microwave ablation described above outweigh these risks.
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11. adverse events and device

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; https://www.iso.org/obp/ui/\#iso:std:iso:14155:ed-2:v1:en), which is aligned with MEDDEV 2.7/3  
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Revision 3, May 2015 (Guidelines on Medical Devices, Clinical Investigations: Serious Adverse Event Reporting).  
For the purpose of this clinical study investigational plan, the point of enrollment is defined as the insertion of the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology into the EWC. AEs will be collected beginning at the point of enrollment. For safety reporting, only AEs related to the procedure or study devices will be captured and reported until the subject exits the study. Any unresolved procedural or device related events that are still ongoing past study exit will be monitored by the physician per their institutional standard-of-care.  
Anticipated AEs are listed in Section 10.1. AEs related to the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology, accessory devices, or study procedures will be adjudicated by an independent medical monitor. Refer to the NAVABLATE Adverse Event Reference List (Appendix 17.5) for additional definitions.
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11.1.1. adverse event (ae)

An 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.* *For the purposes of this clinical study, AE definitions will be ISO 14155:2011 compliant with the following exception: only those AEs that are related to the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology, accessory devices, or study procedures will be captured and reported. NOTE 1: This definition includes events related to the investigational medical device or the comparator.  
NOTE 2: This definition includes events related to the procedures involved. NOTE 3: For users or other persons, this definition is restricted to events related to investigational medical devices.
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11.1.2. serious adverse event (sae)

For the purposes of this study, a Serious Adverse Event (SAE)* is an AE that has 1. Led to death, 2. Led to serious deterioration in the health of the subject, that either resulted in a. A life-threatening illness or injury, or b. A permanent impairment of a body structure or a body function, or c. In-patient or prolonged hospitalization, or d. Medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function.
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11.1.2. serious adverse event (sae)

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3. Led to foetal distress, foetal death or a congenital abnormality or birth defect  
  
  
NOTE 1: This includes device deficiencies that might have led to an SAE if a) suitable action had not been taken or b) intervention had not been made or c) if circumstances had been less fortunate. These are handled under the SAE reporting system.  
NOTE 2: 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.  
*For the purposes of this clinical study, SAE definitions will be ISO 14155:2011 compliant with the following exception: only those SAEs that are related to the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology, accessory devices, or study procedures will be captured and reported.
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11.1.3. adverse device effect (ade)

An Adverse Device Effect (ADE) is an AE related to the use of the investigational medical device (the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology). NOTE 1: This definition includes AEs resulting from insufficient or inadequate instructions for use, deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. NOTE 2: This definition includes any event resulting from use error or from intentional misuse of the investigational medical device.
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11.1.4. 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 an SAE.
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11.1.5. unanticipated serious adverse device

An Unanticipated Serious Adverse Device Effect (USADE) is defined as serious adverse device effect which by its nature, incidence, severity or outcome has not been identified in the current version of the Risk Management 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.
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11.1.6. device deficiency

Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or performance. Note: Device deficiencies include malfunctions, use errors, and inadequate labelling.
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11.1.7. adverse event relationship classification

Causality assessments define the relationship between the use of the medical device (including the procedure) and the occurrence of each AE. During causality assessment activity, clinical judgment shall be used and the relevant documents, such as the MDR Reportable Event Trend & Risk Analysis Report shall be consulted, as all the foreseeable SAEs 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 AE and SAE will be classified according to five different levels of causality. The following definitions will be used to assess the relationship of the AE to the investigational medical device (the Emprint™
Ablation Catheter Kit with Thermosphere™ Technology), accessory devices, or study procedures:
- *Not related*: Relationship to the device or procedures can be excluded when:
o the event is not a known side effect of the product category the device belongs to or of similar devices and procedures o the event has no temporal relationship with the use of the investigational device or the procedures; o 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; o 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; o the event involves a body-site or an organ not expected to be affected by the device or procedure; o 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);
o the event does not depend on a false result given by the investigational device used for diagnosis, when applicable; o harms to the subject are not clearly due to use error; o 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 investigational 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 investigational device seems relevant and/or the event cannot reasonably be explained by another cause, but additional information may be obtained.
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11.1.7. adverse event relationship classification

