Conditions: Peripheral Artery Disease Vascular Disease Critical Limb Ischemia
Keywords: angioplasty peripheral artery disease peripheral vascular disease atherosclerosis balloon angioplasty dexamethasone drug coated balloon paclitaxel walking claudication
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 33
Healthy volunteers: no

Brief summary:
This is a prospective, multicenter, randomized trial to determine the mechanisms of vascular healing. The study will evaluate subjects with peripheral artery disease (PAD) who require an endovascular intervention of the femoro-popliteal (SFA) artery to restore blood flow to the leg.

Detailed description:
Peripheral artery disease (PAD) affects at least 12 million Americans annually with more than half a million patients undergoing an endovascular or surgical revascularization procedure in order to treat the disease. Unfortunately, about two-thirds of patients still have blockages in the leg arteries, even after these procedures.

Advances in Magnetic resonance imaging (MRI) offer promise for understanding the mechanism of failure through insights into vessel wall composition, remodeling, and inflammation. Restenosis has a known relationship to inflammation. Advances in micro-catheter technologies offer the ability to deliver anti-inflammatory medications such as Dexamethasone (DEX) directly to the adventitia and advances in drug delivery on balloon surfaces to deliver paclitaxel to the intima of the artery.

This study aims to investigate if patient-specific parameters affect angioplasty outcomes, if DEX has a biological effect on the vessel wall, and if this effect is through the reduction of inflammation.

In response to an FDA issued "Letter to Healthcare Providers" dated August 9, 2019 that reported the "relative risk for increased mortality at 5 years was 1.57 (95% confidence interval 1.16 - 2.13), which corresponds to a 57% relative increase in mortality in patients treated with paclitaxel-coated devices," participant enrollment in the paclitaxel drug coated balloon arm was stopped and a plain balloon angioplasty arm was added to the protocol.

Arms:
arm 1: Participants randomized to the Dexamethasone group will receive dexamethasone infusion to the adventitia of the artery following plain-old-balloon-angioplasty (POBA). arm 2: Participants randomized to the Drug Coated Balloon (DCB) group will not receive dexamethasone infusion to the adventitia of the artery following (POBA). They will receive additional angioplasty with a paclitaxel coated balloon. arm 3: Participants randomized to the Plain Balloon Angioplasty will receive balloon angioplasty (POBA) only. They will not receive a dexamethasone infusion to the adventitia or paclitaxel.

Interventions: intervention 1: Dexamethasone infusion intervention 2: Drug coated balloon intervention 3: Plain balloon angioplasty
Intervention descriptions: intervention 1: Participants will receive dexamethasone infusion following plain balloon angioplasty intervention 2: Participants will receive angioplasty with a drug-coated balloon following plain balloon angioplasty intervention 3: Participants will receive plain balloon angioplasty only

Protocol document:
Prot_SAP_001.pdf: 
 
Document type: 
Study Protocol 
Official Title: 
Intima versus adventitia drug delivery to 
elucidate mechanisms of restenosis: 
magnetic resonance imaging 
NCT Number: 
NCT02807779 
Document Date: 
10 October 2019 
 
 


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INtima Versus Adventitia Drug Delivery to Elucidate Mechanisms of Restenosis: 
Magnetic Resonance Imaging 
INVADER MRI 
 
CLINICAL RESEARCH PROTOCOL 
 
Investigator: 
David Saloner, Ph.D. 
Professor of Radiology and Biomedical 
Imaging 
University of California, San Francisco 
Director, Vascular Imaging Research Center 
 
Locations: 
San Francisco VA Medical Center 
4150 Clement St. MS#114D 
San Francisco, CA 94121 
CHANGE LOG 
Version 
Release Date 
Description of Changes 
1.0 
10 AUGUST 2015 
New Release 
1.1 
21 DECEMBER 2015 
Changed name of protocol 
Revised Background to provide more specific 
information about study context and for style. 
Revised Study Rationale for grammar. 
Revised Primary and Secondary Objectives for 
consistency with grant. 
Revised language related to “Investigational 
Product”, Dispensing and Storage Instruction to 
clarify DEX is not an investigational product. 
Changed wording of Secondary Aim #3 (Ktrans) to 
specify measurement at 6 months 
Sec. 9.10 “Research MRI” - removed Ktrans at 24 
hours and 12 months 
Changed Sec 9.2, Research lab measurements to 
include assessment of inflammatory markers at 12 
months to match Secondary Aim #2. 


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Updated screening exclusion criteria to the patient 
is expected to live 1-year or longer. Added 
exceptions to known active malignancy. 
Revised Procedural Inclusion/Exclusion Criteria to 
better define eligible lesions, concomitant 
procedures and medications. 
Changed maximum lesion length from < 20 cm to 
entire superficial femoral/popliteal artery 
Updated Treatment Segment Registration 
procedure to clarify when the investigator has 
discretion for choosing an index lesion. 
Updated Treatment Segment Registration to 
include origin of profunda femoris artery as key 
landmark 
Changed Sec. 9.8.2 “Order of Operations” to clarify 
the Core Lab will grade infusion success 
Removed Sec. 9.9 Clinical MRA due to differences 
in clinical practices between sites 
Added Sec. 9.10.2 Research MRI Protocol with 
specific language about processing modalities 
Added language to “Research MRI” procedure 
description regarding blind reading of MRI studies. 
Changed window for 12 month visit from 28 d to 30 
d 
Amended Data Safety Monitoring section, removing 
two members and specifying expected procedure-
related conditions 
Updated Primary Analysis Plan to include linear 
splines at 6 mo 
Changes wording of Assessments Visit 1 to include 
Rutherford & ABI as part of vascular exam 
Change to Appendix 1 – clarified appropriate tube 
type for MCP-1 
Added Appendix 6: Lutonix DCB IFU 
Added Appendix 7: INPACT Admiral DCB IFU 
Added Appendix 8: Walking Impairment 
Questionnaire (WIQ) 
1.2 
1 JUN 2017 
Change in PI 
Revised List of Abbreviations 
Revised grammar of inclusion/exclusion criteria, for 
clarity 


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Standardized terminology throughout protocol 
Changed Sec 9.8 Order of Operations, items no.4 
& no.7, to reflect modification of Sec 9.9.2 
Changed Sec 9.9.2 to clarify the method used for 
determining the MRI scan location 
Added Sec 9.9.3 Pre-Reintervention MRI to specify 
conditions for imaging in the event of an unplanned 
visit for index leg reintervention 
Revised Sec 10 Schedule of Assessments for 
accuracy, including Inclusion/Exclusion criteria, 
Rutherford Category, Index Lesion Registration & 
PTX Treatment  
Changed Sec 11.2 Visit 2: Procedure (Day 0) to 
match Sec 9.1.4 Concomitant Medications and Sec 
10 Schedule of Assessments by removing 
concomitant medications from Day 0 assessments 
Added Sec 11.8 Unplanned Visit for Index Leg 
Reintervention 
Change in Data Management team 
To eliminate possible confusion, all instances of the 
term “study drug” have been substituted with more 
accurate terminology. This trial uses FDA approved 
drugs and devices in accordance with their IFUs. 
For more information, please refer to Section 8.2 
Formulation of Treatment 
1.3 
13 OCT 2017 
Include eGFR criteria in Protocol Synopsis for 
Subject Screening Inclusion and Exclusion 
Addition of ILLUMENATE PIVOTAL studies to 
Section 1.1 under Drug Coated Balloon 
Addition of literature references for new studies in 
Section 1.2 regarding New Drug Coated Balloon  
Addition of Stellarex DCB Risk in Section 2.1.3.3  
Inlcude eGFR criteria in section 6.2 and 6.3 Subject 
Screening Inclusion and Exclusion Criteria 
Add Stellarex DBC to Section 8.2  
Add Stellarex DCB PTX Dosage to Section 8.3.1 
Add DCE Research MRI protocol to section 9.9.2 
Added an Appendix 8. Stellarex DCB Catheter IFU 
1.4 
26 OCT 2017 
Correction of DEX Infusion Volume in Section 8.3.1 


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1.5 
21 FEB 2018 
Added eGFR will be assessed at Month 12 to 
Section 9.2.2 
Added CE-MRA and post MERGE/DASH at 12 
months on Table 3, Section 9.9.2 
Added Clinical Lab eGFR to Visit 6 in Schedule of 
Assessments Table Section 10 
Changed footnote in Section 10 to "Research and 
Clinical labs must be drawn between POD #1-7" 
Removed Ktrans assessment to Statistical Methods 
2b in Section 16 
Amended the Glow N’ Tell tape protocol in Section 
9.5 Treated Segment Registration and 11.2 Visit 2 
Procedure 
 
1.6 
12 JUN 2018 
Added under subheading 5.2 Secondary Endpoints: 
5. Change in subject study status based on 
subjects receiving reintervention on < or >75% of 
treated segment.”  
Added subheading Section 5.4 under Completion 
Endpoints: Subject Status and Study Completion 
under Section 5 Study Endpoints 
Added Unplanned Visit to the Schedule of 
Assessments in Section 10 
Added under subheading 11.8 Unplanned Visit for 
Index Leg Reintervention, a protocol for subject 
follow up after reintervention.  
Added subheading 11.9 Study Completion under 
Section 11 Evaluation By Visit 
Added under subheading 13.1 Early 
Discontinuation/Withdrawals after Adverse Event 
an example, “(i.e index segment restenosis or 
occlusion <30 days of index segment treatment) 
 
 
 


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1.7 
30 AUG 2019 
Substitution of PTX treatment with POBA treatment 
moving forward, due to safety concerns (changes 
made to List of Abbreviations, Protocol Synopsis, 
Sections 1.1, 2.1.3.3, 5.1, 8.1, 9.6, 9.8, 10, 11.2, 
11.7, 11.8, 16.2, and 16.4) 
Reduction of Number of Subjects to 54 overall, 27 
per site (changes made to Protocol Synopsis, 
Section 16.4) 
Duration of Subject Participation has been 
extended to 36 months, with the addition of two 
telephone follow up visits (changes made to 
Protocol Synopsis, Sections 4.1, 5.4, 9.1.7, 10, 
11.8, 11.11, and 15) 
Mercator MedSystems location revised to 
Emeryville, CA (Section 1.1)  
Section 1.2 (Literature References) includes two 
new references, Nos.74 (Katsanos et. al.) & 75 
(FDA Letter from August 7th 2019) 
Section 11.11 (Study Completion) – 1-month is 
defined as  30 days. 75% of treated segment 
Section 16.4 (Sample Size and Randomization) – 
added calculations determining sample size 
 
1.8 
10 OCT 2019 
Section 5.2 (Secondary Endpoints) – “5. Change in 
subject study status based on subjects receiving 
reintervention on < 75% or  75% of treated 
segment.” 
Section 5.4 (Completion Endpoints) – “2. Subject 
develops restenosis after the 1-month study follow-
up, requiring reintervention of  75% of treated 
segment.” 
Section 5.4 (Completion Endpoints) – “If subject 
develops restenosis after the 1-month study follow-
up, requiring reintervention of <75% of the treated 
segment, please see section 11.10 for specifics on 
recording Unplanned Visits for Index Leg 
Reintervention and continuing follow-up.” 


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Section 11.10 (Unplanned Visit for Index Leg 
Reintervention) – “For further specifics on study 
completion, please see section 11.11 Study 
Completion.” 
Section 11.11 (Study Completion) – “2. Subject 
develops restenosis after the 1-month study follow-
up, requiring reintervention of  75% of treated 
segment.” 
Section 11.11 (Study Completion) – “If subject 
develops restenosis after the 1-month study follow-
up, requiring reintervention of <75% of the treated 
segment, please see section 11.10 for specifics on 
recording Unplanned Visits for Index Leg 
Reintervention and continuing follow-up.” 
Section 13.1 (Early Discontinuation/Withdrawal) – 
“(i.e. treated segment restenosis/occlusion 
occurring between index procedure date and the 1-
month study follow-up date)” 
 


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Clinical Research Protocol 
INtima Versus Adventitia Drug Delivery to Elucidate Mechanisms of Restenosis: Magnetic 
Resonance Imaging 
INVADER MRI 
 
Protocol Number: 
1.8 
Version Date: 
10 OCT 2019 
Investigational Product: 
none 
IND Number: 
n/a 
 
 
Funding Organization: 
National Institutes of Health 
National Heart, Lung, and Blood Institute (NHLBI) 
Principal Investigator: 
Name:  
David Saloner, Ph.D. 
Telephone: 
415-750-2238 
E-mail:  
David.Saloner@ucsf.edu 
 
Approval: 
 
 
 
PI or Sponsor Signature (Name and Title)  
 
Date 
This confidential information about an investigational product is provided for the 
exclusive use of investigators of this product and is subject to recall at any time.  
The information in this document may not be disclosed unless federal or state law 
or regulations require such disclosure.  Subject to the foregoing, this information 
may be disclosed only to those persons involved in the study who have a need to 
know, with the obligation not to further disseminate this information.   
 
