LIFE-BTK (pivotaL Investigation of saFety and Efficacy of BRS Treatment-Below The Knee) Randomized Controlled Trial
Phase: NA
Conditions: Critical Limb Ischemia (CLI)
Sponsor: Abbott Medical Devices



Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 1 of 140
CIP Number:
Study Number: 
LIFE-BTK (pivotaL Investigation of saFety and Efficacy of BRS treatment-Below The Knee)
Randomized Controlled Trial
Version Number
Date
Study Co-Principal Investigators
Planned Number of Sites and 
Region(s)
Approximately 65 clinical sites in the US, Asia, Australia and New Zealand
(maximum 55 sites in the US: 50 sites for the LIFE-BTK RCT plus 5 sites 
for the Pharmacokinetics sub-study).
Clinical Investigation Type
Prospective, randomized (2:1, Esprit™ BTK:PTA), single-blind, multi-
center clinical investigation
Abbott Medical Expert
Sponsor/Trial Monitor/Data 
Monitoring
Abbott Cardiovascular Systems, Inc.,
Registration/Randomization 
Service
Oracle Clinical
Electronic Data Capture Software
Oracle Clinical 
Core Laboratories
Clinical Events Committee
Administration
Data Monitoring Committee
Administration
CIP Author

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 2 of 140
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical investigation.
Site Principal Investigator:
Printed name:
Signature:
Date:

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 3 of 140
STUDY PRINCIPAL INVESTIGATOR 
SIGNATURE PAGE
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical investigation.
Study Principal Investigator:
Printed name:
Signature:
Date:

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 4 of 140
TABLE OF CONTENTS
1.0 
INTRODUCTION............................................................................................................................10 
1.1. 
Background and Rationale .........................................................................................................10 
1.1.1. 
Background .........................................................................................................................10 
1.1.2. 
Rationale for Conducting this Clinical Investigation.............................................................12 
2.0 
CLINICAL INVESTIGATION OVERVIEW......................................................................................12 
2.1. 
Clinical Investigation (LIFE-BTK RCT) Objective .......................................................................12 
2.1.1. 
Pharmacokinetics Sub-Study Objective ..............................................................................12 
2.2. 
Device(s) To Be Used in the Clinical Investigation.....................................................................13 
2.2.1. 
Name of the Device Under Investigation.............................................................................13 
2.2.2. 
Intended Indication for Use..................................................................................................13 
2.2.3. 
Description of the Device Under Investigation.....................................................................14 
2.2.3.1. 
Scaffold design.............................................................................................................15 
2.2.3.2. 
Scaffold polymer...........................................................................................................15 
2.2.3.3. 
Drug/polymer coating ...................................................................................................15 
2.2.3.4. 
Delivery system............................................................................................................17 
2.2.3.5. 
Packaging and Sterilization..........................................................................................17 
2.2.4. 
Control Device(s).................................................................................................................17 
2.2.5. 
Device Handling ..................................................................................................................17 
3.0 
CLINICAL INVESTIGATION DESIGN............................................................................................17 
3.1. 
Clinical Investigation Procedures and Follow-up Schedule........................................................18 
3.2. 
Measures Taken to Avoid and Minimize Bias.............................................................................20 
3.2.1. 
Randomization ....................................................................................................................20 
3.2.2. 
Blinding................................................................................................................................20 
3.3. 
Early Termination of the Clinical Investigation............................................................................21 
3.3.1. 
Subject Follow-up for of Early Termination or Suspension of Study ...................................21 
4.0 
ENDPOINTS ..................................................................................................................................22 
4.1. 
Primary Endpoints and Rationale ...............................................................................................22 
4.2. 
Powered Secondary Endpoints ..................................................................................................22 
4.3. 
Descriptive Secondary Endpoints...............................................................................................22 
4.4. 
Informational Endpoints..............................................................................................................24 
5.0 
SUBJECT SELECTION AND WITHDRAWAL ...............................................................................25 
5.1. 
Subject Population......................................................................................................................25 
5.2. 
Subject Screening and Informed Consent..................................................................................25 
5.2.1. 
Subject Screening ...............................................................................................................25 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 5 of 140
5.2.2. 
Informed Consent................................................................................................................25 
5.2.2.1. 
Special Circumstances for Informed Consent..............................................................26 
5.3. 
Eligibility Criteria .........................................................................................................................27 
5.3.1. 
General Eligibility Criteria ....................................................................................................27 
5.3.2. 
Inclusion Criteria..................................................................................................................27 
5.3.2.1. 
General Inclusion Criteria.............................................................................................27 
5.3.2.2. 
Anatomic Inclusion Criteria...........................................................................................27 
5.3.3. 
Exclusion Criteria.................................................................................................................28 
5.3.3.1. 
General Exclusion Criteria............................................................................................28 
5.3.3.2. 
Anatomic Exclusion Criteria .........................................................................................30 
5.4. 
Subject Enrollment .....................................................................................................................31 
5.4.1. 
Enrollment of Medicare Beneficiaries..................................................................................31 
5.4.2. 
Historically Under-Represented Demographic Subgroups..................................................31 
5.5. 
Subject Deregistration ................................................................................................................32 
5.6. 
Subject Withdrawal.....................................................................................................................32 
5.7. 
Number of Subjects ....................................................................................................................34 
5.8. 
Total Expected Duration of the Clinical Investigation .................................................................34 
6.0 
TREATMENT AND EVALUATION OF ENDPOINTS.....................................................................34 
6.1. 
Baseline Assessments................................................................................................................34 
6.1.1. 
Subject Demographics and Medical History........................................................................34 
6.1.2. 
Medication History...............................................................................................................34 
6.1.3. 
Clinical assessments...........................................................................................................35 
6.1.4. 
Hemodynamic Evaluation....................................................................................................35 
6.1.5. 
Functional Status.................................................................................................................35 
6.1.6. 
Patient Report Outcomes ....................................................................................................35 
6.1.7. 
Laboratory Assessments.....................................................................................................35 
6.1.8. 
Angiographic assessment ...................................................................................................36 
6.2. 
Randomization............................................................................................................................36 
6.3. 
Blinding.......................................................................................................................................37 
6.4. 
Index Procedure .........................................................................................................................37 
6.4.1. 
Procedures Involved in the Use of the Device Under Investigation.....................................37 
6.4.2. 
Pre-procedure Antiplatelet Medications...............................................................................37 
6.4.3. 
Anti-Coagulation Medications..............................................................................................38 
6.4.4. 
Pre-procedure Measurements and Imaging........................................................................38 
6.4.5. 
Treatment Strategy..............................................................................................................38 
6.4.5.1. 
Treatment Strategy for Esprit BTK ...............................................................................39 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 6 of 140
6.4.5.2. 
Treatment Strategy for PTA arm ..................................................................................43 
6.4.5.3. 
Bailout or Alternative Procedures.................................................................................43 
6.4.6. 
Post-procedure Imaging ......................................................................................................43 
6.5. 
Post-procedure Medications.......................................................................................................43 
6.5.1. 
CIP-required antiplatelet therapy.........................................................................................43 
6.5.2. 
Other chronic concomitant medications ..............................................................................44 
6.6. 
Discharge Plan / Assessments...................................................................................................44 
6.7. 
Follow-up Assessments..............................................................................................................45 
6.7.1. 
Duplex Ultrasound...............................................................................................................46 
6.7.2. 
Medication History...............................................................................................................46 
6.7.3. 
Hemodynamic Evaluation....................................................................................................46 
6.7.4. 
Functional Status.................................................................................................................46 
6.7.5. 
Wound Assessment.............................................................................................................46 
6.7.6. 
Patient Reported Outcome (PRO) Measures......................................................................47 
6.7.7. 
Schedule of Events..............................................................................................................49 
6.8. 
Requirement for Clinical Laboratories ........................................................................................51 
6.8.1. 
Health Economic Data Collection........................................................................................51 
7.0 
ADVERSE EVENTS.......................................................................................................................51 
7.1. 
Definition.....................................................................................................................................51 
7.1.1. 
Adverse Event .....................................................................................................................51 
7.1.2. 
Serious Adverse Event........................................................................................................52 
7.1.3. 
Device Deficiency/Device Malfunction.................................................................................52 
7.2. 
Device Relationship....................................................................................................................53 
7.2.1. 
Unanticipated (Serious Adverse) Device Effect [U(S)ADE].................................................53 
7.2.2. 
Serious Health Threat..........................................................................................................53 
7.3. 
Adverse Event and Device Deficiency/Device Malfunction Reporting........................................53 
7.3.1. 
Adverse Event (AE) Reporting ............................................................................................53 
7.3.2. 
Unanticipated Serious Adverse Device Effect Reporting to Sponsor and IRB ....................54 
7.3.3. 
Device Deficiency/Malfunction Reporting............................................................................54 
7.3.4. 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor .....................55 
8.0 
STATISTICAL CONSIDERATIONS ...............................................................................................55 
8.1.1. 
Intent-to-Treat Population (ITT)...........................................................................................55 
8.1.2. 
As-Treated Population (AT).................................................................................................56 
8.1.3. 
Per-Protocol Population (PP) ..............................................................................................56 
8.2. 
Statistical Analyses.....................................................................................................................57 
8.2.1. 
Primary Endpoint(s) Analyses .............................................................................................57 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 7 of 140
8.2.2. 
Powered Secondary Endpoints Analysis.............................................................................58 
8.2.3. 
Descriptive Secondary Endpoints Analyses........................................................................58 
8.3. 
Sample Size Calculation and Assumptions ................................................................................58 
8.3.1. 
Sample Size Calculation and Assumptions for Primary Endpoints .....................................58 
8.3.2. 
Assumptions for Powered Secondary Endpoints ................................................................60 
8.4. 
Timing of Analysis.......................................................................................................................61 
8.5. 
Subgroup Analysis......................................................................................................................61 
8.6. 
Multiplicity ...................................................................................................................................61 
8.7. 
Planned Interim Analysis ............................................................................................................61 
8.8. 
Statistical Criteria for Termination...............................................................................................61 
8.9. 
Success Criteria .........................................................................................................................61 
8.10. 
Deviations from Statistical Plan...............................................................................................62 
9.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.................................................................62 
10.0 
QUALITY CONTROL AND QUALITY ASSURANCE.....................................................................62 
10.1. 
Selection of Clinical Sites and Investigators ...........................................................................62 
10.2. 
Site Principal Investigator Responsibilities..............................................................................62 
10.3. 
Clinical Investigation Finances and Agreements ....................................................................62 
10.4. 
CIP Amendments....................................................................................................................63 
10.5. 
Training ...................................................................................................................................63 
10.5.1. Site Training ........................................................................................................................63 
10.5.2. Training Required for the Use of the Device .......................................................................63 
10.6. 
Monitoring ...............................................................................................................................63 
10.7. 
Deviations from CIP ................................................................................................................64 
10.8. 
Quality Assurance Audit..........................................................................................................65 
10.9. 
Sponsor Auditing.....................................................................................................................65 
10.10. 
Committees.............................................................................................................................65 
10.10.1. Steering Committee.............................................................................................................65 
10.10.2. Publications Committee.......................................................................................................66 
10.10.3. Data Monitoring Committee (DMC) .....................................................................................66 
10.10.4. Clinical Events Committee (CEC)........................................................................................66 
11.0 
DATA HANDLING AND RECORD KEEPING................................................................................66 
11.1. 
Protection of Personally Identifiable Information.....................................................................67 
11.2. 
Data Management Plan ..........................................................................................................67 
11.3. 
Source Documentation ...........................................................................................................68 
11.4. 
Electronic Case Report Form Completion...............................................................................68 
11.5. 
Record Retention ....................................................................................................................68 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 8 of 140
11.6. 
Investigational Devices Accountability ....................................................................................69 
12.0 
ETHICAL CONSIDERATION .........................................................................................................69 
12.1. 
Institutional Review Board/Medical Ethics Committee Review and Approval .........................69 
13.0 
CLINICAL INVESTIGATION COMPLETION..................................................................................70 
14.0 
PUBLICATION POLICY .................................................................................................................70 
15.0 
RISK ANALYSIS ............................................................................................................................70 
15.1. 
Anticipated Clinical Benefits....................................................................................................70 
15.2. 
Foreseeable Adverse Events and Anticipated Adverse Device Effects..................................71 
15.3. 
Residual Risks Associated with the Device Under Investigation, as Identified in the Risk 
Analysis Report .....................................................................................................................................71 
15.4. 
Risks Associated with Participation in this Clinical Investigation ............................................71 
15.5. 
Possible Interactions with Protocol-Required Concomitant Medications (if applicable)..........71 
15.6. 
Steps Taken to Control or Mitigate Risks................................................................................71 
15.7. 
Risk to Benefit Rationale.........................................................................................................73 
APPENDIX I: ABBREVIATIONS AND ACRONYMS.................................................................................74 
APPENDIX II: DEFINITIONS ....................................................................................................................76 
APPENDIX III: SITE CONTACT INFORMATION .....................................................................................86 
APPENDIX IV: LITERATURE REVIEW....................................................................................................87 
APPENDIX V: RATES OF FORSEEABLE ADVERSE EVENTS..............................................................92 
APPENDIX VI: LABELS............................................................................................................................95 
APPENDIX VII: CASE REPORT FORMS.................................................................................................96 
APPENDIX VIII: INFORMED CONSENT FORM ......................................................................................97 
APPENDIX IX: MONITORING PLAN........................................................................................................98 
APPENDIX X: LIFE-BTK Pharmacokinetics sub-study.............................................................................99 
APPENDIX XI: REVISION HISTORY .....................................................................................................108 
APPENDIX XII: CIP SUMMARY .............................................................................................................130 
APPENDIX XIII: ESPRIT BTK Part Numbers .........................................................................................138 
APPENDIX XIV: REFERENCES ............................................................................................................139 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 9 of 140
COMPLIANCE STATEMENT: 
This clinical investigation will be conducted in accordance with this Clinical Investigation Plan, the 
Declaration of Helsinki, applicable Good Clinical Practices and regulations (e.g., US 21 CFR Part 50, 21 
CFR Part 56, 21 CFR Part 812, 45 CFR Part 46 and OUS ISO14155:2020) and the appropriate local 
legislation(s). The most stringent requirements, guidelines or regulations must always be followed. The 
conduct of the clinical investigation will be approved by the appropriate Institutional Review Board 
(IRB)/Ethics Committee (EC) of the respective investigational site and by the applicable regulatory 
authorities (e.g., FDA, TGA, HSA, TFDA, PMDA, etc.).
If the local regulation requires additional process and/or documents, local site must follow the 
requirements.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 10 of 140
1.0     
INTRODUCTION
The LIFE-BTK Randomized Controlled Trial (RCT) is designed to perform a pre-market evaluation of the 
Esprit™BTK Everolimus Eluting Bioresorbable Scaffold System for the planned treatment of narrowed 
infrapopliteal lesions. This is a prospective, single blinded randomized clinical trial (2:1) evaluating 
planned treatment of BTK lesions with Esprit BTK versus planned treatment with PTA (Percutaneous 
Transluminal Angioplasty), in patients with arterial narrowing in infrapopliteal lesions causing CLI (Critical 
Limb Ischemia), who satisfy the key inclusion and exclusion criteria for the trial.
The Esprit BTK system is a bioresorbable polymeric scaffold with the everolimus drug and a
bioresorbable polymeric coating mounted on a balloon dilatation catheter. This device, manufactured by 
Abbott Vascular, is intended to be used for improving luminal diameter in infrapopliteal lesions in patients 
with CLI.
CLI is a debilitating disease affecting 5-10% of patients with peripheral artery disease (PAD)[1] [2]. CLI is 
characterized by impaired blood flow to lower limb and associated with pedal pain. If left untreated, CLI 
can lead to major amputations. Patients experiencing major amputations face a severely decreased 
quality of life. PTA is currently the only approved dilatation device for use in BTK arteries in the United 
States. In Europe, both PTA and drug-eluting stents (DES) are approved therapies. Although reasonable 
rates of acute success are achieved with PTA, residual stenosis post-procedure and progressive 
reduction in patency in the months after intervention have been observed, resulting in a persistent 
reduction of perfusion to the distal extremity with increased morbidity and mortality. Therefore, PTA only 
provides a short term and sub-optimal solution for patients suffering from CLI due to infrapopliteal 
lesions, which highlights an unmet need for this patient population. Likewise, although DES have 
improved upon PTA in terms of patient outcomes, detrimental long-term effects such as having a 
permanent implant with risks of restenosis and stent thrombosis still exist. The Esprit BTK system is an 
innovative technology that offers the potential to address this unmet medical need for patients with BTK 
lesions and suffering from CLI. Like a metallic drug-eluting stent (DES), Esprit BTK provides support to 
the vessel to prevent acute recoil post-procedure and elutes everolimus to prevent arterial re-narrowing. 
Unlike metallic drug-eluting stents, Esprit BTK resorbs over time, leaving the artery free of permanent 
implant. Therefore, Esprit BTK has the potential to combine the benefits of PTA (no implant left behind) 
and DES (vessel support, and prevention of arterial re-narrowing). 
The objective of the LIFE-BTK RCT is to evaluate the safety and efficacy of the Esprit BTK, compared to 
PTA, in the planned treatment of diseased infrapopliteal lesions in patients with critical limb ischemia with 
up to two de novo or restenotic (prior PTA) lesions in separate vessels.
This clinical investigation will be conducted under an investigational device exemption (IDE) and in
accordance with this CIP. All investigators involved in the conduct of the clinical investigation will be 
qualified by education, training, and experience to perform their tasks and this training will be 
documented appropriately.
1.1.  
Background and Rationale
1.1.1.   
Background
Literature on clinical performance of PTA, DES (drug-eluting stent) and Absorb BVS for BTK lesions 
treatment is summarized below, and in Appendix IV.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 11 of 140
PTA is an approved revascularization treatment for arterial narrowing in CLI patients and is the initial 
therapy of choice for CLI patients who are candidates for either surgery or endovascular therapy. Although 
PTA has a high rate of immediate success, clinical studies have consistently documented a progressive 
reduction in patency in the months after intervention.  Meta-analysis results indicate that even after 
treatment with PTA, 1-year death and amputation rates are approximately 15% [3]. Drug coated balloons 
(DCB) have only seen a modest improvement in treatment efficacy when compared to PTA. In a recent 
ongoing trial [4] (LUTONIX) that compares DCB and PTA (N=442), early results only demonstrated a 
modest 10% improved efficacy at 6 months for DCB (73.7%) compared to PTA (63.5%), p=0.0273.
Drug eluting stents (DES) offer advantages that are not provided by balloon angioplasty. The stent provides 
a structurally stable scaffold for the vessel and reduces the rate of acute vessel closure, and the presence 
of drug coating such as everolimus is crucial for reducing restenosis. The benefit of using stents is shown 
by Scheinert et al. who compared safety and efficacy of treating PAD patients using SES (sirolimus-eluting 
stent) or PTA (N=200) [5]. Patient survival (89.9% for SES vs. 88.1% for PTA), freedom from CD-TLR 
(90% for SES vs. 83.5% for PTA) and limb salvage rates (86.2% for SES vs. 80% for PTA) at 1 year were 
found to be high for both devices. Lower angiographic restenosis rates (22.4% for SES vs.41.9% for PTA, 
p=0.019) and greater vessel patency (75.0% for SES vs. 57.1% for PTA, p=0.025) were observed in 
patients treated with SES, showing superior treatment efficacy in SES compared to PTA.
In a separate study (N=140), where Bosiers observed higher 1-year primary patency rate for everolimus-
eluting stent (XIENCE) (85%) than for BMS (54%), p=0.0001 [6]. Similar to observations by Scheinert, 
patient survival rate is high for both devices (84% for BMS and 82% for XIENCE). However, freedom from 
TLR is higher for XIENCE (91.3%) compared to BMS (66.4%), p=0.001. When treatment with XIENCE
was extended to longer lesions (30-100 mm) in DESTINY2 trial, high primary patency rate (75.4%), 
freedom from TLR (84.9%), limb salvage (94.4%) and survival rates (90%) at 1 year were also observed, 
illustrating the successful use of a drug-coated metal stent for treating CLI with longer lesions [7].
The decreased efficacy of BMS is further illustrated by Rastan et al. (N=161), where primary patency rates 
(80.6% for SES vs. 55.6% for BMS, p=0.004) and improvement in Rutherford classification (83.9% for SES
vs. 61.9% for BMS, p=0.004) at 1 year are higher in SES compared to BMS [8].
The above-mentioned studies have demonstrated that the use of DES for treatment of CLI have improved 
patency rates. However, these metallic implants impose detrimental long-term effects on the vessel wall, 
as they inhibit vasomotion, autoregulation and adaptive modeling by leaving behind a permanent implant.
They may cause in-stent restenosis and late stent thrombosis, impede future revascularization, and create 
artifact on cross-sectional imaging. For these reasons, the use of a drug-eluting scaffold such as Esprit
BTK offers both short-term and long-term benefits for the treatment of CLI. The scaffold provides support 
to the vessels and resorbs over time and presents a superior solution for the treatment of CLI. 
The clinical performance of Absorb BVS, the predecessor of Esprit BTK, in treatment of patients with 
chronic lower limb ischemia (Rutherford category 3-6) was demonstrated in the single-arm study by Varcoe 
et al.  (N=48) [9]. The study reported patency rates of 92.2% at 12 months, 90.3% at 24 months and 81.1% 
at 36 months. This was also met by freedom from CD-TLR of 97.2%, at both 12 and 24 months and 87.3% 
at 36 months. There were no reports of death within 30 days in the 48 patients, no reports of amputation 
or target limb bypass surgery through 2 years, and a single patient report of thrombosis. The thrombosis 
event that occurred on day 2 was thought to be related to the patient having been taken off warfarin prior 
to the index procedure and no antiplatelet therapy having been commenced following the procedure. 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 12 of 140
A separate study by Xue [10] and Kum [11] evaluated 1-year outcomes in the use of Absorb GT1 BVS 
treatment in CLI patient population (89.3% Rutherford Becker Category 5-6), where high 1-year rates of 
primary patency (87.1%) and freedom from TLR (96.7%) were reported.  Similar results were seen in a 
study by Shah et al. (N=31) [12]. At 1 year, no stent thrombosis, and high primary patency (96.7%), limb 
salvage (100%) and improved Rutherford classification were observed in 96.8% of patients treated with 
Absorb. 
Given the encouraging results from Absorb studies, where no procedure related mortality or major 
morbidity was observed within 30 days, and the 1-year patency rates and freedom from TLR rates were 
high, Esprit BTK is a promising new technology that offers the potential to tackle an unmet medical need 
for treatment of lower limb lesions.  Esprit BTK provides a unique approach to treat BTK disease by 
scaffolding the treated vessel, preventing acute recoil, eluting everolimus thus reducing risk of re-
narrowing, and resorbing into tissue over time.  It offers superior acute outcomes, lower restenosis and re-
intervention rates similar to XIENCE, and also addresses the inherent limitations of metallic DES by 
resorbing into tissue over time, eliminating the need for a permanent implant.  
1.1.2.   
Rationale for Conducting this Clinical Investigation
The rationale for conducting the proposed clinical investigation is based on the growing concern of PAD 
in infrapopliteal lesions and the limited treatment options for those patients burdened with the disease. 
Currently, the approved therapies (PTA in the United States, PTA/stenting in Europe) to treat narrowed 
infrapopliteal arteries are sub-optimal and/or unsustainable resulting in continuous reintervention and 
disease progression. As detailed in the literature review, recent clinical studies evaluating the Absorb 
BVS, predecessor of the Esprit BTK, showed the potential clinical benefits derived from the use of a 
bioresorbable scaffold for treatment of infrapopliteal lesions.
Esprit BTK has the potential to provide superior outcomes to PTA, by providing:  1) vessel scaffolding 
thus preventing acute recoil; 2) elution of everolimus, thus preventing arterial re-narrowing and reducing 
the risk of revascularization; 3) preservation of additional treatment option for treated vessel thanks to 
scaffold resorption over time.
Given the unmet needs for effective CLI treatment and the potential benefit offered by a bioresorbable 
scaffold, it is appropriate to evaluate Esprit BTK System in this randomized controlled trial.
2.0     
CLINICAL INVESTIGATION OVERVIEW
2.1.  
Clinical Investigation (LIFE-BTK RCT) Objective
The objective of this clinical investigation is to evaluate the safety and efficacy of the Esprit BTK,
compared to PTA, in the planned treatment of diseased infrapopliteal lesions in patients with critical limb 
ischemia with up to two de novo lesions in separate vessels.
2.1.1.   
Pharmacokinetics Sub-Study Objective
The objective of the pharmacokinetics (PK) sub-study is to determine the pharmacokinetics of everolimus 
delivered by the Esprit BTK scaffold in a separate and non-randomized cohort of subjects receiving the 
Esprit BTK for the planned treatment of narrowed infrapopliteal lesions. 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 13 of 140
The LIFE-BTK PK sub-study subjects will not be included in the primary analysis population of the LIFE-
BTK RCT and will not contribute to the determination of the LIFE-BTK RCT primary endpoints.
A total of 7 subjects will be registered in the PK sub-study, in the United States (US) and outside of US, 
with a maximum of 5 sites in the US.
For more details on the PK sub-study, refer to Appendix X. This appendix only applies to sites that will 
be participating in the PK sub-study. For sites only participating in the PK sub-study (and not participating 
in the LIFE-BTK RCT), only some sections of the RCT protocol apply; applicable sections are listed in
the PK sub-study synopsis in Appendix X.
2.2.  
Device(s) To Be Used in the Clinical Investigation
2.2.1.   
Name of the Device Under Investigation
The investigational device to be used in the clinical investigation is the Esprit BTK Everolimus Eluting 
Bioresorbable Scaffold System, which is Abbott’s Next Generation Bioresorbable Vascular Scaffold
System. The investigational device will be referred to “Esprit BTK” throughout this clinical investigation 
plan. The Esprit BTK is not approved by FDA and not commercially available in the United States, or 
outside the United States. This clinical investigation is being conducted under an investigational device 
exemption (IDE).
A diagram of the Esprit BTK, with its delivery catheter, is provided below.
Figure 2.2.1-1: Diagram of Esprit BTK System (product diagram not to scale)
The Esprit BTK is manufactured by Abbott Vascular, Santa Clara. The part numbers for each scaffold 
size are provided in Appendix XIII. Every unit is also assigned a lot number for traceability.
For further details on the device, refer to the Instructions for Use (IFU).
2.2.2.   
Intended Indication for Use
The Esprit BTK is a temporary scaffold that will fully resorb over time and is indicated for improving 
luminal diameter in infrapopliteal lesions in patients with critical limb ischemia (CLI).  In all cases, the 
treated lesion length should be less than the total scaffolding length with a reference vessel diameter of ≥ 
2.5 mm and ≤ 4.00 mm.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 14 of 140
2.2.3.   
Description of the Device Under Investigation
A description of the device under investigation is provided in this section. For further details, refer to the 
IFU.
Esprit BTK was developed using the same principles, design and materials as its predecessor device, 
Absorb GT1 BVS.
The Esprit BTK Everolimus Eluting Bioresorbable Scaffold System is a bioresorbable polymeric scaffold 
with a drug and bioresorbable polymeric coating mounted on a balloon dilatation catheter, the specific 
components of which are:
x
A bioresorbable scaffold backbone comprised of 100% poly(L-lactide) (PLLA), identical to that of the 
Absorb GT1 BVS (
).
x
A coating comprised of the active pharmaceutical ingredient everolimus and bioresorbable poly(D,L-
lactide) (PDLLA), identical to that of the Absorb GT1 BVS.
x
Identical to Absorb GT1 BVS, four platinum markers of the same mass, two each embedded at the 
proximal and distal ends of the scaffold for radiopacity.  
x
A delivery system that incorporates design features from the Absorb GT1 Bioresorbable Vascular 
Scaffold (BVS) System1 and XIENCE Alpine® Everolimus Eluting Coronary Stent System.2
Compared to Absorb GT1 BVS system, Esprit BTK System has reduced strut thickness and an 
expanded size matrix, with a total of 40 product sizes indicated below in Table 2.2.3-1 by the letter “X”. 
The original 14 sizes in the Absorb GT1 BVS System size matrix are highlighted in gray. Four scaffold 
designs encompass these product diameters.  The 2.5/2.75 mm scaffold design includes a total of 16 
sizes, while the 3.0 mm, 3.5 mm, and 3.75 mm scaffold designs includes a total of 8 sizes each. The 
balloon diameter, balloon length, and balloon marker separation are scaled across the size matrix to 
accommodate the diameter and length of the scaffold. The Esprit BTK System will be available in a 
Rapid Exchange (RX) configuration.
Table 2.2.3-1: Esprit BTK Size Matrix
Scaffold 
Design
Scaffold 
Diameter
(mm)
Product Length (mm)
9*
12
15
18
23
28
33
38
2.5/2.75
2.5
X
X
X
X
X
X
X
X
2.75
X
X
X
X
X
X
X
X
3.0
3.0
X
X
X
X
X
X
X
X
3.5
3.5
X
X
X
X
X
X
X
X
3.75
3.75
X
X
X
X
X
X
X
X
* Absorb GT1 BVS has an 8 mm scaffold instead of 9 mm
1 Absorb GT1 BVS System was filed under 
and was approved on July 5, 2016.
2 XIENCE Alpine® Everolimus Eluting Coronary Stent System (XIENCE Alpine Stent System; 
approved September 3, 2014).