- *Causal relationship*: The serious event is associated with the investigational device or with  
  
  
procedures beyond reasonable doubt when:
o the event is a known side effect of the product category the device belongs to or of similar devices and procedures; o the event has a temporal relationship with investigational device use/application or procedures; o the investigational device or procedures have an effect on; o the event involves a body-site or organ that o the investigational device or procedures are applied to; o the serious event follows a known response pattern to the medical device (if the response pattern is previously known);
o 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);
o 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; o harm to the subject is due to error in use; o the event depends on a false result given by the investigational device used for diagnosis, when applicable;
- In order to establish the relatedness, not all the criteria listed above might be met at the same time, depending on the type of device/procedures and the serious event.  
Events will be distinguished between the SAEs related to the device and those related to the procedures (any procedure specific to the clinical investigation). An AE 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 patients also in the absence of device use/application.  
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's Medical Monitor and the Investigators will make the maximum effort to define and categorize the event and avoid these situations. Where the Medical Monitor remains uncertain about classifying the serious event, it should not exclude the relatedness and classify the event as "possible".
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11.1.8. adverse event outcome classification

Outcome of the event will be defined according to the following:
- Fatal: If death was possibly, probably, or causally related to the event
- Not recovered / not resolved: Subject has exited the study and the AE is ongoing and not expected to resolve
- Recovered / resolved: The event has fully resolved prior to study exit  
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- Recovered / resolved with sequelae: The event has resolved prior to study exit, but retained pathological  
  
  
conditions resulting from the prior disease or injury
- Recovering / resolving: The subject has exited the study and the AE is ongoing but expected to resolve - Unknown: The subject has exited the study and the AE outcome is unknown
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11.2. reporting of adverse events

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. AEs will be monitored until a subject completes the study. Any unresolved procedural- or device-related events that are still ongoing past study exit will be monitored by the physician per their institutional standard-of-care. AEs will be documented in the applicable source documentation and reported on an AE eCRF. To the extent possible, the event to be recorded and reported is the event diagnosis as opposed to event outcome (e.g. death) or symptoms (e.g., fever, chills, nausea and vomiting in the presence of a clinically diagnosed infection is to be reported as infection only). The following should not be considered an AE:
- A condition requiring a preplanned procedure unless the condition worsened since enrollment
- A preexisting condition found as a result of screening, unless the condition has worsened since enrollment.
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11.2.1. notification to authorities

The following events are generally considered reportable during the course of this study and should be reported within the timeframes outlined in **Table 2**:
- any AE or SAE related to the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology, accessory devices, or study procedures
- any Device Deficiency
- new findings/updates in relation to already reported events.  
NAVABLATE Clinical Investigation Plan  
  
  
  
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Table 2. Reporting of Adverse Events  
| Type              | Report to                         | Reporting Timeframe (from time of  learning of event)   |
|-------------------|-----------------------------------|---------------------------------------------------------|
| Device Deficiency | Sponsor                           | Recommended within 10 working days                      |
| AE                | Sponsor                           | Recommended within 10 working days                      |
| EC/IRB            | Per EC/IRB reporting requirements |                                                         |
| SAE               | Sponsor                           | Not to exceed 10 working days                           |
| EC/IRB            | Per EC/IRB reporting requirements |                                                         |  
Events will be reviewed by sponsor or designee to determine any sponsor reporting obligations to Regulatory Authority and EC/IRB. All applicable events will be reported to Post-Market Vigilance (PMV) by sponsor clinical team; and PMV will also report to Regulatory Authorities when applicable.  
AEs will be recorded on the **Adverse Event CRF.**
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12. data review committees