 
 


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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and providing  
the University of California, San Francisco Committee on Human Research (CHR) with 
complete and timely information, as outlined in the protocol.  It is understood that all information 
pertaining to the study will be held strictly confidential and that this confidentiality requirement 
applies to all study staff at this site. Furthermore, on behalf of the study staff and myself, I agree 
to maintain the procedures required to carry out the study in accordance with accepted GCP 
principles and to abide by the terms of this protocol. 
 
Protocol Number:   
1.8 
Protocol Title:   
INtima Versus Adventitia Drug Delivery to Elucidate 
Mechanisms of Restenosis: Magnetic Resonance Imaging 
INVADER MRI 
 
Protocol Date:   
10 OCT 2019 
 
 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
1 
 
Site Name 
San Francisco VA Medical Center 
Address 
4150 Clement St. MS 114D 
 
San Francisco, CA 94121 
 
 
Phone Number 415-750-2238 


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TABLE OF CONTENTS 
CHANGE LOG 
2 
PROTOCOL AGREEMENT 
9 
TABLE OF CONTENTS 
10 
LIST OF ABBREVIATIONS 
14 
PROTOCOL SYNOPSIS 
16 
1 
BACKGROUND 
20 
1.1 
Overview of Clinical Studies ............................................................................................... 23 
1.2 
Literature References ......................................................................................................... 28 
2 
STUDY RATIONALE 
34 
2.1 
Risk / Benefit Assessment .................................................................................................. 34 
2.1.1 
Anticipated Clinical Benefits .............................................................................. 34 
2.1.2 
Anticipated Adverse Events to balloon angioplasty of the SFA ......................... 34 
2.1.3 
Possible Risks of Participation in this Clinical Trial ............................................ 35 
3 
STUDY OBJECTIVES 
40 
3.1 
Primary Objective ............................................................................................................... 40 
3.2 
Secondary Objectives ......................................................................................................... 40 
4 
STUDY DESIGN 
40 
4.1 
Study Overview .................................................................................................................. 40 
4.2 
Specific Aims ....................................................................................................................... 40 
5 
STUDY ENDPOINTS 
41 
5.1 
Primary Endpoint ................................................................................................................ 41 
5.2 
Secondary Endpoints .......................................................................................................... 41 
5.3 
Safety Endpoints ................................................................................................................. 41 
5.4 
Completion Endpoints ........................................................................................................ 41 
6 
SUBJECT SELECTION 
42 
6.1 
Study Population ................................................................................................................ 42 
6.2 
Inclusion Criteria................................................................................................................. 42 
6.3 
Exclusion Criteria ................................................................................................................ 42 
7 
CONCURRENT MEDICATIONS 
43 
7.1 
Allowed Medications and Treatments ............................................................................... 43 
8 
STUDY TREATMENTS 
43 
8.1 
Method of Assigning Subjects to Treatment Groups ......................................................... 43 
8.2 
Formulation of Treatment .................................................................................................. 44 


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8.2.1 
Packaging and Labeling ...................................................................................... 44 
8.3 
Supply of DEX at the Site .................................................................................................... 44 
8.3.1 
Dosage/Dosage Regimen ................................................................................... 44 
8.3.2 
Dispensing .......................................................................................................... 44 
8.3.3 
Administration Instructions ............................................................................... 44 
8.3.4 
Storage ............................................................................................................... 44 
8.4 
DEX Accountability ............................................................................................................. 45 
8.5 
Supply of Devices at the Site .............................................................................................. 45 
9 
STUDY PROCEDURES AND GUIDELINES 
45 
9.1 
Clinical Assessments ........................................................................................................... 45 
9.1.1 
Pregnancy Test ................................................................................................... 45 
9.1.2 
Demographics .................................................................................................... 45 
9.1.3 
Medical History .................................................................................................. 45 
9.1.4 
Concomitant Medications .................................................................................. 46 
9.1.5 
Vital Signs ........................................................................................................... 46 
9.1.6 
Physical Examination.......................................................................................... 46 
9.1.7 
Vascular Examination ......................................................................................... 46 
9.2 
Laboratory Measurements ................................................................................................. 48 
9.2.1 
Research Laboratory Measurements ................................................................. 48 
9.2.2 
Clinical Laboratory Measurements .................................................................... 48 
9.3 
Adverse Events ................................................................................................................... 48 
9.4 
Walking Impairment Questionnaire ................................................................................... 48 
9.5 
Treated Segment Registration............................................................................................ 49 
9.6 
Randomization.................................................................................................................... 49 
9.7 
DEX Infusion ....................................................................................................................... 49 
9.7.1 
Equipment .......................................................................................................... 49 
9.8 
Order of Operations ........................................................................................................... 49 
9.9 
Research MRI ...................................................................................................................... 51 
9.9.1 
Equipment .......................................................................................................... 51 
9.9.2 
Protocol .............................................................................................................. 51 
9.9.3 
Pre-Reintervention MRI ..................................................................................... 53 
9.10 Clinical Ultrasound ............................................................................................................. 53 


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10 SCHEDULE OF ASSESSMENTS 
54 
11 EVALUATIONS BY VISIT 
56 
11.1 Visit 1: Screening & Baseline (Day -30 to Day -1) ............................................................... 56 
11.2 Visit 2: Procedure (Day 0) ................................................................................................... 56 
11.3 Visit 3: Post-Operative Assessments (Day 1-7) .................................................................. 56 
11.4 Visit 4: 1 Month Follow-up (Day 30±7) .............................................................................. 57 
11.5 Visit 5: 6 Month Follow-up (Day 180±14) .......................................................................... 57 
11.6 Visit 6: 12 Month Follow-up (Day 365±30) ........................................................................ 57 
11.7 Visit 7: 24 Month Telephone Follow-up (Day 730±30) ...................................................... 57 
11.8 Visit 8: 36 Month Telephone Follow-up (Day 1095±30) .................................................... 58 
11.9 Early Withdrawal Visit ........................................................................................................ 58 
11.10 Unplanned Visit for Index Leg Reintervention ................................................................... 58 
11.11 Study Completion ............................................................................................................... 59 
12 ADVERSE EVENT REPORTING AND DOCUMENTATION 
59 
12.1 Adverse Events ................................................................................................................... 59 
12.2 Serious Adverse Events (SAE) ............................................................................................. 60 
12.2.1 
Serious Adverse Event Reporting ....................................................................... 60 
13 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
60 
13.1 Early Discontinuation/Withdrawal ..................................................................................... 60 
13.2 Replacement of Subjects .................................................................................................... 61 
14 PROTOCOL VIOLATIONS 
61 
15 DATA SAFETY MONITORING 
61 
16 STATISTICAL METHODS AND CONSIDERATIONS 
62 
16.1 Data Sets Analyzed ............................................................................................................. 62 
16.2 Analysis of Primary Endpoint ............................................................................................. 62 
16.3 Analysis of Secondary Endpoints ........................................................................................ 62 
16.4 Sample Size and Randomization ........................................................................................ 63 
17 DATA COLLECTION, RETENTION AND MONITORING 
65 
17.1 Data Collection Instruments ............................................................................................... 65 
17.2 Data Management Procedures .......................................................................................... 65 
17.3 Data Quality Control and Reporting ................................................................................... 65 
17.4 Archival of Data .................................................................................................................. 65 
17.5 Availability and Retention of Investigational Records ....................................................... 65 
17.6 Subject Confidentiality ....................................................................................................... 66 


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18 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
66 
18.1 Protocol Amendments ....................................................................................................... 66 
18.2 Institutional Review Boards and Independent Ethics Committees ................................... 66 
18.3 Informed Consent Form ..................................................................................................... 67 
18.4 Publications ........................................................................................................................ 67 
18.5 Investigator Responsibilities............................................................................................... 67 
APPENDIX 1.  SAMPLE COLLECTION & PROCESSING GUIDELINES 
69 
APPENDIX 2.  DATA MANAGEMENT 
70 
APPENDIX 3.  RESEARCH MRI ACQUISITION PARAMETERS 
71 
APPENDIX 4.  DEXAMETHASONE SODIUM PHOSPHATE MONOGRAPH 
72 
APPENDIX 5.  BULLFROG MICRO-INFUSION CATHETER IFU 
72 
APPENDIX 6. LUTONIX 035 DCB CATHETER IFU 
72 
APPENDIX 7. INPACT ADMIRAL DCB CATHETER IFU 
72 
APPENDIX 8. STELLAREX DCB CATHETER IFU 
72 
APPENDIX 9. WALKING IMPAIRMENT QUESTIONNAIRE (WIQ) 
72 
 
 
 


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LIST OF ABBREVIATIONS 
ABI 
Ankle-Brachial Index 
AE 
Adverse Event 
AUC 
Area Under the Curve 
CFA 
Common Femoral Artery 
CFD 
Computational Flow Dynamics 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
DCB 
Drug Coated Balloon 
DMC 
Data Monitoring Committee 
DEX 
Dexamethasone 
eGFR 
estimated Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
GBCA 
Gadolinium Based Contrast Agent  
GCP 
Good Clinical Practice 
GR 
Glucocorticoid Receptor 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFU 
Instructions For Use 
IL-1β 
Interleukin 1 Beta 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
LRNC 
Lipid Rich Necrotic Core 
LV 
Lumen Volume 
MCP-1 
Monocyte Chemotactic Protein 1 
MERGE 
Motion sensitized driven Equilibrium prepared Rapid Gradient Echo 
MRA 
Magnetic Resonance Angiogram 
MRI 
Magnetic Resonance Imaging 
NIH 
National Institutes of Health 
NHLBI 
National Heart, Lung, and Blood Institute 
NSF 
Nephrogenic Systemic Fibrosis 
OSI 
Oscillatory Shear Stress 
PI 
Principal Investigator 
PAD 
Peripheral Artery Disease 
POBA 
Plain Old Balloon Angioplasty 
PTA 
Percutaneous Transluminal Angioplasty 


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PWA 
Percent Wall Area 
PTX 
Paclitaxel 
PWV 
Percent Wall Volume 
SAE 
Serious Adverse Event 
SFA 
Superficial Femoral Artery 
SMC 
Smooth Muscle Cell 
TOF 
Time-of-Flight 
TVA 
Total Vessel Area 
TVV 
Total Vessel Volume 
WA 
Wall Area 
WV 
Wall Volume 
WIQ 
Walking Impairment Questionnaire 
WSS 
Wall Shear Stress 
WSSG 
Wall Shear Stress Gradient 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
TITLE 
INtima Versus Adventitia Drug Delivery to Elucidate Mechanisms of 
Restenosis: Magnetic Resonance Imaging (INVADER MRI) 
SPONSOR 
National Institutes of Health 
National Heart, Lung, and Blood Institute (NIH NHLBI) 
FUNDING 
ORGANIZATION 
NIH NHLBI 
NUMBER OF SITES 
2 
RATIONALE 
Peripheral artery disease (PAD) affects at least 12 million Americans 
annually with more than half a million patients undergoing an 
endovascular or surgical revascularization procedure for treatment of 
the disease. Unfortunately, about two-thirds of patients still have 
blockages in the leg arteries, even after these procedures.  
 
Advances in Magnetic resonance imaging (MRI) offer promise for 
understanding the mechanism of failure through insights into vessel 
wall composition, remodeling, and inflammation. Restenosis has a 
known relationship to inflammation. Advances in micro-catheter 
technologies offer the ability to deliver anti-inflammatory medications 
such as dexamethasone (DEX) directly to the adventitia.  
 