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 15 of 140
2.2.3.1.
Scaffold design
The Esprit BTK System, like the Absorb GT1 BVS System, is based upon the same design principles as 
metallic balloon expandable stent systems (MULTI-LINK family of coronary stent systems). The Esprit
BTK backbone is fabricated from PLLA and is comprised of a series of circumferentially oriented 
sinusoidal rings connected by linear links (Figure 2.2.3-1). Two permanent platinum markers are 
embedded at each end ring to enable fluoroscopic visualization.
Figure 2.2.3-1: Representative Esprit BTK Pattern Design for the 2.5/2.75 mm Sizes
2.2.3.2.
Scaffold polymer
The backbone of the scaffold is manufactured from 100% PLLA, identical to that used in the Absorb GT1 
BVS. The scaffold is coated with the identical drug/polymer matrix as Absorb GT1 BVS. The PDLLA
polymer contains and controls the release of the antiproliferative drug everolimus.
2.2.3.3.
Drug/polymer coating
The Esprit BTK bioresorbable polymer drug coating is a single drug/polymer matrix layer comprised of 
the amorphous random copolymer PDLLA, which contains and controls the release of the drug 
everolimus.  Everolimus is an antiproliferative drug (Zortress®, Afinitor®, Novartis Pharmaceuticals 
Corp.) that is blended with PDLLA in a 1:1 (w:w) proportion and is applied to the entire surface (i.e., 
sidewalls, luminal, and abluminal) of the scaffold.  The drug compounding and spray processes are 
identical to those of the Absorb GT1 BVS.
Everolimus has been evaluated through a number of different clinical studies and is known to have a 
wide therapeutic window. The drug dose densities for XIENCE V, Absorb GT1 BVS, and Esprit BTK are 
all identical at 100 μg/cm2, and the total content specifications remain the same (90-110% of label claim).  
However, since the surface areas for the three devices are different, the total drug content will vary 
accordingly.  Table 2.2.3-2 presents the Esprit BTK surface area and total nominal everolimus content 
for each length within the size matrix, along with a comparison to Absorb GT1 BVS.  For a given scaffold 
diameter and length, the Esprit BTK drug content is bracketed between XIENCE V on the lower end and 
Absorb GT1 BVS on the upper end.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 16 of 140
In a preclinical study, systemic and local exposure to 1341 μg of everolimus was demonstrated to be 
safe (three 3.0x12 mm XIENCE V stents coated at a maximum drug dose density of 800 μg/cm2, 447 μg
per stent).  The total drug content for the longest Esprit BTK lengths of the largest diameters (3.5/3.75 x 
33 and 38 mm) falls below this maximum dose; the safety limit is more than 3.5 times the total 
everolimus content of the largest size.
Table 2.2.3-2: Comparison of Esprit BTK and Absorb GT1 BVS Size Matrices and Nominal
Everolimus Content
Scaffold 
Diameter,
Nominal
(mm)
Scaffold 
Length
(mm)
Drug Dose 
Density 
(μg/cm2)
Esprit BTK
Nominal 
Everolimus 
Content (μg)
Absorb GT1 
BVS Nominal 
Everolimus 
Content (μg)
2.5, 2.751
8
100
N/A
76
9
69
N/A
12
93
114
15
116
N/A
18
139
181
23
178
228
28
217
276
33
256
N/A
38
295
N/A
3.0
8
100
N/A
76
9
75
N/A
12
98
114
15
121
N/A
18
144
181
23
189
228
28
227
276
33
273
N/A
38
311
N/A
3.5
9
100
94
N/A
12
119
135
15
153
N/A
18
188
197
23
239
246
28
290
308
33
341
N/A
38
391
N/A
3.751
9
100
89
N/A
12
125
N/A
15
161
N/A
18
188
N/A
23
242
N/A
28
296
N/A
33
350
N/A
38
404
N/A
1 2.75, 3.75 mm not available for Absorb GT1 BVS

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 17 of 140
2.2.3.4.
Delivery system
 
The Esprit BTK delivery system incorporates elements of both the Absorb GT1 BVS System and the 
XIENCE Alpine Stent System. The Esprit BTK delivery system utilizes a similar inner member and tip 
design as XIENCE Alpine and is otherwise identical to the Absorb GT1 BVS System.
2.2.3.5.
Packaging and Sterilization
The Esprit BTK System utilizes the same packaging components as the Absorb GT1 BVS System. The
peelable foil pouch containing the final product is then electron beam (e-beam) sterilized, using the same 
process and dose as the Absorb GT1 BVS System.  
2.2.4.   
Control Device(s)
Subjects randomized to the PTA arm will be treated with standard PTA balloon(s), currently approved for
use below the knee and commercially available in the clinical site’s geography. Appropriate balloon 
diameter, balloon length and catheter length will be determined by the investigator. PTA balloons and
catheters will be used per standard of care and following the IFU of the product.
PTA was chosen as the comparator because it is currently the standard of care for treatment of BTK 
lesions in patients with CLI.
2.2.5.   
Device Handling
Information on device handling, usage and storage are included in the IFU.
Sponsor requires all investigational products to be stored according to the investigational product
labeling and Instructions for Use in a secure area to prevent unauthorized access or use.
3.0     
CLINICAL INVESTIGATION DESIGN
This clinical investigation is designed to evaluate the safety and efficacy of the everolimus eluting Esprit
BTK System for the planned treatment of narrowed infrapopliteal lesions.
This is a prospective, single-blinded, randomized controlled clinical investigation randomizing 
approximately 225 subjects between Esprit BTK therapy and PTA therapy. Subjects will be randomized 
in a 2:1 ratio (Esprit BTK:PTA). Subject registration is capped at 45 (20% of total sample size) per site.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 18 of 140
The clinical investigation will be conducted at approximately 65 clinical sites in the US, Asia, Australia,
and New Zealand. 
One pre-specified interim analysis for sample size re-estimation is planned for this study. Per the 
planned interim analysis, if this analysis indicates a need for sample size increase, the sample size can 
be adjusted up to a total of 315 subjects. 
The primary safety endpoint at 6 months and primary efficacy endpoint at 1 year will be evaluated when 
all subjects have completed their 1-year visit. The primary safety endpoint will be tested for non-inferiority 
of Esprit BTK to PTA. The primary efficacy endpoint will be tested for superiority of Esprit BTK as 
compared to PTA.
These primary endpoints will also be analyzed at 1 month, 3, 6 months, and 1, 2, 3, 4 and 5 years.
All secondary endpoints will be analyzed at the same time points as the primary endpoints.
Core laboratories will be used for angiography, duplex ultrasound, IVUS, OCT and wound assessment. 
Adverse events will be adjudicated by a Clinical Events Committee (CEC), as described in the CEC 
charter. A Data Monitoring Committee (DMC), also known as Data and Safety Monitoring Board (DSMB), 
will review cumulative data from the clinical investigation at regular intervals, as described in the DSMB 
charter.
The clinical investigation has been designed to involve as little pain, discomfort, fear, and any other 
foreseeable risk as possible for subjects. Refer to the Risks Analysis section of this clinical investigation 
plan for details. 
For the CIP version  revision, the primary efficacy endpoint is updated and the sample size is adjusted 
to approximately 260 subjects.
3.1.  
Clinical Investigation Procedures and Follow-up Schedule
Subjects who satisfy eligibility criteria become registered in the clinical investigation. Subjects have 
follow-up visits at 14 days, 30 days, 42 days, 3 months, 6 months, 1 year and annually through 5 years.
A detailed description of procedures/assessments performed at each follow-up visit can be found in 
Section 6.7.
The subject screening and registration flow chart, and follow-up requirements, for this clinical 
investigation are described below in Figure 3.1-1

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 19 of 140
Figure 3.1-1: Clinical Investigation Flow Chart
No
Yes
Yes
Yes
Informed consent signed
Anatomic 
inclusion/exclusion 
criteria met
Guidewire successfully 
crossed target lesion
Follow-up visits in-hospital and at 14 days, 
30 days, 42 days, 3 months, 6 months, 1 
year and annually through 5 years
Screen failure, do not 
randomize
No
All in-flow and non-target 
lesions(s) treated 
successfully
ESPRIT BTK
         PTA
Yes
Yes
No
No
Subject registered 
and randomized
Subject is in
ITT population
Yes
Balloon successfully crossed
lesion and inflated?
Subject 
deregistered
No
Yes
Subject was screened and met 
general inclusion/exclusion criteria

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 20 of 140
3.2.
Measures Taken to Avoid and Minimize Bias
In the LIFE-BTK RCT, several measures will be taken to avoid and minimize bias, such as randomization 
and blinding. Additionally, as mentioned above, core laboratories, DMC and CEC will be used in this 
clinical investigation.
3.2.1.
Randomization
Subjects will be randomized 2:1 in the primary analysis (test device: Esprit BTK vs. control 
device/treatment strategy: PTA). Randomization will be performed after all eligibility criteria have been 
met, all in-flow and non-target lesion(s) have been treated successfully, and the guidewire successfully 
crossed the target lesion. For laboratory assessments where multiple values for that test are present, it
will be up to the physician’s discretion to determine which value will be used to assess subject eligibility,
as long as one of the laboratory values is within the eligibility range. In cases where two target lesions 
are being treated, there needs to be strong assurance that both target lesions can be successfully 
crossed by the guidewire.
Once randomization is completed and a treatment is assigned, crossover to the other treatment group is
not permitted. Regardless of the actual device the subject received, the subject will be included in the ITT
population per the original randomization assignment. An Esprit BTK may never be used in a subject 
randomized to PTA. However, if the subject is randomized to Esprit BTK and the scaffold cannot be 
delivered, any device approved for BTK in that geography may be used as per label indication. If a
complication occurs in a patient randomized to Esprit BTK, such as dissection, another BVS should be
used (first choice), or any other approved device in the geography, as necessary in the best interests of 
the subject.
Randomization assignments will be given through the Oracle EDC system. 
The subject is considered to be successfully registered in this study and considered in the ITT population 
at the point of randomization.
3.2.2.
Blinding
This is a single-blinded clinical investigation. 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 21 of 140
3.3.  
Early Termination of the Clinical Investigation
No formal statistical rule for early termination of the trial is defined.
While no formal statistical rule for early termination of the clinical investigation for insufficient 
effectiveness of the device under investigation is defined, the Sponsor reserves the right to discontinue 
the clinical investigation at any stage or reduce the follow-up period with suitable written notice to the 
investigator. Possible reason(s) may include, but are not limited to:
x
Unanticipated adverse device effect (e.g., UADE) occurs and it presents an unreasonable risk to the 
participating subjects
x
An oversight committee (e.g., Steering/Executive Committee, Data Monitoring Committee) makes a 
recommendation to stop or terminate the clinical investigation (such as higher frequency of 
anticipated adverse device effects)
x
Further product development is cancelled.
3.3.1.   
Subject Follow-up for of Early Termination or Suspension of Study
If the Sponsor suspends or prematurely terminates the clinical investigation at an individual site in the 
interest of safety, the Sponsor will inform all other Principal Investigators.
If suspension or premature termination occurs, the Sponsor will remain responsible for providing 
resources to fulfill the obligations from the CIP and existing agreements for following the subjects 
enrolled in the clinical investigation. Details for such subjects follow up will be provided. The Principal 
Investigator or authorized designee will promptly inform the enrolled subjects at his/her site, if 
appropriate.
The investigator will be return all clinical investigation materials (including devices) to the Sponsor, 
unless instructed otherwise and provide a written statement to the IRB/EC (if applicable). All applicable 
clinical investigation documents shall be subject to the same retention policy as detailed in Section 11.5
of the CIP.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 22 of 140
A Principal Investigator, IRB/EC or regulatory authority may suspend or prematurely terminate 
participation in the clinical investigation at the investigational site(s) for which they are responsible. The 
investigators will follow the requirements specified in the Clinical Trial Agreement. 
If a suspended investigation is to be resumed, a prior approval should be obtained from the EC/IRB and 
a notification should be sent to the regulatory bodies, and if subjects were informed of suspension, they 
shall be informed of the resumption of the clinical investigation.
4.0     
ENDPOINTS
4.1.  
Primary Endpoints and Rationale
The LIFE-BTK RCT has two primary endpoints: a primary efficacy endpoint and a primary safety 
endpoint.
The primary efficacy endpoint is a composite of limb salvage and primary patency at 1 year. It includes 
freedom from: above ankle amputation in index limb, 100% total occlusion of target vessel, binary 
restenosis of target lesion, and clinically-driven target lesion revascularization (CD-TLR). This efficacy 
endpoint was chosen because it allows to assess whether Esprit BTK is efficacious at maintaining 
patency (CD-TLR and binary restenosis), and at preventing catastrophic limb events such as total vessel 
occlusion or major amputation. Other than showing how the vessel maintains patency, binary restenosis 
at the target lesion can support evaluating disease progression over time. 
The primary safety endpoint is freedom from MALE+POD (Major Adverse Limb Event + Peri-Operative 
Death). MALE includes above ankle amputation in index limb, major re-intervention on index limb at 6 
months and POD includes perioperative (30-day) mortality. This safety endpoint was chosen because it 
is a commonly used endpoint to assess the safety of devices used in lower limb treatment, including 
treatment of lesions below the knee. Additionally, this endpoint assesses whether the device is 
associated with acute and sub-acute harm such as death and limb loss.
4.2.  
Powered Secondary Endpoints
LIFE-BTK RCT has two powered secondary endpoints. The first powered secondary endpoint is binary 
restenosis of the target lesion at 1 year. This endpoint was added to better evaluate the device 
performance as binary restenosis can be used as a marker for disease progression over time.
The second powered secondary endpoint is a composite endpoint that includes freedom from: above 
ankle amputation in index limb, 100% total occlusion of target vessel and clinically-driven target lesion 
revascularization (CD-TLR) at 1 year. This endpoint was chosen because it is important to assess 
whether Esprit BTK is efficacious at maintaining patency and preventing catastrophic limb events beyond 
1 year.
4.3.  
Descriptive Secondary Endpoints
The following secondary endpoints will be evaluated during the course of the clinical trial:
Procedural:

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 23 of 140
x
Acute procedure success
x
Device success - for Esprit arm only
x
Technical success
x
Clinical success
x
Angiographic acute gain (in-segment)
x
Angiographic acute gain (in-device) - for Esprit arm only
Clinical endpoints evaluated at 1 month, 3 months, 6 months, 1 year and annually through 5 years are:
x
Composite of limb salvage and primary patency (primary efficacy endpoint)
x
Freedom from MALE+POD (primary safety endpoint)
x
Freedom from: above ankle amputation in index limb, 100% total occlusion of target vessel and 
clinically-driven target lesion revascularization (CD-TLR)
x
Freedom from major amputation and clinically-driven target lesion revascularization (CD-TLR)
x
Freedom from above ankle amputation
x
Freedom from restenosis
x
Binary restenosis of the target lesion (first powered secondary endpoint)
x
Amputation-free survival §
x
All-cause death
x
Arterial thrombosis
x
Major re-intervention on index limb
x
Primary assisted patency
x
Secondary patency
x
Clinically-driven target lesion revascularization (CD-TLR)
x
Clinically-driven target vessel revascularization (CD-TVR)
x
Clinically-driven target vessel revascularization distal to the target lesion
x
Clinically-driven target vessel revascularization proximal to the target lesion

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 24 of 140
x
Index wound assessment for healing (14 days, 30 days, 42 days, 90 days, 180 days and 1 year)*
x
Index wound assessment for infection (14 days, 30 days, 42 days, 90 days, 180 days and 1 year)*
x
Rutherford Becker clinical category, and change from baseline for the treated limb
x
Occurrence of new wound †
x
Acute limb ischemia
x
Peripheral embolization
Note: Patency by duplex ultrasound will be assessed 30 ± 14 days post-procedure, and at 6 months, 
1, 2, and 3 years.
§ Amputation-free survival includes freedom from above ankle amputation and death.
* Index wound assessment for healing and infection will be assessed by the core laboratory through 
90 days (14 days, 30 days, 42 days and 90 days). For index wounds that are not healed by 90 days,
the index wound will be assessed by the core laboratory at 180 days. If the index wound is not 
healed by 180 days, index wound assessment by the core laboratory will be carried out at 1 year.
Index wounds that have healed by 90 days will not be assessed by the core laboratory at 180 days 
and 1 year.
† New wound is defined as wound below the knee in the index limb that was not identified at the time 
of the index procedure or wound that has recurred in the same location following the healing of the 
index wound. The new wound will be assessed firstly by the wound assessment core laboratory for 
etiology. Subsequently, the new wound will be evaluated by the site per protocol until the wound is 
healed through the 5-year follow-up. After the etiology assessment, the wound will no longer be 
evaluated by the core laboratory. If a new wound is first observed at 5-year follow-up, a picture will be 
taken for etiology assessment by the core laboratory. As this will be the final patient visit for the trial, 
no additional pictures of the new wound will be required following the initial picture submitted to the 
core laboratory.
4.4.  
Informational Endpoints
Patient Reported Outcomes:
The following Patient Reported Outcomes will be analyzed as informational endpoints at baseline, 30 
days, 3 months, 6 months and 1 year:
x
Overall health status using the EQ-5D-5L (EuroQoL-5D-5L) questionnaire 
x
Walking capacity using WIQ (Walking Impairment Questionnaire) 
x
Disease-specific health status using PAQ (The Peripheral Arterial Questionnaire)
Cost-Effectiveness:

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 25 of 140
Cost per quality adjusted life year (QALY) and cost per clinical event avoided will be evaluated using 
standardized methods [13].
5.0     
SUBJECT SELECTION AND WITHDRAWAL 
5.1.  
Subject Population
This clinical investigation will enroll subjects from all genders with arterial narrowing in infrapopliteal 
lesions causing critical limb ischemia. Subjects must meet all eligibility criteria and provide written 
informed consent prior to conducting any investigation-specific procedures not considered standard of 
care.
5.2.  
Subject Screening and Informed Consent
5.2.1.   
Subject Screening
Subjects admitted for a lower limb revascularization procedure must be screened for clinical investigation 
eligibility by a member of the clinical investigation team (physician and/or research coordinator) 
previously trained to the clinical investigation protocol and if applicable will be entered into a site-specific 
screening log.
In case the subject does not meet all inclusion criteria or meets any of the exclusion criteria, the subject 
is considered a screening failure. It is extremely important that the Principal Investigator or the delegated 
clinical investigation personnel record the screening failure in the hospital records and on a screening 
log.
Subjects meeting the general inclusion criteria and none of the exclusion criteria will be fully informed 
about the clinical investigation and asked to sign an informed consent. Pre-procedure (or baseline) 
imaging will be used for the final assessment of subject eligibility (details are described in Section 5.3). 
Subjects who do not satisfy the anatomic inclusion and exclusion criteria are considered screen failures 
and will not be registered and proceed further in the trial. All screened subjects will be entered into the 
screening log. Also, the reason for screen failure as well as supporting data will be entered into the log. 
Subjects satisfying the anatomic inclusion/exclusion criteria, and in whom the following two conditions 
are met, will be randomized:
x
All in-flow and non-target lesion(s) successfully treated
x
Guidewire successfully crossed the target lesion
Subjects will be registered into the clinical investigation at the point of randomization.
Subject data will be collected following enrollment into the clinical investigation.
5.2.2.   
Informed Consent
The Investigator or his/her authorized designee (if applicable) will conduct the Informed Consent 
process, as required by applicable regulations and the center’s IRB/EC. This process will include a 
verbal discussion with the patient on all aspects of the clinical investigation that are relevant to the 
patient’s decision to participate, such as details of clinical investigation procedures, anticipated benefits, 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 26 of 140
and potential risks of clinical investigation participation. Sites must inform patients about their right to 
withdraw from the clinical investigation at any time and for any reason without sanction, penalty or loss of 
benefits to which the patient is otherwise entitled. Withdrawal from the clinical investigation will not 
jeopardize their future medical care or relationship with the investigator. 
During the discussion, the Principal Investigator or his/her authorized designee will avoid any improper 
influence on the patient and will respect patient’s legal rights. Financial incentives will not be given to the 
patients. Patients may be compensated for time and travel directly related to the participation in the 
clinical investigation. The site shall provide the patient with the Informed Consent form written in a 
language that is understandable to the patient and that has been approved by the center’s IRB/EC. The
patient shall have adequate time to review, ask questions, and consider participation. The Principal 
Investigator or his/her authorized designee will make efforts to ensure that the patient understands the 
information provided. If the patient agrees to participate, they must sign and date the Informed Consent 
form, along with the person obtaining the consent prior to any clinical investigation-specific procedures. 
The site will file the signed original in the patient’s hospital or research chart, and provide a copy to the 
patient.
Sites should report any failure to obtain informed consent from a patient to the Sponsor within 5 working 
days and to the reviewing center’s IRB/EC according to the IRB’s/ EC’s reporting requirements.
If, during the clinical investigation, new information becomes available that can significantly affect a 
subject's future health and medical care, the Principal Investigator or his/her authorized designee (if 
applicable) will provide this information to the subject. If relevant, sites will ask the subject to confirm their 
continuing informed consent in writing.
5.2.2.1.
Special Circumstances for Informed Consent 
This clinical investigation excludes individuals unable to make the decision to participate in a clinical 
investigation on their own or who are unable to fully understand all aspects of the investigation that are 
relevant to the decision to participate, or who could be manipulated or unduly influenced as a result of a 
compromised position, expectation of benefits or fear of retaliatory response.
This clinical investigation excludes individuals under the age of 18 or age of legal consent from the 
clinical investigation population.
Sites may enroll individuals unable to read or write in this clinical investigation. Sites will obtain informed 
consent through a supervised oral process. An independent witness will be present throughout the
Informed Consent process. A member of the site’s clinical investigation team previously trained to the 
CIP will read the written Informed Consent form and any other information aloud and explain to the 
prospective subject or his/her legally acceptable representative and will sign and personally date the 
Informed Consent form. The witness will also sign and personally date the Informed Consent form 
attesting that the information was accurately explained, and that informed consent was freely given. In 
addition, no incentives or financial inducements will be provided to these patients or their legally 
authorized representatives for their participation in the clinical investigation.
The clinical investigation excludes pregnant or breastfeeding women.
In addition, sites must obtain an authorization for use and disclosure of the subject’s protected health 
information, in accordance with the Health Insurance Portability and Accountability Act (HIPAA), from the 
subject or their legally acceptable representative.
All other aspects of the Informed Consent process will follow Section 5.2.2.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 27 of 140
For live cases at congresses, the patients need to sign a specific Live Case ICF, approved by the 
IRB/EC and by the Sponsor, as well as by the respective regulatory or competent authorities (e.g., FDA), 
as applicable. The investigator must request Sponsor approval prior to performing a Live Case.
5.3.  
Eligibility Criteria
5.3.1.   
General Eligibility Criteria
Assessment for general eligibility criteria is based on medical records of the site and interview with a 
candidate subject. If any of the clinical and laboratory tests are not included in site standard tests, they 
must be done but after written informed consent is obtained. Subjects must meet ALL of the inclusion 
criteria to be considered for the clinical investigation. If ANY of the exclusion criteria are met, the subject
is excluded from the clinical investigation and cannot be registered.
5.3.2.   
Inclusion Criteria
5.3.2.1.
General Inclusion Criteria
1.
Subject must provide written informed consent prior to any clinical investigation related procedure.
2.
Subject has symptomatic Critical Limb Ischemia (CLI), Rutherford Becker Clinical Category 4 or 5.
3.
Subject requires primary treatment of up to two de novo or restenotic (treated with prior PTA) 
infrapopliteal lesions
4.
Subject must be at least 18 years of age.
5.
Female subject of childbearing potential should not be pregnant and must be on birth control.
Note: Female subjects of child-bearing potential must have a negative pregnancy test done within 
7 days prior to the index procedure per site standard test.
5.3.2.2.
Anatomic Inclusion Criteria
1.
Up to two native infrapopliteal lesions, each lesion located in separate infrapopliteal vessel in the 
same limb. Restenotic (from prior PTA) lesions are allowed.
a.
Lesion must be located in the proximal 2/3 of native infrapopliteal vessels, with vessel diameter of 
≥ 2.5 mm and ≤ 4.00 mm by investigator visual assessment.
Note: see vessel sizing under “treatment strategy” section.
b.
Total scaffold length to completely cover/treat a target lesion must not exceed 170 mm (total 
everolimus drug dose of 1790 μg). 
c.
The total scaffold length among all target lesions must not exceed 170 mm.
d.
The target vessel cannot have any other angiographic significant lesions (≥50%).
e.
Tandem lesions are allowed if they are < 3 cm apart and the total scaffold length used to cover 
the entire diseased segment is ≤ 170 mm. Each tandem lesion is considered one lesion.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 28 of 140
2.
Target lesion(s) must have ≥ 70% stenosis, per visual assessment at the time of the procedure. If 
needed, quantitative imaging (angiography, IVUS, and/or OCT) can be used to aid accurate sizing of 
the vessels.
3.
The distal margin of the target lesion must be located ≥ 10 cm proximal to the proximal margin of the 
ankle mortise.  The vessel segment distal to the target lesion must be patent all the way to the ankle, 
with no significant lesion (≥ 50% stenosis). 
4.
Significant lesion (≥ 50% stenosis) in the inflow artery(ies) must be treated successfully (as per 
physician’s assessment of the angiography) through standard of care prior to the treatment of the 
target lesion. Treatment can be done within the same trial procedure
5.
Non-target lesion(s) (if applicable) must be located in separate infrapopliteal vessel(s) from the target 
lesion, and suitable to be treated per institution standard of care.
6.
Guidewire must cross the target lesion successfully. Crossing in an antegrade fashion is preferred, 
but retrograde crossing may be used. However, the treatment must be delivered antegrade.
5.3.3.   
Exclusion Criteria
5.3.3.1.
General Exclusion Criteria
1.
Subject is currently participating in another clinical investigation that has not yet completed its 
primary endpoint.
2.
Pregnant or nursing subjects and those who plan pregnancy during the clinical investigation follow-up
period. 
3.
Presence of other anatomic or comorbid conditions, or other medical, social, or psychological 
conditions that, in the investigator’s opinion, could limit the subject’s ability to participate in the clinical 
investigation or to comply with follow-up requirements.
4.
Incapacitated individuals, defined as persons who are mentally ill, mentally handicapped, or 
individuals without legal authority, are excluded from the study population.
5.
Subject has had any amputation to the ipsilateral extremity other than the toe or forefoot, or subject 
has had major amputation to the contralateral extremity < 1 year prior to index procedure and is not
independently ambulating.
6.
Subject has known hypersensitivity or contraindication to device material and its degradants 
(everolimus, poly (L-lactide), poly (DL-lactide), lactide, lactic acid) and cobalt, chromium, nickel, 
platinum, tungsten, acrylic and fluoro polymers that cannot be adequately pre-medicated. Subject 
has a known contrast sensitivity that cannot be adequately pre-medicated.
7.
Subject has known allergic reaction, hypersensitivity or contraindication to aspirin; or to ADP
antagonists such clopidogrel, prasugrel or ticagrelor; or to anticoagulants such as heparin or
bivalirudin, and therefore cannot be adequately treated with study medications. Subject with planned 
surgery or procedure necessitating discontinuation of antiplatelet medications, within 12 months after 
index procedure. Planned amputation that will necessitate discontinuation of antiplatelet medications
is allowed.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 29 of 140
8.
Subject has life expectancy ≤ 1 year.
9.
Subject has had a stroke within the previous 3 months with residual Rankin score of ≥ 2.
10. Subject has renal insufficiency as defined as an estimated GFR < 30 ml/min per 1.73m2.
11. Subject is currently on dialysis.
12. Subject has platelet count < 100,000 cells/mm3 or > 700,000 cells/mm3, a WBC < 3,000 cells/mm3, or 
hemoglobin < 9.0 g/dl.
13. Subject has known serious immunosuppressive disease (e.g., human immunodeficiency virus), or 
has severe autoimmune disease, that requires chronic immunosuppressive therapy (e.g., systemic 
lupus erythematosus, etc.), or subject is receiving immunosuppression therapy for other conditions.
Subjects treated for HIV (Human Immunodeficiency Virus) and who have undetectable viral load, 
such that their immune system is not considered compromised, are eligible.
14. Subject has Body Mass Index (BMI) <18.
15. Subject is receiving or scheduled to receive anticancer therapy for malignancy within 6 months prior 
to index procedure or within 1 year after the procedure. Patients taking medications classified as 
chemotherapy but who have been in remission for at least 6 months are eligible.
16. Subject has coagulation disorder that increases the risk of arterial thrombosis. Subjects with deep 
vein thrombosis and disorders that increase the risk of deep vein thrombosis can be included in the 
study.
17. Subject who requires thrombolysis as a primary treatment modality or requires other treatment for 
acute limb ischemia of the target limb.
18. Subject has previously had, or requires surgical revascularization involving any vessel of the 
ipsilateral extremity. Prior femoropopliteal or aortobifemoral bypass is allowed. Any bypass to the 
tibial arteries is not allowed.
19. Subject has signs or symptoms of advanced limb infection or septicemia (fever > 38.5, WBC > 
15,000 cells/microliter, hypotension) at the time of assessment.  Osteomyelitis of the phalanges or 
metatarsal heads (as described in exclusion criteria #21a) or cellulitis of the foot amenable to 
treatment with IV antibiotics at the time of revascularization is acceptable.
20. Subject is bedridden or unable to walk (with assistance is acceptable). Subjects in wheelchair who 
are able to mobilize on their own can be enrolled. 
21. Subject with extensive tissue loss salvageable only with complex foot reconstruction or non-
traditional transmetatarsal amputations [14]. This includes subjects with:
a
Osteomyelitis that extends proximal to the metatarsal heads. Osteomyelitis limited to the 
phalanges or metatarsal heads is acceptable for enrollment.
b
Gangrene involving the plantar skin of the forefoot, midfoot, or heel

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 30 of 140
c
Deep ulcer or large shallow ulcer (> 3 cm) involving the plantar skin of the forefoot, midfoot, 
or heel
d
Full thickness heel ulcer with/without calcaneal involvement
e
Any wound with calcaneal bone involvement
f
Wounds that are deemed to be neuropathic or non-ischemic in nature
g
Wounds that would require flap coverage or complex wound management for large soft 
tissue defect
h
Full thickness wounds on the dorsum of the foot with exposed tendon or bone.
22. Subject is unable or unwilling to provide written consent prior to enrollment
23. Subject has active symptoms and/or a positive test result of COVID-19 or other rapidly spreading 
novel infectious agent within the prior 2 months.
5.3.3.2.
Anatomic Exclusion Criteria
1.
Lesions with severe calcification, in which there is a high likelihood that successful pre-dilatation
cannot be achieved.
2.
Lesion that has prior metallic stent implant.
3.
Significant (≥50% stenosis) lesion in a distal outflow artery that would be perfused by the target 
vessel and that requires treatment at the time of the index procedure.
4.
Subject has had or will require treatment in any vessel with an everolimus drug-coated or drug-
eluting device < 30 days pre-study procedure, or during the index procedure, such that the
cumulative (Esprit BTK plus everolimus-eluting device) everolimus drug dose exceeds 1790 μg.
5.
Target or (if applicable) non-target vessel contains visible thrombus as indicated in the angiographic 
images. 
6.
Subject has angiographic evidence of thromboembolism or atheroembolism in the ipsilateral 
extremity. (Pre- and post-angiographic imaging must confirm the absence of emboli in the distal 
anatomy.) 
7.
Unsuccessfully treated proximal inflow limiting arterial stenosis or inflow-limiting arterial lesions left 
untreated.
8.
No angiographic evidence of a patent pedal artery. 
9.
Target or (if applicable) non-target lesion location requiring bifurcation treatment method that requires 
scaffolding of both branches (provisional treatment, without intention of scaffolding both branches is 
acceptable).