There will be no Data Monitoring Committee or Clinical Events Committee as these are not required for a post-market study of a commercially available product.
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13. statistical design and methods

All statistical analyses will be performed using Statistical Analysis System (SAS) for Windows (version 9.4 or higher, SAS Institute Inc. Cary, NC) or other widely accepted statistical or graphical software.  
Descriptive statistics will be used to present the data and to summarize the results. Continuous variables will be summarized with number of subjects (n), mean, standard deviation, median, and ranges.  
Categorical variables will be summarized by frequencies and percentages. The sample size of this study is not based on power calculations of a statistical hypothesis test.  
There are no pre-planned interim or subgroup analyses. Any post-hoc subgroup analyses will be exploratory in nature for the purpose of evaluating the safety and performance of the study device under various clinical conditions.  
Due to the post-market and observational nature of the study, no imputation is planned for missing data in the primary and secondary endpoints, if any. All available data from enrolled subjects will be reported.
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13. statistical design and methods

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A detailed Statistical Analysis Plan (SAP) will be prepared prior to data analysis. Any deviations from this analysis plan will be documented in the final clinical study report.
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14. ethics 14.1. statement(s) of

This clinical investigation will be conducted in accordance with this CIP, the ethical principles that have their origin in the Declaration of Helsinki, as well as with ISO 14155:2011 (Clinical Investigation of Medical Devices for Human Subjects - Good Clinical Practice), the European Union Medical Device Regulation, and the International Conference on Harmonisation (ICH) of Technical Requirements For Registration of Pharmaceuticals For Human Use, ICH Harmonised Tripartite Guideline for Good Clinical Practice E6 (R1). This investigation will also be conducted per applicable local regulatory requirements and laws in which the study will be conducted. The study will be compliant with ISO 14155:2011 with the following exceptions:
- The point of enrollment is defined as the insertion of the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology into the EWC, rather than at the time of informed consent. Subjects will be approached to obtain written informed consent prior to any institution non-standard-of-care assessments or study specific data being collected. Subjects who provide study consent but then are determined to be ineligible prior to the insertion of the ablation catheter will be considered screen failures and documented as such in the database (see Section 8.2).  
- For the purposes of this clinical study, AE definitions will be ISO 14155:2011 compliant with the following exception: only those AEs deemed to be related to the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology, accessory devices, or study procedures will be captured and reported (see Section 11.1.1).  
The principles of the Declaration of Helsinki have all been implemented by means of the patient informed consent process, EC approval, study training, clinical study registration, preclinical testing, risk benefit assessment, and publication policy. Pediatric, legally incompetent, or other vulnerable subjects are not eligible for the study.  
The clinical investigation will not begin until all necessary approvals/favorable opinions are obtained from the appropriate EC/IRBs or Regulatory Authority, as appropriate. Should an EC/IRB 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.  
Additionally, the results of this study will be submitted for publication in an appropriate journal.  
No insurance or compensation will be provided to study subjects.  
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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/IRB.
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15. study administration 15.1. monitoring