This study aims to investigate if patient-specific parameters affect 
angioplasty outcomes, if DEX has a biological effect on the vessel 
wall, and if this effect is through the reduction of inflammation. 
STUDY DESIGN 
Prospective, multi-center randomized Phase IV trial. 
PRIMARY OBJECTIVE 
The primary objective is to assess the mechanisms of vascular 
healing following balloon angioplasty treatment to stenotic arteries 
from atherosclerosis.  Vascular healing will be assessed by MRI 
determined percent wall volume change (PWV) from 24 hours post-
angioplasty to 12 months  
 
SECONDARY 
OBJECTIVES 
1. To determine whether DEX infusion will result in less 
inflammation as measured by blood (MCP-1, CRP, and IL-1β) 
and tissue imaging (Ktrans) markers of inflammation 
2. To determine whether patient-specific physiological factors 
correlate with vascular healing  
NUMBER OF 
SUBJECTS 
54 overall 
27 per site 
 
 


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SUBJECT SELECTION 
CRITERIA 
Screening Inclusion Criteria: 
1. Male or non-pregnant female ≥ 35 years of age 
2. Atherosclerotic, infrainguinal PAD 
3. Rutherford Clinical Category 2-6 
4. Stenosis detected by radiology that in the clinician’s opinion is 
the reason for the PAD symptoms 
5. Patient is willing to provide informed consent and comply with 
the required follow up visits, testing schedule, and medication 
regimen 
6. eGFR ≥ 30 and/or threshold established by the local 
Institutional Review Board or Committee of Human Research 
Procedural Inclusion Criteria: 
1. De novo atherosclerotic lesion qualifying for angioplasty 
2. A patent artery proximal to the index lesion. Concomitant 
inflow procedures, including open femoral artery 
endarterectomy and/or stenting of the iliac arteries, are 
permissible.  
3. >50% diameter stenosis of the superficial femoral artery 
and/or popliteal artery (between the profunda and 
tibioperoneal trunk) 
4. Reference vessel diameter ≥3 mm and ≤ 8mm 
5. Successful wire crossing of lesion 
6. Successful angioplasty of the index lesion or part of the index 
lesion, defined as ≤30% residual lumen stenosis compared 
with adjacent non-diseased lumen diameter, without flow-
limiting dissection 
 
Screening Exclusion Criteria: 
1. Any contraindication to receiving an MRI 
2. Pregnant, nursing, or planning on becoming pregnant in < 
2yrs 
3. Life expectancy of < 1 yr 
4. History of solid organ transplantation 
5. Patient actively participating in another investigational device 
or drug study 
6. History of hemorrhagic stroke within 3 months of index 
procedure 
7. Previous or planned surgical or interventional procedure 
within 30 days of index procedure 


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8. Chronic renal insufficiency with eGFR < 30 
9. Prior bypass surgery, stenting, atherectomy or angioplasty of 
the index lesion 
10. Inability to take required study medications 
11. Contra-indication or known hypersensitivity to dexamethasone 
sodium phosphate, contrast media, gadolinium, aspirin or 
Plavix 
12. Systemic fungal infection 
13. Acute limb ischemia 
14. Prior participation of the index limb in the current study 
(contralateral treatment is allowed) 
15. Patient is being treated with long-term steroids (not including 
treatment of a bronchial condition with inhaled steroids) 
Procedural Exclusion Criteria: 
1. Index lesions extending into the tibial trifurcation or above the 
profunda. Note: the outflow tibial artery can be treated 
concomitantly. Similarly, the common femoral artery can be 
treated concomitantly, either with open endarterectomy and 
patch angioplasty or with endovascular methods.  However, 
the index lesion cannot be contiguous with either the CFA or 
the tibial trifurcation. 
2. Circumferential calcification at index lesion, which in the 
judgment of the investigator would prevent penetration of the 
Micro-Infusion catheter needle through the vessel wall 
3. Inadequate distal outflow defined as no patent tibial arteries 
(>50% stenosis).  The outflow vessel can be established at 
the time of primary treatment 
4. Use of adjunctive therapies other than angioplasty. Chocolate 
balloons and/or scoring balloons are allowed, if used below 
reference diameter. 
DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Subjects will be on study for up to 36 months 
Screening:  up to 30 days 
Follow-up:  36 months 
The total duration of the study is expected to be 60 months.  3.5 
years for subject recruitment, twelve months for final subject follow-
up, and six months for final data clean-up.  
PRIMARY ENDPOINT 
The primary endpoint for this study will be percent wall volume (PWV) 
change of the treated segment from the 24-hour post-intervention 
MRI scan to 12 months between DEX treated and non-DEX (PTX or 
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The treated segment is defined as the length of vessel, 
encompassing the index lesion, that has undergone primary 
revascularization, from normal back to normal artery. 
STATISTICS 
Primary Analysis Plan 
The primary analysis will be an intention-to-treat (ITT) comparison of 
observed change in mean ΔPWV between treatment groups at 12 
months using a t-test. Because ΔPWV may be nonlinear in time, 
linear splines with knots at 24 hours, 1 month,6 months, and 12 
months will be used to fit the model. 
Multivariable regression models will be constructed to determine 
independent variables associated with ΔPWV controlling for 
demographic and anatomical variables, statin use, inflammatory 
markers, and smoking.  
We will also investigate effects by treatment received by constructing 
generalized linear models controlling for demographic, clinical, and 
anatomic variables. Predictors of PWV will be evaluated via 
univariate and multivariate regression analysis. 
Rationale for Number 
of Subjects 
The sample size for this study is based on the statistical hypothesis 
for the primary endpoint, observed change in mean ΔPWV between 
groups at 12 months.  
While there are no predicate serial studies of PWV changes in 
femoral artery restenosis following angioplasty to estimate the 
sample size, previous work on the progression of de novo 
atherosclerosis in similar sized peripheral arteries (carotids) forms the 
basis of this estimation.  
Based on the power calculations outlined in Sec 16.4, we estimate 
the need for 22 subjects per treatment assignment to detect a 2.7% 
difference in PWV at a power level of 80%.  
Assigning a 20% attrition rate due to loss to follow up and/or index 
lesion revascularization, 27 subjects will be enrolled per arm. 
Calculation is based on an unpaired t-test at a 5% significance level. 
 
 
 


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1 
BACKGROUND 
 
Population to be studied 
This is a randomized trial designed to explore the mechanisms of restenosis following balloon 
angioplasty.  This trial will evaluate subjects with peripheral artery disease who require an 
endovascular intervention of the femoropopliteal arterial segment (SFA/Popliteal) to restore 
blood flow to the leg. Peripheral artery disease (PAD) is a condition defined by extensive 
accumulation of atherosclerotic plaque below the distal aorta that reduces lower limb arterial 
perfusion and results in ischemia on demand noted as intermittent claudication or ischemic rest 
pain or ulceration known as critical limb ischemia. The SFA is the most common peripheral 
artery affected in patients with PAD and percutaneous transluminal angioplasty (PTA) is the 
most common mode of treatment. PTA may be used alone or in combination with another 
treatment modality such as a stent or debulking device but it serves as the primary treatment 
platform for restoring blood flow to the leg. There is an estimated 800,000 SFA procedures 
performed worldwide annually, representing a market of approximately $1.5 billion. Roughly 
450,000 of those cases are performed in the United States with an overall market growth 
estimated in the mid-single digits.  
 
The Current Treatment of PAD and the Epidemic of Restenosis 
Balloon angioplasty (PTA) is the cornerstone of endovascular treatment of arteries.  A balloon is 
used to deploy, or used for post-dilation of, vascular stents (balloon expandable). PTA is also 
used in conjunction with debulking therapy. However, until recently PTA was rarely used as a 
single modality to treat arterial stenosis except in the short lesions, (TASC II A, < 5 cm), due to 
the high rate of binary restenosis 67% (primary patency 33%, Krisna Rocha Singh). This high 
rate of failure for PTA was also noted in the control arm of the Zilver PTX study which evaluated 
a paclitaxel covered stent compared to balloon angioplasty alone.   More recently, better PTA 
techniques have resulted in decreased restenosis rates of PTA to about 50%.  This 
improvement occurred as a result of 1) sequential dilation of the stenosis with progressively 
larger balloons, 2) slower inflation of each balloon to reach nominal dilation, and 3) longer 
inflation times of each balloon at nominal pressure often exceeding 2 minutes, and limiting the 
inflation atmospheres and barotrauma.   Further improvement was attained by adding a 
proprietary matrix to the balloon surface to allow paclitaxel (PTX) to be delivered into the artery 
wall.  These are known as drug-coated balloons (DCB) and there are 3 approved by the FDA: 
the INPACT Admiral DCB (Medtronic Inc, Minneapolis MN), the Lutonix 035 DCB (C. R. Bard 
Inc, Covington GA) and the Stellarex DCB (Spectranetics Corp, Colorado Springs CO). In 
general, the effectiveness and safety profiles of these devices are not substantially 
different. Primary patency rates in selected lesions can approach 75% with these devices 
under trial conditions (<10cm lesions, claudication patients) and they are reported to attain 
clinically-driven target lesion revascularization (cd-TLR), similar to stents.  One concern about 
DCBs is that the depot drug delivery is at the intima surface.  To reach the deeper layers of the 
arterial wall the drug must diffuse down its concentration gradient in accordance with Fick’s Law 
𝜕
𝜕𝑡=-D2, where 
𝜕
𝜕𝑡 is the diffusion flux, D is the diffusion coefficient, 2 is the Laplacian 
operator, and  is the amount if drug in dimensions mol/mm3. =(x,t) is a function which 
depends on location x and time, t, in seconds. Therefore, the initial concentration of the drug will 
be highest in the intima until, over time, the drug diffuses evenly through the vessel wall. This 
potentially could inhibit re-endothelialization of the treated area and cause increased restenosis 
after the drug is no longer retained in the wall.  This would be referred to as late catch up where 
the treatment arm would catch up to the control arm after a specified period of time.  In the 


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coronaries first generation paclitaxel stents have been known to cause late stent thrombosis 
due to delinquent endothelialization over the stent struts.  This phenomenon necessitates 
prolonged dual antiplatelet therapy (DAPT). Because of these reasons and others, as will be 
explained below, the adventitia is an alternative to the intima in drug delivery.    
It is desirable to avoid stents in leg arteries if possible as vascular stents are susceptible to 
micro-abrasion, friction, and fatigue.1 Constant micro-forces associated with daily ambulation 
lead to stent fractures and restenosis. Once restenosis occurs within a stent, it is very difficult to 
regain and maintain patency of the artery.2 Further, future therapy options such as bypass 
surgery become limited due to the stent implant and many consider this to “burn bridges” for 
future revascularization options. In fact, more bypass surgery is now being performed after 
failed stenting than for de novo lesions, and studies show that bypass surgery performed after 
failed stenting have worse outcomes.3 This truly is an epidemic of restenosis.4  
  
The Tunica Adventitia is an Active Participant in Arterial Restenosis 
Once thought to be a passive layer of the arterial wall, the tunica adventitia is now known to be 
extremely metabolically active and capable of regulating vascular hemostasis.8, 9 The adventitia 
contains a rich variety of immune cells, including T cells, B cells, dendritic cells, progenitor cells, 
and fibroblasts that can differentiate into myofibroblasts.10-13 There is extensive microvascular 
architecture, which can traffic inflammatory cells into the vessel wall following injury.14 Balloon 
angioplasty experiments in pig coronary arteries demonstrate that the adventitia is the primary 
site for acute inflammation after mechanical vascular injury.15 The hypothesis that these cells 
contribute to intimal hyperplasia and restenosis is supported by several lines of evidence in 
animals. In porcine models of angioplasty, injections with 5-bromo-2-deoxyuridine (BrDU) have 
identified proliferating cells located in the adventitia as early as two days following injury which 
appear to migrate into the inner vessel in subsequent time points.16, 17 Shi et al. noted that 
adventitial myofibroblasts contribute to increases in wall volumes via synthesis of extracellular 
matrix and collagen and migration to the intima following balloon injury.18, 19 Finally, utilizing in 
vivo reporter gene transfer studies into adventitial cells, Siow et al. demonstrated adventitial 
myofibroblast migration into the media and intima following balloon injury.20 Collectively, these 
studies support an “outside-in” hypothesis of vascular inflammation and provide important 
biological rationale to target the adventitia to reduce restenosis.  
 
Restenosis is an Inflammatory Process 
Balloon angioplasty produces a barotraumatic (8-15 atmospheres) mechanical injury, resulting 
in stress signals and homing of inflammatory cells into the artery.15, 21, 22 We have shown in a 
porcine balloon injury model that inflammatory cells peak in the adventitia early after injury and 
then slowly decline over the next 28 days.23 P-selectin and vascular cell adhesion molecule-1 
(VCAM-1) is up-regulated in vasa vasorum endothelial cells soon after balloon injury thus 
providing a means for increased inflammatory cell trafficking.15 Vasa vasorum expansion occurs 
in de novo atherosclerosis and following balloon injury, and drugs targeting neoangiogenesis 
are potential therapies to reduce restenosis.24-26 Microcomputed tomography imaging 
demonstrates a direct correlation between the computed tomography-determined extent of 
adventitial angiogenesis and the extent of intimal hyperplasia.27-29 In addition to an increase in 
microvascular density, vascular inflammation is also associated with increased adventitial 
microvasculature permeability. Examination of atherosclerotic coronary arteries from autopsy 
specimens show that vasa vasorum invading the media from the adventitia lack mural coverage 
and inter-endothelial contact at endothelial junctions is either incomplete or absent in 76% of the 
vessels.24, 30, 31 These histological factors make them inherently more permeable.30 MRI 
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which is a function of both the permeability and the surface area of the adventitial vasculature. 
This highly validated technology forms the basis of in vivo assessment of vascular inflammation 
and the therapeutic response of mitigating drugs. 
  