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 31 of 140
10. Aneurysm in the iliac, common femoral, superficial femoral, popliteal or target artery of the ipsilateral 
extremity.
11. Visual assessment of the target lesion suggests that the investigator is unable to pre-dilate the lesion 
according to the vessel diameter. 
12. Target lesion has a high probability that atherectomy will be required at the time of index procedure 
for treatment of the target vessel.
5.4.  
Subject Enrollment
A patient is considered enrolled in the clinical investigation from the moment the patient provides written 
informed consent.
Subjects who satisfy all inclusion and exclusion criteria (general and anatomic) after pre-procedure 
screening, and in whom the guidewire has successfully crossed the target lesion, will be registered and 
proceed further to randomization.
If subjects are registered into the clinical investigation and are later found to have met exclusion criteria 
or not all inclusion criteria, these subjects will continue follow-up in the clinical investigation and will be 
included in the intent-to-treat analysis population. These subjects will not be deregistered from the 
clinical investigation. These subjects are considered CIP deviations.
5.4.1.   
Enrollment of Medicare Beneficiaries
This section is only applicable to sites enrolling subjects in the United States.
This clinical investigation will enroll Medicare beneficiaries and therefore conforms to all standards of 
Medicare coverage requirements. The Risks and Benefits section describes how all enrolled subjects, 
including Medicare beneficiaries, may be affected by the device under investigation.
A portion of the subjects enrolled in the clinical investigation display characteristics consistent with the 
Medicare population based on age.  The clinical investigation results will be analyzed by age (< 65 years 
and ≥65 years) and compared to ensure that the outcomes are similar between the Medicare and non-
Medicare populations.
5.4.2.   
Historically Under-Represented Demographic Subgroups
The Sponsor intends to implement FDA's guidance on sex-specific data in medical device clinical 
investigations to ensure adequate representation of women and other traditionally under-represented 
demographic subgroups in this clinical investigation.  As noted in the guidance, some barriers to 
participation of women and ethnic minorities in clinical investigations have traditionally been:
x
Lack of understanding about main obstacles to participation of such subgroups in clinical research 
x
Inclusion/exclusion criteria potentially not needed to define the clinical investigation population
may unintentionally exclude specific subgroups 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 32 of 140
x
Under diagnosis of disease etiologies and pathophysiology leading to under referral of 
demographic subgroups 
x
Avoidance of specific subgroups by investigators and Sponsors due to the perception that it 
takes more time and resources to recruit them 
x
Fear of fetal consequences (for female participants) 
x
Family responsibilities limiting women's ability to commit time for follow-up requirements
The Sponsor will take the following steps to ensure adequate representation of women and racial or 
ethnic minorities in this clinical investigation: 
x
The Sponsor will provide training to investigational site personnel to ensure adequate 
representation of these demographic subgroups 
x
The Sponsor will regularly review enrollment data to investigate whether there is under-
representation of these demographic subgroups 
x
The Sponsor will regularly review withdrawal rates for under-represented subgroups and 
compare these rates with that in the overall clinical investigation population
x
As appropriate and necessary, the Sponsor will retrain sites on the importance of recruiting and 
retaining subjects in the clinical investigation
x
The Sponsor will approach sites without bias or consideration for specific demographic 
subgroups 
x
The Sponsor will have informed consent materials in alternative languages and will work with 
sites and IRBs/ECs on recruitment materials 
5.5.  
Subject Deregistration
If balloon is unable to cross the lesion or to inflate at nominal size, the subject will be deregistered. The
subject will be followed for 30 days and will not be included in the intent-to-treat analysis population.
5.6.  
Subject Withdrawal
Each registered subject shall remain in the clinical investigation until completion of the required follow-up
period; however, a subject’s participation in any clinical investigation is voluntary and the subject has the 
right to withdraw at any time without penalty or loss of benefit. Conceivable reasons for discontinuation
may include, but not be limited to, the following:
x
Subject death
x
Subject voluntary withdrawal 
x
Withdrawal by the investigator as clinically-indicated

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 33 of 140
x
Subject lost-to follow-up as described below 
x
Subject’s follow-up is terminated according to Section 3.3 Early termination of the Clinical 
Investigation
The Sponsor must be notified of the reason(s) for subject discontinuation. The site will provide this 
information to the Sponsor. Investigators must also report this to their respective IRB/EC as defined by 
their institution’s procedure(s). 
No additional follow–up will be required or data recorded from subjects once withdrawn from the clinical 
investigation, except for the status (deceased/alive).
However, if a subject withdraws from the investigation due to problems related to the safety or 
performance of the device under investigation, the investigator shall ask for the subject's permission to 
follow his/her status/condition outside of the clinical investigation.
In case of subject withdrawal of consent, the site should make attempts to schedule the subject for a final 
clinical investigation visit. At this final follow-up visit, the subject will undergo the following assessments:
x
Review of adverse events
x
Review of protocol and concomitant medications
x
Administration of patient reported outcomes
Lost-to-Follow-up
If the subject misses two consecutive scheduled follow-up time points and the attempts at contacting the 
subject detailed below are unsuccessful, then the subject is considered lost-to-follow-up. Site personnel 
shall make all reasonable efforts to locate and communicate with the subject (and document these efforts 
in the source documents), including the following, at each contact time point:
x
A minimum of two telephone calls on different days over the specified follow-up windows to
contact the subject should be recorded in the source documentation, including date, time and 
initials of site personnel trying to make contact.
x
If these attempts are unsuccessful, a letter (certified if applicable) should be sent to the subject.
x
If a subject misses one or more non-consecutive follow-up contact time points, it will be 
considered a missed visit. The subject may then return for subsequent visits. If the subject 
misses two consecutive time points and the above-mentioned attempts at communicating with 
the subject are unsuccessful, the subject will be considered lost-to-follow-up.
Note: Telephone contact with General Practitioner, non-clinical investigation cardiologist or relative 
without the presence of the subject or indirect documentation obtained via discharge letters will not be 
considered as subject contact.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 34 of 140
Missed visits
If a subject misses one or more non-consecutive follow-up contact time points, the visit will be 
considered a missed visit and subject is not lost-to-follow-up.
If subject responds via written communication (including email correspondence), providing the protocol 
required data, these data will be collected in the case report form and the visit will not be considered a 
missed visit.  
5.7.  
Number of Subjects 
Approximately 225 subjects were originally planned to be registered in the clinical investigation.
5.8.  
Total Expected Duration of the Clinical Investigation
. The expected duration of each subject’s participation 
is 5 years, including the scheduled visits and data collection for this clinical investigation that will occur 
in-hospital and at 14 days, 30 days, 42 days, 3 and 6 months, and at 1, 2, 3, 4 and 5 years. Subjects will 
be exited from the trial at the conclusion of their 5-year (60 months) follow-up visit. Therefore, the total 
duration of the clinical investigation is expected to be 
6.0     
TREATMENT AND EVALUATION OF ENDPOINTS
6.1.  
Baseline Assessments
Subject preparation will occur in accordance with standard hospital policy for the care of interventional 
endovascular subjects.  The baseline assessments described below must be obtained within 30 days 
prior to study procedure, unless indicated otherwise.  They will be documented in the subject medical 
record and on the eCRF as appropriate.
The schedule of events for this trial is located in Section 6.7.7.
6.1.1.   
Subject Demographics and Medical History
Subject history will include but not be limited to the following demographics, risk factors and 
comorbidities: age, height, weight, body mass index (BMI), gender, hypertension, hyperlipidemia, 
diabetes mellitus, smoking, ischemic heart disease (history of myocardial infarction, angina pectoris, 
previous percutaneous or surgical coronary revascularization), history of peripheral vascular disease 
(previous percutaneous or surgical revascularization), congestive heart failure, renal insufficiency, liver 
disease, cerebrovascular disease (known carotid artery disease, history of minor or major stroke or 
transient ischemic attack), and chronic obstructive pulmonary disease (COPD).
6.1.2.   
Medication History
A medication history should be documented which includes chronic concomitant medications and 
protocol required medications.  This history should include:

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 35 of 140
x
Anticoagulants (warfarin, unfractionated or low molecular weight heparins, etc.); 
x
Antithrombotic agents (acetylic salicylic acid, thienopyridines, glycoprotein IIb/IIIa inhibitors, direct 
thrombin inhibitors, etc.); 
x
Statins or other lipid lowering agents; beta-blockers; angiotensin converting enzyme inhibitors; 
angiotensin-II receptor antagonists; 
x
Insulin and oral hypoglycemic agents; 
x
Medications for the treatment of intermittent claudication (IC) (e.g., Cilostazol, pentoxifylline, etc.).
6.1.3.   
Clinical assessments
The systolic blood pressure in the dorsalis pedis or posterior tibial arteries will be obtained for the target 
limb. Any index wounds (present at baseline) in the distal ipsilateral extremity shall be assessed. New
wound is defined as wound below the knee in the index limb that was not identified at the time of the 
index procedure or wound that has recurred in the same location following the healing of the index 
wound. The new wound will be assessed firstly by the wound assessment core laboratory for etiology. 
Subsequently, the new wound will be evaluated by the site per protocol until the wound is healed through 
the 5-year follow-up. If a new wound is first observed at 5-year follow-up, a picture will be taken for 
etiology assessment by the core laboratory. As this will be the final patient visit for the trial, no additional 
pictures of the new wound will be required following the initial picture submitted to the core laboratory.
6.1.4.   
Hemodynamic Evaluation
Ankle brachial index (ABI) measurement will be obtained for the target limb.  In cases in which the ABI is 
above 1.4 or cannot be reliably measured, toe pressure measurement and determination of the toe 
brachial index (TBI) should be used.  
The visit at baseline will be used to determine if a reliable ABI measurement is possible for the subject. If 
a reliable ABI measurement is not possible at baseline and TBI measurement was taken, the TBI
measurements should be performed on the subject throughout the follow-up period.
6.1.5.   
Functional Status
Functional status using the Rutherford Becker Clinical Categories [15] will be determined for the target 
limb.
6.1.6.   
Patient Report Outcomes
The overall health status (EQ-5D-5L), disease-specific health status (PAQ) and walking performance 
(WIQ) assessment tools should be completed.
6.1.7.   
Laboratory Assessments
A pregnancy test must be administered to all female subjects of childbearing potential within 7 days prior 
to the procedure.
The following laboratory tests must be obtained for all subjects within 30 days prior to the index 
procedure.
x
Hematology 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 36 of 140
x
hemoglobin, 
x
hematocrit, 
x
absolute platelet count,
x
white blood cell count (differential is highly recommended)
Blood chemistry 
x
serum creatinine, 
x
blood urea nitrogen (BUN) 
It is also highly recommended to obtain the following laboratory tests within 30 days prior to index 
procedure:
x
fasting blood glucose
x
glycosylated hemoglobin (HbA1c)
x
serum bilirubin
x
serum glutamic-pyruvic transaminase (SGPT/ALT),
x
serum glutamic-oxaloacetic transaminase (SGOT/AST)
x
lipid profile (total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides)
6.1.8.   
Angiographic assessment
Anatomic characteristics should be obtained during the baseline or pre-procedure angiogram that 
includes ipsilateral runoff to the distal foot to allow evaluation of the entire ipsilateral arterial vasculature.  
Presence of multilevel disease by anatomic level or arterial segment, inflow and outflow, specific location 
of the lesion, lesion length, stenosis or occlusion, and presence of calcification should be documented in 
the angiographic image and in the eCRF.
In the case of a vessel occlusion within a stenosed segment, both the length of the stenosed segment 
and length of the occluded segment should be recorded.
6.2.  
Randomization
Subject will be randomized after the following is confirmed:
x
Investigator has assessed vessel diameter and confirmed it meets the inclusion criterion (RVD 
between 2.5 mm and 4.00 mm). Refer to the vessel sizing section under “Treatment Strategy” for 
more details on sizing. 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 37 of 140
x
All other eligibility criteria (general and anatomic) are met
x
All in-flow and non-target lesion(s) have been treated successfully 
x
The guidewire successfully crossed the target lesion. If there are two target lesions, there needs to 
be strong assurance that both lesions can be crossed successfully. Randomization will occur after 
successful crossing of the first lesion.
During the randomization phase, the subject is considered randomized after the randomization 
assignment has been provided through the Oracle Clinical EDC system and a device has been assigned 
(Esprit BTK or PTA). The subject is considered registered and in the ITT population at the point of 
randomization. Once randomization is completed and a treatment arm is assigned, crossover to the other 
arm is not permitted. Regardless of the actual device the subject received, the subject will be included in 
ITT population per the original randomization assignment.
Registered subjects are counted toward the total sample size in LIFE-BTK RCT.
6.3.  
Blinding
This is a single-blind clinical investigation. Subjects will be blinded to the treatment arms and the site 
personnel will be trained not to disclose the treatment arm to the subject. Subject blinding must be 
maintained until completion of the final follow-up visit for all subjects.
More details on blinding are provided in Section 3.2.2.
6.4.  
Index Procedure
6.4.1.   
Procedures Involved in the Use of the Device Under Investigation
For appropriate use of the Esprit BTK device, refer to the IFU, the physician’s training materials, and the 
treatment strategy section below. 
6.4.2.   
Pre-procedure Antiplatelet Medications
Subjects selected for treatment with Esprit BTK or PTA must receive a loading dose of ≥ 300 mg of 
aspirin within 24 hours. Subjects are also required to receive a loading dose of an ADP antagonist within 
24 hours prior to the index procedure (preferred), but in all cases no greater than 1 hour after the end of 
the procedure.  ADP antagonist administered must include one of the following: a peri-procedural loading 
dose at least 300 mg of clopidogrel bisulfate, or 60 mg of prasugrel or 180 mg of ticagrelor. 
The aspirin loading dose can be omitted if the subject was on chronic aspirin for ≥ 7 days prior to the 
index procedure, and the subject received their maintenance dose on the day of the index procedure. 
The prasugrel loading dose may be omitted for those subjects on chronic prasugrel therapy (5 or 10 mg 
daily, or according to prescribing information) for ≥ 7 days prior to the index procedure; however, it is 
recommended that a loading dose (≥ 30 mg) be re-administered. The ticagrelor loading dose may be 
omitted for those subjects on chronic ticagrelor therapy (90 mg twice daily, or according to prescribing 
information). The clopidogrel loading dose may be omitted for those subjects on chronic clopidogrel 
therapy (minimum of 75 mg daily, or according to prescribing information) for ≥ 7 days prior to the index 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 38 of 140
procedure; however, it is recommended that a loading dose (≥ 300 mg) be re-administered. A loading 
dose of prasugrel or ticagrelor may be safely given to patients maintained on chronic clopidogrel therapy, 
or even in those in whom a clopidogrel loading dose was recently administered. Ticlopidine may be used 
as a substitute at a dose in accordance with standard hospital practice only if the subject develops 
hypersensitivity or intolerance to clopidogrel, prasugrel, or ticagrelor.  
For subjects on chronic aspirin and chronic ADP antagonist, loading of both antiplatelet can be omitted if
the subject received their maintenance dose on the day of index procedure. 
For subjects on chronic oral anticoagulants, loading with a single antiplatelet is acceptable, as per 
physician’s decision.
Refer to respective prescribing information for ADP antagonist for further details regarding loading 
practice.
6.4.3.   
Anti-Coagulation Medications
Subjects must receive appropriate anticoagulation and other therapy according to standard hospital 
practice. Either unfractionated heparin or bivalirudin may be used for procedural anticoagulation, as per 
the discretion of the investigator. Subjects having been treated with low molecular weight heparin 
(LMWH) prior to the procedure must receive their last dose more than 8 hours prior to the index 
procedure. LMWH and fondaparinux are not permitted as procedural anticoagulants in this protocol. 
Use of glycoprotein IIb/IIIa inhibitors will be at the discretion of the investigator. Any change in medication 
regime performed per the protocol, and not as routine hospital practice, can only occur after obtaining 
Informed Consent.
6.4.4.   
Pre-procedure Measurements and Imaging
ABI measurement for the target limb (as described in the “Baseline Assessments” section), or TBI in 
cases where ABI cannot be reliably measured, and angiographic assessment will be performed pre-
procedure. Angiography will be completed as per the core laboratory manual of operations.
Angiographic assessment of the potential target lesion(s) to be treated must be done to ensure anatomic 
criteria are met with special attention to the vessel diameter. This clinical investigation allows treatment 
of lesions in vessel with diameters of ≥ 2.5 mm and ≤ 4.00 mm by investigator visual assessment. 
Therefore, initial assessment of vessel diameter must be performed using visual estimation. Quantitative 
method such as IVUS or OCT is strongly recommended if the site is experienced with these techniques. 
Sites using IVUS or OCT for vessel sizing will be asked to provide their IVUS or OCT images in addition 
to their angiographic images, to the core laboratory. Analysis will be conducted to assess vessel sizing.
6.4.5.   
Treatment Strategy
All inclusion criteria (general and anatomic), and none of the exclusion criteria (general and anatomic), 
must be met for subjects to be registered in the clinical investigation.
The clinical investigation allows for the treatment of up to two lesions in two separate native infrapopliteal 
lesions in separate arteries located in the proximal 2/3 of the vessel with angiographically visible above 
the ankle reconstitution; restenotic lesions from prior PTA treatment are allowed. 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 39 of 140
Planned minor amputations are allowed at the time of the index procedure or within one month post
index procedure per site standard of care. These planned minor amputations will not be considered an 
adverse event. However, if there are any complications of these amputations, they will be considered 
adverse events. Any unplanned amputation at the time of the index procedure will be considered an 
adverse event.
Significant lesion (≥ 50% stenosis) in the inflow artery(ies) must be treated successfully, per standard of 
care, prior to the treatment of the target lesion (treatment can be done within same procedure). 
Non-target lesion treatment can occur only in a non-target vessel and must be treated successfully prior 
to randomization. All non-target lesions should be treated per standard of care.
Success for treatment of non-target and in-flow arteries is defined as per site standard of care.
For treatment of inflow lesions and non-target lesions using atherectomy, it is highly recommended to 
use embolic protection device such as Emboshield NAV6 Embolic Protection System, for collection of 
debris.
Randomization can only occur following successful crossing of the target lesion with the guidewire. Each 
target vessel and lesion should also be such that the operator believes that it can be treated by Esprit
BTK.
Atherectomy, scoring/cutting balloons and shock wave lithotripsy are not allowed for treatment of target 
lesion, in either arm.
Type of access (contralateral or ipsilateral) and guide catheter sizes used will be per investigator 
discretion and standard of care at the site. 
Staged procedures are allowed in the trial. Angiographic assessments and treatment of inflow and non-
target lesions can be done first, in a procedure separate from the index procedure. The treatment of 
these inflow and non-target lesions must be successful before the index procedure can be performed on 
the subject. The patient can be brought back for the trial index procedure within 4 weeks of the treatment 
of the inflow or non-target lesions.   During the index procedure, the wire must successfully cross the 
lesion before the subject is randomized.
For treatment of two target lesions, the following process should be followed. Wire crossing should be 
performed first on the lesion that can be treated more easily. Once the wire has successfully crossed the 
first target lesion, the subject can then be randomized. For subjects randomized to Esprit arm, this first 
lesion will then be treated with Esprit. For subjects randomized to PTA, treatment of the first lesion can 
proceed after successful wire crossing. Once the first lesion has been treated, wire crossing and 
treatment of the second target lesion, as per randomization assignment, can occur. If the wire does not 
successfully cross the second lesion, it will be considered a non-target lesion and will be treated per 
institution standard of care.
6.4.5.1.
Treatment Strategy for Esprit BTK
6.4.5.1.1.
Pre-dilatation and Device Sizing
x
Pre-dilatation must be performed with an angioplasty balloon. Non-compliant balloons (if available) 
are strongly recommended for pre-dilatation.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 40 of 140
x
If non-compliant balloon is not available, a semi-compliant balloon can be used. To prevent 
dissection, the balloon compliance chart should be used as a reference; do not inflate the balloon 
beyond the estimated RVD.
x
The pre-dilatation balloon should be sized 1:1 to the visually estimated RVD and should be no more 
than 0.25 mm smaller than RVD. 
x
As the goal of pre-dilatation is to achieve a 1:1 (balloon: RVD) ratio, a step-wise approach using
increasing balloon sizes can be done to achieve this goal.
x
The pre-dilatation balloon length should be such that the balloon goes from healthy-to-healthy tissue,
on each side of the target lesion.
x
Pre-dilatation of the planned target lesions(s) must be performed and be successful before Esprit
BTK device implantation in that lesion. Full balloon expansion with the pre-dilatation balloon must be 
achieved before device implantation. If there is any question that the target lesion has residual 
stenosis ≥ 30% or that any significant resistance to expansion from the lesion remains, the lesion 
should be re-dilated with a non-compliant balloon (sized 1:1 to the RVD) at higher pressure. Every
attempt should be made to ensure < 30% residual stenosis is achieved. It is understood that after 
achieving <30% stenosis and the pre-dilatation balloon is removed, slight acute recoil may occur. If 
this occurs, Esprit BTK may still be implanted.
x
If intravascular imaging is not used, check that pre-dilatation balloon is fully expanded using 2
orthogonal views.
x
The final diameter achieved with pre-dilatation balloon will be used to determine the choice of 
scaffold size for treatment.
x
To re-estimate vessel size after pre-dilatation, and determine appropriate Esprit BTK size for 
implantation, the compliance chart for the final/largest pre-dilatation balloon should be used.
x
Successful pre-dilatation is defined as diameter stenosis of < 30%, lesion length still within the 
requirements of the protocol/CIP and no angiographic complications.
6.4.5.1.2.
Re-assessment of Vessel Size and Device Size after Pre-dilatation
x
Vessel size must be re-assessed after pre-dilatation, to ensure that RVD size criterion is still met 
(RVD must be between 2.5 mm and 4.00 mm by visual assessment)
x
To exclude enrollment of excessively small vessels, if the operator believes that based on visual 
angiographic assessments, the distal reference vessel diameter is ≤ 2.75 mm such that the plan is to 
implant a 2.5 mm scaffold in a target lesion, it is strongly recommended that intravascular imaging 
(ultrasound or optical coherence tomography) is used and demonstrates that the measured distal 
RVD for this target lesion is ≥ 2.50 mm (by at least one of these imaging modalities). This 
measurement must be done prior to randomization. If the distal RVD measures <2.5 mm, that lesion 
IS NOT ELIGIBLE for randomization. Such a lesion may be treated as a non-target lesion
x
Quantitative methods such as IVUS is strongly recommended. OCT can also be used if the site is 
experienced with these techniques; it needs to be taken into account that IVUS tends to over-
estimate lumen RVD compared to visual estimation and OCT.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 41 of 140
x
If the reassessed RVD after pre-dilatation exceeds the original assessment but remains within the 
allowed range, the investigator can select a different size scaffold. 
x
The scaffold size to implant for the vessel sizes can be referred to in Table 6.4.5.1.2-1.
Table 6.4.5.1.2-1: Esprit scaffold sizes for implantation with different vessel sizes
Vessel Size
2.5 mm
2.75 mm
3.0 mm
3.25 mm
3.5 mm
3.75 mm
4.0 mm
Scaffold Size
2.5 mm
3.0 mm
3.5 mm
3.75 mm
6.4.5.1.3.
Lesion treatment
x
It is strongly recommended that the length of the Esprit BTK be selected to allow at least 2 mm of 
normal or nearly normal reference vessel at each edge. The area of vessel that was pre-dilated
should be covered with scaffold(s).
x
If the Esprit BTK cannot reach or cross the lesion or additional lesion preparation is required, the 
Esprit BTK must be removed and a new Esprit BTK must be introduced after subsequent pre-
dilatation(s) with the same sized or larger non-compliant balloon at higher pressure. Note: the Esprit
BTK should not be “dottered” across the lesion if it does not cross easily.
x
If the Esprit BTK is unable to reach or cross the target lesion after multiple attempts (maximum of two 
Esprit BTK; including additional lesion preparation), any device approved for BTK use in that 
geography may be used as per label indication. If the device used contains a drug it should ideally be
olimus based. 
x
Successful target lesion treatment is defined as final diameter stenosis < 30% with final number of
run-off vessels equivalent to or greater than number of run-off vessels at pre-procedure, with no 
residual dissection NHLBI grade ≥ type C, and no transient or sustained angiographic complications 
(e.g., distal embolization, perforation, thrombosis)
x
For Esprit BTK, the scaffold should be deployed slowly, by pressurizing the delivery system in 2 atm 
increments each over 5 seconds, until the scaffold is completely expanded. Pressure should be 
maintained for 30 seconds.
x
For Esprit BTK and the delivery balloon, do not exceed the rated burst pressure (RBP) per the IFU 
for the individual device.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 42 of 140
x
When using multiple scaffolds, an abutted (non-overlapping) configuration is preferred. When 
abutting the devices, the operator must consider that the scaffold extends 0.8 mm beyond the 
proximal marker and 0.3 mm beyond the distal marker. When scaffold abutting is used, ensure that 
the gap between the two scaffolds is no more than 1 mm. If overlap is used, it is recommended to 
aim for ~ 1 mm overlap by lining up the balloon markers (proximal or distal depending on overlap 
direction) [16].
x
For planned use of multiple Esprit BTK, the distal scaffold should be deployed first, followed by 
deployment of proximal scaffold.  Treatment performed in this order alleviates the need to cross the 
proximal scaffold in placement of the distal scaffold and reduces the chances for dislodging the 
proximal scaffold.
6.4.5.1.4.
Post-dilatation
Post-dilatation of the scaffold must be performed for all Esprit BTK treated lesions.  For post-dilatation of 
the target lesion treated with Esprit BTK, the following guidance is given:
x
If a scaffold cannot be re-crossed easily, excessive force with the balloon dilatation catheter or 
imaging catheter should be avoided. If it is necessary to re-cross the device, options to consider 
include changing the guide catheter orientation to reduce wire bias; consider use of a different wire or 
a wiggle wire or a buddy wire; attempt to cross the device with a balloon at 0 atm (rather than 
negative pressure); or inflate and deflate the balloon to wing it to help centralize the tip.
x
A low profile, high pressure, non-compliant or semi-compliant, balloon dilatation catheter that has not 
been previously inflated must be used.
x
Post-dilatation must always be performed with either a non-compliant or semi-compliant balloon,
sized 1:1 to the vessel.
x
For non-compliant balloons, use > 16 atm of pressure.
x
For semi-compliant balloons, select a pressure between the nominal pressure and the rated burst 
pressure that will size the balloon between 1:1 and no more than 0.5 mm above the nominal scaffold 
diameter.
x
The post-dilatation balloon length must be selected such that the balloon stays within the margins of 
the scaffold so as to avoid an edge dissection.
x
The Esprit BTK must not be expanded beyond the dilatation limit which is 0.5 mm above the nominal 
diameter. Doing so may result in scaffold damage. Thus, the compliance chart of the non-compliant 
balloon selected must be carefully reviewed prior to dilatation and an appropriate maximum pressure 
must be used to ensure that the scaffold is not over-dilated.
x
Ensure post-dilatation is done on the entire treated segment.
After treatment of the target lesion(s), the vessel distal to the treated segment must be patent (< 50% 
stenosis) with in-line blood flow to the forefoot and (if applicable) wound area. 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 43 of 140
6.4.5.2.
Treatment Strategy for PTA arm
Treatment of target lesions with PTA should be per standard of care. It is highly recommended that 
length of the PTA balloon chosen to treat the target lesion be selected to allow at least 2 mm of normal or 
nearly normal reference vessel at each edge of the lesion. 
6.4.5.3.
Bailout or Alternative Procedures
The use of a non-study implantable device or treatment strategy in either the treatment or control arms to
achieve acute procedure success (defined in Section 6.4.5.3.1 and Appendix II), will be counted as a
target lesion revascularization event at the time of index procedure. Although off-label use of devices is 
allowed under the practice of medicine and is at the discretion of the treating physician, it is 
recommended that the treating physician consider use of the non-study implantable device such as 
XIENCE to avoid potential drug interactions. If another DES is used, it would ideally be olimus based.
The location of the non-study implantable device (proximal or distal to the index-procedure device) must 
be documented on the appropriate case report form.  If the bailout procedure was a result of an adverse 
event/serious adverse event, the appropriate case report form must be completed for this event.  If a 
non-study stent or Esprit BTK is used for bailout, an appropriate length should be placed; abutting 
configuration is preferred, ensuring that the gap between the two devices (stent/scaffold) is no more than 
1 mm. If overlap is used, it is recommended to aim for ~ 1 mm overlap.
6.4.6.   
Post-procedure Imaging
At a minimum, the following angiographic views must be recorded post-procedure:
x
Anterior posterior shot from the knee to mid-lower leg
x
Anterior posterior shot from the mid-lower leg to the ankle joint
x
Lateral foot view
For more details on post-procedure imaging, refer to the angiographic core laboratory manual of 
operations. 
6.5.  
Post-procedure Medications
6.5.1.   
CIP-required antiplatelet therapy
Subjects implanted with Esprit will be treated with aspirin and one of the P2Y12 inhibitors (clopidogrel, 
prasugrel, or ticagrelor) for a minimum of 12 months. After the 12 months, subjects implanted with Esprit 
must receive a daily dose of aspirin monotherapy or one of the P2Y12 medications (clopidogrel, 
prasugrel, or ticagrelor) through 5 years follow-up during the study (except for subjects on chronic oral 
anticoagulant; see paragraph below for antiplatelet regimen in these subjects). In subject implanted with 
Esprit, the monotherapy of either aspirin or P2Y12 inhibitor should continue indefinitely. A P2Y12 assay 
is recommended if, after 12 months, the subject will be on P2Y12 monotherapy instead of aspirin 
monotherapy.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 44 of 140
Subjects treated with only PTA will receive treatment with aspirin and one of the P2Y12 inhibitors 
(clopidogrel, prasugrel, or ticagrelor) for a minimum of one month. After one month, subjects treated with 
PTA treatment must receive aspirin monotherapy or one of the P2Y12 medications (clopidogrel, 
prasugrel, or ticagrelor) daily through 5 years of follow-up during the study (except for subjects on 
chronic oral anticoagulant; see paragraph below for antiplatelet regimen in these subjects). A P2Y12 
assay is recommended if, after 1 month, the subject will be on P2Y12 monotherapy instead of aspirin 
monotherapy.
A daily aspirin dosage between ≥75 to ≤ 100 mg is strongly recommended, but 325 mg daily is also 
allowed. It is recommended to take a minimum of 75 mg of clopidogrel daily or 5 or 10 mg of prasugrel 
daily (10 mg preferred in most patients), or 90 mg twice daily of ticagrelor. Ticagrelor can be used per 
standard of care for countries outside the United States. For prasugrel subjects < 60 kg in weight or ≥75 
years of age, a maintenance dose of 5 mg per day is allowable. Patients with prior stroke or TIA should 
receive clopidogrel or ticagrelor, not prasugrel. 
In cases where subjects are implanted with Esprit in one lesion and treated with PTA in the second 
lesion, the subject will follow the medication regimen in the Esprit arm.
Subjects that were on chronic oral anticoagulants before the procedure may be maintained on oral 
anticoagulants plus a single antiplatelet agent for a minimum of 12 months following the procedure. After
12 months, the use of aspirin or a monotherapy of one of the P2Y12 medications (clopidogrel, prasugrel 
or ticagrelor) in subjects that were treated with PTA at index procedure is strongly recommended; 
however, per physician’s discretion, subjects may be maintained on chronic oral anticoagulants alone if
there is any bleeding concern. Subjects on chronic oral anticoagulants who were treated with Esprit BTK
must receive aspirin or one of the P2Y12 medications (clopidogrel, prasugrel or ticagrelor) daily through 
5 years follow-up and are recommended to continue aspirin or one of the P2Y12 medications indefinitely 
after 5 years. 
These medications can be halted for medical necessity, if required, however, reporting as protocol
deviation is required to document medical justification and the medication regimen must be resumed as 
soon as possible per physician discretion.
The start of antiplatelet medications, any changes to and termination of will be documented in the eCRF.
6.5.2.   
Other chronic concomitant medications
It is also highly recommended that subjects be maintained on high intensity statin or other lipid lowering 
agents and guideline directed anti-hypertensive therapy. The dosage for each drug shall be determined 
by physician per standard of care and label indication. 
6.6.  
Discharge Plan / Assessments
Discharge is defined as the subject leaving the treating or referral hospital. Discharge will be performed
per standard of care. 
Subjects that smoke or use tobacco products should be asked to attend at least one tobacco cessation 
class. Subjects that are diabetic should be counseled on blood sugar control in which the recommended 
HbA1c target is < 7%.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 45 of 140
6.7.  
Follow-up Assessments
All subjects registered into the clinical investigation will have follow-up assessments, which include an 
office/hospital visit at the investigational center, or if necessary, to aid in follow-up compliance, an 
independent service may be utilized to provide in-home visits for clinical follow-up at the time points listed 
below. The assessments performed at each time point are listed in Table 6.7.1-1.
In addition, for an unscheduled visit that required re-intervention to the index limb, a duplex ultrasound
for all vessels (target, non-target, and inflow vessels) of the index limb that were re-intervened on, is
required within 30 days-day (±14 days) of post-reintervention.
Table 6.7.1-1: Summary of follow-up time points and assessments
Contact Period
Assessments
14 days (± 3 days)
Index wound assessment1, *
30 days (± 7 days)
Medications review, adverse events review, ABI/TBI measurement, 
functional status (Rutherford Becker), index wound assessment1, new
wound assessment2, WIQ, PAQ, EQ-5D-5L
30 days (± 14 days)
Duplex Ultrasound3
42 days (± 7 days)
Index wound assessment1, *
90 days (± 14 days)
Medications review, adverse events review, ABI/TBI measurement, 
functional status (Rutherford Becker), index wound assessment1, new
wound assessment2, WIQ, PAQ, EQ-5D-5L
180 days (± 28 days)
Duplex Ultrasound3, medications review, adverse events review, ABI/TBI
measurement, functional status (Rutherford Becker), index wound 
assessment1, new wound assessment2, WIQ, PAQ, EQ-5D-5L
1 year (± 28 days)
Duplex Ultrasound3, medications review, adverse events review, ABI/TBI
measurement, functional status (Rutherford Becker), index wound 
assessment1, new wound assessment2, WIQ, PAQ, EQ-5D-5L
2 years (± 28 days)
Duplex Ultrasound3, medications review, adverse events review, ABI/TBI
measurement, functional status (Rutherford Becker), new wound 
assessment2
3 years (± 28 days)
Duplex Ultrasound3, medications review, adverse events review, ABI/TBI
measurement, functional status (Rutherford Becker), new wound 
assessment2
4 years (± 28 days)
Medications review, adverse events review, ABI/TBI measurement, 
functional status (Rutherford Becker), new wound assessment2
5 years (± 28 days)
Medications review. adverse events review, ABI/TBI measurement, 
functional status (Rutherford Becker), new wound assessment2
1 Index wound assessment for healing and infection will be assessed by the core laboratory through 90 days (14 days, 30 days, 42 days and 90 
days). For index wounds that are not healed by 90 days, the index wound will be assessed by the core laboratory at 180 days. If the index 
wound is not healed by 180 days, index wound assessment by the core laboratory will be carried out at 1 year. Index wounds that have healed 
by 90 days will not be assessed by the core laboratory at 180 days and 1 year. A formal office visit is highly recommended at 14-day and 42-day 
follow-up for evaluation of index wound. The option to take wound pictures remotely at 14 days and 42 days in accordance to the core laboratory 
wound imaging guidelines is for subjects that are unable to complete an office visit. No wound images will be collected outside of the protocol 
defined timepoints.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 46 of 140
* If a subject does not have an index wound at baseline, they will not need to return to the site at 14 days and 42 days.
2 New wound is defined as wound below the knee in the index limb that was not identified at the time of the index procedure or wound that has 
recurred in the same location following the healing of the index wound. The new wound will be assessed firstly by the wound assessment core 
laboratory for etiology. Subsequently, the new wound will be evaluated by the site per protocol until the wound is healed through the 5-year 
follow-up. If a new wound is first observed at 5-year follow-up, a picture will be taken for etiology assessment by the core laboratory. As this will 
be the final patient visit for the trial, no additional pictures of the new wound will be required following the initial picture submitted to the core 
laboratory.
3 Duplex ultrasound is required at 30 ± 14 days post-procedure, at 180 days and 1-year, 2-year and 3-year follow-up; if a patient is symptomatic 
or occlusion is suspected, duplex as well as angiogram should be completed.
6.7.1.   
Duplex Ultrasound
Lesion patency will be assessed by duplex ultrasound (DUS). Refer to the DUS core laboratory manual 
for detailed information.
6.7.2.   
Medication History
The medication history should be updated as needed to include modifications to the chronic concomitant 
medications and protocol required antiplatelet therapy.
6.7.3.   
Hemodynamic Evaluation
Ankle brachial index (ABI) measurement will be obtained for the target limb.  In cases in which the ABI is 
above 1.4 or cannot be reliably measured, toe pressure measurement and determination of the toe 
brachial index (TBI) should be used.  
The visit at baseline will be used to determine if a reliable ABI measurement is possible for the subject. If 
a reliable ABI measurement is not possible at baseline and TBI measurement was taken, then TBI 
measurements should be performed on the subject throughout the follow up period.
6.7.4.   
Functional Status 
To assess a change in post-study procedure functional status Rutherford Becker Clinical Categories will 
be determined for the target limb. 
These results will be compared to baseline measures.
6.7.5.   
Wound Assessment
Index wound
Any index wounds (present at baseline) in the distal ipsilateral extremity shall be assessed for healing 
and infection.
Pictures of index wound are only required for subjects that have a wound at the time of index procedure. 
This is to allow the healing of this index wound after treatment to be documented. A formal office visit is 
highly recommended at 14-day and 42-day follow-up for evaluation of index wound. The option to take 
wound pictures remotely at 14 days and 42 days in accordance to the core laboratory wound imaging
guidelines is for subjects that are unable to complete an office visit.
For subjects that do not have any wound at index procedure, the 14-day and 42-day visits will not be 
required. These missed visits will not be classified as protocol deviation for visit not done or required 
testing/assessment not done at these 2 follow-ups.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 47 of 140
During the first 90 days post-procedure, subjects are required to have wound assessments until the 
index wound is completely healed, as assessed by the site. At the 30-day visit, sites will assess if index 
wound is healed and will acquire a picture of the site of the index wound to document healing. If the 
index wound is healed by the 30-day visit, subjects will not be required to return for wound assessment 
at 42 days. This missed visit will not be classified as protocol deviation for visit not done or required 
testing/assessment not done at 42 days. However, all subjects that had a wound at the time of the index 
procedure are required to have the picture of the site of the index wound taken and assessed by the core 
laboratory at the 90-day follow-up even if the index wound was healed by 30-day visit. This will confirm 
that the index wound remains healed. 
After the 90-day follow-up, pictures of the index wound are only required for subjects whose index wound 
was not healed by 90 days post-procedure. These subjects will have index wound pictures taken at 6
months and 1 year, as needed. However, if the index wound is healed by the 6-month visit, no picture will 
be required at 1-year visit unless the recurrence of the wound has occurred in the same location. No
wound images will be collected outside of the protocol defined timepoints.
New wound
During the course of the trial, any new wound which is defined as wound below the knee in the index 
limb that was not identified at the time of the index procedure or wound that has recurred in the same 
location following the healing of the index wound, will be assessed firstly by the wound assessment core
laboratory for etiology. Subsequently, the new wound will be evaluated by the site per protocol until the 
wound is healed through the 5-year follow-up. If a new wound is first observed at 5-year follow-up, a 
picture will be taken for etiology assessment by the core laboratory. As this will be the final patient visit 
for the trial, no additional pictures of the new wound will be required following the initial picture submitted 
to the core laboratory.
Planned minor amputation
In the case of a planned minor amputation, two pictures must be taken and sent to the core laboratory. 
The first picture is the identified area prior to the amputation and the second picture is the surgical site
post minor amputation. If the minor amputation re-opens, it needs to be assessed as a new wound and
will be sent to core laboratory for adjudication.
6.7.6.   
Patient Reported Outcome (PRO) Measures
The Coordinator or designee will administer patient-reported outcome questionnaires. It is important the 
subject understands the meaning of all words and instructions in the questionnaires. The subject should 
be instructed to ask any questions about the questionnaires if further explanation is needed. Once the 
questionnaires are completed, the Coordinator or designee will review for completeness to verify that all 
questions have been answered according to the directions provided.
The following PRO measures will be collected according to the CIP requirements at baseline and at each 
follow-up time points up to and including at 1 year (30 days, 3 months, 6 months and 1 year).
• EQ-5D-5L
• WIQ
• PAQ