Authorized Medtronic representatives will conduct site initiation visits prior to first subject enrolled at a site. Site initiation visits include activities such as verification that training was conducted and documented. Site monitoring visits will be conducted by an authorized Medtronic representative to inspect study data, subjects' medical records, and CRFs in accordance with current ISO 14155 and ICH GCPs and the respective local and national government regulations and guidelines (if applicable). The study investigator and the investigating site will permit authorized clinical research personnel and clinical monitors from Medtronic and/or designee(s) employed by Medtronic to review completed CRFs, EC/IRB decisions, and Investigator, clinical site records, and facilities relevant to this study at regular intervals throughout the study per the monitoring plan. Additionally, subject charts and clinical records will be requested and reviewed so that protocol adherence and source documentation can be verified. The accuracy and quality of the data obtained from the investigator and maintained by the Sponsor will be confirmed through a structured program of clinical field auditing and internal review detailed in the monitoring plan. 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 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 CIP and use of the study devices. If the monitor discovers that an investigator is not complying with the signed Investigator Statement, the investigational plan, applicable laws, or any conditions of approval imposed by the reviewing EC/IRB or Regulatory Authority, the monitor will report to the Sponsor and take such steps necessary to promptly secure compliance. If compliance cannot be secured, the investigator's participation in the investigation may be terminated. Because there are no required medications for this study or other subject-generated reporting requirements, monitoring of subject compliance is not applicable to this study. A minimum of 80% source data verification is required, though a higher percentage of verification will be attempted. All ICFs and eligibility criteria are required to be 100% source-data verified.  
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Authorized Medtronic representatives will also conduct site close-out visits. Site close-out visits include activities such as ensuring site files are complete and accurate, essential documents are collected, and reminding the site of their study closure responsibilities.
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15.2. data management

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. No data points will be collected directly on the eCRF. In order to accurately collect all information, subject worksheets may also be provided for study specific data (e.g. specific nodule and procedure data points, etc.) not found in the medical records and will be considered the source document. The Principal Investigator must ensure the accuracy and completeness of the recorded data and then provide his/her electronic signature on the appropriate CRFs. The Investigator's signature for specific CRFs 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. Visual and/or computer data review will be performed to identify possible data discrepancies. Manual and/or automatic discrepancies 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 discrepancies in the database.
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15.3. direct access to source

The investigator(s)/institution(s) will permit inspection and study-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), including direct access to source data/documents per applicable laws and regulations.
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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 CRF, and if the subject name appears on any other document, it must be removed.  
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, or Regulatory Authorities may inspect their medical records to verify the information collected, and that all personal information  
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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 www.clinicaltrials.gov. If the results of the trial are published, the subject's identity will remain confidential.
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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/IRB.
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15.6. cip amendments

Should any amendment to the CIP be required, the CIP Author will collect and review all proposed updates. These will be incorporated as needed and approved per the CIP Approval Process, including EC/IRB approval and Regulatory Authority.
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15.7. record retention

The investigator will maintain the records of the study including all pertinent correspondence, the CIP with any/all amendments, all correspondence with and approval from the EC/IRB, the clinical investigation agreement, the Investigator Agreement, individual subject records, and signed ICFs. Subject files and other source data must be maintained per required storage periods defined by the applicable laws. Records may need to be maintained by the study investigator for a longer duration if agreed to in writing with Medtronic. All data and documents should be made available if requested by relevant authorities.
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15.8. publication and use of

The Medtronic Publication and Authorship Policy is aligned with the International Committee of Medical Journal Editors (ICMJE) recommendations (www.icmje.org). The Sponsor 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 the Sponsor, 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 protocol, the Medtronic Publication and Authorship Policy, and the Clinical Investigation Agreement. Investigators must submit a copy of all  
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manuscripts and/or abstracts to the Sponsor for review and comment at least 30 days prior to the 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 substudies, 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 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 patients 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, Section 801 of the Food and Drug Administration Amendments Act (FDAAA 801) and the Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11, January 18, 2017).
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15.9. suspension or early termination

At the time of a study close-out, the investigators will be notified by the sponsor. Appropriate notification and the final study report will be provided to EC/IRB and Regulatory Authority, if required per local laws and regulations.  
Medtronic reserves the right to discontinue the study at any stage, with suitable written notice to the investigator, the reviewing EC/IRB, and applicable Regulatory Authority. Similarly, the investigator 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 the investigator 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 shall be reported to Medtronic on the appropriate CRF.
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15.10. study contact information

| Medtronic Clinical Research                                                                                                       | Medtronic Medical Affairs Jennifer Mattingley MD Medical Affairs Director MITG, Surgical Innovations, Lung Health 161 Cheshire Lane, Suite 100 Plymouth, MN 55441   |
|-----------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Jennifer Wolvers Clinical Research Manager MITG, Surgical Innovations, Lung Health 161 Cheshire Lane; Suite 10 Plymouth, MN 55441 |                                                                                                                                                                     |
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15.11. financial information