Glucocorticoid Receptor as a Therapeutic Target for Vascular Injury 
The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily of 
ligand-activated transcription factors. Activation of GR results in binding of receptor homodimers 
to glucocorticoid response elements in target genes, leading to initiation or repression of 
transcription. Cortisol is the naturally occurring ligand to the GR and unbound fraction of cortisol 
can diffuse through the cell wall to interact with the cytosolic receptor. DEX is a synthetic 
glucocorticoid with 25-fold higher binding affinity to GR than cortisol and no mineralocorticoid 
activity.32 GRs are present in vascular smooth muscle and endothelial cells.  
DEX may inhibit restenosis in several possible ways as it is known to repress angioplasty-
induced immune response programs by inhibiting inflammatory transcription factors, NFκB and 
AP-1, and their downstream mediators.33, 34 In vitro and preclinical studies have demonstrated 
that DEX down-regulates monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor α 
(TNF-α), and interleukin 1β in nano- and micromolar concentrations in vascular SMCs.35, 36 IL-1β 
is known to stimulate SMC proliferation and to induce basic fibroblast growth factor in vascular 
SMCs. Intra-muscular DEX treatment demonstrated decreased macrophages present in 
atherosclerotic lesions and inhibition of macrophage accumulation following balloon angioplasty 
in cholesterol fed rabbits.37 DEX has been shown to inhibit the proliferation and migration of 
smooth muscle and inflammatory cells as well as adventitial myofibroblasts through effects on 
thymidine kinase, matrix metalloproteinases, and retinoblastoma protein.38-40 DEX inhibits the 
autocrine induction of PDGF-α chains – a known potent SMC mitogen. DEX induces the anti-
inflammatory proteins annexin 1 and mitogen activated kinase phosphatase 1, while repressing 
the transcription of pro-inflammatory molecules such as cyclooxygenase 2.32 DEX also markedly 
inhibits the production of ROS by inflammatory cells in vivo. DEX increases the immune-
modulatory cytokine IL-10, which is known to inhibit the pro-inflammatory TH1 cells.41 DEX also 
inhibits collagen production and extracellular matrix synthesis, which is responsible for late 
lumen loss following PTA42, 43 and thought to be due to negative (shrinkage) arterial 
remodeling.44 The latter is pertinent to the present application as Derksen et al., noted that 
fibrotic plaques rich in collagen and SMCs were associated with more constrictive remodeling 
following PTA.45  
Clinical studies demonstrate that DEX treatment has shown an ability to mitigate the initial 
inflammatory response to vascular injury. For example, patients with unstable angina treated 
with DEX-eluting stents had lower plasma concentrations of CRP, ICAM- 1, and VCAM-1 post-
intervention compared to patients treated with a bare metal stent.46, 47 Two coronary studies 
independently tested the use of the BiodivYsio Matrix Lo stent loaded with DEX versus the 
same stent platform without drug as control. Han et al. randomly assigned a total of 92 patients 
to the DEX or control group.48 The use of DEX-eluting stents was the only independent predictor 
for the major adverse cardiac event at 12 months (relative risk 0.20, 95% CI 0.06-0.68, P = 
.009) and binary restenosis at 6 months (relative risk 0.17, 95% CI 0.05-0.60, P = .006) by 
multivariate analysis. In a similar study, Konig et al. randomly assigned 120 patients with acute 
coronary syndrome to revascularization using the Dexamet stent or BMS.49 The target lesion 
revascularization rate was lower in the Dexamet group (16.67% vs 33.33% patients; P = .031) 
and angiography revealed improved lumen restoration in the Dexamet stent group (late lumen 
loss, 0.55 ± 0.65 vs. 1.07 ± 0.92 mm P = .001).  
 
 
 


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1.1 
Overview of Clinical Studies 
 
Pharmacokinetic Studies of Dexamethasone In Porcine Carotid Arteries 
The DEX pharmacokinetic (PK) profile has been demonstrated in a study of the Micro-Infusion 
catheter delivery into the adventitial tissue of porcine carotid arteries, Figure 1. In this study, 
therapeutic levels in the range of 10 to 100 nM were seen at 7 days after infusion of 1 mg.  
 
Figure 1. Dexamethasone levels measured in pig carotid arteries 1, 4, and 7 days after 
confirmed delivery of 1 mg dexamethasone sodium phosphate in 3 ml volume to the carotid 
artery adventitia with the Bullfrog Micro-Infusion catheter. Each line represents a single artery.  
While the exact duration of the therapeutic window to treat vascular inflammation is unknown, 
based on preclinical PTA models, the optimal time frame is 7-30 days. This is supported by 
another porcine preclinical study employing femoral artery balloon injury model,23 where it was 
determined that the adventitial leukocyte infiltration is decreased by 60% of peak value within 28 
days, Figure 2. Clinical experience with steroids also support this time frame as a pulsed, 
intensive therapy for 3-7 days is sufficient to treat most soft tissue inflammatory processes.  
 
 
Results of the safety and feasibility study 
We conducted a Phase 1, first-in-man safety and feasibility study of DEX delivery to femoral and 
popliteal adventitia (NCT 01507558) with the Bullfrog Micro-Infusion
 
catheter (Mercator 
MedSystems, Emeryville, CA).7 Patients with SFA stenosis or occlusions up to 15 cm were 
eligible for this study. Mean lesion length was 8.9±5.3 cm, N=20 with 80% located in the distal 
SFA/popliteal artery, which has traditionally been considered a no stent zone. The mean 
number of infusions required to completely treat each lesion was 3.0 ± 1.3, minimum 1 and 
maximum 6. The mean volume injected was 3.8 ± 1.9 ml which contained a mean of 12.1 ± 6.1 


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mg of DEX and .80 ± .4 ml of contrast. This equated to a mean of 1.6 ± 1.1 mg of DEX per 
centimeter of lesion length. The minimal dose was 3.2 mg and the maximal dose a patient 
received was 24 mg of DEX. Accordingly, there was a positive linear correlation between the 
amount of DEX received and length of lesion treated, R2=.27, P=.019.  
Procedural safety was seen in 100% of patients, with a lack of drug-related or device-related 
serious adverse events or major adverse limb events within 30 days of the procedure. At the 6 
month follow up, two subjects had experienced a target lesion restenosis, as defined by a peak 
systolic velocity ratio (PSVlesion/PSVreference) > 2.4 or occlusion noted by ultrasound for a 
90% patency rate. The ankle-brachial index improved from 0.67 ± 0.17 pre-op to 0.88 ± 0.18 at 
6 months (P<0.003) and Rutherford classification scores decreased from 3.1 ±. 71 to 0.5 ± .70, 
p<.001 indicating improved hemodynamic and clinical benefit with DEX.  
 
Update on the DANCE single arm multi-institutional study 
 
Figure 3. Data from the ongoing DANCE trial.  Baseline and 24 hours blood markers of 
inflammation were built in as a surrogate endpoint.  From left to right, Schillinger CRP levels in 
patients undergoing peripheral artery endovascular treatment, data generated from the DANCE-
Pilot, and DANCE PTA and DANCE ATX arms.  CRP- C reactive protein, ATX-atherectomy 
 
Markers of technical success using the Micro-Infusion catheter 
The Micro-Infusion catheter (Mercator MedSystems, Emeryville, CA), a FDA 510K-cleared 
device, is a rapid- exchange, wire-guided catheter with a balloon-sheathed 1.5 mm long, 35-
gauge (140 μm diameter) needle that delivers infusions to adventitial and perivascular tissues. 
Using standard angioplasty inflation equipment, the balloon is inflated exposing the needle. 
When the balloon contacts the arterial wall opposite the needle tip, contact pressure forces the 
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Figure 4. The fluoroscopy picture to the left demonstrates three 
separate infusions of DEX and contrast along the artery wall. A 
.014 wire can be seen within the lumen of the artery and the 
Glow ‘N Tell tape provides a reference. After about three 
minutes, further longitudinal diffusion within the adventitia 
obscures the border between the separate infusions.  
 
The contact pressure of the balloon against the artery wall is limited to 2 atmospheres by a 
pressure release valve, which prevents damage to the artery wall. A mixture of infusate and 
contrast (4:1) is then delivered under fluoroscopic guidance at a rate of 1 ml/min to the 
adventitia and perivascular tissues. When the infusion is complete, the balloon is deflated, 
sheathing the needle, and allowing the catheter to be withdrawn. The drug contrast admixture 
can be seen as “staining” along the blood vessel providing visual confirmation of successful 
drug delivery, Figure 4 (left). It is our experience that a single injection produces 360° delivery of 
drug around the circumference of the vessel coverage and extends approximately 1-2 cm 
proximally and distally from the point of injection. Thus, a single injection circumferentially treats 
3-4 cm of artery. This catheter has been shown to be one of the most efficient modes of drug 
delivery as it maximizes tissue concentration while minimizing off-target drug deliver.50 The 
micro-infusion catheter has been used to deliver stem cells into the adventitia of coronary 
arteries to improve myocardial function following infarction.51  
 
Drug Coated Balloon 
In this study, angioplasty must be carried out with an FDA-approved DCB balloon catheter for 
treatment of arteries and veins according to the manufacturer’s instructions for use. The 
INPACT SFA, LEVANT 2, ILLUMENATE PIVOTAL and ILLUMENATE EU trials were 
paramount Investigational Device Exemption (IDE) safety and effectiveness trials.   
The LEVANT 2 study was a prospective, multicenter, single-blind, randomized, safety and 
efficacy study which randomized in a 2:1 assignment of 316 subjects treated with Lutonix DCB 
and 160 subjects treated with POBA.  Balloon angioplasty had to be successful prior to 
enrollment.  Only 11 patients were excluded due to unsuccessful balloon angioplasty.  
Physicians evaluating the patients in follow up were blinded to the treatment assignment of the 
patient.  The study population consisted mostly of Rutherford 2 and 3 patients.  Freedom from 
the primary safety endpoint (composite all cause 30 day death, device related death at 365 
days, index limb amputation, target vessel revascularization) evaluated graphically by Kaplan-
Meier analysis (ITT) was 86.7% in the test DCB arm and 81.5% in the control arm.  The primary 
effectiveness endpoint was freedom from binary restenosis or target lesion revascularization 
was 73.5% in the DCB text arm and 56.8% in the control arm.   
 


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The INPACT SFA study was a multicenter, single-blind, randomized controlled safety and 
efficacy study with a 2:1 randomization scheme that included 220 subjects treated with INPACT 
DCB and 111 subjects treated with POBA. Randomization occurred once the lesion was 
crossed and successful initial balloon angioplasty was performed.  It is not known how many 
subjects were excluded due to unsuccessful balloon angioplasty. Freedom from the primary 
safety endpoint, freedom from device or procedural related death at 30 days or index limb 
amputation or target vessel revascularization, occurred in 95.6% in the test DCB group and 
76.6% in the control group.  Primary patency was 78.4% in the DCB test group and 49.5% in the 
control group. Although the subject was blinded to the treatment provided, the local research 
team was not. All primary endpoint events were adjudicated by a core laboratory and Clinical 
Events Committee, both of whom were blinded to the treatment provided. 
 
The ILLLUMENATE PIVOTAL study was a multicenter, single-blind, randomized controlled 
safety and efficacy study with a 2:1 randomization scheme that included 200 subjects treated 
with Stellarex DCB and 100 subjects treated with POBA. Randomization occurred after 
successful lesion crossing and initial balloon angioplasty with 11 subjects excluded due to 
unsuccessful initial balloon angioplasty.  Although the subject was blinded to the treatment 
provided, the local research team was not. All primary endpoint events were adjudicated by a 
core laboratory and Clinical Events Committee, both of whom were blinded to the treatment 
provided. Freedom from the primary safety endpoint (composite of 30-day freedom from device 
and procedure-related death and 1 year freedom from target limb major amputation and CD-
TLR) was 92.1% in the DCB group and 83.2% in the control group. Freedom from primary 
effectiveness endpoint (restenosis or CD-TLR at 1 year) was 76.3% in the DCB group and 
57.6% in the control group. 
 
All DCBs lose paclitaxel during the delivery and inflation of the balloon. The ILLLUMENATE 
PIVOTAL trial included a 25 subject pharmacokinetic substudy that found plasma paclitaxel was 
measurable in all subjects at 24 hours after Stellarex DCB treatment and was no longer 
detectable in all but 1 subject at 7 days. It appears that the proprietary paclitaxel formulation and 
excipient combination for each brand of DCB determines the nature of the shed paclitaxel. In a 
comparison of healthy swine femoral arteries treated with INPACT or Lutonix DCBs, there was 
measurable paclitaxel in the downstream (non-target) tissues at 90 days, with significantly 
higher levels measured after INPACT DCB. In addition, embolized “crystalline-like material” was 
seen in the downstream tissue after treatment with INPACT but not Lutonix DCB. 
 
In December 2018, a meta-analysis of published randomized clinical trials demonstrated a 
significantly increased late (3-5 year) mortality rate in subjects treated with paclitaxel-coated 
devices for femoropopliteal peripheral artery disease. In response to this meta-analysis, the 
FDA has issued 3 letters advising health care practitioners and convened a "public meeting of 
the Circulatory System Devices Panel of the Medical Devices Advisory Committee" from June 
19-20, 2019. An FDA "Letter to Healthcare Providers" from August 9, 2019 summarized the 
FDA's analysis of available trial data with the conclusion that "the crude mortality rate at 5 years 
was 19.8% (range 15.9% - 23.4%) in patients treated with paclitaxel-coated devices compared 
to 12.7% (range 11.2% - 14.0%) in subjects treated with uncoated devices. The relative risk for 
increased mortality at 5 years was 1.57 (95% confidence interval 1.16 – 2.13), which 
corresponds to a 57% relative increase in mortality in patients treated with paclitaxel-coated 
devices. A meta-analysis performed by VIVA (Vascular InterVentional Advances) Physicians of 
patient-level data provided by manufacturers reported similar findings with a hazard ratio of 1.38 
(95% confidence interval 1.06 - 1.80)." 
 