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 48 of 140
The EuroQoL 5D (EQ-5D-5L) [17] is a validated self-administered two-part instrument.  The first part 
consists of 5 questions to assess current health state in 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  The second part is a 20 cm visual analog scale that ranges 
from 0 (worst imaginable health state) to 100 (best imaginable health state used to assess Overall Health 
Status.  
The Walking Impairment Questionnaire (WIQ) [18] is a validated questionnaire used to assess patient-
perceived walking performance.  The self-administered questionnaire consists of 4 domains (symptom 
severity, walking distance, walking speed, and stair climbing) across 22 questions and takes 
approximately 6 minutes to complete. 
The Peripheral Arterial Questionnaire (PAQ) [19] is a validated questionnaire used to assess disease-
specific health status.  The self-administered questionnaire consists of 5 domains (physical limitation, 
symptoms, quality of life, social function, and treatment satisfaction) across 20 questions and takes 
approximately 5 minutes to complete.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 49 of 140
6.7.7.   
Schedule of Events
PROCEDURE/TEST
Baseline
(within 30 days prior 
to index procedure)
Pre-Procedure
(within 24 hours)
Procedure
Post-Procedure
14 days (r 3 d) office 
visit/ remote index 
wound image*
30 days (r 7 d)   office
visit*
30 days (r 14 d)   
office visit*
42 days (r 7 d) office 
visit/ remote index 
wound image*
90 days (r 14 d)   
office visit*
180 days (r 28 d)
office visit*
1 yr (r 28 d)
office visit*
2yrs (r 28 d)
office visit*
3 yrs (r 28 d)
office visit*
4 yrs (r 28 d)
office visit*
5 yrs (r 28 d)
office visit*
Unscheduled visits
Subject Medical/Clinical 
History (Age, Sex, Risk 
Factors)
9
Subject Informed Consent 
(Must be obtained prior to any 
study related testing or 
procedures)1
9
General Inclusion/Exclusion 
Criteria
9
Anatomic Inclusion/Exclusion 
Criteria2
9
9
9
Pregnancy Test (if applicable)3
9
Hematology and blood 
chemistry4
9
Vascular Angiogram, IVUS5
9
9
9
Duplex Ultrasound6
9
9
9
9
9
9
ABI/TBI measurement7
9
9
9
9
9
9
9
9
9
9
9
Study device information
9
Per Protocol Medications
9
9
9
9
9
9
9
9
9
9
9
9
Concomitant Medications
9
9
9
9
9
9
9
9
9
9
9
9
Adverse Events
9
9
9
9
9
9
9
9
9
9
9
Patient Reported Outcome 
Instruments (WIQ, PAQ, EQ-
5D-5L)
9
9
9
9
9
Rutherford Becker category 
assessment 
9
9
9
9
9
9
9
9
9
9
Index wound assessment8
9
9
9
9
9
9
9
9
9
New wound assessment9
9
9
9
9
9
9
9
9
9
1 Informed consent can be obtained any time prior to study related procedure.
2 Anatomic inclusion/exclusion criteria can be verified at baseline during a diagnostic catheterization and/or pre-procedure; some of the criteria need to be verified during the procedure.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 50 of 140
3 Pregnancy test (if applicable) must be conducted within 7 days prior to the procedure.
4 For complete list of tests, refer to section 6.1.7 (Laboratory Assessments). Baseline laboratory assessments must be obtained for all subjects within 30 days prior to index procedure, and 
these results must be entered in the electronic case report form. However, if it is not possible to undertake the laboratory assessments 30 days prior to the index procedure, laboratory results
longer than 30 days prior to index procedure are acceptable, and these results can be used per physician’s discretion to confirm patient’s eligibility.
5 Angiogram to confirm eligibility criteria can be done within 30 days prior to index procedure or during the procedure, as long as it is carried out prior to randomization of the patient. IVUS 
should only be captured if it is the standard-of-care of the site PI to use IVUS in his/her patients in this population.  
6 Duplex ultrasound is required at 30 days ± 14 days post-procedure, at 180 days, and at 1, 2 and 3 years; if a patient is symptomatic or occlusion is suspected, duplex as well as angiogram 
should be completed. Additionally, a duplex ultrasound must be completed within 30 days (±14 days) post-reintervention to the index limb.  
7 While ABI/TBI measurement is listed at both “baseline” and “pre-procedure” time points, this measurement only needs to occur once before the procedure (either at baseline or at pre-
procedure time point).
8Index wound needs to be assessed before the procedure to confirm patient eligibility (ischemic arterial wound). If the picture of the wound was taken within 7 days prior to index procedure, 
the picture does not need to be repeated the day of index procedure. If the picture was taken > 7 days prior to index procedure, a second picture must be taken the day of index procedure and
can be taken up to 24 hours post-procedure. In cases where picture is taken on the day of index procedure, baseline will be defined as “within 24 hours post-procedure”.  Index wound
assessment for healing and infection will be assessed by the core laboratory through 90 days (14 days, 30 days, 42 days and 90 days). For index wounds that are not healed by 90 days, the 
index wound will be assessed by the core laboratory at 180 days. If the index wound is not healed by 180 days, index wound assessment by the core laboratory will be carried out at 1 year. 
Index wounds that have healed by 90 days will not be assessed by the core laboratory at 180 days and 1 year. A formal office visit is highly recommended at 14-day and 42-day follow-up for 
evaluation of index wound. The option to take wound pictures remotely at 14 days and 42 days in accordance to the core laboratory wound imaging guidelines is for subjects that are unable to 
complete an office visit.  No wound images will be collected outside of the protocol defined timepoints.
9 New wound is defined as wound below the knee in the index limb that was not identified at the time of the index procedure or wound that has recurred in the same location following the 
healing of the index wound. The new wound will be assessed firstly by the wound assessment core laboratory for etiology. Subsequently, the new wound will be evaluated by the site per 
protocol until the wound is healed through the 5-year follow-up. If a new wound is first observed at 5-year follow-up, a picture will be taken for etiology assessment by the core laboratory. As 
this will be the final patient visit for the trial, no additional pictures of the new wound will be required following the initial picture submitted to the core laboratory. The 14-day and 42-day visits 
are not required for subjects with new wounds.
* To aid in follow-up compliance, if necessary, an independent service may be utilized to provide in-home visits for clinical follow-up.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 51 of 140
6.8.  
Requirement for Clinical Laboratories
The following core laboratories will be used in this clinical investigation, for independent evaluation of the 
clinical investigation data:
x
Angiographic core laboratory will be used for analysis of angiographies associated with baseline, 
index procedure and adverse events
x
IVUS core laboratory will be used for analysis of intravascular images associated with baseline, index 
procedure and adverse events
x
Duplex ultrasound core laboratory will be used at each follow-up time points, as described in the 
schedule of events above
x
Wound assessment core laboratory will be used for analysis of wounds, as described in section 6.7.5 
Wound Assessment.
x
OCT core laboratory will be used for analysis of intravascular images captured using OCT (for sites 
that are experienced).
6.8.1.   
Health Economic Data Collection
Data on resource utilization will be collected prospectively for the index hospitalization and the full follow-
up period using standardized case report forms. Procedural costs will be assessed using a resource-
based approach to convert standard measures such as procedural duration and device utilization (e.g., 
scaffolds, balloons, guidewires, etc.) into costs. Other hospital costs will be assessed using an “event-
driven” approach in which specific complications and outcomes are assigned standard costs based on 
external data. Additional costs will be assigned for follow-up hospitalizations and repeat revascularization 
procedures, emergency room visits, outpatient diagnostic testing, and cardiovascular medications. In 
each case, costs will be assessed from the perspective of the U.S. healthcare system.
Cost and quality of life data will be used to perform a cost-effectiveness analysis from the perspective of
the U.S. healthcare system.
7.0     
ADVERSE EVENTS
To comply with worldwide standards and guidelines on clinical investigation adverse event reporting, the
Sponsor has adopted uniform and worldwide applicable standard definitions and reporting timelines to be
used and adhered to by the investigators.
7.1.  
Definition
7.1.1.   
Adverse Event
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons in the context of 
a clinical investigation, whether or not related to the investigational medical device.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 52 of 140
As part of ISO14155 Section 3.2, the Adverse Event definition has the following notes:
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 medical devices under 
investigation.
7.1.2.   
Serious Adverse Event
Serious Adverse Event is an AE that led to any of the following:
a). death,
b). serious deterioration in health of the subject, that resulted in any of the following:
1. life-threatening illness or injury, 
2. permanent impairment of a body structure or a body function, 
3. hospitalization or prolongation of patient hospitalization
4. medical or surgical intervention to prevent life threatening illness or injury or permanent 
impairment to a body structure or a body function.
5. chronic disease 
c). fetal distress, fetal death or a congenital physical or mental impairment or birth defect.
Note: A planned hospitalization for pre-existing condition, or a procedure required by the CIP, without a 
serious deterioration in health, is not considered SAE.
7.1.3.   
Device Deficiency/Device Malfunction
Device deficiency is defined as any inadequacy in the identity, quality, durability, reliability, usability,
safety or performance of an investigational device including malfunction, use errors or inadequacy in the 
information supplied by the manufacturer including labeling. 
Note 1: The definition includes the device deficiencies related to the investigational medical device or 
comparator.
Note 2: Cyber-security incidents related to the investigational product, shall be reported as device 
deficiencies
A device malfunction is the failure of an investigational device to perform in accordance with its intended
purpose when used in accordance with the instructions for use or CIP, or IB.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 53 of 140
7.2.  
Device Relationship
Determination of whether there is a reasonable possibility that an investigational product or device under 
investigation caused or contributed to an AE is to be determined by the Investigator and recorded on the 
appropriate CRF form. Determination should be based on assessment of temporal relationships, 
evidence of alternative etiology, medical/biologic plausibility, and patient condition (pre-existing 
condition).
7.2.1.   
Unanticipated (Serious Adverse) Device Effect [U(S)ADE]
Unanticipated serious adverse device effect (USADE) refers to any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.
7.2.2.   
Serious Health Threat
Serious Health Threat is a signal from any adverse event or device deficiency that indicates an imminent 
risk of death or a serious deterioration in the health in subjects, users or other persons, and that requires 
prompt remedial action for other subjects, users or other persons
Note: This would include events that are of significant and unexpected nature such that they become 
alarming as a potential serious health hazard or possibility of multiple deaths occurring at short intervals.
7.3.  
Adverse Event and Device Deficiency/Device Malfunction Reporting
7.3.1.   
Adverse Event (AE) Reporting
General AE Reporting
Safety surveillance and AE reporting, for all randomized subjects, starts when the guiding catheter enters 
the subject’s vasculature. Safety surveillance and reporting will continue until the last follow-up visit has 
been performed, the subject is deceased, the subject concludes participation in the clinical investigation
or the subject withdraws from the clinical investigation. Adverse event data, including deaths and device
deficiency data, will be collected throughout the time period defined above and will be reported to the 
Sponsor on a CRF. Additional information with regards to an adverse event should be updated within the 
appropriate CRF.
Unchanged, chronic, non-worsening or pre-existing conditions are not AEs and should not be reported. 
An offline form will be made available to allow the investigator to report SAEs in the event the entry 
cannot be made in the EDC. This does not replace the EDC reporting system. All information must still 
be entered in the EDC system as soon as feasible.
All adverse events will be collected on each subject through the 1-year follow-up visit. After 1-year, only 
the following will be collected:

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 54 of 140
x
All serious AEs. This includes deaths, arterial thrombosis (including occlusion), any amputation, 
major limb re-intervention, any revascularization of the target limb.
x
All trial device-related events and events for which the relationship to the trial device is unknown
x
All unanticipated adverse device effects
x
New wound on the index limb
In addition, the following adverse events will be collected:
x
Revascularization, including the use of bail-out device during the index procedure
x
Stent/scaffold thrombosis
x
Occlusion or stenosis of 50% or more of the target vessel 
Abnormal laboratory values, in themselves, will not be considered AEs unless:
x
The investigator determined that the value is clinically significant.
x
The abnormal laboratory value required intervention, or
x
The abnormal laboratory value required subject withdrawal from the clinical investigation.
SAE Reporting
The investigator should report all SAEs to the Sponsor as soon as possible but no later than outlined 
below. 
Clinical Site
Reporting timelines
All Sites
SAEs must be reported to the Sponsor no later than 3 calendar days from the 
day the site personnel became aware of the event or as per the investigative 
site’s local requirements, if the requirement is more stringent than those outlined.
The date the site staff became aware the event met the criteria of an SAE must be recorded in the 
source document.  The Investigator will further report the SAE to the local IRB/EC according to the 
institution’s IRB/EC reporting requirements.
7.3.2.   
Unanticipated Serious Adverse Device Effect Reporting to Sponsor and IRB
The Sponsor requires the Investigator to report any USADE to the Sponsor within 3 calendar days of the 
investigator’s knowledge of the event, unless local requirements are more stringent, and to the IRB/EC 
per IRB/EC requirements.
7.3.3.   
Device Deficiency/Malfunction Reporting