Medtronic contracts with participating institutions/investigators through a Clinical Trial Agreement that defines the scope and responsibilities and associated compensation related to carrying out the obligations under a clinical study sponsored by Medtronic.
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16. references

1. National Cancer Institute, Cancer Therapy Evaluation Program, United States Department of Health and Human Services, National Institutes of Health. Common Terminology Criteria for Adverse Events
(CTCAE) Version 5.0. Available at:
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_50. Accessed January 23, 2018.  
2. Ahmed M, Solbiati L, Brace CL, Breen DJ, Callstrom MR, Charboneau JW, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria--a 10-year update. J Vasc Interv Radiol. 2014;25(11):1691-705 e4. doi: 10.1016/j.jvir.2014.08.027. PubMed PMID: 25442132.  
3. National Comprehensive Cancer Network. Non–Small Cell Lung Cancer, Version 3.2018, NCCN
Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. 2018.  
4. Hinshaw JL, Lubner MG, Ziemlewicz TJ, Lee FT, Jr., Brace CL. Percutaneous tumor ablation tools:
microwave, radiofrequency, or cryoablation-what should you use and why? Radiographics. 2014;34(5):1344-62. doi: 10.1148/rg.345140054. PubMed PMID: 25208284.  
  
5. Roberton BJ, Liu D, Power M, Wan JM, Stuart S, Klass D, et al. Pulmonary ablation: a primer. Can Assoc Radiol J. 2014;65(2):177-85. doi: 10.1016/j.carj.2013.01.003. PubMed PMID: 23942193.  
6. Dupuy DE. Image-guided thermal ablation of lung malignancies. Radiology. 2011;260(3):633-55. doi:
10.1148/radiol.11091126. PubMed PMID: 21846760.  
7. Dupuy DE, Zagoria RJ, Akerley W, Mayo-Smith WW, Kavanagh PV, Safran H. Percutaneous radiofrequency ablation of malignancies in the lung. AJR Am J Roentgenol. 2000;174(1):57-9. doi: 10.2214/ajr.174.1.1740057. PubMed PMID: 10628454.  
8. Howington JA, Blum MG, Chang AC, Balekian AA, Murthy SC. Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e278S-313S. doi:
10.1378/chest.12-2359. PubMed PMID: 23649443.  
9. Lanuti M, Sharma A, Willers H, Digumarthy SR, Mathisen DJ, Shepard JA. Radiofrequency ablation for stage I non-small cell lung cancer: management of locoregional recurrence. Ann Thorac Surg. 2012;93(3):921-7; discussion 7-88. doi: 10.1016/j.athoracsur.2011.11.043. PubMed PMID:
22296982.  
10. Casal RF, Tam AL, Eapen GA. Radiofrequency ablation of lung tumors. Clin Chest Med.  
2010;31(1):151-63. doi: 10.1016/j.ccm.2009.08.021. PubMed PMID: 20172441.  
11. de Baere T, Deschamps F. New tumor ablation techniques for cancer treatment (microwave, electroporation). Diagnostic and interventional imaging. 2014;95(7-8):677-82. doi:
10.1016/j.diii.2014.04.001. PubMed PMID: 24818966.  
12. Howk K, Ladtkow C, Peterson D, Cafaro A. Consistent and Predictable Spherical Ablation Shape in Both Liver and Lung: Performance of the Emprint Ablation System with Thermosphere Technology in an In Vivo Porcine Model [Poster 129]. J Vasc Interv Radiol. 2015;26(5):e89-e90.  
13. Howk K, Ladtkow C, Peterson D, Cafaro A. Performance of the Emprint™ Ablation System in an In Vivo Porcine Lung Model: Correlation between CT and Gross Measurements [Poster 131]. J Vasc Interv Radiol. 2015;26(5):e91.  
14. Alonzo M, Bos A, Bennett S, Ferral H. The Emprint Ablation System with Thermosphere Technology:
One of the Newer Next-Generation Microwave Ablation Technologies. Semin Intervent Radiol.  
2015;32(4):335-8. doi: 10.1055/s-0035-1564811. PubMed PMID: 26622094; PubMed Central PMCID:
PMC4640908.  
15. Ierardi AM, Coppola A, Lucchina N, Carrafiello G. Treatment of lung tumours with high-energy microwave ablation: a single-centre experience. Medical oncology. 2017;34(1):5. doi:
10.1007/s12032-016-0861-6. PubMed PMID: 27900591.  
16. Gex G, Pralong JA, Combescure C, Seijo L, Rochat T, Soccal PM. Diagnostic yield and safety of electromagnetic navigation bronchoscopy for lung nodules: a systematic review and meta-analysis.  
Respiration. 2014;87(2):165-76. doi: 10.1159/000355710. PubMed PMID: 24401166.  
17. Heerink WJ, de Bock GH, de Jonge GJ, Groen HJ, Vliegenthart R, Oudkerk M. Complication rates of CT-guided transthoracic lung biopsy: meta-analysis. Eur Radiol. 2017;27(1):138-48. doi:
10.1007/s00330-016-4357-8. PubMed PMID: 27108299; PubMed Central PMCID: PMC5127875.  
  