 


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Dynamic Contrast Enhanced-MRI Measurement of Adventitial Inflammation 
The tunica adventitia thickness of human peripheral arteries can be visualized with imaging 
modalities with sub-millimeter spatial resolution. For example, MRI can detect this layer 
following contrast injection due its ring-like enhancement. We have demonstrated the feasibility 
of applying dynamic contrast-enhanced MRI (DCE-MRI) with kinetic modeling to study 
adventitial perfusion, which generates physiological parameters of vasa vasorum.52 
Characterization of microvessel density is pertinent to the present application as adventitial 
inflammation and restenosis is associated with increased microvessel density necessary to 
support the increase in wall volume. We have shown in a porcine balloon injury model that 
microvessels were associated with restenosis.23 In validation studies in individuals with carotid 
stenosis, Ktrans was positively and significantly correlated with plasma CRP, thus providing an in 
vivo link between vascular wall inflammation and a blood marker of inflammation. Human 
validation histologic studies were also completed in patients having DCE-MRI scans prior to 
carotid endarterectomy. These studies demonstrated correlation of Ktrans and endarterectomy 
specimen neovasculature (R=0.41, P=.04) and macrophages (R=0.49, P=.01) supplied by vasa 
vasorum.53  
DCE-MRI has also been used to provide information on the therapeutic effect of drugs on the 
vascular wall. In a study evaluating the effects of intensive lipid therapy targeting low density 
lipoprotein to below 60 mg/dl in subjects with extant cardiovascular disease, there were 
significant differences in adventitial Ktrans at 12 months after lipid therapy (0.067 ± 0.028 min-1) 
compared with baseline (0.085 ± 0.037 min-1, p=.02).  
 
 
Figure 5. Left: Kinetic analysis of dynamic contrast enhanced MRI of carotid atherosclerosis 
yields a parametric image “vasa vasorum” displaying the value of fractional blood volume (νp) in 
red and transfer constant (Ktrans) in green. The rapid transfer in the vessel adventitia is indicated 
using yellow arrows. Right: Image is derived from kinetic modeling of changing intensity in serial 
images coinciding with contrast agent.  
 
Computational Fluid Dynamics 
Balloon angioplasty induces barotrauma (8-16 atmospheres) to the artery to redistribute the 
arterial wall mass, expand the arterial volume, with the goal to increase the lumen volume of the 
treated segment. This results in luminal irregularities, dissections, and residual stenosis within 
the artery. We propose that the resulting flow disturbances and shear stress gradients 
predispose to areas of restenosis due to increased wall thickening or negative remodeling. 
Surprisingly, there has been relatively little attention given to serial changes in blood flow and 
shear stress following angioplasty in the leg. CFD methodologies developed by our group are 


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pertinent to the present application.54-56 To examine the relationship between arteriovenous 
fistula remodeling and flow parameters, we have conducted serial CFD-derived flow analysis 
that was carried out at three time points: 5 days, 30 days, and 90 days following creation of the 
anastomosis. Non-contrast enhanced time-of-flight (TOF) magnetic resonance angiogram 
(MRA) datasets were used to acquire patient-specific geometries at each time point. Phase 
contrast magnetic resonance velocimetry (PC-MRV) measurements were obtained at each 
imaging session and used to prescribe time- dependent velocity boundary conditions for the 
computational models. CFD simulations were carried out using the methodology described 
below. Velocity fields and wall shear stress (WSS) distributions obtained at each time point were 
then compared. The computational results in Figure 5 show that the size of the vessels 
increased and the WSS values substantially reduced with the maturation of the fistula.  
 
Plaque compositional analysis and arterial remodeling assessment with MRI 
It is unlikely that one specific type of therapy will be suited for every SFA plaque type. For 
example, Derksen et al. determined that femoral plaques with more fibrous tissue had higher 
rates of restenosis. Therefore, knowledge of plaque composition and adventitial perfusion by 
MRI may help guide the type of therapy. MRI has been shown to provide an accurate virtual 
histological map of vascular plaques in femoral and carotid arteries based on pixel signal 
intensity (see section below) using multicontrast MRI.57,58 In prior studies, we have matched 
carotid endarterectomy histology sections via landmarks to MRI images obtained in vivo prior to 
surgery to ascertain the sensitivity and specificity of MRI tissue characterization.59,60 For plaques 
> 2 mm2, in vivo assessment of plaque composition can be accomplished with high sensitivity 
(79% to 95%) and moderate to high specificity (76% to 91%).61 We have also examined the 
inter- and intra- reader reproducibility for detecting tissue areas with respect to total vessel area. 
The interclass correlation coefficient (ICC) for lipid rich necrotic core (LRNC), calcification, and 
fibrous tissue was between .88 and .95.62,63 In this application, we will characterize SFA plaque 
composition and associate each with response to DEX or PTX (control) treatment.  
1.2 
Literature References 
1. Tzafriri AR, Vukmirovic N, Kolachalama VB, Astafieva I, Edelman ER. Lesion complexity 
determines arterial drug distribution after local drug delivery. J Control Release. 
2010;142:332-338  
2. Tosaka A, Soga Y, Iida O, Ishihara T, Hirano K, Suzuki K, Yokoi H, Nanto S, Nobuyoshi M. 
Classification and clinical impact of restenosis after femoropopliteal stenting. Journal of the 
American College of Cardiology. 2012;59:16-23  
3. Goodney PP, Beck AW, Nagle J, Welch HG, Zwolak RM. National trends in lower extremity 
bypass surgery, endovascular interventions, and major amputations. J Vasc Surg. 
2009;50:54-60  
4. Owens CD. Commentary: Is the drug-eluting balloon the answer to the epidemic of 
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balloons-and-paclitaxel)] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2 
STUDY RATIONALE 
The fundamental hypothesis of this trial is that inhibition of inflammation at the site of 
injury will result in improved vascular healing and a sustained patent artery.  
This trial is designed to explore the mechanism of restenosis by using two alternative 
approaches to drug delivery, intimal-based antiproliferative (paclitaxel) and adventitial-based 
anti-inflammatory (Dexamethasone). Safety concerns about paclitaxel have halted that 
treatment arm in favor of plain balloon angioplasty. Angioplasty creates a mechanical injury to 
the atherosclerotic vascular wall resulting in an inflammatory response as a multitude of growth 
factors and cytokines, catalysts for cellular proliferation and restenosis, are released. 
Subsequent restenosis is related to the magnitude of the inflammatory response which is more 
pronounced in the femoral artery than in other vascular beds. Clinical trials of therapies to 
suppress vascular inflammation were initially successful, but were not fully developed in favor of 
anti-proliferative drugs, which have been highly successful in the coronary arteries, but not in 
leg arteries. Hence, the hypothesis that inhibition of vascular inflammation at the time of 
treatment can improve outcomes remains to be tested. Information on the healing response of 
the vessel wall following treatment is limited. Duplex ultrasound and quantitative angiography 
are sensitive to changes in the vessel lumen but provide no information on the vessel wall or 
remodeling. Recent advances in magnetic resonance imaging (MRI) with black-blood and multi-
contrast imaging techniques now offer a non-invasive means to evaluate the geometric and 
compositional morphology of the vessel wall at sub-millimeter resolution. Further insights into 
the vascular wall can be obtained with dynamic-contrast imaging techniques, which is capable 
of providing information on vessel wall perfusion arising from adventitial vasa vasorum. Thus, 
modern MRI affords deep structural and physiological insights into the vasculature and is ideally 
suited for serial in vivo studies to monitor the biologic response to therapy.    
  
2.1 
Risk / Benefit Assessment 
2.1.1 Anticipated Clinical Benefits 
In this trial, balloon angioplasty of the superficial femoral or popliteal artery will be followed with 
either: 
1. an adventitial infusion of dexamethasone sodium phosphate (USB, 4mg/mL) 
or  
2. no further treatment. 
There are no guaranteed benefits for subjects participating in the trial.   
2.1.2 Anticipated Adverse Events to balloon angioplasty of the SFA 
• 
Additional intervention 
• 
Allergic reaction to drugs or contrast 


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• 
Aneurysm or pseudoaneurysm 
• 
Arrhythmias 
• 
Embolization 
• 
Hematoma 
• 
Hemorrhage including at the puncture site 
• 
Hypotension/hypertension 
• 
Inflammation 
• 
Occlusion 
• 
Pain or tenderness 
• 
Pneumothorax or hemothorax 
• 
Sepsis/infection 
• 
Shock 
• 
Stroke 
• 
Thrombosis 
• 
Vessel dissection, perforation, or rupture 
2.1.3 Possible Risks of Participation in this Clinical Trial 
2.1.3.1 Procedural Risks of Adventitial Infusion 
Likely: (likelihood >5%) 
• 
Irritation or extravasation of blood at the perivascular injection site – typically mild and 
self-limited. Less damage than balloon angioplasty or atherectomy. 
• 
Perivascular air injection – due to incorrect preparation of catheter for injection; 
harmless, involves a volume of <1.5mL and is typically self-limited (air is reabsorbed). 
• 
Device balloon rupture – due to incorrect preparation of the device balloon; low 
frequency event in prior device use and testing as there is a pressure relief valve to 
prevent over-inflation of the device balloon; there are no adverse effects due to simple 
balloon rupture (device is discarded after removal from the patient). 
Rare: (likelihood <1%) 
• 
Vessel spasm – due to incorrect catheter sizing for target vessel; usually self-limited, but 
may require further treatment (balloon angioplasty) if severe. 
• 
Vessel dissection – due to incorrect catheter sizing for target vessel, excessive vessel 
wall thickness or mis-administration of medication; may require further treatment 
(balloon angioplasty or stent) if severe. 
• 
Vessel thrombosis – due to incorrect catheter sizing for target vessel or prolonged 
inflation of catheter balloon; may require further treatment (balloon angioplasty, stent, 
embolectomy, thrombolysis) if severe. 
• 
Distal emboli – due to incorrect catheter sizing for target vessel or disruption of vessel 
wall plaque; may require further treatment (embolectomy, thrombolysis) if severe. 


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Extremely Rare: (likelihood <0.1%) 
• 
Arteriovenous fistula – complication of perivascular injection; extremely rare given 
needle length and diameter; may require further treatment (stent) if severe. 
• 
Pseudoaneurysm – bleeding complication at site of perivascular injection, extremely rare 
given needle length and diameter; may require further treatment if severe. 
• 
Device balloon fragmentation with emboli – device failure, extremely rare event in prior 
device use and testing as there is a pressure relief valve to prevent over-inflation of the 
device balloon; may require further treatment (embolectomy, thrombolysis) if severe. 
• 
Device component separation - due to incorrect use of the device or manufacturing 
failure; rare event in prior device use testing as there is a pressure relief valve to prevent 
over-inflation of the device balloon; may require further treatment (embolectomy) if 
components embolize. 
2.1.3.2 Risks of Dexamethasone 
The Contraindications, Warnings, Precautions, Adverse Reactions and Overdosage sections of 
the Dexamethasone Sodium Phosphate Injection, USP, package insert should be consulted 
prior to administration of the drug. 
We plan to administer a single dose of dexamethasone in the perivascular space. Therefore, we 
expect the risk of systemic adverse effects typically associated with repeated, long-term, supra-
physiologic doses of dexamethasone will be very low. This expectation is based on the following 
data: 
1. Delivery of dexamethasone (DEX) will be localized to the perivascular tissues. Thus we 
expect the pharmacokinetics to be similar to the local administration of dexamethasone 
in soft tissue. A study comparing adventitial drug delivery of DEX vs. a drug-infusion 
balloon vs. intravenous administration of DEX in swine coronary arteries found that 
adventitial delivery was the only method with a high-concentration of study drug in the 
target tissue (myocardium) and negligible levels in liver, lungs, blood or urine [50]. 
2. Each infusion of dexamethasone in the range of 2 to 7.5 mL (1.6 mg dexamethasone per 
1 cm of target artery, with a total dose of 6.4 to 24 mg for expected treated segment 
lengths of approximately 4-15 cm) is within the common dose range of dexamethasone 
for adults per the manufacturer’s dosing instructions. 
Likely: (likelihood >5%) 
• 
None 
Less Likely: (likelihood <5%) 
• 
Hyperglycemia, particularly in patients with diabetes - effect is likely transient 
(<24hrs), possible need for increased insulin or oral hypoglycemic agents. 
Rare: (likelihood <1%) 
• 
Hypertension - likely transient, possible need for increased antihypertensive therapy. 
Extremely Rare: (likelihood <0.1%) 
• 
Allergic reaction - typically in response to preservatives in the medication. Can range 
from allergic dermatitis to severe, life-threatening anaphylactic reactions supportive 
care and monitoring. Dexamethasone will be administered in the OR with the patient 
under observation by both the surgeon and anesthesiologist. 