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 55 of 140
All device deficiencies/malfunctions for the investigational device should be reported on the appropriate 
CRF form. 
The investigator should report all device deficiencies/malfunctions to the Sponsor as soon as possible 
but no later than outlined below. 
Clinical Sites
Reporting timelines
All Sites
Device deficiencies/malfunctions must be reported to the Sponsor no later 
than 3 calendar days from the day the site personnel became aware of the 
event or as per the investigative site’s local requirements, if the requirement 
is more stringent than those outlined.
The device, if not implanted or not remaining in the subject, should be returned to the Sponsor.  
Device deficiencies/malfunctions should be reported to the IRB/EC per the investigative site’s local
requirements.
An offline form will be made available to allow the investigator to report device deficiencies/malfunctions 
in the event that the entry cannot be made in the EDC system. This does not replace the EDC reporting 
system. All information must still be entered in the EDC system as soon as feasible. 
In case a device deficiency/malfunction occurred before the subject ID and/or randomization number has 
been assigned, the device deficiency should be reported to the Sponsor via the offline reporting form.
7.3.4.   
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor 
The Sponsor will report SAEs and reportable device deficiencies/malfunctions to the country regulatory 
authority, per local requirements. 
Note: Reportable device deficiencies/malfunctions include device deficiencies/malfunctions 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.
8.0     
STATISTICAL CONSIDERATIONS
The following section describes the statistical methods for the clinical investigation. 
.
8.1.1.   
Intent-to-Treat Population (ITT)

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 56 of 140
8.1.2.   
As-Treated Population (AT)
8.1.3.   
Per-Protocol Population (PP)
x

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 57 of 140
x
This is the secondary analysis population for the primary endpoint analysis. 
8.2.  
Statistical Analyses 
8.2.1.   
Primary Endpoint(s) Analyses
The primary efficacy endpoint, a composite of limb salvage and primary patency at 1 year , will be 
evaluated using the difference in endpoint rates in the ITT population. The hypothesis test is designed to 
show superiority of Esprit BTK to PTA for the primary efficacy endpoint with one-sided alpha of 0.025.
The null (H0) and alternative (H1) hypotheses are:
H0: ܲ஻்௄െܲ௉்஺൑Ͳ
H1: ܲ஻்௄െܲ௉்஺൐Ͳ
where ܲ஻்௄and ܲ௉்஺are the primary efficacy endpoint rates for the Esprit BTK arm and PTA arm 
respectively.  
A sensitivity analysis for the primary efficacy endpoint will be performed for the AT, modified AT and PP
populations.
The primary safety endpoint, will be evaluated using the difference in endpoint rates in the AT population. 
The hypothesis test is designed to show non-inferiority of Esprit BTK to PTA for the primary safety 
endpoint with one-sided alpha of 0.025. The null (H0) and alternative (H1) hypotheses are:
H0: ݍ஻்௄െݍ௉்஺൑ߜ
H1: ݍ஻்௄െݍ௉்஺൐ߜ
where ݍ஻்௄and ݍ௉்஺are the primary safety endpoint rates for the Esprit BTK arm and PTA arm,
respectively. The non-inferiority margin of ߜis set at -0.1.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 58 of 140
A sensitivity analysis for the primary safety endpoint will be performed for the modified AT, ITT and PP 
populations. In addition, landmark Kaplan-Meier analyses will be performed for the primary safety and 
efficacy endpoints from 0 to 30 days, 30 days to 6 months, and 30 days to 1 year.
8.2.2.   
Powered Secondary Endpoints Analysis
The first powered secondary endpoint, binary restenosis of target lesion at 1 year, will be evaluated using 
the difference in endpoint rates in the ITT population at 1 year. The hypothesis test is designed to show 
superiority of Esprit BTK to PTA with one-sided alpha of 0.025.
The null (H0) and alternative (H1) hypotheses are:
H0: ܴ஻்௄െܴ௉்஺൒Ͳ
H1: ܴ஻்௄െܴ௉்஺൏Ͳ
where ܴ஻்௄and ܴ௉்஺are the first secondary endpoint rates for the Esprit BTK and PTA arms 
respectively.  
The second powered secondary endpoint, a composite of freedom from: above ankle amputation in 
index limb, 100% total occlusion of target vessel and CD-TLR. The hypothesis test is designed to show 
superiority of Esprit BTK to PTA with one-sided alpha of 0.025.
The null (H0) and alternative (H1) hypotheses are:
H0: ܵ஻்௄െܵ௉்஺൑Ͳ
H1: ܵ஻்௄െܵ௉்஺൐Ͳ
where ܵ஻்௄and ܵ௉்஺are the second secondary endpoint rates for the Esprit BTK and PTA arms 
respectively.
8.2.3.   
Descriptive Secondary Endpoints Analyses
Secondary endpoints will be summarized descriptively for the ITT population. For further details refer to 
the statistical analysis plan (SAP).
8.3.  
Sample Size Calculation and Assumptions
8.3.1.   
Sample Size Calculation and Assumptions for Primary Endpoints

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 59 of 140
For the primary efficacy endpoint, 
The power calculation is based on the statistical hypotheses and the following 
assumptions:
H0: ܲ஻்௄െܲ௉்஺൑Ͳ
H1: ܲ஻்௄െܲ௉்஺൐Ͳ
x
One-sided type I error rate = 0.025
x
Randomization ratio is 2:1 (Esprit BTK vs. PTA)
x
x
Superiority test
 
For the primary safety endpoint, 
The power calculation is based on the statistical hypotheses and the 
following assumptions:
H0: ݍ஻்௄െݍ௉்஺൑ߜ
H1: ݍ஻்௄െݍ௉்஺൐ߜ
x
One-sided non-inferiority test
x
One-sided type I error rate = 0.025
x
Randomization ratio is 2:1 (Esprit BTK vs. PTA)
x
x
Non-inferiority margin (ߜ) of -10%
l 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 60 of 140
8.3.2.   
Assumptions for Powered Secondary Endpoints
For the first powered secondary endpoint of target lesion binary restenosis at 1 year, the binary 
restenosis will be determined as the presence of a hemodynamically significant restenosis ≥ 50% by 
angiography, or PSVR ≥ 2.0 by duplex ultrasound.
The power calculation is based on the statistical hypotheses and the following assumptions:
H0: ܴ஻்௄െܴ௉்஺൒Ͳ
H1: ܴ஻்௄െܴ௉்஺൏Ͳ
x
One-sided type I error rate = 0.025
x
Randomization ratio is 2:1 (Esprit BTK vs. PTA)
x
x
Superiority test
For the second powered secondary endpoint of  freedom from: above ankle amputation in index limb, 
100% total occlusion of target vessel and CD-TLR at 1 
The power calculation is based on the statistical hypotheses and the following assumptions:
H0: ܵ஻்௄െܵ௉்஺൑Ͳ
H1: ܵ஻்௄െܵ௉்஺൐Ͳ
x
One-sided type I error rate = 0.025
x
Randomization ratio is 2:1 (Esprit BTK vs. PTA)

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 61 of 140
x
x
Superiority test
8.4.  
Timing of Analysis
The primary endpoint analysis will be performed when all subjects in ITT population have completed their 
1-year follow-up visit and the clinical investigation becomes unblinded.
8.5.  
Subgroup Analysis
Subgroup analyses will be performed per gender, race, and age. 
8.6.  
Multiplicity
8.7.  
Planned Interim Analysis
8.8.  
Statistical Criteria for Termination
There are no statistical criteria for termination of this clinical investigation.
8.9.  
Success Criteria

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 62 of 140
8.10.  
Deviations from Statistical Plan
Any major changes to the statistical plan will be documented in an amendment to the statistical analysis 
plan. Less significant changes to the planned analyses will be documented in the final report.  
9.0     
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/institution will permit direct access to source data/documents for the purpose of 
performing clinical investigation-related monitoring, audits, IRB/EC review and regulatory inspections.
Subjects providing informed consent are agreeing to allow clinical investigation monitors or regulatory 
authorities including foreign countries to review, in confidence, any records identifying the subjects in this 
clinical investigation. This information may be shared with regulatory agencies; however, Sponsor 
undertakes not to otherwise release the subject's personal and private information.
10.0     
QUALITY CONTROL AND QUALITY ASSURANCE
10.1.  
Selection of Clinical Sites and Investigators
The Sponsor will select investigators qualified by training and experience to participate in the clinical 
investigation. Sites will be selected based upon review of a recent site assessment, if applicable, and the 
qualifications of the investigators who will participate in the clinical investigation.
10.2.  
Site Principal Investigator Responsibilities
The role of the Site Principal Investigator is to implement, oversee the management of the day-to-day 
conduct of the clinical investigation as well as ensure data integrity and the rights, safety and well-being
of the subjects involved in the clinical investigation. The principal investigator shall support monitoring 
and reporting to IRB/EC and local competent authorities as necessary, throughout the conduct of the 
clinical investigation.
The principal investigator is responsible for ensuring adequate training and qualification of the 
investigation site team and for maintaining oversight of their activities. The principal investigator may
delegate tasks to members of the investigation site team but retains responsibility for the clinical 
investigation. This also applies when activities are outsourced to an external organization by the principal 
investigator in which case he/she shall exercise oversight to ensure the integrity of all tasks performed 
and any data generated by this external organization.
10.3.  
Clinical Investigation Finances and Agreements
The clinical investigation will be financed by Abbott. Investigational sites will be compensated by Abbott 
for participation in the clinical investigation per the conditions of agreement between the Sponsor and the 
Investigational site.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 63 of 140
10.4.  
CIP Amendments 
Approved CIP amendments will be provided to the Investigators by the Sponsor prior to implementing the 
amendment. The Principal Investigator is responsible for notifying the IRB/EC or equivalent committee of 
the CIP amendment (administrative changes) or obtaining IRB’s/EC’s approval of the CIP amendment 
(changes in subject care or safety), according to the instructions provided by the Sponsor with the CIP
amendment.  
Acknowledgement/approval by the IRB/EC of the CIP amendment must be documented in writing prior to 
implementation of the CIP amendment. Copies of this documentation must also be provided to the 
Sponsor.
10.5.  
Training
10.5.1.   
Site Training
All Investigators and clinical investigation personnel are required to attend Sponsor training sessions, 
which may be conducted at an Investigator's meeting, a site initiation visit, or other appropriate training 
sessions. Over-the-phone or self-training may take place as required. Training of Investigators and
clinical investigation personnel will include, but is not limited to, the CIP requirements, investigational 
device usage, electronic case report form completion and clinical investigation personnel responsibilities. 
All Investigators and clinical investigation personnel that are trained must sign a training log (or an 
equivalent) upon completion of the training. Prior to signing the training log, Investigators and clinical 
investigation personnel must not perform any CIP-related activities that are not considered standard of 
care at the site. 
10.5.2.   
Training Required for the Use of the Device
All physicians will be trained on the use of the device, as per the training plan described in the 
physician’s training materials. Proof of training will be documented and stored in the appropriate 
archiving system.
Additionally, each physician will have to provide images, from a requested number of their standard of
care cases, to the core laboratory for analysis before being allowed to enroll in the trial.
10.6.  
Monitoring
Sponsor and/or designee will monitor the clinical investigation over its duration according to the CIP-
specific monitoring plan which will include the planned extent of source data verification. 
Prior to initiating any procedure, the Sponsor monitor (or delegate) will ensure that the following criteria 
are met: 
x
The investigator understands and accepts the obligation to conduct the clinical investigation
according to the CIP and applicable regulations, and has signed the Investigator Agreement (for US 
clinical sites) or the Clinical Trial Agreement (for OUS clinical sites).
x
The Investigator and his/her staff should have sufficient time and facilities to conduct the clinical 
investigation and should have access to an adequate number of appropriate subjects to conduct the 
clinical investigation.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 64 of 140
x
Source documentation (including original medical records) must be available to substantiate proper 
informed consent procedures, adherence to CIP procedures, adequate reporting and follow-up of 
adverse events, accuracy of data collected on case report forms, and device information. 
x
The Investigator/site will permit access to such records. A monitoring visit sign-in log will be 
maintained at the site. The Investigator will agree to dedicate an adequate amount of time to the 
monitoring process. The Investigator and/or research coordinator will be available for monitoring 
visits. It is expected that the Investigator will provide the monitor with a suitable working environment 
for review of clinical investigation-related documents.
10.7.  
Deviations from CIP
The Investigator should not deviate from the CIP for any reason except in cases of medical emergencies 
when the deviation is necessary to protect the rights, safety and well-being of the subject or eliminate an 
apparent immediate hazard to the subject. In that event, the Investigator will notify Sponsor immediately 
by phone or in writing.
No waivers for CIP deviations will be granted by the Sponsor.  All deviations must be reported to the 
Sponsor using the Deviation CRF. The occurrence of CIP deviations will be monitored by the Sponsor for 
evaluation of investigator compliance to the CIP and regulatory requirements and dealt with according to 
written procedures. Investigators will inform their IRB/EC or equivalent committee of all CIP deviations in 
accordance with their specific IRB/EC or equivalent committee reporting policies and procedures. 
In the event of repeated non-compliance, as determined by the Sponsor, a Sponsor’s monitor or 
company representative will attempt to secure compliance by one or more of the following (and not 
limited to): 
x
Visiting the investigator and/or delegate
x
Telephoning the investigator and/or delegate
x
Corresponding with the investigator and/or delegate
Repeated non-compliance with the signed agreement, the CIP or any other conditions of the clinical 
investigation may result in further escalation in accordance with the Sponsor’s written procedures,
including securing compliance or, at its sole discretion, Sponsor may terminate the investigator's 
participation in the clinical investigation.
The following categories of protocol deviations will be considered major:
x
Informed Consent deviation
x
Eligibility deviation (General/Anatomic)
x
Serious adverse event reporting deviation
x
Treatment/procedure compliance deviation
x
Registration/randomization

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 65 of 140
x
Unauthorized personnel performing study related procedures
x
Missing data
x
Missed visit
Other types of deviations will be considered minor.
10.8.  
Quality Assurance Audit
A Sponsor representative or designee may request access to all clinical investigation records, including 
source documentation, for inspection during a Quality Assurance audit. 
In the event that an investigator is contacted by a Regulatory Agency in relation to this clinical 
investigation, the Investigator will notify the Sponsor immediately. The Investigator and Research 
Coordinator must be available to respond to reasonable requests and audit queries made during the 
audit process. The Investigator must provide Sponsor with copies of all correspondence that may affect 
the review of the current clinical investigation (e.g., Form FDA 483, Inspectional Observations, Warning 
Letters, Inspection Reports, etc.). The Sponsor may provide any needed assistance in responding to
regulatory audits.
10.9.  
Sponsor Auditing
The Sponsor shall prepare an audit plan as well as the operating procedures for the related duties, and 
conduct audits in accordance with the audit plan and the operating procedures.
x
Individual engaged in auditing (hereinafter referred to as "auditor") shall be different than those in 
charge of medical device development or monitoring.
x
The auditor shall prepare an audit report documenting the matters confirmed in the audit to certify 
and verify that the audit has been conducted, and submit them to the Sponsor.
10.10.
Committees
10.10.1.   
Steering Committee
The Steering Committee is assigned by the Sponsor and consists of investigators. The Sponsor will also 
be represented on the committee. The Chairman of the core laboratories and other sponsor’s personnel 
may also participate in the Committee meetings if appropriate. Meeting minutes from this committee will 
be filed with the sponsor.
The Steering Committee is responsible for overseeing the scientific and operational aspects of the 
clinical investigation. This committee will meet regularly to monitor subject enrollment, general data 
collection and non-compliance with the CIP at individual centers, to review and act upon 
recommendations of the Data Monitoring Committee (DMC), also known as Data and Safety Monitoring 
Board (DSMB), to review operational issues that may arise and warrant a CIP amendment or other 
corrective action and to determine policy regarding any publications arising from data generated from the 
performance of the clinical investigation.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 66 of 140
10.10.2.   
Publications Committee
A Publication Committee shall be established to oversee clinical investigations publications, including 
publication planning and authorship determinations. Publication Committee membership may include 
members of the Steering Committee, Principal Investigators, a representative of the Sponsor and a 
statistician. The Publication Committee will determine policy and strategies regarding individual 
presentations and/or publications arising from clinical investigation generated data. The committee will 
also review all external requests for accessing clinical investigation-related data and strategies aligning 
with the Sponsor’s presentation and publication team expectations. The committee will also follow the
Sponsor’s applicable policies and Standard Operating Procedures.
10.10.3.   
Data Monitoring Committee (DMC)
The Data Monitoring Committee (DMC), also known as Data and Safety Monitoring Board (DSMB), is an 
independent multidisciplinary group restricted to individuals free of apparent significant conflicts of 
interest. The source of these conflicts may be financial, scientific, or regulatory in nature. The DMC is 
typically composed of at least two physicians with experience relevant to the clinical investigation and a 
biostatistician.
The DMC will serve in an advisory role to the Sponsor to ensure safety by reviewing cumulative data 
from the clinical investigation at prescribed intervals for the purpose of safeguarding the interests of 
enrolled subjects and those patients yet to be enrolled, as well as the continuing validity and scientific 
merit of the clinical investigation. The composition, frequency of the meetings and the statistical 
monitoring guidelines are described in detail in the DMC charter.
The DMC may consider a recommendation for modifications or termination of the clinical investigation 
based on any perceived safety concerns regardless of statistical significance. The recommendations of 
the DMC are not binding, and all final decisions related to clinical investigations modifications rest with 
the Sponsor.
10.10.4.   
Clinical Events Committee (CEC)
The Clinical Events Committee (CEC) is an independent adjudication body comprised of qualified 
physicians who are not participants in the clinical investigation. The CEC will review and adjudicate pre-
specified events reported by investigators or identified by Safety personnel for the clinical investigation 
as defined in the CEC charter and according to definitions provided in this CIP.
11.0     
DATA HANDLING AND RECORD KEEPING
Sponsor and/or its affiliates will maintain documentation of the systems and procedures used in data 
collection for the duration of the clinical investigation.
CRF data collection will be performed through a secure web portal and only authorized personnel will
access the Electronic Data Capture (EDC) system using a unique username and password to enter, 
review or correct data. Passwords and electronic signatures will be strictly confidential.  
The data will be subjected to consistency and validation checks within the EDC system and 
supplemental review by the Sponsor. 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 67 of 140
At the conclusion of the clinical investigation, completed CRF images with the date-and-time stamped 
electronic audit trail indicating the user, the data entered, and any reason for change (if applicable) will 
be provided to the investigational sites.
For the duration of the clinical investigation, the Investigator will maintain complete and accurate 
documentation including, but not limited to, medical records, clinical investigation progress records, 
laboratory reports, CRFs, signed ICFs, device accountability records, correspondence with the IRB/EC
and clinical investigation monitor/Sponsor, adverse event reports, and information regarding subject 
discontinuation or completion of the clinical investigation.
11.1.  
Protection of Personally Identifiable Information
The Sponsor respects and protects personally identifiable information collected or maintained for this 
clinical investigation.
The Sponsor implements technical and physical access controls to ensure that Personal Information is 
accessible only to and processed only on a ‘need to know’ basis, including periodic review of access 
rights, and revocation of access when an individual’s employment is terminated or the individual 
transitions to a role that does not require access to Personal Information, and appropriate restrictions on 
physical access to premises, facilities, equipment, and records containing Personal Information. 
The Sponsor requires the investigational sites to enter only pseudonymous Personal Information (key-
coded) necessary to conduct the Clinical Investigation, such as the patient’s medical condition, 
treatment, dates of treatment, etc., into Sponsor’s data management systems. The Sponsor discloses as 
part of the clinical investigation informed consent process that some Sponsor representatives still may 
see Personal Information at the participating sites for technical support of the participating physicians on 
the device implant or procedures, monitoring and quality control purposes. All parties will observe 
confidentiality of Personal Information always throughout the clinical investigation. All reports and data 
publications will preserve the privacy of each subject and confidentiality of his/her information.
The Sponsor data management systems and processes were designed, developed, and tested 
according to industry standards to appropriately safeguard Confidential Information (including any 
Personal Information) against unauthorized access and/or interference by third parties, intrusion, 
theft, destruction, loss or alteration. Clinical Investigation data are encrypted in transit and at rest. 
The Sponsor maintains a Privacy Incident procedure that complies in all respects with Applicable 
Law and industry best practices.
11.2.  
Data Management Plan
A Data Management Plan (DMP) will describe procedures used for data review, data cleaning, and 
issuing and resolving data discrepancies. If appropriate, the DMP may be updated throughout the 
duration of the clinical investigation. All revisions will be tracked and document controlled.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 68 of 140
11.3.  
Source Documentation
Regulations and GCP require the Investigator to maintain information in the subject’s original medical 
records that corroborates data collected on the CRFs. In order to comply with these regulatory 
requirements/GCP, the following information should be included in the subject record at a minimum and 
if applicable to the clinical investigation:
x
Medical history/physical condition of the subject before involvement in the clinical investigation
sufficient to verify CIP entry criteria
x
Dated and signed notes on the day of entry into the clinical investigation referencing the Sponsor, 
CIP number, subject ID number and a statement that informed consent was obtained
x
Dated and signed notes from each subject visit (for specific results of procedures and exams)
x
Adverse events reported and their resolution, including supporting documents, such as discharge 
summaries, catheterization laboratory reports, ECGs, and lab results including documentation of site 
awareness of SAEs and of investigator assessment of device relationship for SAEs.
x
CIP-required laboratory reports, reviewed and annotated for clinical significance of out-of-range 
results. 
x
Notes regarding CIP-required and prescription medications taken during the clinical investigation
(including start and stop dates)
x
Subject’s condition upon completion of or withdrawal from the clinical investigation
x
Any other data required to substantiate data entered into the CRF
x
Patient reported outcome measures may be completed using CRF worksheets. These serve as the 
source documentation.
11.4.  
Electronic Case Report Form Completion
Primary data collection based on source-documented hospital and/or clinic chart reviews will be 
performed clearly and accurately by site personnel trained on the CIP and eCRF completion. The
investigator will ensure accuracy, completeness, legibility and timeliness of the data reported to the 
Sponsor on the eCRFs and in all required reports. eCRF data will be collected for all subjects that are 
registered into the trial.
Only authorized site personnel will be permitted to enter the eCRF data through the EDC system 
deployed by the Sponsor. An electronic audit trail will be used to track any subsequent changes of the 
entered data.
11.5.  
Record Retention
The Sponsor and Investigator/Site will archive and retain all documents pertaining to the clinical 
investigation as per the applicable regulatory record retention requirements. The Investigator must obtain 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 69 of 140
permission from Sponsor in writing before destroying or transferring control of any clinical investigation
records.
11.6.  
Investigational Devices Accountability
The Sponsor ships investigational products (Esprit BTK) only to the Principal Investigator (the 
responsible leader of the investigational site) or his/her legal designee of each site, after sites receive 
documentation of site activation and shipping authorization is complete.  
The Investigator or an authorized designee must maintain adequate records of the receipt and 
disposition of each investigational device, including part number, batch number, and serial number (if 
applicable), date used, subject identification, and treating physician.
Storage locations for the devices at investigational sites must be locked with access restricted only to 
investigators and authorized personnel.
Inventory Accountability Log supplied by the Sponsor will be used. The Inventory Accountability Log 
must document the disposition of all investigational devices including those that have been returned to 
Sponsor.
All investigational devices that are associated with a device failure or device deficiency must be returned 
immediately to the Sponsor.
12.0     
ETHICAL CONSIDERATION
12.1.  
Institutional Review Board/Medical Ethics Committee Review and Approval
Institutional Review Board (IRB)/ Ethics Committee (EC) approval for the CIP and ICF/other written 
information provided to the patient will be obtained by the Principal Investigator at each investigational 
site prior to consenting and enrolling patients in this clinical investigation. The approval letter must be 
received prior to the start of this clinical investigation and a copy must be provided to the Sponsor. 
Any amendments to the CIP as well as associated ICF changes will be submitted to the 
IRB/EC/Competent Authority and written approval obtained prior to implementation, according to each 
institution’s IRB/EC requirements. 
No changes will be made to the CIP or ICF or other written information provided to the patient without 
appropriate approvals, including IRB/EC, the Sponsor, and the regulatory agencies (if applicable). 
Until the clinical investigation is completed, the Investigator will advise his/her IRB/EC of the progress of 
this clinical investigation, per IRB/EC requirements. Written approval must be obtained from the IRB/EC 
yearly to continue the clinical investigation, or according to each institution’s IRB/EC requirements. 
No investigative procedures other than those defined in this CIP will be undertaken on the enrolled
subjects without the written agreement of the IRB/EC and the Sponsor.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 70 of 140
13.0     
CLINICAL INVESTIGATION COMPLETION
The clinical investigation will end when the last visit of the last subject enrolled has been completed. 
The clinical investigation will be concluded when:
x
All sites are closed AND
x
The final report has been provided to investigators or the Sponsor has provided formal 
documentation of clinical investigation closure.
14.0     
PUBLICATION POLICY
The data and results from the clinical investigation are the sole property of the Sponsor. The Sponsor 
shall have the right to access and use all data and results generated during the clinical investigation. The 
Investigators will not use this clinical investigation-related data without the written consent of the Sponsor 
for any purpose other than for clinical investigation completion or for generation of publication materials, 
as referenced in the Clinical Trial Agreement. Single-center results are not allowed to be published or 
presented before the multi-center results. Any proposals for publications or presentations by the 
investigators must be reviewed and approved by the Sponsor in a timely manner to enable Sponsor 
review in compliance with the Sponsor’s publication policy set forth in the Clinical Trial Agreement.
This clinical investigation is registered on ClinicalTrials.gov (NCT04227899). A full report of the pre-
specified outcomes, including any negative outcomes, will be made public through the ClinicalTrials.gov 
website no later than 12-months after clinical trial completion, as required by section 801 of the FDA 
Amendments Act. If this clinical investigation is terminated early for safety, the Sponsor will make every 
effort to hasten the release of the pre-specified outcomes through the ClinicalTrials.gov website.
15.0     
RISK ANALYSIS
15.1.  
Anticipated Clinical Benefits
Treatment options for peripheral artery disease are few, with PTA being the only approved dilatation 
device for use in BTK arteries in the United States. Although acute clinical outcomes with PTA are 
acceptable, clinical studies have consistently shown that this treatment strategy is not durable, as 
evidenced by progressive reduction in patency in the months following the intervention. Given the 
limitations of PTA, amputation and re-interventions are common clinical sequelae. These shortcomings 
of PTA underscore the need for lumen stabilization to improve its mechanical results and reduce the 
debilitating and devastating outcomes that can result from unsuccessful PTA treatment.
Esprit BTK offers the potential to address an unmet medical need for treatment of BTK lesions given the 
poor treatment options available today. As described in Section 1.1.1, the Absorb BVS, which is the 
predecessor of Esprit BTK, has shown lasting clinical benefit in BTK evaluations, with high rates of 
patency at 1 year, which were maintained at 3 years. The Absorb BTK results from the Varcoe and 
Xue/Kum studies are consistent with XIENCE BTK treatment, showing that everolimus elution is effective 
across multiple platforms. There is a realistic expectation of patient benefit with fewer repeat procedures 
with Esprit BTK given the growing body of clinical evidence with Absorb BVS. 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 71 of 140
Given the above unmet needs, Esprit BTK offers the following potential benefits: 1) potential for superior 
outcomes to PTA by scaffolding the treated segment for prevention of acute recoil; 2) eluting everolimus 
to prevent arterial re-narrowing 3) preserving long term treatment options for the target vessel since the 
scaffold resorbs over time
15.2.  
Foreseeable Adverse Events and Anticipated Adverse Device Effects
Risks associated with the Esprit BTK and the procedure, together with their likely incidence, are 
described in the IFU and Appendix V.  There may be risks related to the device under investigation that
are unknown at present.  Likewise, the exact frequency of the risk may be unknown.
15.3.  
Residual Risks Associated with the Device Under Investigation, as Identified 
in the Risk Analysis Report
The residual risks to the patient were identified from literature review or the complaint data review.
Risk analysis of the Esprit BTK device has been performed in accordance with the Risk Management
Plan (Ref:
) and the Failure Mode Effect Analysis (FMEA) (Ref: 
) to
systemically identify potential hazards associated with the design and use of this device. Based upon 
bench testing and prior Abbott sponsored clinical study data, all risks have been identified and mitigated 
as far as possible through application of appropriate controls and inspections and determined to be 
within acceptable levels.  
Residual risks are likewise disclosed in the IFU in the form of clear instructions of what actions to take or 
to avoid, to avoid a hazardous situation of harm from occurring (contra-indications, warnings, and 
precautions). The anticipated AEs disclosed in the IFU (and CIP Appendix V) provide further information 
to enable the user, and potentially the patient, to make an informed decision that weighs the residual risk 
against the benefit of using the device.
15.4.  
Risks Associated with Participation in this Clinical Investigation
The risks related to the procedure have been included in Appendix V.
15.5.  
Possible Interactions with Protocol-Required Concomitant Medications (if
applicable)
The most prevalent risks associated with the anticoagulant and antiplatelet medications have been 
included in Appendix V.
15.6.  
Steps Taken to Control or Mitigate Risks
In-depth recommendations, special precautions and instructions regarding patient selection, device 
handling, device placement and system removal are included in the IFU.
Risks associated with the use of the Esprit BTK during this clinical study are minimized through device 
design, investigator selection and training, pre-specified patient eligibility requirements, study monitoring 
to ensure adherence to the protocol and the use of a DMC.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 72 of 140
These risk management aspects are detailed below:
Device Design: the design of the Esprit BTK includes many features aimed at minimizing potential risks. 
The major safety features of the device are described below:
x
Investigator Selection and Training: It is also stated in the IFU that the devices can only be used by 
physicians who have received appropriate training on how to use the device. This statement is 
interpreted to mean that the physician users are expected to be aware of the known and foreseeable 
safety risks associated with the use of the devices including the surgical and/or non-surgical treatment of 
these conditions.
x
Only physicians who are skilled in the manipulation of catheter-based technology in the vasculature 
and heart and have a good understanding of the risks associated with these manipulations, will be 
selected as investigators for this trial. In addition, site investigators will undergo training on the 
techniques required to optimally place the device in the BTK arteries. The physician users are 
expected to be aware of the known and foreseeable safety risks associated with the use of the 
devices including the surgical and/or non-surgical treatment of these conditions.
x
Emergency surgical back-up should be available as per the institution’s standard procedures.
x
The Sponsor will be available to provide technical support to answer questions regarding the function 
of the Esprit BTK.
x
Pre-specified patient eligibility requirements - as stated in Section 5 of the protocol.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 73 of 140
Ensuring strict adherence to the clinical investigation protocol
The clinical investigation will be carefully monitored by the Sponsor monitor (or designee) to ensure 
adherence to the Clinical Investigational Plan.  Adverse events and device deficiencies will be reported to 
Abbott/designee and will be monitored internally for safety surveillance purposes. A DMC will be used for 
the study.  Stopping rules will be discussed with the DMC and applied for subject safety through 
enrollment.
15.7.  
Risk to Benefit Rationale
The foreseeable rates of the anticipated adverse events associated with the procedure and implantation 
of Esprit BTK are all below 10% (see Appendix V). Moreover, as detailed in Section 15.1, there is an 
unmet need for treatment of BTK lesions, with limited options currently available. Recent clinical data on 
the Absorb BVS, the predecessor of Esprit BTK, have shown the benefit of bioresorbable scaffold for the 
treatment of stenotic infrapopliteal lesions.
Taking these into consideration, the clinical benefit that may be expected from treatment of BTK lesions 
with the Esprit BTK outweigh the possible risks that patients may experience when participating in this 
trial.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 74 of 140
APPENDIX I: ABBREVIATIONS AND ACRONYMS
Acronym/ 
Abbreviation
Term
%DS
Percent Diameter Stenosis
ABI
Ankle-brachial index
ACR
American College of Radiology
AE
Adverse Event
AFS
Amputation-Free Survival
AHA/ACC
American Heart Association/American College of Cardiology
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
BMI
Body Mass Index
BMS
Bare metal stent
BVS
Bioresorbable Vascular Scaffold
CA
Competent Authority
CEC
Clinical Events Committee
CFA
Common Femoral Artery
CIP
Clinical Investigation Plan
CL
Clearance
CLI
Critical Limb Ischemia
Cm
Centimeter
CRA
Clinical Research Associate
CRF
Case Report Form
DES
Drug Eluting Stent
dL
Deciliter
DMC
Data Monitoring Committee
DSMB
Data and Safety Monitoring Board 
DS
Diameter Stenosis
DUS
Duplex Ultrasound
EC
Ethics Committee
ECG
Electrocardiogram
EES
Everolimus-Eluting Stent
EQ-5D-5L
EuroQoL (Quality of Life)-5D-5L
FDA
Food and Drug Administration
F/U
Follow-up
GCP
Good Clinical Practice
GI
Gastrointestinal
HDL
High Density Lipoprotein
ICAVL
International Commission for the Accreditation of Vascular 
Laboratories
ICH
International Committee on Harmonization
IFU
Instructions for Use
ITT
Intent-to-treat