  
18. Berber E. The first clinical application of planning software for laparoscopic microwave thermosphere ablation of malignant liver tumours. HPB (Oxford). 2015;17(7):632-6. doi:
10.1111/hpb.12423. PubMed PMID: 25980481; PubMed Central PMCID: PMC4474511.  
19. Ierardi AM, Mangano A, Floridi C, Dionigi G, Biondi A, Duka E, et al. A new system of microwave ablation at 2450 MHz: preliminary experience. Updates in surgery. 2015;67(1):39-45. Epub March 17. doi: 10.1007/s13304-015-0288-1. PubMed PMID: 25776064.  
20. De Cobelli F, Marra P, Ratti F, Ambrosi A, Colombo M, Damascelli A, et al. Microwave ablation of liver malignancies: comparison of effects and early outcomes of percutaneous and intraoperative approaches with different liver conditions: New advances in interventional oncology: state of the art. Medical oncology. 2017;34 (4) (no pagination)(49). doi: 10.1007/s12032-017-0903-8.  
21. Floridi C, Radaelli A, Pesapane F, Fumarola EM, Lecchi M, Agostini A, et al. Clinical impact of cone beam computed tomography on iterative treatment planning during ultrasound-guided percutaneous ablation of liver malignancies. Medical oncology. 2017;34 (6) (no pagination)(113).  
doi: 10.1007/s12032-017-0954-x.  
22. Takahashi H, Kahramangil B, Berber E. Local recurrence after microwave thermosphere ablation of malignant liver tumors: Results of a surgical series. Surgery. 2017. doi: 10.1016/j.surg.2017.10.026.  
23. Vogl TJ, Basten LM, Nour-Eldin NA, Kaltenbach B, Bodelle B, Wichmann JL, et al. Evaluation of microwave ablation of liver malignancy with enabled constant spatial energy control to achieve a predictable spherical ablation zone. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. 2017:1-9. doi:
10.1080/02656736.2017.1358408. PubMed PMID: 28774210.  
24. Vogl TJ, Panahi B, Albrecht MH, Naguib NNN, Nour-Eldin NA, Gruber-Rouh T, et al. Microwave ablation of pancreatic tumors. Minim Invasive Ther Allied Technol. 2018;27(1):33-40. doi: 10.1080/13645706.2017.1420664. PubMed PMID: 29278340.  
25. Steinfort DP, Einsiedel P, Irving LB. Radiation dose to patients and clinicians during fluoroscopicallyguided biopsy of peripheral pulmonary lesions. Respir Care. 2010;55(11):1469-74. Epub 2010/10/29.  
PubMed PMID: 20979674.  
26. Hohenforst-Schmidt W, Banckwitz R, Zarogoulidis P, Vogl T, Darwiche K, Goldberg E, et al. Radiation exposure of patients by cone beam CT during endobronchial navigation-a phantom study. J Cancer.  
2014;5(3):192.  
NAVABLATE Clinical Investigation Plan  
  