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• 
Vessel wall necrosis - multiple studies with dexamethasone eluting stents in lab 
animals and humans have not found evidence of vessel wall necrosis (see 
background studies) but this is a theoretical risk that would require further 
intervention (stenting) to treat. 
• 
Fluid and electrolyte disturbances: sodium retention, fluid retention, congestive heart 
failure in susceptible patients, potassium loss, hypokalemic alkalosis, or 
hypertension. 
• 
Musculoskeletal: muscle weakness, steroid myopathy, loss of muscle mass, 
osteoporosis, vertebral compression fractures, aseptic necrosis of femoral and 
humeral heads, pathologic fracture of long bones, or tendon rupture. 
• 
Gastrointestinal: peptic ulcer with possible subsequent perforation and hemorrhage, 
perforation of the small and large bowel, particularly in patients with inflammatory 
bowel disease, pancreatitis, abdominal distention, or ulcerative esophagitis. 
• 
Dermatologic: impaired wound healing, thin fragile skin, petechiae and ecchymosis, 
erythema, increased sweating, may suppress reactions to skin tests, burning or 
tingling, especially in the perineal area (after I.V. injection), or other cutaneous 
reactions, such as allergic dermatitis, urticaria, angioneurotic edema. 
• 
Neurologic: convulsions, increased intracranial pressure with papilledema 
(pseudotumor cerebri) usually after treatment, vertigo, headache, or psychic 
disturbances. 
• 
Endocrine: menstrual irregularities, development of cushingoid state, suppression of 
growth in children, secondary adrenocortical and pituitary unresponsiveness, 
particularly in times of stress, as in trauma, surgery, or illness, decreased 
carbohydrate tolerance, manifestations of latent diabetes mellitus, increased 
requirements for insulin or oral hypoglycemic agents in diabetics, or hirsutism. 
• 
Ophthalmic: posterior subcapsular cataracts, increased intraocular pressure, 
glaucoma, or exophthalmos. 
• 
Metabolic: negative nitrogen balance due to protein catabolism. 
• 
Cardiovascular, myocardial rupture following recent myocardial infarction (see 
WARNINGS in drug labeling). 
• 
Other: anaphylactoid or hypersensitivity reactions, thromboembolism, weight gain, 
increased appetite, nausea, malaise, or hiccups. 
• 
The following additional adverse reactions are related to parenteral corticosteroid 
therapy: rare instances of blindness associated with intralesional therapy around the 
face and head, hyperpigmentation or hypopigmentation, subcutaneous and 
cutaneous atrophy, sterile abscess, infection, postinjection flare (following intra-
articular use), or charcot-like arthropathy 
2.1.3.3 Risks of Paclitaxel 
Paclitaxel is the active agent on FDA approved DCBs.  Paclitaxel inhibits smooth muscle cell 
(SMC) and fibroblast proliferation, migration, and matrix synthesis by modulating microtubule 
polymerization (stabilizes). Because SMCs and fibroblasts are the primary cellular components 
of the neointimal hyperplastic response, they are thought to be the mechanism by which 
paclitaxel improves the patency of arteries.  Other agents that are known as excipients are 
carried on the balloon to allow the paclitaxel to be delivered to the target artery and then to 
partition into the artery when the balloon contacts the arterial wall.  INPACT Admiral DCB uses 


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urea as the excipient, the Lutonix 035 DCB uses sorbitol and polysorbate and the Stellarex uses 
polyethylene glycol, a polymer excipient.  Urea is a natural occurring product of protein 
metabolism and carried in the blood stream as blood urea nitrogen.  The urea released from a 
DCB is about 20,000 fold lower than what is normally produced in the body.  Both sorbitol and 
polysorbate are FDA approved and regulated and are ubiquitous in many household products 
such as toothpaste, cough syrup, hard candy, diabetic sweeteners (sorbitol), and shampoo, 
lubricants, cosmetics (polysorbate).  Similarly, polyethylene glycol is used in household products 
like creams, lubricants, toothpaste, gum and has several industrial and biologic uses as well. 
The combination of [paclitaxel + urea], [paclitaxel + sorbitol and polysorbate] and [crystalline 
paclitaxel + polyethylene glycol] are known as the matrix on the balloon surface.   
The pharmacokinetics of paclitaxel release following treatment with a balloon catheter has been 
studied.  The time to maximal plasma concentration following DCB inflation is about 10 minutes 
and the Cmax is less than 8 ng/ml in each balloon. Typical infusions of paclitaxel for cancer 
treatment are 135 – 175 mg/m2, yielding a Cmax that is 2170-3650 ng/ml. Hence maximal 
plasma levels of paclitaxel are over 200-fold less than typical levels used to treat cancer. 
Plasma levels fall to less than 3 ng/ml within one hour’s time. The pharmacokinetics of paclitaxel 
demonstrated a bi-exponential decay characterized by a rapid redistribution and then and log-
linear elimination phase. The half-life is 72 hours.  The metabolism of paclitaxel is catalyzed by 
cytochrome P450 enzymes CYP2C8 and CYP3A4 as well as being a substrate for P-
glycoprotein.  No formal drug-drug interactions studies have been performed but drugs 
metabolized by the same enzymes may interfere with paclitaxel metabolism. 
Concerns about the safety of paclitaxel (PTX) coated devices have led to recommendations by 
the FDA that “for many patients, alternative treatment options for paclitaxel-coated balloons and 
paclitaxel-eluting stents provide a more favorable benefit-risk profile.” Subjects are no longer 
treated with paclitaxel DCBs. In this study, those subjects already treated with PTX will be 
monitored for adverse events. 
Potential adverse events 
Likely: (likelihood >5%) 
• 
None 
Less Likely: (likelihood <5%) 
• 
increased risk of death 
Rare: (likelihood <1%) 
• 
none 
Extremely Rare: (likelihood <0.1%) 
• 
Hypersensitivity reaction to paclitaxel manifested as a cutaneous rash 
• 
Emboli of the matrix INPACT balloon 
• 
Peripheral neuropathy 
 
2.1.3.4 Risks of MRI and Gadolidium Contrast Agent 
Gadolinium reactions may occur but they are extremely rare. The incidence of adverse 
reactions ranges from 1-1.4% and may consist of nausea and vomiting to anaphylaxis. Life-
threatening reactions to gadolinium are extremely rare. Mild reactions are also rare and usually 
self-limited. In patients who have compromised kidney function, the use of gadolinium agents 
has also been associated with a rare but serious condition, called Nephrogenic Systemic 


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Fibrosis (NSF). Kidney function is measured by a value termed eGFR (estimated Glomerular 
Filtration Rate) in units of ml/min/1.73m2. There have been no reported cases of NSF in 
individuals with eGFR > 60 ml/min/1.73m2. Following the guidelines of the MR Safety 
Committee at UCSF/SFVAMC and UW, we will measure creatinine levels and determine the 
eGFR in all patients in this study as part of their preoperative assessment. If eGFR is < 30 
ml/min/1.73m2 then subjects are excluded from participation in this research study. If eGFR is < 
60 ml/min/1.73m2 but > 30 ml/min/1.73m2 the minimal dose of gadolinium necessary will be 
used after consultation with a radiologist. 
The FDA is investigating the risk of brain deposits following the repeated use of gadolinium 
based contrast agents (GBCAs) for MRI. Recent publications in the medical literature have 
reported that deposits of GBCAs remain in the brains of some patients who undergo four or 
more contrast MRI scans, long after the last administration.  It is unknown whether these 
gadolinium deposits are harmful or can lead to adverse health effects. These effects have only 
been seen in the linear chelates of Gd.  For this reasons, the protocol will avoid the use of linear 
chelates.   
The additional risk of magnetic resonance imaging (MRI) requires that the subject be placed in a 
small and confined space for periods of time, and this can lead to claustrophobia in some 
patients. Electric implants, such as cardiac pacemakers, may be susceptible to interference 
from the magnet and RF fields produced by the MR instrument. Persons with cardiac 
pacemakers or other implanted electronic devices are prohibited from entering a zone where the 
magnetic field exceeds five gauss. The magnetic field of the MR instrument is strong enough to 
forcefully attract ferromagnetic objects. The inadvertent introduction of ferromagnetic materials 
in the proximity to the magnet may result in such objects becoming projectiles, which could 
present a risk to subjects and other persons. This force can cause a ferromagnetic implant, 
such as an aneurysm clip, surgical clip, or prosthesis, to move or be dislodged. Entry to the 
magnet area is possible only through a single door beside the operator’s console, which is 
guarded by the technologist during the study. A technologist screens all persons before they 
enter the magnet area. In addition, warning signs are posted. 
The Bureau of Radiologic Health has issued guidelines for the amount of radiofrequency energy 
which may be employed in imaging subjects in order to ensure that the procedure does not 
entail more than minimal risk. If energy beyond this value is used, some subjects may undergo 
an evaluation in body temperature. If energy which grossly exceeds this guideline is used, the 
subject may receive soft tissue burns. Both the Siemens and the GE MR System includes both 
software and hardware limits, which prevent selection of imaging sequences from exceeding the 
energy deposition guidelines of the Bureau of Radiologic Health. All studies will be conducted 
below this energy limit. 
2.1.3.5 Other Risks 
The following study activities involve only minimal risk to participants: 
• 
Blood Draw - Phlebotomy involved in this study poses minimal risk to the subject; 
however, bruising may be expected around the venipuncture site. Occasional, 
dizziness and vasovagal episodes occur. 
• 
Ankle Brachial Index (ABI) - May involve minor discomfort similar to a standard 
brachial blood pressure measurement. 


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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to assess the mechanisms of vascular healing following balloon 
angioplasty treatment to stenotic arteries from atherosclerosis.  Vascular healing will be 
assessed by MRI determined percent wall volume change (PWV) from 24 hours post-
angioplasty to 12 months  
3.2 
Secondary Objectives 
Secondary objectives include: 
1. To determine whether DEX infusion will result in less inflammation as measured by 
blood (MCP-1, CRP, and IL-1β) and tissue imaging (Ktrans) markers of inflammation 
2. To determine whether patient-specific physiological factors correlate with vascular 
healing 
 
 
 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a prospective, multicenter, randomized trial to determine the mechanisms of vascular 
healing. The study will evaluate subjects with peripheral artery disease (PAD) who require an 
endovascular intervention of the femoropopliteal arterial segment (SFA/Popliteal) to restore 
blood flow to the leg. 
The total duration of subject participation will be 36 months. Total duration of the study is 
expected to be five years. 
4.2 
Specific Aims 
1. To determine whether adventitial DEX infusion will result in improved vascular 
healing following femoral artery angioplasty, with the following Statistical 
Hypotheses: 
a. Adventitial DEX infusion will result in reduced change in percent wall volume 
(ΔPWV) within the treated segment. 
b. Adventitial DEX infusion will result in improved vascular remodeling of the treated 
segment. 
2. To determine whether DEX infusion will result in less inflammation as measured by 
blood (MCP-1, CRP, and IL-1β) and imaging (Ktrans) markers of inflammation, with the 
following Statistical Hypotheses: 
a. Adventitial DEX infusion will result in reduced peri-operative inflammatory profile. 
b. Adventitial DEX infusion will result in less adventitial perfusion (a surrogate of 
inflammation) as measured by kinetic modeling of dynamic contrast-enhanced 
MRI. 
c. Peri-operative inflammatory profile will be associated with ΔPWV. 
3. To determine whether patient-specific physiological factors correlate with 
vascular healing, with the following Statistical Hypotheses: 
a. Treated segment remodeling will be associated with the fibrous volume in 
plaques. 


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b. Treated segment remodeling will be associated with wall shear stress provided 
by MRI determined, patient-specific, geometry and computational fluid dynamics. 
 
5 
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
The primary endpoint for this study will be PWV change of the treated segment from the 24 hour 
post- intervention MRI scan to 12 months between DEX treated and non-DEX (PTX or POBA) 
treated patients. 
The treated segment is defined as the length of vessel, encompassing the index lesion, that has 
undergone successful revascularization, from normal back to normal artery. 
5.2 
Secondary Endpoints 
Secondary endpoints include: 
1. Change in wall volume (WV) without a change in total vessel volume (TVV) at 12 months 
2. Change in perioperative inflammatory profile (MCP-1, CRP, IL-1) at 12 months 
3. Change in Ktrans from 1 month to 6 months 
4. Change in lumen volume (LV) relative to total vessel volume (TVV) at 12 month 
5. Change in subject study status based on subjects receiving reintervention on < 75% or 
 75% of treated segment.  
5.3 
Safety Endpoints 
The incidence of adverse events will be the primary metric for the evaluation of safety.  A Data 
Safety Monitoring Committee will meet on a regular, semi-annual basis to review the trial and 
address all safety issues (See Sec. 15 Data Safety Monitoring) 
5.4 
Completion Endpoints  
Subject Status & Study Completion: 
For subject to complete their participation in this study they must:   
1. Undergo follow-up for 36-month period after index procedure, completing all 
assessments in the Schedule of Assessments.  
 
2.  Subject develops restenosis after the 1-month study follow-up, requiring 
reintervention of  75% of treated segment.  
If subject does not complete the study following the above indications, please see section 13.1 
for specifics on Early Discontinuation/Withdrawals.  
If subject develops restenosis after the 1-month study follow-up, requiring reintervention of 
<75% of the treated segment, please see section 11.10 for specifics on recording Unplanned 
Visits for Index Leg Reintervention and continuing follow-up. 