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 75 of 140
LDL
Low-density lipoprotein
MAE
Major Adverse Events
mg
Microgram
MALE
Major Adverse Limb Events
mg
Milligram
MHLW
Ministry of Health, Labor and Welfare (Regulatory Agency)
MLD
Minimum Luminal Diameter
mm
Millimeter
MOP
Manual of Operations
MR
Magnetic Resonance
NHLBI
National Heart, Lung, and Blood Institute
OCT
Optical Coherence Tomography
PAD
Peripheral Arterial Disease
PAQ
Peripheral Arterial Questionnaire
PI
Principal Investigator
PLA
Poly Lactic Acid
POD
Peri-operative (30-day) death
PSV
Peak Systolic Velocity
PSVR
Peak Systolic Velocity Ratio
PTA
Percutaneous Transluminal Angioplasty
RCT
Randomized Clinical Trial 
RVD
Reference Vessel Diameter
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SD
Standard Deviation
SES
Sirolimus-eluting stent
SPTA
Standard Percutaneous Transluminal Angioplasty
TASC
Trans-Atlantic Inter-Society Consensus 
TBI
Toe Brachial Index
TLR
Target Lesion Revascularization
TVR
Target Vessel Revascularization
US
United States
VO
Volume Obstruction
WBC
White Blood Cell Count
WIQ
Walking Impairment Questionnaire

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 76 of 140
APPENDIX II: DEFINITIONS
Acute Gain
Acute gain is defined as the difference between post- and preprocedural minimal lumen 
diameter (MLD).
Acute Limb Ischemia
A rapid decrease in lower limb blood flow due to acute occlusion of peripheral artery or 
bypass graft.
Acute Procedure Success
Successful target lesion treatment is defined as final diameter stenosis < 30% with final 
number of run-off vessels equivalent to or greater than number of run-off vessels at pre-
procedure, with no residual dissection NHLBI grade ≥ type C, and no transient or sustained 
angiographic complications (e.g., distal embolization, perforation, thrombosis). Achieved 
using balloons plus Esprit BTK in the treatment arm and balloons in the control arm. This is 
defined on a per lesion basis.
Amputation 
The removal of a body extremity by surgery.  For this study, the definition of amputation will 
only apply to amputations of the limb that was treated.  
Minor amputation refers to toe amputation(s), ray amputation(s) limited to the metatarsal head 
and distal half of the metatarsal bone, and trans-metatarsal amputation. Major amputation will be 
defined as limb loss at or proximal to the transtibial level.  Major amputations will be specified as 
below-the-knee and above-the-knee amputations.
Analysis lesion
Analysis lesion is defined as the target lesion. 
Aneurysm
A localized abnormal expansion or protrusion of a blood vessel resulting from a disease or 
weakening of the vessel’s wall (all 3 layers) that exceeds the reference vessel diameter (RVD) 
of the vessel by 1.5 times. 
Ankle Brachial Index (ABI)
The ABI is the ratio of the ankle to arm pressure, and it is calculated by dividing the systolic 
blood pressure in the ankle of the one leg by the higher of the two systolic blood pressures in 
the arms.  
An ABI of 0.9 – 1.4 is a normal range.  A reduced ABI (less than 0.9) is consistent with 
peripheral artery occlusive disease, with values below 0.8 indicating moderate disease and 
below 0.5 indicates severe disease.  A value greater than 1.4 is considered abnormal 
suggesting calcification of the walls of the arteries and noncompressible vessels, reflecting 
severe peripheral vascular disease.  Subjects with ABI values greater than 1.4 will be 
excluded from the analysis.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 77 of 140
Calculation of the Ankle Brachial Index: 
(Highest Ankle Systolic Pressure/Highest Brachial Systolic Pressure = ABI)
Arterial Inflow
Good inflow implies that vessels proximal to a target treatment site are free of 
hemodynamically significant lesions (≥ 50%).
Arterial Outflow
For a lesion in the infrapopliteal artery, outflow refers to combined levels distal to the lesion, 
including the following arteries: dorsalis pedis, plantar and pedal.  Good outflow implies that 
the distal arteries is free of hemodynamically significant lesions (≥ 50%) and that there is in-
line flow into the foot.
Arterial Thrombosis
Arterial thrombosis is defined as a total occlusion documented by duplex ultrasound and/or 
angiography at the site of the treated lesion with or without symptoms.
x
Acute thrombosis: 
0 - 24 hours post study procedure 
x
Subacute thrombosis: 
> 24 hours - 30 days post study procedure
x
Late thrombosis:
31 days – 1 year post-procedure
x
Very late thrombosis:
> 1 year post-procedure
Thrombosis should be reported as a cumulative value at the different time points and with the 
different separate time points.  Time 0 is defined as the time point after the arterial sheath has 
been removed and the subject has left the interventional lab.
Bleeding (Hemorrhagic) Complications
These may include hematoma requiring transfusion or surgical repair, and any bleeding event 
associated with hemoglobin drop > 5 g/dl or requiring transfusion or surgical repair (e.g., 
retroperitoneal bleed, GI bleed, access site bleed).
Binary Restenosis 
Binary restenosis will be presented as the presence of a hemodynamically significant 
restenosis > 50% by angiography, or PSVR ≥ 2.0 by duplex ultrasound. In the presence of 
abnormal reference PSV, the core lab uses the following additional secondary criteria 
(correlating factors) to identify target lesion stenoses >50% in severity:
x
Focal increase in the absolute PSV at the area of visible plaque
x
Spectral broadening of the waveform at the area of stenosis
x
Post-stenotic turbulence (PST) and/or change in the waveform shape and/or drop in velocity 
distal to the stenosis

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 78 of 140
x
Review of the B-mode images for plaque burden
If both angiogram and Duplex Ultrasound (DUS) were performed, the angiogram data will take 
precedence over DUS for the determination of binary restenosis.
Chronic Concomitant Medications
Medication that has been:
x
prescribed or over-the-counter (OTC) that has been taken or will continue to be taken 
regularly for at least a period of 6 months, or
x
is required to be taken indefinitely by the subject, or 
x
prescribed or OTC that has been taken multiple times (each time for at least 6 months)
Death
When possible, death will be classified according to underlying cause.  Death within 30 days 
of the study procedure will be classified as procedure related unless medical history or 
autopsy findings demonstrate otherwise.  
Cardiac death: 
Any death due to proximate cardiac cause (e.g., MI, low-output failure, fatal arrhythmia), 
unwitnessed death, or death of unknown cause.
Vascular death:
Death caused by noncoronary vascular causes, such as cerebrovascular disease, pulmonary 
embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular diseases.
Non-cardiovascular death:
Any death not covered by the above definitions, such as death caused by infection, 
malignancy, sepsis, pulmonary causes, accident, suicide, or trauma.
Clinical Success
Defined on a per patient basis, as the attainment of a final residual stenosis of < 30% using 
the study device(s) and/or any adjunctive device at all intended target lesion(s) without 
complications within 2 days after the index procedure or at hospital discharge, whichever is 
sooner. 
Device Malfunction
A malfunction is a failure of a device to meet its performance specifications or otherwise 
perform as intended.  Performance specifications include all claims made in the labeling of 
the device. The intended performance of a device refers to the intended use for which the 
device is labeled.
Device Success

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 79 of 140
Defined on a per device basis, as the achievement of successful delivery and deployment of 
the study device(s) at the intended target lesion and successful withdrawal of the delivery 
catheter. 
Diabetes Mellitus: 
Criteria for diagnosis of diabetes mellitus [26]
Symptoms of diabetes plus casual plasma glucose concentration ≥ 200 mg/dl (11.1 mmol/l).  
Casual is defined as any time of day without regard to time since the last meal. 
or
Fasting plasma glucose (FPG) ≥ 126 mg/dl (7.0 mmol/l).  Fasting is defined as no caloric intake 
for at least 8hours. 
or
The subject takes insulin or oral hypoglycemic medication 
Dissection Grades 
National Heart, Lung, and Blood Institute (NHLBI) Dissection Classification System:
A.
Minor radiolucencies within the lumen during contrast injection with no persistence after 
dye clearance.
B.
Parallel tracts or double lumen separated by a radiolucent area during contrast injection 
with no persistence after dye clearance.
C.
Extraluminal cap with persistence of contrast after dye clearance from the lumen.
D.
Spiral luminal filling defects.
E.
New persistent filling defects.
F.
Non-A-E types that lead to impaired flow or total occlusion.
Note:  Type E and F dissections may represent thrombus.
Edge Dissections 
Edge dissections for OCT and IVUS will be tabulated as:
x
Major (%): ≥60 degrees of the circumference of the vessel at the site of dissection and ≥3 
mm in length
x
Minor (%): any visible edge dissection <60 degrees of the circumference of the vessel or 
<3 mm in length
Edge dissections will be further classified as:
x
Intimal (limited to the intima layer, i.e., not extending beyond the internal elastic lamina) 
x
Medial (extending into the media layer)
x
Adventitial (extending through the external elastic membrane/lamina)
Embolism

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 80 of 140
Formation of a thrombus within the target lesion with migration or atherosclerotic emboli 
migration to a distal artery
Enrollment 
The subject will be considered enrolled into the clinical investigation from the moment the subject 
provides written informed consent. 
Hematoma
A localized collection of blood in a space or tissue.
Hypertension
As defined by the Joint National Committee on Prevention, Detection, and treatment of High 
Blood Pressure [27] or if the subject is on antihypertensive therapy for the indication of 
hypertension:
x
Normal blood pressure: systolic < 120 mmHg and diastolic <80 mmHg
x
Prehypertension: systolic 120-139 mmHg or diastolic 80-89 mmHg
x
Stage 1 hypertension: systolic 140-159 mmHg or diastolic 90-99 mmHg
x
Stage 2 hypertension: systolic ≥ 160 mmHg or diastolic ≥ 100 mmHg
Hyperlipidemia
Per accepted standards or National Cholesterol Education Program Adult Treatment Panel III 
or if the subject is taking blood lipid-lowering medication for the indication of hyperlipidemia 
[28].
Intent-to-Treat (ITT) Population
All subjects in the analysis who are randomized into the clinical trial/investigation, regardless 
of the treatment actually received.  
Major Adverse Event
Major amputation of the ipsilateral extremity, new bypass graft, jump/interposition graft 
revision, thrombectomy/thrombolysis related to the target lesion, Q-wave myocardial 
infarction, death.
Major Limb Re-interventions
Includes the creation of a new bypass graft, bypass graft revision, the use of thrombectomy 
or thrombolysis [29].
MALE+POD
Major adverse limb events (major amputation or major re-interventions including new bypass 
graft, jump/interposition graft revision, or thrombectomy / thrombolysis related to the target 
lesion) occurring within 6 months, or peri-procedural (or peri-operative) (30-day) death 
(MALE+POD).

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 81 of 140
Non-Traditional Transmetatarsal Amputation
Non-traditional transmetatarsal amputation does not allow for standard division of the 
metatarsal bones and rotation of the plantar flap up over the end of the wound.  Examples 
would be an “open” transmetatarsal amputation, or any other partial foot amputation such as 
a Symes or Choparts.  
Occlusion
Angiography: Incomplete vessel opacification distal to the lesion or if the distal vessel fills 
via collateral circulation.
Duplex ultrasound: Pulsed wave Doppler: no detectable flow from within vessel segment, 
complete filling of the artery by b-mode image, no flow detected by color Doppler, high 
resistance waveform proximal to occluded segment and delayed systolic upstroke with 
decreased velocities distal to occluded segment.  
Chronic Occlusion
An occlusion presumed to have been present for at least 1 month prior to the procedure.
Total Occlusion:
Angiography: A complete occlusion with no ante grade filling of contrast to the distal 
segment
Duplex Ultrasound: A complete occlusion with no detected flow signals in the lumen of 
an imaged vessel. Distal (collateral) waveforms are monophasic with reduced systolic 
velocities.
Sub-total Occlusion:
Angiography: A small amount of contrast flows through the stenosis but fails to opacify 
the 
artery 
beyond, 
and 
there 
is 
collateral 
filling 
of 
the 
distal 
segment.
Duplex Ultrasound: Focal increase in the peak systolic velocity, with visible lumen loss 
by b-mode image and or presence of post stenotic turbulence or decrease in PSV distal 
to stenosis.
Percent Diameter Stenosis
The value calculated as 100 * (1 - MLD/RVD) using the mean values from two orthogonal 
views (when possible) by QA.
Persisting Dissection
Dissection at follow-up that was present post-procedure.
Primary Assisted Patency
Defined as patency of the target lesion following endovascular reintervention at the target 
vessel site in case of symptomatic restenosis [30]
Primary Patency and Limb Salvage
The composite of primary patency and limb salvage is defined as freedom from: above ankle 
amputation in index limb, 100% total occlusion of target vessel, binary restenosis of target 
lesion, and clinically-driven target lesion revascularization (CD-TLR). Primary patency ends 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 82 of 140
at the first occurrence of one of the following: 100% total occlusion of the target vessel, binary 
restenosis of target lesion, clinically-driven target lesion revascularization, or above ankle 
amputation due to target lesion restenosis or occlusion.
Popliteal Artery
Defined as the vessel located between Hunter’s canal and the trifurcation of the anterior tibial, 
posterior tibial and peroneal arteries.
Principal Investigator
A physician responsible for conducting the clinical trial at each investigational site, which is 
responsible for the overall conduct of the trial at their site and compliance with protocol and 
relevant regulatory requirements.
Reference Vessel Diameter (RVD)
An approximation of the diameter of the vessel at the location of the target lesion.  RVD is 
visually estimated during angiography by the Investigator and it is measured during QA by 
the Angiographic Core Laboratory.
Registration
The subject will be considered registered into the study upon the completion of all of the
following:
x
A signed subject informed consent,
x
General inclusion criteria for enrollment have been met,
x
Anatomic criteria for enrollment have been met, 
x
Successful treatment of the ipsilateral inflow artery(ies), and non-target lesion(s) without 
complication, if applicable,
x
Target lesion(s) successfully crossed by the guidewire (as evidenced by guidewire 
placement in the distal arterial lumen) without complication
Restenosis
Re-narrowing of the artery following the alleviation of a previous narrowing.  It is defined as 
the presence of a hemodynamically significant restenosis (≥ 50%), as determined by 
angiography.  
Revascularization
Target Lesion Revascularization (TLR)
Target lesion revascularization (TLR) is defined as any repeat percutaneous intervention 
of the target lesion or bypass surgery of the target vessel performed for restenosis or 
other complication of the target lesion.  
Clinically-Driven Target Lesion Revascularization (CD-TLR)

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 83 of 140
Repeat intervention on the target lesion due to recurrent symptoms AND stenosis > 70% 
by angiography. Bailout with metallic stent, in either study arm, due to acute closure or to 
achieve < 30% stenosis during index procedure will be considered a CD-TLR. Recurrent 
symptoms are such as delayed or worsening wound healing, new or recurrent wound at 
the treatment site, or worsening Rutherford class.
Clinically-driven target vessel revascularization (CD-TVR)
Repeat intervention on the target vessel due to recurrent symptoms AND stenosis > 70% 
by angiography. Recurrent symptoms are such as delayed or worsening wound healing, 
new or recurrent wound at the treatment site, or worsening Rutherford class.
Clinically-driven target vessel revascularization (CD-TVR) distal to the target lesion 
CD-TVR that occurred at least 5 mm of tissue distal to the target lesion
Clinically-driven target vessel revascularization (CD-TVR) proximal to the target lesion
CD-TVR that occurred at least 5 mm of tissue proximal to the target lesion
Rutherford/Becker Categories - Chronic Limb Ischemia [15]
Grade
Category
Clinical Description
Objective Criteria
0
Asymptomatic, no 
hemodynamically 
significant occlusive 
disease
Normal results of treadmill*/stress 
test
I
1
Mild claudication
Treadmill* exercise complete, post 
exercise AP is greater than 50 mm 
Hg but more than 25 mm Hg less 
than normal
2
Moderate claudication
Symptoms between those of 
categories 1 and 3
3
Severe claudication
Treadmill* exercise cannot be 
completed post exercise AP is less 
than 50 mm Hg
II
4
Ischemic rest pain
Resting AP of 40 mm Hg or less, flat 
or barely pulsatile ankle or 
metatarsal plethysmographic tracing, 
toe pressure less than 30 mm Hg
III
5
Minor tissue loss, non-
healing ulcer, or focal 
gangrene with diffuse 
pedal ischemia
Resting AP of 60 mm Hg or less, flat 
or barely pulsatile ankle metatarsal 
plethysmographic tracing flat or 
barely pulsatile, toe pressure less 
than 40 mm Hg
6
Major tissue loss, 
extending above 
transmetatarsal level, 
functional foot no longer 
salvageable
Same as category 5

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 84 of 140
*5 minutes at 2 mph on a 120 incline
Worsening Rutherford Becker Clinical Category
A deterioration (an increase) in the Rutherford Becker Clinical Category by more than 2 
categories from the earliest post-procedural measurement or to a category 6.
Secondary Patency
Patency of the target lesion after treatment of a (re)occlusion of the index lesion [30].
Study Principal Investigator
A physician-specialist, related to the study, which is responsible for the overall conduct of the 
trial at all sites.
Successful Pre-Dilatation
Pre-dilatation has been successfully completed without complications if all of the following 
apply:
x
diameter stenosis < 30% (by visual estimation)
x
lesion length still within the requirements of the protocol/CIP
x
no angiographic complications 
Target Lesion
The continuous diseased segment that is intended to be treated by the study device(s) during 
the index procedure.  
Target Extremity
Target extremity includes any arterial segment(s) outside of the target lesion.
Toe Brachial Index (TBI)
Toe brachial index (TBI) is a calculation based on the systolic blood pressures of the arm 
and the systolic blood pressures of the toes. A TBI is performed when the ABI is abnormally 
high due to plaque and calcification of the arteries in the leg. The abnormally high 
ABI is >1.4.
The TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial 
Disease (TASC II) defined a TBI <0.70 as an abnormal finding [31].
Technical Success
Defined on a per lesion basis as the attainment of a final residual stenosis of < 30% at the 
intended target lesion(s) following use of the study device(s).  Standard pre-dilatation 
catheters and post-dilatation catheters (if applicable) may be used. Bailout at lesion level does 
not impact technical success if the above criteria are met.  
Treated Site
Located within the margins of the scaffold, or PTA balloon.
Treated Segment

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 85 of 140
Located within the margins of the scaffold, or PTA balloon, including 5 mm proximal and/or 
distal to the scaffold.
Vascular Complications
Access Site Occlusion 
Access site occlusion is defined as total obstruction of the artery usually by thrombus (but 
may have other causes) usually at the site of access requiring surgical repair.  
Arteriovenous Fistula 
AV Fistula is defined as a connection between the access artery and the accompanying 
vein that is demonstrated by angiography or ultrasound and most often characterized by 
a continuous bruit.  Indicate whether an arteriovenous (AV) Fistula occurred at the site of 
percutaneous entry during the procedure or after lab visit but before any subsequent lab 
visits. 
Peripheral Embolization 
Peripheral embolization refers to the evidence of distal embolization subsequent to the 
index procedure and peri-procedural period.  Signs and symptoms suggest of peripheral 
embolization may include 1) acute change in vascular exam (sudden onset rest pain, 
pallor, coolness, or other signs of acute ischemia), 2) petechiae, or 3) sub-ungal 
hemorrhage.
Pseudoaneurysm 
Pseudoaneurysm is defined as the occurrence of a disruption and dilation of the arterial 
wall without identification of the arterial wall layers demonstrated by angiography or 
ultrasound.  The location of the pseudoaneurysm should be indicated. 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 86 of 140
APPENDIX III: SITE CONTACT INFORMATION
A list of trial site coordinators can be obtained upon request from the Clinical Project Manager 
for the clinical investigation.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 87 of 140
APPENDIX IV: LITERATURE REVIEW
A summary of results from the literature review is provided below.
Clinical Investigation
Objective
Treatment arms
Patient population
Endpoints
Results
“A Prospective 
Randomized Multicenter 
Comparison of Balloon 
Angioplasty and 
Infrapopliteal Stenting
With the Sirolimus-Eluting 
Stent in Patients With
Ischemic Peripheral 
Arterial Disease: 1-Year
Results From the 
ACHILLES Trial”
To investigate the 
efficacy and safety of 
a balloon 
expandable, 
sirolimus-eluting 
stent (SES) in 
patients with 
symptomatic 
infrapopliteal arterial 
disease.
Patients were
randomized to 
receive SES stent
or percutaneous
transluminal 
balloon angioplasty 
(PTA) for 
treatment.
Inclusion: Patients with
symptomatic peripheral 
arterial disease (PAD; 
Rutherford class 3-5)
manifested in the 
infrapopliteal arterial
territory.
Exclusion: Patients with 
significant stenoses
(>50%) distal to the 
target lesion that might 
require revascularization 
or impede runoff; 
angiographically evident
thrombus or history of 
thrombolysis within 72 h; 
untreated lesions (>75%
stenosis) in the common 
or external iliac; common
or superficial femoral 
and popliteal artery; 
infrapopliteal trifurcation 
lesions requiring 2- or 3-
branch treatment; stent
placement across or 
within 1 cm of the knee 
joint or in an artery
subject to external 
compression; prior
stenting within the target
vessel(s) or aneurysm in 
the SFA or popliteal 
artery; history of
thrombophlebitis, deep 
venous thrombosis, or 
impaired renal function 
(Cr >2.5 mg/dl); life 
expectancy <12 months; 
1°: 12-month in-segment binary restenosis 
(in and/or 5 mm proximal/distal to treated
length) determined by quantitative 
angiography.
2°: Death, repeat revascularization, index-
limb amputation, various angiographic 
parameters, stent fractures (plain x-ray film 
assessment) at 12 months, and index-limb 
wound status at screening, 6 weeks, and 6 
and 12 months.
x
Primary endpoint at 1 year: 22.4% 
(SES), 41.9% (PTA), p=0.019
x
Survival at 1 year: 89.9% (SES), 
88.1% (PTA), p=0.822
x
CD-TLR at 1 year: 10.0% (SES), 
16.5% (PTA), p=0.257
x
TVR at 1 year: 6.4% (SES), 2.4% 
(PTA), p=0.263
x
Vessel patency at 1 year: 75% 
(SES), 57.1% (PTA), p=0.025
x
Index limb amputation at 1 year: 
13.8% (SES), 20% (PTA), p=0.307
x
Stent fractures at 1 year: 0.9% 
(SES), 0% (PTA)
x
Rutherford class improvement at 1 
year: 76.06% (SES), 67.11% (PTA) 
at 1 year (p=0.2315)
Scheinert et al. 2012 J Am 
Coll Cardiol 
2012;60:2290–5
Randomized multi-center 
study consisting of 2 arms 
that compared safety and 
efficacy of using sirolimus-
eluting stent (SES) or 
percutaneous transluminal 
balloon angioplasty (PTA)
to treat patients with 
critical limb ischemia
(N=200).