  
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17. appendices 17.1. user manual

See attached document, "Appendix 17.1_User Manual" for the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology Bronchoscopic Ablation Instructions for Use (CA108L1).
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17.2. product label

See attached document, "Appendix 17.2_Product Label" for the Emprint™ Ablation Catheter Kit with Thermosphere™ Technology Bronchoscopic Ablation Shipping Label (CA108L1).
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17.6. sample informed consent form

See attached document, "Appendix 17.6_NAVABLATE Sample ICF"  
| Version                                     | Summary of Changes                                 | Author(s)/Title               |                                                                                                          |
|---------------------------------------------|----------------------------------------------------|-------------------------------|----------------------------------------------------------------------------------------------------------|
| History 1.0                                 | -                                                  | Not applicable (new document) | Jennifer Wolvers, Principal Clinical  Research Specialist Kristin Hood, Senior Principal Medical  Writer |
| 2.0                                         | -                                                  | To Appendix 17.3, added MRC   | Jennifer Wolvers, Principal Clinical                                                                     |
| Breathlessness Scale Medtronic Confidential |                                                    |                               |                                                                                                          |
| This document is electronically controlled  | 056-F275, v A Clinical Investigation Plan Template |                               |                                                                                                          |  
Medtronic Confidential  
This document is electronically controlled 056-F275, v A Clinical Investigation Plan Template
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17.6. sample informed consent form