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6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects with a diagnosis of peripheral artery disease who require an endovascular intervention 
of the femoropopliteal arterial segment (SFA/Popliteal) to restore blood flow to the leg may be 
eligible for the study. Screening criteria will be used to identify subjects eligible for enrollment. 
Final eligibility and randomization will occur intra-operatively following adjudication of Procedural 
Inclusion/Exclusion criteria.  
6.2 
Inclusion Criteria 
Screening Inclusion Criteria: 
1. Male or non-pregnant female ≥ 35 years of age 
2. Atherosclerotic, infrainguinal PAD 
3. Rutherford Clinical Category 2-6 
4. Stenosis detected by radiology that in the clinician’s opinion is the reason for the 
PAD symptom 
5. Patient is willing to provide informed consent and comply with the required follow up 
visits, testing schedule, and medication regimen 
6. eGFR ≥ 30 or threshold established by the radiology safety committee of study site 
Procedural Inclusion Criteria: 
1. De novo atherosclerotic lesion qualifying for angioplasty 
2. A patent artery proximal to the index lesion.  Concomitant inflow procedures, 
including open femoral artery endarterectomy or stenting of the iliac arteries, are 
permissible.  
3. >50% diameter stenosis of the superficial femoral artery and/or popliteal artery 
(between the profunda and tibioperoneal trunk) 
4. Reference vessel diameter ≥3 mm and ≤ 8mm 
5. Successful wire crossing of lesion  
6. Successful angioplasty of the index lesion or part of the index lesion, defined as 
≤30% residual lumen stenosis compared with adjacent non-diseased lumen 
diameter, without flow-limiting dissection 
6.3 
Exclusion Criteria 
Screening Exclusion Criteria: 
1. Any contraindication to receiving an MRI 
2. Pregnant, nursing, or planning on becoming pregnant in < 2yrs 
3. Life expectancy of <1 yr 
4. History of solid organ transplantation 
5. Patient actively participating in another investigational device or drug study 
6. History of hemorrhagic stroke within 3 months of index procedure 


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7. Previous or planned surgical or interventional procedure within 30 days of index 
procedure 
8. Chronic renal insufficiency of eGFR < 30 
9. Prior bypass surgery, stenting, atherectomy or angioplasty of the index lesion 
10. Inability to take required study medications 
11. Contra-indication or known hypersensitivity to dexamethasone sodium phosphate, 
contrast media, gadolinium, aspirin or Plavix 
12. Systemic fungal infection 
13. Acute limb ischemia 
14. Prior participation of the index limb in the current study (contralateral treatment is 
allowed) 
15. Patient is being treated with long-term steroids (not including treatment of a bronchial 
condition with inhaled steroids) 
 
Procedural Exclusion Criteria: 
1. Index lesions extending into the tibial trifurcation or above the profunda. Note: the 
outflow tibial artery can be treated concomitantly. Similarly, the common femoral 
artery can be treated concomitantly, either with open endarterectomy and patch 
angioplasty or with endovascular methods.  However, the index lesion cannot be 
contiguous with either the CFA or the tibial trifurcation. 
2. Circumferential calcification at index lesion, which in the judgment of the investigator 
would prevent penetration of the Micro-Infusion catheter needle through the vessel 
wall 
3. Inadequate distal outflow defined as no patent tibial arteries (>50% stenosis). The 
outflow vessel can be established at the time of primary treatment 
4. Use of adjunctive therapies other than angioplasty. Chocolate balloons and/or 
scoring balloons are allowed, if used below reference diameter. 
7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study period, 
as medically feasible, with no introduction of new chronic therapies. 
7.1 
Allowed Medications and Treatments 
Standard therapies for pre-existing or emergent conditions are allowed except for treatments 
noted in the exclusion criteria described above.   
 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
Upon confirming eligibility, and after consultation with treating physicians, patients will be 
assigned to a treatment group (DEX infusion or POBA) using a block randomization scheme. A 
unique set of blocks will be created for each site.  


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8.2 
Formulation of Treatment 
This trial uses FDA approved drugs and devices and therefore there is no test product. This trial 
will use commercially available dexamethasone sodium phosphate USP and iodixanol contrast 
medium (320 mg I/ml).  A copy of the dexamethasone sodium phosphate USP label is included 
as Appendix 4. The trial also uses a Micro-Infusion catheter, used in accordance with the IFU.  
8.2.1 Packaging and Labeling 
 DEX is widely available throughout the hospital and carried in the hospital formulary.  It is 
available in all anesthesia carts and is commonly used intravenously to treat allergic reactions 
during surgery.  
8.3 
Supply of DEX at the Site 
Each site is responsible for obtaining DEX and maintaining inventory. 
8.3.1 Dosage/Dosage Regimen 
This protocol will utilize a 4 mg/ml preparation of Dexamethasone Sodium Phosphate Injection, 
USP. Each milliliter of the solution contains 4.37 mg of dexamethasone sodium phosphate 
equivalent to 4 mg of dexamethasone phosphate or 3.33 mg of dexamethasone. The 
Dexamethasone Sodium Phosphate Injection, USP will be mixed 80%:20% with iodinated 
contrast medium (iodixanol, 320 mg I/mL) to diagnose the distribution of injectate. This will 
result in a final concentration of 3.2 mg dexamethasone phosphate (3.5 mg dexamethasone 
sodium phosphate, or 2.67 mg dexamethasone) and 60-74 mg iodine in each mL of solution. 
The dosage proposed for this clinical trial is 1.6 mg of Dexamethasone Sodium Phosphate per 
cm of lesion. The typical length of lesions range from 4 -15 cm in length so each infusion will 
range from 2 to 7.5 ml for a total one-time perivascular dosage in each patient of 6.4 to 24 mg.  
Multiple infusions are possible and thus allowance of up to 20% loss due to variability in 
anatomy, distribution pattern, or intravascular diagnostics. The 4 mg/ml dexamethasone solution 
will be diluted to 3.2 mg/ml with contrast medium to track infusions. Based on the distribution 
seen with similar infusions, each 0.5 mL of infusion would be intended to treat 1.0 cm of vessel 
segment, with multiple doses as needed to treat longer diseased regions.   
8.3.2 Dispensing 
This study is an open label study. The primary operator performing the angioplasty is not 
blinded to the treatment assignment of the patient. Therefore, DEX may be obtained from the 
clinical pharmacy.  DEX will be diluted with contrast under sterile conditions in the OR and 
delivered to the tissue using the Bullfrog Micro-Infusion catheter device. 
8.3.3 Administration Instructions  
DEX, which will be mixed with contrast in the operating or the catheterization room, will be 
labelled with name, concentration, and date, in accordance with standard operating procedures 
per institutional policy. 
8.3.4 Storage 
 DEX will be stored in accordance with the manufacturer’s label or IFU.  The expiration date will 
be noted prior to use and any expired drug or device will be discarded and will not be used in 
this study.    


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8.4 
DEX Accountability 
An accurate and current accounting of the dispensing of DEX for each subject will be 
maintained by study staff.   
8.5 
Supply of Devices at the Site 
The intent of this trial is to study the mechanisms of angioplasty failure.  Therefore, there are no 
investigational devices used in the trial.  All devices and drugs used in the study are FDA 
approved and are being used as indicated.  The site is responsible for buying angioplasty 
balloons and equipment including adventitial infusion catheters. 
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Section 10 “Schedule of Assessments”. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and dated by 
the subject. If appropriate, assent must also be obtained prior to conducting any study-related 
activities.  
 
9.1 
Clinical Assessments 
9.1.1 Pregnancy Test 
Female subjects of childbearing potential will receive a serum βHCG pregnancy test. Only 
women who are surgically sterile or postmenopausal may be considered to not be of 
childbearing potential and thus are exempt from this test.  
Postmenopausal is further defined: 
1. If the woman is over 50 years of age and has experienced no menstruation for 12 
consecutive months, she is “postmenopausal”. 
2. If the woman is under 50 years of age, has experienced no menstruation for 12 
consecutive months, and provides verification by an endocrinologist or gynecologist, 
then she is “postmenopausal”. 
Assessment will occur at: Screening. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded. 
Assessment will occur at: Baseline. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent cardiovascular 
history, and information regarding underlying diseases will be recorded. 
Assessment will occur at: Baseline. 


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9.1.4 Concomitant Medications 
All concomitant medication and concurrent therapies will be recorded during the study visits 
described below and at early termination when applicable.  Dosage, units, route, frequency of 
administration, and dates of medication will be captured. 
Assessments will occur at: Baseline, Post-Op, Month 1, Month 6, and Month 12. 
9.1.5 Vital Signs 
Body temperature, blood pressure, pulse and respirations will be recorded as part of their 
standard clinical care. Results from these exams will be recorded by study staff.  
Assessments will occur at: Baseline, Post-Op, Month 1, Month 6, and Month 12. 
9.1.6 Physical Examination 
An appropriate physical examination will be performed by qualified clinical staff (MD, NP, PA, 
RN or trained research assistant) as part of their standard clinical care. Results from these 
exams will be recorded by study staff. 
Assessments will occur at: Baseline, Post-Op, Month 1, Month 6, and Month 12. 
9.1.7 Vascular Examination 
A complete vascular pulse examination, Ankle-Brachial Index (ABI), and Rutherford 
Categorization will be performed by qualified clinical staff (MD, NP, RN, or PA) or research staff 
under the supervision of a study investigator. Results of the exam will be recorded by study 
staff. 
The Ankle-Brachial Index (ABI) examination will be performed according to current, accepted 
guidelines.  Subjects will rest 10 minutes in a supine position prior to the exam. The ABI will be 
defined as the ratio between the higher of the two pedal systolic blood pressures (dorsalis pedis 
and posterior tibialis) and the higher of the two systolic brachial pressures. A continuous wave 
Doppler, between 5 and 12 MHz, will be used to measure the systolic pressures in both the 
dorsalis pedis and posterior tibial arteries in each leg, as well as the brachial arteries in each 
arm. The ABI will be calculated for both legs. In the event the pedal / tibial vessels are 
noncompressible, a toe brachial index may be used. 
Rutherford Categories will be defined by patient-reported pain-free walking distance. Table 1 
related Rutherford Categories to objective criteria and to common patient-reported distances. 
 
 


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Table 1. Rutherford Categories  
Category Clinical description 
Objective criteria 
0 
Asymptomatic—no 
hemodynamically significant 
occlusive disease 
Normal treadmill or reactive hyperemia test 
1 
Mild claudication 
Completes treadmill exercise†; AP after 
exercise >50 mm Hg but at least 20 mm 
Hg lower than resting value 
2 
Moderate claudication 
Between categories 1 and 3 
3 
Severe claudication 
Cannot complete standard treadmill 
exercise† and AP after exercise <50 mm 
Hg 
4 
Ischemic rest pain 
Resting AP <40 mm Hg, flat or barely 
pulsatile ankle or metatarsal PVR; TP <30 
mm Hg 
5 
Minor tissue loss—
nonhealing ulcer, focal 
gangrene with diffuse pedal 
ischemia 
Resting AP <60 mm Hg, ankle or 
metatarsal PVR flat or barely pulsatile; TP 
<40 mm Hg 
6 
Major tissue loss—extending 
above TM level, functional 
foot no longer salvageable 
Same as category 5 
*Grades II and II, categories 4, 5, and 6 are embraced by the term chronic critical ischemia. 
†Five minutes at 2 mph on a 12% incline. 
 
Assessments will occur at: Baseline, Post-Op, Month 1, Month 6, and Month 12. 
 
Telephone assessment of changes in medical history (medications, cardiovascular events, 
hospitalizations, etc.) will occur at 24 and 36 months. 
 
 


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9.2 
Laboratory Measurements 
9.2.1 Research Laboratory Measurements 
Research laboratory assessments include: 
1. Serum C-Reactive Protein (CRP) 
2. Monocyte Chemotactic Protein 1 (MCP-1) 
3. Interleukin-1 Beta (IL-1β).   
A complete description of the collection requirements are outlined in Appendix 2. Briefly, a 20 ml 
sample will be obtained (1x10 ml EDTA and 1x10 ml SST tubes). The samples will be 
centrifuged, aliquoted, and stored at -80°C. 
Assessment will occur at: Baseline, Post-Operative Day #1, Month 1, and Month 12. 
9.2.2 Clinical Laboratory Measurements 
Clinical labs performed as part of routine clinical care will be extracted from the subject’s chart 
by study staff.  
Assessment of clinical labs for baseline will occur within 30 days prior to the index procedure 
(Day 0) 
Analyses recorded at baseline include:  
1. Serum chemistry 
2. Complete blood count (hemoglobin, hematocrit, white blood cell count, white 
blood cell differential, and platelet count) 
3. Lipid panel 
4. Coagulation studies. 
Following a successful index procedure at Day 0, only eGFR will be collected for clinical labs.  
Assessments of eGFR will occur at: POD Day #1, Month 1, Month 6, and Month 12. 
9.3 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity/grade, outcome, treatment and relation to the index 
procedure will be recorded on the case report form (CRF). 
9.4 
Walking Impairment Questionnaire 
The Walking Impairment Questionnaire may be administered by study staff or self-administered 
by the subject.   
Please refer to Appendix 8. Walking Impairment Questionnaire for more details 
Assessments will occur at: Baseline, Month 1, Month 6, and Month 12. 
 