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 88 of 140
or known intolerance to 
antiplatelet medication.
“Randomized comparison 
of everolimus-eluting
versus bare-metal stents 
in patients with critical limb 
ischemia and infrapopliteal 
arterial occlusive disease.”
DESTINY trial: To 
test if treatment of
infrapopliteal arterial 
occlusive lesions with 
an everolimus-eluting 
stent (Xience V) 
would provide 
superior patency to
treatment with a 
bare-metal stent 
(Multi-Link Vision).
Patients with 
critical limb 
ischemia and 
infrapopliteal 
arterial occlusive
disease were
randomized to 
receive either 
everolimus-eluting 
stent (Xience V) or
bare-metal stent 
(Multi-Link Vision)
for treatment.
Inclusion: Symptomatic 
PAD (Rutherford 
category 4-5) due to a 
maximum of two focal de 
novo atherosclerotic 
target lesions in one or
more infrapopliteal 
vessels. Lesions with 
≥50% diameter stenosis 
with length ≤40 mm and 
diameters of 2.0 to 3.5 
mm. All patients were 
required to have at least 
one patent tibial artery 
that provided in-line 
circulation to the foot. At 
least single-vessel 
outflow to the foot (distal 
to the target lesion).
Exclusion: Not specified
1°: Primary patency (absence of ≥50% in-
stent binary restenosis at 12 months).
2°: Clinical success (defined as an 
improvement of Rutherford classification of 
one or more classes at the 12- month 
follow-up), freedom from target lesion 
revascularization (TLR), limb salvage 
(defined as freedom from major amputation 
at or above the ankle), and patient survival.
x
Amputation at 12 months: 2 for 
Vision, 1 for Xience V.
x
Primary patency: 85% (Xience), 
54% (Vision), p=0.0001
x
Clinical success at 12 months: 56% 
(Vision), 60% (Xience), p=0.68
x
12-month patient survival: 84% 
(Vision), 82% (Xience), p=0.96
x
12-month freedom from TLR: 66.4%
(Vision), 91.3% (Xience), p=0.001
Bosiers et al. J Vasc Surg 
2012;55:390-9.
Prospective, randomized, 
controlled multicenter trial 
to compare treatment of 
patients with chronic 
symptomatic peripheral 
arterial disease using 
everolimus-eluting stent 
(Xience V) or bare-metal 
stent (Multi-Link Vision)
(N=140).
“Outcome of a drug-
eluting stent in longer 
below-the-knee lesions in 
patients with critical limb 
ischemia.”
DESTINY2 trial: To
evaluate the 
immediate and long-
term (up to 12 
months) outcome of 
the Xience Prime™ 
Everolimus-Eluting 
Coronary Stent 
System (Abbott 
Vascular) in a 
controlled, 
prospective, multi-
center investigation 
for long lesions up to 
10 cm.
Patients with 
critical limb 
ischemia and long 
infrapopliteal
lesions between 30 
and 100 mm were 
treated with Xience 
Prime™ 
Everolimus-Eluting 
Coronary Stent 
System.
Inclusion: Patients with 
critical limb ischemia and 
total lesion length 
between 3-10 cm with a 
diameter between 2.0-
3.5 mm. An inflow 
stenosis needed to be 
treated without 
complications.
Exclusion: Previous 
surgery, aneurysm or 
non-atherosclerotic 
disease and acute 
thrombosis. Patients with 
severe comorbidities 
resulting in a life 
expectancy of <1 year 
and patients presenting 
with sepsis or 
bacteremia.
1°: Primary patency at 12 months (absence 
of restenosis (≥50% stenosis) or occlusion)
2°: Technical success, clinical success 
(improvement of Rutherford classification of 
one class or more), limb-salvage rate 
(defined as absence of major amputation), 
freedom from target lesion 
revascularization (TLR), secondary patency 
and survival.
x
Primary patency: 75.4%
x
Technical success: 100%
x
Freedom from TLR: 84.9%
x
Freedom from amputation at 12 
months: 94.4%
x
Improvement in Rutherford 
classification: 85.7%
x
Survival at 1 year: 89.3%
Bosiers et al. J Cardiovasc 
Surg 2017;58:49-54.
Prospective, multi-center, 
non-randomized, single 
arm study of patients 
undergoing treatment of 
atherosclerotic lesions 
BTK with the Xience 
Prime™ Everolimus-
Eluting Coronary Stent 
System (N=60).

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 89 of 140
“Sirolimus-eluting stents 
vs. bare-metal stents for
treatment of focal lesions 
in infrapopliteal arteries: a 
double-blind, multi-centre,
randomized clinical trial.”
YUKON trial: To 
compare a polymer-
free sirolimus-eluting 
stent (SES) with a 
placebo-coated bare-
metal stent (BMS) in 
patients with 
intermittent
claudication or critical 
limb ischaemia who 
had a de-novo lesion 
in an infrapopliteal 
artery.
Inclusion: Patients with 
peripheral artery disease 
with Rutherford–Becker 
class of 3 to 5. Patients 
with lifestyle-limiting 
claudication RC 2 can be
included after successful
intervention of TASC A 
(single stenosis less 
than 3 cm of the 
superficial femoral artery 
or popliteal artery) 
femoro-popliteal lesions 
to improve run-off status. 
Presence of a single 
primary target lesion in a 
native IPA that was 2.5–
3.5 mm in diameter and 
that did not exceed 45 
mm in length; diameter 
stenosis of at least over 
70%.
Exclusion: Visible 
thrombus within target 
lesion, known systemic 
coagulopathy, Buerger’s 
disease, acute limb 
ischaemia, and life 
expectancy less than 1 
year, or an intolerance of
aspirin, clopidogrel, and 
heparin.
1°: Primary patency rate after 1 year
(freedom from in-stent-restenosis (luminal 
narrowing of <50%) detected with DU or 
angiography).
2°: 6-month primary patency rate, 
secondary patency rate, and changes in 
Rutherford–Becker classification after 1 
year.
x
Primary patency at 1 year: 80.6% 
(SES), 55.6% (BMS), p=0.004
x
6-month primary patency rate: 
85.9% (SES), 68.7% (BMS), p=0.02
x
Secondary 1-year patency rates: 
91.9% (SES), 71.4% (BMS), 
p=0.005
x
Improvement in Rutherford 
classification at 1 year: 83.9% 
(SES), 61.9% (BMS), p=0.004
x
Rastan et al. Eur Heart J 
2011;32:2274-81.
Prospective, randomized, 
double-blind trial to
compare a polymer-free 
sirolimus-eluting stent with 
a placebo-coated bare-
metal stent in patients with 
either intermittent 
claudication or critical limb 
ischaemia who had a de-
novo lesion in an 
infrapopliteal artery
(N=161).
LUTONIX® BTK Trial: A
Prospective, Multicenter, 
Single Blind, Randomized, 
Controlled Trial 
Comparing the Lutonix 
Drug Coated Balloon vs. 
Standard
Balloon Angioplasty for 
Treatment of Below-the-
Knee (BTK) Arteries
To demonstrate the 
superior efficacy and 
non-inferior safety of 
the Lutonix DCB by 
direct comparison to
standard PTA for 
treatment of stenosis 
or occlusion of 
below-the-knee 
arteries
Patients with CLI 
were randomized 
to receive either
Lutonix DCB or 
standard PTA 
catheter.
Inclusion: Patients with 
CLI Rutherford 3-5, life 
expectancy ≥1 year, 
≥70% stenosis, patent
inflow artery, target 
vessel diameter 2-4 mm.
Exclusion: Patients with 
history of stroke within 3 
months, history of MI, 
thrombolysis or angina 
within 30 days of 
enrollment, GFR ≤ 30 
ml/min per 1.73m2, acute 
limb ischemia, in-stent 
1° Safety
Freedom from Major Adverse Limb Events 
(MALE) & All-Cause Perioperative Death 
(POD) at 30 days (above ankle amputation 
and major re-intervention). 
1° Efficacy
Freedom from a composite of above ankle 
amputation, target vessel occlusion, and 
clinically-driven target lesion 
revascularization at 6 months.
x
Freedom from primary safety event 
at 30 days: 99.3% (DCB), 99.4% 
(PTA), p<0.0001
x
Freedom from primary efficacy 
failure at 6 months: 73.7% (DCB), 
63.5% (PTA), p=0.0273
Mustapha, Vascular 
Interventional Advances
(VIVA), November 2018.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 90 of 140
Prospective, multicenter, 
single blind, randomized 
controlled trial comparing 
Lutonix Drug Coated 
Balloon and Standard 
Balloon Angioplasty for 
Treatment of BTK Arteries 
(N=442).
restenosis of target 
lesion.
"Three-Year Results of the 
Absorb Everolimus-Eluting 
Bioresorbable Vascular 
Scaffold in Infrapopliteal 
Arteries. "
To examine the 
efficacy of Absorb in 
de novo 
atherosclerotic 
lesions of the 
infrapopliteal arteries.
Each target lesion 
was pre-dilated 
with a 
noncompliant 
angioplasty balloon 
before
implantation.
Inclusion:  Patients with 
chronic lower limb 
ischemia (Rutherford 
category 3–6) and with 
>60% de novo stenosis 
င5 cm long in distal 
popliteal or tibial arteries 
measuring 2.5 to 4.0 mm 
in diameter.
1°: Binary restenosis based on color-flow 
Doppler examination and a sensitive peak 
systolic velocity ratio >2.0.
x
100% technical success (defined as 
no amputation, death, or target limb 
bypass surgery within 30 days of 
the index procedure.)
x
Freedom from CD-TLR was 
estimated as 97.2%, 97.2%, and 
87.3% at 12, 24, and 36 months. 
x
Primary patency rate was 92.2% at 
12 months, 90.3% at 24 months, 
and 81.1% at 36 months. 
x
At ultrasound follow-up, 6 (8%) of 
71 scaffolds had developed a binary 
restenosis. 
x
All but one binary restenosis was in 
the 50% to 75% range, and only 
two resulted in clinical deterioration 
that required revascularization at 24 
and 26 months, respectively, after 
scaffold implantation. 
x
No late scaffold thrombosis. 
x
For wound status and patient 
symptoms, 51 (93%) of 55 limbs 
were clinically improved, 4 (7%)
were unchanged, and none was 
worse.
x
Of the 39 limbs with ischemic tissue 
loss (Rutherford category 5 or 6), 
36 (92%) had completely healed 
wounds during the follow-up period.
Varcoe et al. J Endovas 
Ther 2018 Dec;25(6):694-
701
Single-arm study that 
used Absorb to treat 
patients with critical limb 
ischemia (N=48).
Exclusion:  Patients who
had a short life 
expectancy (<12 
months), allergy/renal 
impairment that 
precluded angiography, 
or where known to be 
intolerant to dual 
antiplatelet therapy.
2°: Clinically driven target lesion 
revascularization (CD-TLR), major or minor 
amputation, bypass surgery, cardiovascular 
and all-cause mortality, as well as any 
related morbidity.
"Outcomes of Bio-
absorbable stent for Below 
Knee Critical Limb 
Ischaemia."
To investigate the 
outcomes, efficacy 
and safety of 
bioabsorbable 
vascular stents 
(BVS) in patients with 
Absorb was 
implanted in 
patients. A 
minimum of 1mm 
stent overlap was 
placed if multiple 
Inclusion: Patients with 
critical limb ischemia 
(Rutherford category 4–
6).
1°: Vessel patency, target lesion 
revascularization (TLR) and limb salvage 
rates.
x
100% technical success rate 
(defined as successful delivery and 
deployment of the stent at the 
intended target lesion, successful 
withdrawal of the delivery catheter, 
Xue and Ho, Asian 
Society for Vascular 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 91 of 140
Surgery (ASVS) 
Congress, October 2016.
below knee critical 
limb ischaemia.
BVS stents were 
used. Post BVS 
insertion, 
ultrasound duplex 
was used to 
evaluate vessel 
patency and 
arterial flow.
and attainment of a final residual 
stenosis of <30%).
x
High primary patency rates of 
96.7%, 93.5% and 90.3% at 1 
month, 6 months and 1 year 
respectively.
Retrospective analysis of 
cases where patients with 
critical limb ischemia were 
treated using Absorb 
(N=28).
Exclusion:  Not 
specified.
2°: Not specified.
“1 Year Results in Real 
World Patients with 
ABSORB BTK.”
To study the safety 
and clinical efficacy 
of a novel 
Bioabsorbable 
Everolimus Eluting 
Bioresorbable 
Vascular Scaffold 
System (BVS, Abbott 
Vascular) in subjects 
with critical limb 
ischemia (CLI) 
following 
percutaneous 
transluminal 
angioplasty (PTA) of 
the tibial arteries.
Infrapopliteal 
stenting using 
Absorb.
Inclusion: Symptomatic 
critical limb ischemia 
(Rutherford 4, 5, 6)
1°: Vessel patency, target lesion 
revascularization (TLR) and limb salvage 
rates.
x
100% technical success rate. 
x
Safe: no 30 day MACE or MALE. 
x
Primary patency 93.5%, 90.3% and 
87.1% at 1 month, 6 months and 1 
year.
x
Freedom from TLR rate was 96.7%. 
x
Limb salvage at 6 months was 
96.7%.
Kum, Leipzig 
Interventional Course, 
January 2017.
Treatment of patients with 
critical limb ischemia 
treated using Absorb 
(N=28).
Exclusion: Not specified.
2°: Not specified.
“Clinical Effectiveness of 
the ABSORB
Bioresorbable Scaffold in 
Patients with Complex 
Infrapopliteal Disease.”
To assess safety and 
efficacy of Absorb 
BVS for treatment of 
patients with complex 
infrapopliteal 
disease.
Patients were 
treated with the 
ABSORB BVS.
Inclusion: Patients with
critical limb ischemia 
(Rutherford category 3-
6) with life expectancy > 
12 months
Clinical endpoints: Stent thrombosis, 
primary patency (defined as freedom from 
target vessel occlusion and clinically driven 
target lesion revascularization evaluated at 
12 months), limb salvage (defined as 
freedom from major amputation above the 
ankle), and ultrasound designated patency 
(cutoff velocity of 2m/sec).
x
At 12 months: 0% stent thrombosis, 
96.7% primary patency, 100% limb 
salvage.
x
Improved Rutherford Becker 
classification for 30/31 (96.8%) 
patients.
Shah et al. LINC 19, 
January 2019.
Single center, 
retrospective study that 
used Absorb to treat 
patients with critical limb 
ischemia or complex 
infrapopliteal disease 
(N=31).
Exclusion: Not specified

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 92 of 140
APPENDIX V: RATES OF FORSEEABLE ADVERSE EVENTS
Potential risks associated with the PTA procedure are similar to those for standard limb salvage, 
angiography and catheterization techniques, administration of anesthesia, and use of fluoroscopy. 
Although anticipated risks for PTA are described below, due to the nature of this study, there may also 
be other risks, which are not known at this time. Likewise, the exact frequency of the risk may be 
unknown.
The frequencies of the foreseeable events indicated in the table below are based on clinical trials using
the DESTINY Trial, where XIENCE V drug-eluting stent (DES) was used to treat focal infrapopliteal 
peripheral arterial disease (140 patients were randomized 1:1 (XIENCE V DES: MULTI-LINK VISION 
bare metal stent) at 5 clinical sites in the European Union). Currently no data is available for the same 
indication using the Esprit BTK. The rationale for basing frequencies on the DESTINY Trial is that the 
indications for this trial and the DESTINY Trial are identical; moreover, the Esprit BTK also contains the 
drug Everolimus, albeit in a bioresorbable scaffold. Other adverse events that were not observed in the 
DESTINY Trial but where reported as commercial complaints for XIENCE stents used for BTK/ 
infrapopliteal were included in the list and rates provided are based on said complaints.
Additionally, the foreseeable adverse events related to Everolimus included in this CIP, the ICF, and the 
IFU are associated with daily oral administration of everolimus in doses varying from 1.5 mg to 10 mg 
daily, and can be found in the Summary of Product Characteristics (SPC) and labels for the drug
(1,2,3,4,5). The risks related to Everolimus described in the Adverse Events section include the 
anticipated adverse events relevant for the peripheral artery disease population referenced in the 
contraindications, warnings and precaution sections of the everolimus labels and/or SPCs. They are 
observed at incidences ≥ 10% in clinical trials with oral everolimus for different indications. Please refer 
to the drug SPCs and labels 1, 2, 3, 4, 5 for more detailed information and less frequent adverse events. 
[1-Certican® UK label Mar 2015. 2-Animator® EU authorization SPC Dec 2014. 3-Votubia® EU SPC 
Sept 2014. 4-Animator® US label Jan 2015. 5-Zortress® US label Sept 2015. Refer to 
www.MHRA.gov.uk, www.ema.europa.eu, and www.fda.gov for the most recent versions of these 
SPC/labels.]

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 93 of 140
Anticipated adverse event
Frequency observed in the DESTINY I clinical study
Very common:
≥10%
Common:
≥1.0% to < 10%
Uncommon:
≥0.1% to < 1.0%
Rare:
≥0.01% to < 0.1%
Very Rare:
< 0.01%
Allergic reactions or hypersensitivity to latex, contrast agent,
anaesthesia, stent material (everolimus, cobalt, chromium), and
drug reactions to anticoagulation, or antiplatelet drugs
X
Vascular access complications which may require transfusion or
vessel repair, including:
 
Catheter site reactions
X
Bleeding (including ecchymosis, oozing, hematoma, hemorrhage,
retroperitoneal hemorrhage)
X
Arteriovenous fistula, pseudoaneurysm, aneurysm, dissection,
perforation/rupture vascular occlusion
X
Emboli (air, thrombotic material, device, device component)
X
Target artery complications which may require additional
intervention, including:
Total occlusion or abrupt closure
X
Arteriovenous fistula, pseudoaneurysm, aneurysm, dissection, 
perforation/rupture, vessel spasm
X
Embolism (air, tissue, plaque, thrombotic material, or device)
X
Stenosis or restenosis
X
Vasospasm
X
Peripheral nerve injury, neuropathy or nerve injury, neurologic 
complication
      X
Cardiac arrhythmias (including conduction disorders, atrial and
Ventricular arrhythmias)
X
Cardiac ischemic conditions (including myocardial ischemia, 
myocardial infarction (including acute), coronary artery spasm,
and unstable or stable angina pectoris):
X
Amputation
X
Other Infarction/Ischemia including: Other Infarction/Ischemia 
including: Bowel ischemia, Tissue/organ infarction or ischemia, 
Worsening or exacerbation of the pre-existing condition, Blue toe 
syndrome, Tissue necrosis, Gangrene, Ulcer, And Acute limb 
ischemia
X

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 94 of 140
New or worsening Pain
X
Nausea and vomiting
X
Blood cell disorders including heparin induce thrombocytopenia 
and other coagulopathy
X
Hypotension/hypertension
X
Hyperperfusion syndrome
X
Infection - local and systemic (including post-procedural)
X
X
Fever
X
Death
X
Stroke/Cerebrovascular accident (CVA) and Transient Ischemic 
Attack(TIA)
X
System organ failures:
Cardiac failure
X
Cardio-respiratory arrest (including pulmonary edema)
X
Respiratory failure
X
Renal failure
X
Shock
X

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 95 of 140
APPENDIX VI: LABELS
Label information for the investigational product, including the IFU and packaging information, are 
provided under a separate cover.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 96 of 140
APPENDIX VII: CASE REPORT FORMS
Final draft CRFs will be sent under a separate cover.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 97 of 140
APPENDIX VIII: INFORMED CONSENT FORM
A template informed consent form, will be sent under a separate cover.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 98 of 140
APPENDIX IX: MONITORING PLAN
A copy of the Monitoring Plan can be obtained upon request from the Sponsor Clinical Project Manager 
for the clinical investigation.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 99 of 140
APPENDIX X: LIFE-BTK Pharmacokinetics sub-study
CIP Number: 
Study Number: 
LIFE-BTK
PHARMACOKINETICS (PK) SUB-STUDY SYNOPSIS
 
Version Number
Date
Planned Number of Sites and 
Region(s)
Subjects will be enrolled in the United States (US) and outside the US with 
a maximum of 5 sites in the US.
Note: these 5 sites are additional sites, and not included in the maximum 
50 US sites for the LIFE-BTK RCT study.
Clinical Investigation Type
Prospective, single-arm, open-label, non-blinded clinical investigation
Abbott Vascular Medical Expert
Sponsor / Trial Monitor/Data 
Monitoring
Abbott Cardiovascular Systems, Inc.,
Registration/Randomization 
Service
Oracle Clinical 
Electronic Data Capture Software
Oracle Clinical
Blood Sample Analysis Core 
Laboratory
Clinical Events Committee
Data Monitoring Committee 
Administration
Sub-study Author

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 100 of 140
Study Name 
LIFE-BTK PK Sub-study
CIP Number: 
Study Number: 
Investigational Device
Esprit™ BTK Everolimus Eluting Bioresorbable Scaffold System 
Scaffold diameters: 2.5, 2.75, 3.0, 3.5 and 3.75 mm 
Scaffold lengths: 9, 12, 15, 18, 23, 28, 33 and 38 mm 
Objective
To determine the pharmacokinetics of everolimus delivered by the 
Esprit BTK scaffold in a separate and non-randomized cohort of 
subjects receiving the Esprit BTK for the planned treatment of 
narrowed infrapopliteal lesions. 
The LIFE-BTK PK sub-study subjects will not be included in the primary 
analysis population and will not contribute to the determination of the 
LIFE-BTK primary endpoints.
Sub-study Design
A prospective, single-arm, open-label, non-blinded, non-randomized 
sub-study enrolling approximately 7 subjects treated with Esprit BTK at 
selected clinical trial sites.
Subjects will be distributed as follows:
x
4 subjects treated with Esprit BTK in below the knee artery(ies) 
in whom drug-coated balloons (DCB) were not used
x
3 subjects treated with Esprit BTK in below the knee artery(ies) 
in whom DCB were used for treatment of inflow disease
Note: The use of DCB will be at the investigator discretion and 
recorded in the Case Report Form. Number of registered subjects with 
and without DCB use, towards enrollment total, will be tracked by the 
Sponsor.
Subject Number and Drug Doses
Total number of subjects: approximately 7 subjects treated with 
multiple scaffolds such that the total length of scaffold received by the 
subject is between 170 and 256 mm. 
The targeted everolimus drug dose range, based on a total scaffold 
length of 170 to 256 mm, is 1319 to 2714 μg.
The drug content for each size of Esprit BTK is indicated in Table 1.
Shown in bold are the scaffold sizes available in the LIFE-BTK trial. 
The same sizes will be available in the PK sub-study.
Table 1: Drug Content in Esprit BTK
Esprit BTK 
Diameter
(mm)
Esprit BTK Length
(mm)
Drug Dose
(μg)
2.5, 2.75
9
69
2.5, 2.75
12
93
2.5, 2.75
15
116
2.5, 2.75
18
139
2.5, 2.75
23
178
2.5, 2.75
28
217
2.5, 2.75
33
256
2.5, 2.75
38
295
3.0
9
75

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 101 of 140
3.0
12
98
3.0
15
121
3.0
18
144
3.0
23
189
3.0
28
227
3.0
33
273
3.0
38
311
3.5
9
94
3.5
12
119
3.5
15
153
3.5
18
188
3.5
23
239
3.5
28
290
3.5
33
341
3.5
38
391
3.75
9
89
3.75
12
125
3.75
15
161
3.75
18
188
3.75
23
242
3.75
28
296
3.75
33
350
3.75
38
404
Subjects will be included in the PK analysis only if all intended Esprit 
BTK scaffolds are implanted.
Blood Sampling Timing for 
Analysis of Everolimus 
Pharmacokinetics
Pre-Esprit BTK implantation: Baseline
Baseline is defined as prior to implantation of the first Esprit BTK; the 
blood sample will be drawn on the day of the index procedure either 
through a heparin lock, venous sheath, or venipuncture. 
During Esprit BTK implantation:
x
Collect a blood sample immediately after the first scaffold has been 
implanted
x
Collect one blood sample every 15 min after the first scaffold has 
been implanted until the last scaffold has been implanted
Post-Esprit BTK implantation: 0 min (immediately after last scaffold 
implantation), 10 and 30 minutes, 1 hr, 2 hrs, 4 hrs, 6 hrs, 12 hrs, 
24 hrs (1 day), 48 hrs (2 days), 72 hrs (3 days), 96 hrs (4 days), 
120 hrs (5 days), 168 hrs (7 days), 336 hrs (14 days), and 720 hrs 
(30 days), 1440 hrs (60 days) 
Post-final scaffold implantation blood samples will be drawn at the time 
intervals stated above; timing of the post-implantation sampling will 
begin when the last Esprit BTK is deployed, i.e., last Esprit BTK 
delivery catheter is removed from the body.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 102 of 140
Table 2: Blood Sample Collection Time Windows:
Time Point
Allowed Time Window
Pre-procedure
On the day of index procedure prior to 
implantation of the first Esprit BTK
During Index 
procedure 
First blood draw Immediately after first 
Esprit BTK has been implanted, this can be 
arterial from sheath
Additional blood draws every 15 minutes 
after first Esprit BTK has been implanted 
until the last Esprit BTK has been implanted, 
the blood samples can be draw arterial from 
sheath
Post Procedure
0 minute
When the last Esprit BTK is deployed, i.e. 
last Esprit BTK delivery catheter is removed 
from the body.
10 minutes
± 2 minutes
30 minutes
± 6 minutes
1 hour
± 12 minutes
2 hours
± 24 minutes
4 hours
± 48 minutes
6 hours
± 72 minutes
12 hours
± 144 minutes
24 hours (1 day)
± 4.8 hours
48 hours (2 days)
± 9.6 hours
72 hours (3 days)
± 14.4 hours
96 hours (4 days)
± 19.2 hours
120 hours (5 days)
± 24 hours
168 hours (7 days)
± 33.6 hours 
336 hours (14 days)
± 67.2 hours
720 hours (30 days)
± 144 hours
1440 hours (60 days)
± 288 hours
Note: Each post-procedure time point allows an up to +/- 20% time-
window (based on time duration from 0 minute to the intended time 
point) for blood sample collection. For example, time window for 1 hour 
post procedure is ± (1 hour * 20%) = ±12 minutes.
Clinical Follow-up
30 days, 60 days, 90 days, 180 days, 1, 2, 3, 4 and 5 years
Follow-up for PK sub-study subjects will not include administration of 
the Patient Reported Outcomes (PRO) tools (WIQ, PAQ and EQ-5D-
5L) nor wound imaging follow-up. Wound assessment will be per site 
standard of care.
Duplex ultrasound for the PK study subjects will be conducted at 30 
days ,180 days and 1 year.
PK Parameters
x
tmax
x
Cmax
x
AUC0-24h