MDT18010ILSBA Version 4.0 26-SEP-2019 Page 48 of 50  
| Research Specialist Kristin Hood, Senior Principal Medical  Writer                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                             |                                                                                                                                                      |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|
| 3.0                                                                                                                                                                                                                                                                                                                                                                                                     | Requested updates per radiation expert. - To Table 1: Added standard of care CT  scan at baseline, noting this is already  done prior to consent. - Modified section 10.1.3 "Radiation  Exposure" to be more generalizable. | Jennifer Wolvers, Principal Clinical  Research Specialist Kristin Hood, Senior Principal Medical  Writer                                             |
| 4.0                                                                                                                                                                                                                                                                                                                                                                                                     | -                                                                                                                                                                                                                           | Updated to most current version of  056-F275, version A, Clinical  Investigation Plan Template (no  required changes other than updating  footnote). |
| -                                                                                                                                                                                                                                                                                                                                                                                                       | Updated names, addresses, and titles  of sponsor and study contacts on Title  page, and in Section 3 and 15.10                                                                                                              |                                                                                                                                                      |
| -                                                                                                                                                                                                                                                                                                                                                                                                       | Added name and address of co-lead  principal investigator (Dr. Calvin Ng) to  the title page                                                                                                                                |                                                                                                                                                      |
| -                                                                                                                                                                                                                                                                                                                                                                                                       | Added most current IFU to Appendix  17.1                                                                                                                                                                                    |                                                                                                                                                      |
| -                                                                                                                                                                                                                                                                                                                                                                                                       | Corrected typo in Appendix 17.5,  NAVABLATE Adverse Event Reference  List                                                                                                                                                   |                                                                                                                                                      |
| -                                                                                                                                                                                                                                                                                                                                                                                                       | Added Section 17.6, Sample Informed  Consent Form                                                                                                                                                                           | Jennifer Wolvers, Clinical Research  Manager Kristin Hood, Senior Principal Medical  Writer                                                          |
| The following updates were made for  compliance to the European Union  Medical Device Regulation (EU MDR): - Added name and address of Europe  Authorized Representative to the title  page, Section 1, and Section 3. - Added statement of compliance to the  EU MDR to Section 1 and Section 14.1 - Added EU MDR, IFU, and PMV to  Section 2.1 - Added statement to Section 3  Medtronic Confidential |                                                                                                                                                                                                                             |                                                                                                                                                      |
| This document is electronically controlled                                                                                                                                                                                                                                                                                                                                                              | 056-F275, v A Clinical Investigation Plan Template                                                                                                                                                                          |                                                                                                                                                      |  
MDT18010ILSBA Version 4.0 26-SEP-2019 Page 49 of 50  
| regarding device use per the IFU   |                                                                                                                                                                                 |
|------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| -                                  | Added statement to Section 3 that  there is no required number of  subjects and 20 is the approximated  minimum                                                                 |
| -                                  | Added statement to Section 7.1  indicating that the device is used for  the ablation of lung tissue                                                                             |
| -                                  | Added statement to Section 7.1  regarding anticipated product changes                                                                                                           |
| -                                  | Added statement to Section 7.4 that  products are packaged and labeled  accordingly                                                                                             |
| -                                  | Added statement to Section 7.5  regarding the population of patients  being evaluated                                                                                           |
| -                                  | Statement added to Section 7.6  allowing use of the CrossCountry™  Transbronchial Access Tool to obtain  access                                                                 |
| -                                  | Added statement that no CIP waivers  will be granted to Section 9.10                                                                                                            |
| -                                  | Added statement to Section 9.10 to  address how study deviations will be  reported to the Regulatory Authority                                                                  |
| -                                  | Added statement to Section 9.11  indicating that standard of care will be  followed for all subjects after  withdrawal, discontinuation, or  completion of the study follow-ups |
| -                                  | Added statement to Section 10.1 that  the study has been designed to have  as little foreseeable risk as possible for  patients                                                 |
| -                                  | Added foetal events Serious Adverse  Event definition in Section 11.1.2                                                                                                         |
| -                                  | Added definition of an anticipated  serious adverse device effect to  Section 11.1.5                                                                                            |
| -                                  | Added statement to Section 11.2.1 Medtronic Confidential                                                                                                                        |  
  
  
Medtronic Confidential  
This document is electronically controlled 056-F275, v A Clinical Investigation Plan Template  
MDT18010ILSBA Version 4.0 26-SEP-2019 Page 50 of 50  
| that applicable events will be reported  to PMV, who will report necessary  events to Regulatory Authorities   |                                                                                                           |
|----------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------|
| -                                                                                                              | Updated record retention period to be  per applicable laws rather than  defined timeframe in Section 15.7 |
| -                                                                                                              | Statement added to Section 15.9  regarding the notification of the final  study report                    |
| -                                                                                                              | Added Section 15.11 regarding  financial information                                                      |
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emprinttm

Ablation Catheter Kit with Thermosphere™ Technology Bronchoscopic Ablation en **Instructions for Use**
fr **Instructions d'utilisation**
de **Gebrauchsanleitung**
es **Instrucciones de uso**
it **Istruzioni per l'uso**
nl **Gebruiksaanwijzing**
sv **Bruksanvisning**
da **Brugsanvisning**
no Bruksanvisning Symbols on Product and Packaging The following symbols may appear on product or packaging:
Sterile using ethylene oxide Not made with natural rubber latex  
  
  
Single use Federal law (USA) restricts this device to sale by or on the order of a physician Do not resterilize Do not use if package is opened or damaged Type BF applied part Consult instructions for use Keep dry Catalog number Manufacturer Use by Batch code Date of manufacture China RoHS (reduction of hazardous substances)
Authorized representative in the European Community CE mark. Designates that the product is authorized for sale in European countries 1