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 103 of 140
x
AUC0-t
x
AUC0-∞
x
Oz
x
t1/2term
x
CL
Safety Monitoring
Refer to Section 7.0 Adverse Events
Subject Enrollment and 
Registration
A subject is considered enrolled in the PK sub-study upon signing the 
informed consent form.
Subjects will not be registered into the sub-study until after a) 
successful pre-dilatation and b) completion of the index procedure, with 
total scaffold length implanted between 170 and 256 mm.
Blood collection post-Esprit BTK implantation will not be conducted if 
the subject did not receive the required total scaffold length (170 to 256 
mm).
Exclusion from Analysis and 
Follow-up
Subjects in whom Esprit BTK enters the body but no scaffold were 
implanted will be excluded from the sub-study analysis. A 30-day safety 
follow-up will be required for these subjects.
Subjects who received at least one Esprit BTK scaffold, but in whom 
some of the intended scaffolds were not implanted successfully will be 
excluded from the sub-study analysis and will require 5-year follow-up 
as per the time points described above in the “Clinical Follow-up” 
section. These subjects may have their follow-up via phone visit. The 
following assessments will not be required for these subjects: duplex 
ultrasound, wound imaging, completion of PRO tools. 
Subjects who received less than the required total scaffold length (170 
to 256mm) will be excluded from the sub-study analysis and will require 
5-year follow-up as per the time points described above in the “Clinical 
Follow-up” section. These subjects may have their follow-up via phone 
visit. The following assessments will not be required for these subjects: 
duplex ultrasound, wound imaging, completion of PRO tools. 
In all the above cases, subjects will be replaced in the PK sub-study.
Inclusion Criteria
General Inclusion Criteria: Refer to Section 5.3.2.1 General 
Inclusion Criteria of the LIFE-BTK protocol for complete list. The
general inclusion criteria for LIFE-BTK PK sub-study are the same as 
those for the RCT, except for general inclusion criterion # 3 below.
General Inclusion Criterion # 3: Subject requires primary treatment of 
one or more de novo or restenotic (treated with prior PTA) 
infrapopliteal lesions.
Anatomic Inclusion Criteria:
1.
One or more native infrapopliteal lesions, including de novo 
lesions in the same limb. Restenotic (from prior PTA) lesions 
are allowed.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 104 of 140
a.
Lesion must be located in the proximal 2/3 of native 
infrapopliteal vessels, with vessel diameter of ≥ 2.5 mm 
and ≤ 4.00 mm by investigator visual assessment.
i.
Note: see vessel sizing under “treatment 
strategy” section within the LIFE-BTK protocol.
b.
Total scaffold length to completely cover/treat target 
lesion(s) must be between 170 and 256 mm (maximum 
total everolimus drug dose of 2714 μg).
c.
The target vessel can have any other angiographic 
significant lesions (≥50%) that should be treated per 
institution standard of care prior to treatment of the 
target lesion.
d.
Tandem lesions are allowed and the total scaffold 
length used to cover the entire diseased segment must 
be ≤ 256 mm. 
2.
Target lesion(s) must have ≥ 70% stenosis, per visual 
assessment at the time of the procedure. If needed, 
quantitative imaging (angiography, IVUS, and/or OCT) can be 
used to aid accurate sizing of the vessels.
3.
The distal margin of the scaffold must be located ≥ 10 cm 
proximal to the proximal margin of the ankle mortise.  . If the 
vessel segment distal to the target lesion has a significant 
lesion (> 50% stenosis), it should be treated per institution 
standard of care prior to deployment of the scaffold.
4.
Significant lesion (≥ 50% stenosis) in the inflow artery(ies) must 
be treated successfully (as per physician’s assessment of the 
angiography) through standard of care prior to the treatment of 
the target lesion. Treatment must be done within the same trial 
procedure. Treatment allowed for inflow artery lesions are PTA, 
atherectomy, cutting/scoring balloon, Shockwave balloon, bare 
metal stent, drug-eluting stents or drug-coated balloon. 
Everolimus-coated or eluting devices are not allowed.
5.
It is acceptable for non-target lesion(s) (if applicable) to be 
located in the same infrapopliteal vessel(s) as the target lesion, 
and suitable to be treated per institution standard of care. Non-
target lesions must be treated successfully prior to target 
lesions and not requiring re-cross of the scaffold.
6.
Crossing of the target lesion in an antegrade fashion is 
preferred, but retrograde crossing may be used. However, the 
treatment must be delivered antegrade.
Exclusion Criteria
General Exclusion Criteria: Refer to Section 5.3.3.1 General 
Exclusion Criteria of the LIFE-BTK protocol for the complete list.
Anatomic Exclusion Criteria: 
1.
Lesions with severe calcification, in which there is a high 
likelihood that successful pre-dilatation cannot be achieved.
2.
Lesion that has prior metallic stent implant.
.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 105 of 140
3.
Coronary or peripheral artery treated with everolimus-eluting
device during index procedure, or within 90 days prior to index 
procedure.
4.
Target or (if applicable) non-target vessel contains visible 
thrombus as indicated in the angiographic images. 
5.
Subject has angiographic evidence of thromboembolism or 
atheroembolism in the ipsilateral extremity. (Pre- and post-
angiographic imaging must confirm the absence of emboli in 
the distal anatomy.) 
6.
Unsuccessfully treated proximal inflow limiting arterial stenosis 
or inflow-limiting arterial lesions left untreated.
7.
No angiographic evidence of a patent pedal artery. 
8.
Target or (if applicable) non-target lesion location requiring 
bifurcation treatment method that requires scaffolding of both 
branches (provisional treatment, without intention of scaffolding 
both branches is acceptable).
9.
Aneurysm in the iliac, common femoral, superficial femoral, 
popliteal or target artery of the ipsilateral extremity.
10. Visual assessment of the target lesion suggests that the 
investigator is unable to pre-dilate the lesion according to the 
vessel diameter. 
11. Target lesion has a high probability that atherectomy will be 
required at the time of index procedure for treatment of the 
target vessel.
Note: staged procedures are not allowed in LIFE-BTK PK sub-study.
Index Procedure and Treatment 
Strategy
Refer to Section 6.4 Index Procedure in the LIFE-BTK protocol.
In the PK sub-study, all target lesions are to be treated with the Esprit 
BTK only
Subjects in the PK sub-study will not be randomized; any references to 
randomization should be disregarded
Post-procedure medications
Refer to Section 6.5 Post-procedure Medications of the LIFE-BTK 
protocol for required antiplatelet medications and highly recommended 
concomitant medications.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 106 of 140
LIFE-BTK PK Sub-study: Schedule of Events
PROCEDURE/
TEST
Baseline
Baseline (within 7 days)
Pre-procedure (within 24 hours)
Procedure#
Post-procedure up to 12 hours
1-14 days post-procedure 
30 days 
60 days 
90 days (r 14 d)   
180 days (r 28 d)
1 year (r 28 d)
2, 3, 4, 5 years (r 28 d)
Unscheduled visits
Exact Timing
0 minute*
10 minutes
30 minutes
1 hour
2 hours
4 hours
6 hours
12 hours
24 hours (1 day)
48 hours (2 days)
72 hours (3 days)
96 hours (4 days)
120 hours (5 days)
168 hours (7 days)
336 hours (14 days)
720 hours (30 days)
1440 hours (60 days)
Blood draw for PK study
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
9
Subject Medical/Clinical 
History (Age, Sex, Risk 
Factors)
9
Subject Informed 
Consent (Must be 
obtained prior to any 
study related testing or 
procedures)
9
General 
Inclusion/Exclusion 
Criteria
9
Angiographic 
Inclusion/Exclusion 
Criteria
9
9
Pregnancy Test (if 
applicable)
9

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 107 of 140
Hgb, Platelet Count, 
Creatinine, HbA1c, 
eGFR, WBC
9
Vascular Angiogram, 
IVUS or OCT
9
9
Duplex Ultrasound
9
9
9
9
ABI/TBI measurement
9^
9^
9
9
9
9
9
9
Study device 
information
9
Per Protocol 
Medications
9
9
9
9
9
9
9
9
9
9
9
Concomitant 
Medications
9
9
9
9
9
9
9
9
9
9
Adverse Events
9
9
9
9
9
9
9
9
9
9
Rutherford Becker 
category assessment 
9
9
9
9
9
9
9
Wound assessment (site 
reported only, no images 
will be taken)
9
9
9
9
9
9
9
9
Note: each post-procedure visit can be a Study Doctor’s office visit, a hospital visit, or an in-home visit.
Note: Each post-procedure time point allows an up to +/- 20% time-window (based on time duration from 0 minute to the intended time point) for blood sample 
collection. For example, time window for 1 hour post procedure is ± (1 hour * 20%) = ±12 minutes.
# Collect a blood sample immediately after the first scaffold has been implanted. Collect one blood sample every 15 min after the first scaffold has been implanted until
the last scaffold has been implanted
*0 minute is defined as when the last Esprit BTK is deployed, i.e., last Esprit BTK delivery catheter is removed from the body.
^ Only one ABI/TBI measurement is needed at either baseline or pre-procedure. 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 108 of 140
APPENDIX XI: REVISION HISTORY
.
Amendment 
Number 
Version 
Date 
Details 
Rationale 
 
 
 
 
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 109 of 140
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 110 of 140
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 111 of 140
 
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 112 of 140
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 113 of 140
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 114 of 140

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 115 of 140
 
 
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 116 of 140
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 117 of 140

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 118 of 140

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 119 of 140
 
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 120 of 140

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 121 of 140

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 122 of 140
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 123 of 140
 
 
 
 
 
 
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 124 of 140
 
 
 
 
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 125 of 140
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 126 of 140
 
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 127 of 140
 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 128 of 140
   

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 129 of 140

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 130 of 140
APPENDIX XII: CIP SUMMARY
Trial Name
LIFE-BTK Randomized Controlled Trial
Purpose
Pre-market clinical evaluation of the everolimus eluting Esprit BTK
System for the planned treatment of narrowed infrapopliteal lesions. 
Study Design Prospective, randomized clinical trial (2:1) evaluating planned treatment of 
below-the-knee (BTK) lesions with Esprit BTK versus planned treatment with 
PTA.
Approximately 225 subjects and up to 315 subjects, in approximately 65 clinical 
sites in the US, Asia, Australia and New Zealand (maximum 55 sites in the 
US: 50 sites for the LIFE-BTK RCT plus 5 sites for the pharmacokinetics 
sub-study). Subject registration is capped at 45 (20% of total sample size) 
per site.
Study Device
Esprit BTK
Study
Population
Patients with arterial narrowing in infrapopliteal lesions causing CLI who 
satisfy the key inclusion and exclusion criteria described below.
Primary 
Endpoints
Primary Efficacy Endpoint
x
Composite of limb salvage and primary patency at 1 year testing for 
superiority
o
Includes freedom from above ankle amputation in index limb, 100% 
total occlusion of target vessel, binary restenosis of target lesion,
and clinically-driven target lesion revascularization
Primary Safety Endpoint
x
Freedom from MALE+POD testing for non-inferiority
Above ankle amputation in index limb; Major re-intervention on index 
limb at 6 months and perioperative (30 day) mortality
Key Inclusion
Criteria
General Inclusion Criteria
1. Subject must provide written informed consent prior to any clinical 
investigation related procedure.
2. Subject has symptomatic Critical Limb Ischemia (CLI), Rutherford 
Becker Clinical Category 4 or 5.
3. Subject requires primary treatment of up to two de novo or 
restenotic (prior PTA) infrapopliteal lesions
4. Subject must be at least 18 years of age.
5. Female subject of childbearing potential should not be pregnant and 
must be on birth control.
Note: Female subjects of child-bearing potential must have a negative 
pregnancy test done within 7 days prior to the index procedure per site 
standard test.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 131 of 140
Anatomic Inclusion Criteria
1. Up to two native infrapopliteal lesions, each lesion located in 
separate infrapopliteal vessel, in the same limb. Restenotic (prior 
PTA) lesions are allowed.
a. Lesion must be located in the proximal 2/3 of native 
infrapopliteal vessels, with vessel diameter of ≥ 2.5 mm and ≤ 
4.00 mm by investigator visual assessment.
Note: see vessel sizing under “treatment strategy” section.
b. Total scaffold length to completely cover/treat a target lesion 
must not exceed 170 mm (total everolimus drug dose of 1790 
μg).
c. The total scaffold length must not exceed 170 mm.
d. The target vessel cannot have any other angiographic 
significant lesions (≥50%). 
e. Tandem lesions are allowed if they are < 3 cm apart and the total 
scaffold length used to cover the entire diseased segment is ≤ 170 
mm. Each tandem lesion is considered one lesion.
2. Target lesion(s) must have ≥ 70% stenosis, per visual assessment 
at the time of the procedure. If needed, quantitative imaging 
(angiography, IVUS, and/or OCT) can be used to aid accurate 
sizing of the vessels.
3. The distal margin of the target lesion must be located ≥ 10 cm 
proximal to the proximal margin of the ankle mortise.  The vessel 
segment distal to the target lesion must be patent all the way to the 
ankle, with no significant lesion (≥ 50% stenosis).  
4. Significant lesion (≥ 50% stenosis) in the inflow artery(ies) must be
treated successfully (as per physician’s assessment of the 
angiography) through standard of care prior to the treatment of the 
target lesion. Treatment can be done within same trial procedure.
5. Non-target lesion(s) (if applicable) must be located in separate 
infrapopliteal vessel(s) from the target lesion, and suitable to be 
treated per institution standard of care 
6. Guidewire must cross the target lesion successfully. Crossing in an 
antegrade fashion is preferred, but retrograde crossing may be 
used. However, the treatment must be delivered antegrade.
Key 
Exclusion
Criteria
General Exclusion Criteria
1.
Subject is currently participating in another clinical investigation 
that has not yet completed its primary endpoint.
2.
Pregnant or nursing subjects and those who plan pregnancy 
during the clinical investigation follow-up period. 
3.
Presence of other anatomic or comorbid conditions, or other 
medical, social, or psychological conditions that, in the 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 132 of 140
investigator’s opinion, could limit the subject’s ability to participate 
in the clinical investigation or to comply with follow-up
requirements.
4.
Incapacitated individuals, defined as persons who are mentally ill, 
mentally handicapped, or individuals without legal authority, are 
excluded from the study population.
5.
Subject has had any amputation to the ipsilateral extremity other 
than the toe or forefoot, or subject has had major amputation to 
the contralateral extremity < 1 year prior to index procedure and 
is not independently ambulating.
6.
Subject has known hypersensitivity or contraindication to device 
material and its degradants (everolimus, poly (L-lactide), poly 
(DL-lactide), lactide, lactic acid) and cobalt, chromium, nickel, 
platinum, tungsten, acrylic and fluoro polymers that cannot be 
adequately pre-medicated. Subject has a known contrast 
sensitivity that cannot be adequately pre-medicated.
7.
Subject has known allergic reaction, hypersensitivity or 
contraindication to aspirin; or to ADP antagonists such clopidogrel, 
prasugrel or ticagrelor; or to anticoagulants such as heparin or 
bivalirudin, and therefore cannot be adequately treated with study 
medications.  Subject with planned surgery or procedure necessitating 
discontinuation of antiplatelet medications, within 12 months after 
index procedure. Planned amputation that will necessitate 
discontinuation of antiplatelet medications is allowed.
8.
Subject has life expectancy ≤ 1 year.
9.
Subject has had a stroke within the previous 3 months with 
residual Rankin score of ≥ 2.
10.
Subject has renal insufficiency as defined as an estimated GFR < 
30 ml/min per 1.73m2.
11.
Subject is currently on dialysis.
12.
Subject has platelet count < 100,000 cells/mm3 or > 700,000 
cells/mm3, a WBC < 3,000 cells/mm3, or hemoglobin < 9.0 g/dl.
13.
Subject has known serious immunosuppressive disease (e.g., human 
immunodeficiency virus), or has severe autoimmune disease, that 
requires chronic immunosuppressive therapy (e.g., systemic lupus 
erythematosus, etc.), or subject is receiving immunosuppression 
therapy for other conditions. Subjects with HIV and who have 
undetectable viral load, such that their immune system is not 
considered compromised, are eligible.
14.
Subject has Body Mass Index (BMI) <18.
15.
Subject is receiving or scheduled to receive anticancer therapy 
for malignancy within 6 months prior to index procedure or within 
1 year after the procedure. Patients taking medications classified 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 133 of 140
as chemotherapy but who have been in remission for at least 6 
months are eligible.
16.
Subject has coagulation disorder that increases the risk of arterial 
thrombosis. Subjects with deep vein thrombosis and disorders 
that increase the risk of deep vein thrombosis can be included in 
the study.
17.
Subject who requires thrombolysis as a primary treatment 
modality, or requires other treatment for acute limb ischemia of 
the target limb
18.
Subject has previously had, or requires surgical revascularization 
involving any vessel of the ipsilateral extremity. Prior femoropopliteal 
or aortobifemoral bypass is allowed. Any bypass to the tibial arteries is 
not allowed.
19.
Subject has signs or symptoms of advanced limb infection or 
septicemia (fever > 38.5, WBC > 15,000 cells/microliter, 
hypotension) at the time of assessment.  Osteomyelitis of the 
phalanges or metatarsal heads (as described in exclusion criteria 
#21a) or cellulitis of the foot amenable to treatment with IV 
antibiotics at the time of revascularization is acceptable.
20.
Subject is bedridden or unable to walk (with assistance is 
acceptable). Subjects in wheelchair who are able to mobilize on 
their own can be enrolled. 
21.
Subject with extensive tissue loss salvageable only with complex 
foot reconstruction or non-traditional transmetatarsal 
amputations. This includes subjects with: Osteomyelitis including 
and/or proximal to the metatarsal head
a.
Osteomyelitis that extends proximal to the metatarsal heads.
Osteomyelitis limited to the phalanges or metatarsal heads is 
acceptable for enrollment.
b.
Gangrene involving the plantar skin of the forefoot, midfoot, or 
heel
c.
Deep ulcer or large shallow ulcer (> 3 cm) involving the plantar 
skin of the forefoot, midfoot, or heel
d.
Full thickness heel ulcer with/without calcaneal involvement
e.
Any wound with calcaneal bone involvement
f.
Wounds that are deemed to be neuropathic or non-ischemic in 
nature
g.
Wounds that would require flap coverage or complex wound
management for large soft tissue defect
h.
Full thickness wounds on the dorsum of the foot with exposed 
tendon or bone
22.
Subject is unable or unwilling to provide written consent prior to 
enrollment

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 134 of 140
23.
Subject has active symptoms and/or a positive test result of COVID-19
or other rapidly spreading novel infectious agent within the prior 2 
months.
Anatomic Exclusion Criteria
1.
Lesions with severe calcification, in which there is a high 
likelihood that successful pre-dilatation cannot be achieved.
2.
Lesion that has prior metallic stent implant.
3.
Significant (≥50% stenosis) lesion in a distal outflow artery that 
would be perfused by the target vessel and that requires 
treatment at the time of the index procedure.
4.
Subject has had or will require treatment in any vessel with an
everolimus drug-coated stent or drug-eluting device < 30 days
pre-study procedure, or during the index procedure, such that the 
cumulative (Esprit BTK plus everolimus-eluting device) 
everolimus dose exceeds 1790 μg.
5.
Target or (if applicable) non-target vessel contains visible 
thrombus as indicated in the angiographic images. 
6.
Subject has angiographic evidence of thromboembolism or 
atheroembolism in the ipsilateral extremity. (Pre- and post-
angiographic imaging must confirm the absence of emboli in the 
distal anatomy.) 
7.
Unsuccessfully treated proximal inflow limiting arterial stenosis or 
inflow-limiting arterial lesions left untreated.
8.
No angiographic evidence of a patent pedal artery. 
9.
Target or (if applicable) non-target lesion location requiring 
bifurcation treatment method that requires scaffolding of both 
branches (provisional treatment of target lesions, without 
intention of scaffolding both branches is acceptable).
10. Aneurysm in the iliac, common femoral, superficial femoral, 
popliteal or target artery of the ipsilateral extremity.
11. Visual assessment of the target lesion suggests that the 
investigator is unable to pre-dilate the lesion according to the 
vessel diameter. 
12. Target has a high probability that atherectomy will be required at 
the time of index procedure for treatment of the target vessel.
Primary
Analysis 
Sample Size 
justification
Primary Efficacy Endpoint:
Sample size of this study is based on primary efficacy endpoint of 1 year
composite of limb salvage and patency based on the following assumptions: 
x
One-sided alpha =0.025 (Superiority)
x
x
x

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 135 of 140
Primary Safety Endpoint
Non-inferiority analysis for the primary safety endpoint based on the following 
assumptions:
x One-sided alpha =0.025
x
x Non-inferiority margin - 10%
x
Quality of Life
Endpoints
Quality of Life at baseline, 30 days, 3 and 6 months, and 1 year follow-
up. The following questionnaires will be used in this study till 1 year 
follow-up:
x Walking Improvement Questionnaire (WIQ)
x Peripheral Arterial Questionnaire (PAQ) in CLI module
x Measure of Health Outcome (EQ-5D-5L)

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 136 of 140
Follow-up
Schedule
The follow-up schedule§ and endpoint assessments are shown below.  
Time
Endpoints assessed
14 days (± 3 days)
Index wound assessment1,*
30 days (± 7 days)
Medications review, adverse events review, 
ABI/TBI measurement, functional status 
(Rutherford Becker), index wound assessment1,
new wound assessment2, WIQ, PAQ, EQ-5D-5L
30 days (± 14 days)
Duplex Ultrasound3
42 days (± 7 days)
Index wound assessment1,*
90 days (± 14 days)
Medications review, adverse events review,
ABI/TBI measurement, functional status 
(Rutherford Becker), index wound assessment1,
new wound assessment2, WIQ, PAQ, EQ-5D-5L
180 days (± 28
days)
Duplex Ultrasound3, medications review, adverse 
events review, ABI/TBI measurement, functional 
status (Rutherford Becker), index wound 
assessment1, new wound assessment2, WIQ,
PAQ, EQ-5D-5L
1 year (± 28 days)
Duplex Ultrasound3, medications review, adverse 
events review, ABI/TBI measurement, functional 
status (Rutherford Becker), index wound 
assessment1, new wound assessment2, WIQ,
PAQ, EQ-5D-5L
2 years (± 28 days)
Duplex Ultrasound3, medications review, adverse 
events review, ABI/TBI measurement, functional 
status (Rutherford Becker), new wound 
assessment2
3 years (± 28 days)
Duplex Ultrasound3, medications review, adverse 
events review, ABI/TBI measurement, functional 
status (Rutherford Becker), new wound 
assessment2
4 years (± 28 days)
Medications review, adverse events review,
ABI/TBI measurement, functional status 
(Rutherford Becker), new wound assessment2
5 years (± 28 days)
Medications review. adverse events review,
ABI/TBI measurement, functional status 
(Rutherford Becker), new wound assessment2
1 Index wound assessment for healing and infection will be assessed by the 
core laboratory through 90 days (14 days, 30 days, 42 days and 90 days). For 
index wounds that are not healed by 90 days, the index wound will be 

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 137 of 140
assessed by the core laboratory at 180 days. If the index wound is not healed 
by 180 days, index wound assessment by the core laboratory will be carried 
out at 1 year. Index wounds that have healed by 90 days will not be assessed 
by the core laboratory at 180 days and 1 year. A formal office visit is highly 
recommended at 14-day and 42-day follow-up for evaluation of index wound. 
The option to take wound pictures remotely at 14 days and 42 days in 
accordance to the core laboratory wound imaging guidelines is for subjects 
that are unable to complete an office visit.  No wound images will be collected 
outside of the protocol defined timepoints.
* If a subject does not have an index wound at baseline, they will not need to 
return to the site at 14 days and 42 days.
2 New wound is defined as wound below the knee in the index limb that was 
not identified at the time of the index procedure or wound that has recurred in 
the same location following the healing of the index wound. The new wound 
will be assessed firstly by the wound assessment core laboratory for etiology. 
Subsequently, the new wound will be evaluated by the site per protocol until 
the wound is healed through the 5-year follow-up. If a new wound is first 
observed at 5-year follow-up, a picture will be taken for etiology assessment 
by the core laboratory. As this will be the final patient visit for the trial, no
additional pictures of the new wound will be required following the initial 
picture submitted to the core laboratory.
3 Duplex ultrasound is required at 30 ± 14 days post-procedure, at 180 days 
and at 1, 2 and 3 years; if a patient is symptomatic or occlusion is suspected, 
duplex as well as angiogram should be completed.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 138 of 140
APPENDIX XIII: ESPRIT BTK Part Numbers
Scaffold size
Part Number
2.5 x 9 mm
2.5 x 12 mm
2.5 x 15 mm
2.5 x 18 mm
2.5 x 23 mm
2.5 x 28 mm
2.5 x 33 mm
2.5 x 38 mm
2.75 x 9 mm
2.75 x 12 mm
2.75 x 15 mm
2.75 x 18 mm
2.75 x 23 mm
2.75 x 28 mm
2.75 x 33 mm
2.75 x 38 mm
3.0 x 9 mm
3.0 x 12 mm
3.0 x 15 mm
3.0 x 18 mm
3.0 x 23 mm
3.0 x 28 mm
3.0 x 33 mm
3.0 x 38 mm
3.5 x 9 mm
3.5 x 12 mm
3.5 x 15 mm
3.5 x 18 mm
3.5 x 23 mm
3.5 x 28 mm
3.5 x 33 mm
3.5 x 38 mm
3.75 x 9 mm
3.75 x 12 mm
3.75 x 15 mm
3.75 x 18 mm
3.75 x 23 mm
3.75 x 28 mm
3.75 x 33 mm
3.75 x 38 mm

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 139 of 140
APPENDIX XIV: REFERENCES
1.
Norgren, L., et al., Inter-Society Consensus for the Management of Peripheral Arterial Disease 
(TASC II). J Vasc Surg, 2007. 45 Suppl S: p. S5-67.
2.
MR Jaff, G.B., An overview of critical limb ischemia: today’s therapeutic advances are changing 
the way we evaluate and treat this common and often fatal disorder. Endovascular Today, 2004. 
3(2): p. 45-48.
3.
Romiti, M., et al., Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. J
Vasc Surg, 2008. 47(5): p. 975-981.
4.
Mustapha, J., LUTONIX® BTK Trial: A Prospective, Multicenter, Single Blind, Randomized, 
Controlled Trial Comparing the Lutonix Drug Coated Balloon vs. Standard Balloon Angioplasty for 
Treatment of Below-the-Knee (BTK) Arteries. Vascular Interventional Advances (VIVA), 2018.
5.
Scheinert, D., et al., A prospective randomized multicenter comparison of balloon angioplasty and
infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial 
disease: 1-year results from the ACHILLES trial. J Am Coll Cardiol, 2012. 60(22): p. 2290-5.
6.
Bosiers, M., et al., Randomized comparison of everolimus-eluting versus bare-metal stents in 
patients with critical limb ischemia and infrapopliteal arterial occlusive disease. J Vasc Surg, 
2012. 55(2): p. 390-8.
7.
Bosiers, M.J., et al., Outcome of a drug-eluting stent in longer below-the-knee lesions in patients
with critical limb ischemia. J Cardiovasc Surg (Torino), 2017. 58(1): p. 49-54.
8.
Rastan, A., et al., Sirolimus-eluting stents vs. bare-metal stents for treatment of focal lesions in 
infrapopliteal arteries: a double-blind, multi-centre, randomized clinical trial. Eur Heart J, 2011. 
32(18): p. 2274-81.
9.
Varcoe, R.L., S.D. Thomas, and A.F. Lennox, Three-Year Results of the Absorb Everolimus-
Eluting Bioresorbable Vascular Scaffold in Infrapopliteal Arteries. J Endovasc Ther, 2018. 25(6):
p. 694-701.
10.
Xue, J., Outcomes of Bio-absorbable stent for Below Knee Critical Limb Ischaemia. Asian Society 
for Vascular Surgery (ASVS) Congress., 2016.
11.
Kum, S., 1 Year Results in Real World Patients with ABSORB BTK. Leipzig Interventional 
Course, 2017.
12.
Shah, A.D., A.; Venturini, J.M.; Paul, J.;Blair, J.; Friant, J.; Nathan, S., Clinical Effectiveness of 
the ABSORB Bioresorbable Scaffold in Patients with Complex Infrapopliteal Disease. LINC 19, 
2019.
13.
Eisenberg, J.M., Clinical economics. A guide to the economic analysis of clinical practices. JAMA, 
1989. 262(20): p. 2879-86.
14.
Mills, J.L., Sr., et al., The Society for Vascular Surgery Lower Extremity Threatened Limb 
Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI). J
Vasc Surg, 2014. 59(1): p. 220-34 e1-2.
15.
Rutherford, R.B., et al., Recommended standards for reports dealing with lower extremity 
ischemia: revised version. J Vasc Surg, 1997. 26(3): p. 517-38.
16.
Varcoe, R.L., et al., Lessons Learned Regarding Handling and Deployment of the Absorb 
Bioresorbable Vascular Scaffold in Infrapopliteal Arteries. J Endovasc Ther, 2017. 24(3): p. 337-
341.
17.
Herdman, M., et al., Development and preliminary testing of the new five-level version of EQ-5D
(EQ-5D-5L). Qual Life Res, 2011. 20(10): p. 1727-36.
18.
Nicolai, S.P., et al., The walking impairment questionnaire: an effective tool to assess the effect of 
treatment in patients with intermittent claudication. J Vasc Surg, 2009. 50(1): p. 89-94.
19.
Hoeks, S.E., et al., Clinical validity of a disease-specific health status questionnaire: the 
peripheral artery questionnaire. J Vasc Surg, 2009. 49(2): p. 371-7.

Study Name: LIFE-BTK RCT
Clinical Investigation Plan
Page 140 of 140
20.
Farrington, C.P. and G. Manning, Test statistics and sample size formulae for comparative 
binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med, 
1990. 9(12): p. 1447-54.
21.
Mustapha, J., LUTONIX BTK Trial - A Prospective, Multicenter, Single Blind, Randomized, 
Controlled Trial Comparing the Lutonix Drug Coated Balloon vs. Standard Balloon Angioplasty for 
Treatment of Below-the-Knee (BTK) Arteries. Vascular InterVentional Advances congress, 2018.
22.
Zeller, T., et al., Drug-Eluting Balloon Versus Standard Balloon Angioplasty for Infrapopliteal 
Arterial Revascularization in Critical Limb Ischemia: 12-Month Results From the IN.PACT DEEP 
Randomized Trial. Journal of the American College of Cardiology, 2014. 64(15): p. 1568-1576.
23.
Elmariah, S., et al., Design and rationale of a randomized noninferiority trial to evaluate the 
SurVeil drug-coated balloon in subjects with stenotic lesions of the femoropopliteal artery - the
TRANSCEND study. Am Heart J, 2018. 209: p. 88-96.
24.
Hintze, J., NCSS and PASS. Number Cruncher Statistical Systems. Kaysville, Utah, 2017.
25.
Geraghty, P.J. Lutonix BTK IDE Study: 12-Month Results & Interim Safety Analyses at Three 
Years. in LINC 20. 2020.
26.
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.
Diabetes Care, 1997. 20(7): p. 1183-97.
27.
The Seventh Report of the Joint National Committee on Prevention, Detection and Treatment of 
High Blood Pressure: US Department of Health and Human Sciences: 2004.
28.
Grundy, S.M., et al., Implications of recent clinical trials for the National Cholesterol Education 
Program Adult Treatment Panel III guidelines. Circulation, 2004. 110(2): p. 227-39.
29.
Conte, M.S., et al., Suggested objective performance goals and clinical trial design for evaluating 
catheter-based treatment of critical limb ischemia. J Vasc Surg, 2009. 50(6): p. 1462-73 e1-3.
30.
Zeller, T., Current state of endovascular treatment of femoro-popliteal artery disease. Vasc Med, 
2007. 12(3): p. 223-34.
31.
Høyer, C., J. Sandermann, and L.J. Petersen, The toe-brachial index in the diagnosis of 
peripheral arterial disease. Journal of Vascular Surgery, 2013. 58(1): p. 231-238.