 


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9.5 
Treated Segment Registration 
During the index procedure, the investigator will identify an “index lesion”, which is a segment of 
the SFA and/or popliteal artery that meets the procedural inclusion/exclusion criteria (see 
Section 6). The index lesion will fall within the following constraints: 
1. The index lesion will be between the femoral bifurcation and the infrapopliteal trifurcation 
(specifically, the take-off of the anterior tibial artery).  
2. If the femoropopliteal arterial segment has diffuse disease, there must be at least 2 cm 
of “normal” vessel proximal and distal to the index lesion. A “normal” vessel is defined as 
having < 20% stenosis. 
3. If a subject has multiple lesions that meet the procedural inclusion/exclusion criteria, the 
investigator may choose any qualified lesion as the index lesion.  
A Glow ‘N Tell radiopaque tape (LaMaitre Vascular, Burlingame MA) will be placed at the 
subject’s medial tibial spine as the “0 cm” mark, topographically overlying the knee cap and the 
numbers increase proximally. The lesion length, location, and degree of stenosis/occlusion will 
be documented. 
Following a successful revascularization, the treated segment will be registered to the nearest 
millimeter on the tape, including 5 mm proximal and 5 mm distal to the actual treated lesion. 
9.6 
Randomization 
An opaque envelope scheme will be used to reveal the allocation intra-operatively. Prior to the 
procedure, study staff will identify the next sequential Randomization ID and bring this envelope 
to the OR.  Once Procedural Criteria have been assessed and the subject passes, study staff 
will record the Randomization ID on procedural CRFs, open the envelope, and reveal the 
assignment (DEX vs POBA).    
A full description of the Randomization process is given in Sec. 16.4 “Sample Size & 
Randomization”. 
9.7 
DEX Infusion 
Patients randomized to the DEX group will receive dexamethasone infusion after the primary 
revascularization procedure and before any provisional stenting. The equipment, order of 
operations, and dosing instructions are described below. 
9.7.1 Equipment 
A micro-infusion catheter (Mercator Cricket, Bullfrog, or Bullfrog XL) will be used to deliver FDA-
approved Dexamethasone Sodium Phosphate Injection, USP, 4 mg/ml, mixed with FDA-
approved non-ionic contrast medium to the index lesion 
9.8 
Order of Operations 
Research procedures will be performed in between steps of a clinical procedure. In general, the 
order of operations is as follows: 
1. Establish vascular access 
2. Initial angiogram 
3. Place Glow ‘N Tell tape 
4. Index lesion registration with respect to knee joint 


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5. Primary revascularization 
6. Assessment of Procedural Inclusion/Exclusion Criteria 
7. Treated segment registration with respect to knee joint 
8. Randomization 
9. DEX infusion or POBA 
10. Provisional stenting 
11. Completion angiography 
 
Primary Revascularization: A balloon shall be selected such that the diameter is 1 mm less 
than the vessel reference diameter. To secure good results, slow inflation, prolonged inflation (3 
min) at nominal pressure should be used. One additional inflation may be used to ensure good 
results. If there is > 30% residual stenosis, that portion of the stenosis is ineligible to be included 
and a stent will be placed. However, if there is a portion of the lesion that has adequate results 
and there is no anticipation of a stent, then the successfully PTA treated, but non-stented, 
segment can be registered as the treated segment. 
  
For subjects randomized to POBA, If the patient is randomized to POBA, then an appropriate 
sized device may be used according to the IFU, at a 1:1 artery:balloon size ratio. The 
Investigator will complete the clinical portions of the procedure (e.g. completion angiograms) per 
standard of care, Provisional stenting of the treated segment is allowed if clinically indicated. 
For subjects randomized to DEX, the Investigator will infuse dexamethasone (1.6 mg / cm 
lesion length). The investigator may administer DEX at multiple sites along the treated segment 
and may reposition the Micro-Infusion Catheter as needed to establish successful distribution of 
the drug along the treated segment. 
Imaging will be saved for the Core Lab (UCSF VipeRx Lab) to assess the technical success of 
drug administration, the extent of circumferential (or lateral using 2-dimensional X-ray 
fluoroscopic guidance) and longitudinal coverage of the artery by the contrast. The following 
scale will be used to grade the pattern of distribution: 
Technical success is defined as grades A, B or C   
 
Table 2: Diffusion grades and distribution patterns 
 
Provisional stenting of the treated segment is allowed if clinically indicated. 
 


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9.9 
Research MRI 
A research MRI will be performed to assess change in Percent Wall Volume (ΔPWV) and 
transfer constant (Ktrans) following the procedure. Specific details of the protocol are discussed 
below. 
Assessments of ΔPWV will occur: at Post-Op, Month 6, and Month 12.  
Assessments of Ktrans will occur at: Month 1 and Month 6. 
9.9.1 Equipment 
A research MRI will be obtained on either a 3T Siemens Skyra MRI (Erlangen Germany) 
(SFVAMC/UCSF) or a 3T Philips Achieva MRI (Philips Healthcare, Netherlands) (UW) using a 
phased-array coil wrapped around the leg at the level of the region of interest. 
9.9.2 Protocol 
Patients will be scanned with a phased array coil placed such that the anterior portion covers 
the femoral segment and the posterior section coverage includes the popliteal segment of the 
artery. The scan landmark will be positioned at a point approximately 20 cm proximal to the 
knee joint, and that location will be advanced to the center of the magnet.  The 3D black blood 
study will be performed centered with zero offset in the head-foot direction. The superior tip of 
the medial tibial spine will be identified on the 3D black blood images.  The targeted 2D T1, T2 
and DCE sequences will be centered 20 centimeters proximal to the medial tibial spine 
landmark, in the adductor canal, as this is considered to be the most likely location of the 
treated segment.  
After the location of the treated segment is identified, a specific set of MRA sequences will be 
performed. The sequences vary by study visit. A description of the sequences and requirements 
is provided in Table 3. 
  
Table 3: Research MRI Sequences 
Sequence 
Baseline 
(-30 days) 
Within 7 
days 
Post-Op 
1 Mo 
6 Mo 
12 Mo 
Immediately 
pre re-
intervention 
Pre MERGE 
/DASH 
X 
X 
X 
X 
X 
X 
2D-T1 
X 
X 
X 
X 
X 
X 
2D-T2 
X 
X 
X 
X 
X 
X 
MP RAGE 
X 
X 
X 
X 
X 
X 
DCE 
X 
 
X 
X 
 
X 
CE-MRA 
 
X 
 
 
X 
 
Post MERGE 
/DASH 
X 
X 
X 
X 
X 
X 
PC-MRI 
 
X 
 
 
 
 
 
 


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Pre MERGE/DASH (DANTE prepared-FLASH): These sequences are high-resolution, 3D 
black-blood imaging of the vessel wall, which are achieved by using a preparation pulse to null 
the signal from flowing blood. MERGE uses an MSDE (Motion Sensitive Driving Equilibrium) 
prep-pulse, with a Rapid Gradient Echo acquisition. DASH uses a DANTE prep-pulse (Delay 
Alternating with Nutation for Tailored Excitation) with a FLASH sequence (Flash Low Angle 
Shot). These sequences are essentially different implementations to achieve the same goal of 
vessel wall imaging, and they both contain a motion-sensitive preparation (to null the signal from 
the blood) coupled to a fast gradient echo acquisition. 
 
2D-T1: This is a 2D, high-resolution, T1 weighted sequence. T1 image weighting measures the 
spin-lattice relaxation time of hydrogen protons in a tissue.  
 
2D-T2: This is a 2D, high-resolution, T2 weighted sequence. T2 image weighting measures the 
spin-spin relaxation time of hydrogen protons in a tissue. 
 
MP RAGE: This is a 3D, T1-weighted, Magnetization Prepared Rapid Acquisition Gradient Echo 
sequence and provides information about blood degradation products in tissues. 
 
DCE: Dynamic Contrast Enhanced MRI is a T1-weighted sequence with high temporal 
resolution, acquired after the injection of a gadolinium-based contrast agent (e.g. Omniscan, 
Gadavist, or ProHance). This sequence allows for measurement of the passage of contrast 
agent, which gives information about physiological tissue characteristics such as the integrity 
and perfusion/permeability of the vessel wall. This imaging sequence is used to calculate Ktrans. 
 
The protocol for the Delayed Contrast Enhancement for this study requires an injection of Gd 
contrast agent: 
A half dose of Gadolinium is injected.  For Magnevist this corresponds to (0.1ml of 
Magnevist)/(kg patient weight) and for Gadavist this corresponds to (0.05ml of Gadavist)/(kg 
patient weight of Gadavist).  If Gadavist is used it is diluted 50:50 with saline.  This ensures that 
the total volume injected is the same independent of whether Magnevist or Gadavist is used.   
Injection timing: 
The DCE scan is first started.  The contrast should then be injected at the end of the first 
dynamic run, at an injection rate of 1cc/sec, and immediately followed by a saline flush of 15 cc 
saline also at 1cc/sec.  Dynamic scanning should not be not interrupted during the injection 
delivery. 
 
CE-MRA: Contrast-Enhanced Magnetic Resonance Angiography is a pulse sequence acquired 
with the simultaneous intravenous injection of a gadolinium-based contrast agent. Gadolinium 
shortens the T1 relaxation time of blood. This allows for fast image acquisition, with high signal 
intensity in the lumen of vessels (where gadolinium is present), and low signal in extravascular 
territories (where gadolinium is not present). This sequence will give the geometry of the lumen 
used for CFD simulations. 
This sequence is usually acquired after using a timing bolus in order to evaluate the time it takes 
from injection to the arrival of the contrast bolus to the vessel of interest (scan delay). Contrast 


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agent is generally delivered at 2mL/second.) Typically, the timing bolus is 2mL, 1:1 
gadolinium:saline while the full bolus for CE-MRA is 20mL, also 1:1 gadolinium/saline. 
 
Post MERGE/DASH: These 3D black blood sequences are acquired shortly after contrast 
administration to evaluate for contrast enhancement (uptake of gadolinium in the vessel wall). 
PC-MRI:  Phase Contrast Magnetic Resonance Imaging is a technique that allows for the 
measurement of blood flow. This is accomplished by placing a bipolar gradient along a vessel of 
interest. As hydrogen protons of blood flow along this vessel of interest, they accumulate a 
phase shift that is proportional to their speed. In this way, we are able to non-invasively 
measure the velocity and flow of blood. This sequence will allow description of the inlet flow 
conditions which will be used to generate CFD models. 
The acquisitions parameters are provided in Appendix 3. 
Data files from SFVAMC research MRIs will be sent to the University of Washington for 
analysis. Data files from University of Washington will be sent to SFVAMC for CFD modelling. 
Study staff performing the analysis of MRIs will be blinded as to the subject ID and study visit.  
 
9.9.3 Pre-Reintervention MRI 
If the patient proceeds to a reintervention during the study period, and it has been longer than 
30 days since the last research MRI study, an additional MRI study of the treated segment will 
be performed prior to the reintervention. 
9.10 Clinical Ultrasound 
A standard-of-care clinical ultrasound will be obtained at follow-up visits. The exam will cover 
the iliac, femoropopliteal, and infrapopliteal arterial segments and will include Doppler pulse 
wave velocities and B-mode diameter measurements of each segment.


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10 SCHEDULE OF ASSESSMENTS 
Schedule of Assessments continues on the next page 
 
VISIT 1 
VISIT 2 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6 
VISIT 7 
VISIT 8 
UNPLANNED 
VISIT (UV) 
SCREENING 
& BASELINE 
(S & B) 
PROCEDURE 
POST-OP 
MONTH 1 
MONTH 6 
MONTH 12 
MONTH 24 
(BY PHONE) 
MONTH 36 
(BY PHONE) 
 
(-30 days) 
(Day 0) 
(Day 1-7) 
(Day 30±7) 
(Day 
180±14) 
(Day 
365±30) 
(Day 
730±30) 
(Day 
1095±30) 
 
Informed Consent 
X  
 
 
 
 
 
 
 
 
Inclusion Criteria 
X 
 
 
 
 
 
 
 
 
Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
Demographics 
X  
 
 
 
 
 
 
 
 
Medical History 
X  
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs  
X 
 
X 
X 
X 
X 
 
 
X 
Physical Exam 
X 
 
X 
X 
X 
X 
 
 
X 
Vascular Exam1 
X 
 
X 
X 
X 
X 
 
 
X 
Rutherford Category 
X 
 
X 
X 
X 
X 
 
 
X 
Research Labs2 
X 
 
X3 
X 
 
X 
 
 
X 
Clinical Labs 
X4 
 
X3 5 
X5 
X5 
X5 
 
 
X 
Walking Impairment 
Questionnaire 
X 
 
 
X 
X 
X 
 
 
 
Research MRI 
X 
 
X 
X 
X 
X 
 
 
X8 
Clinical Ultrasound 
 
 
 
X 
X 
X 
 
 
X 
Index Lesion 
Registration 
 
X 
 
 
 
 
 
 
 


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Schedule of Assessments, continued. 
 
1Vascular exam CRF includes ABI’s 
2Research labs include CRP, MCP-1, and IL-1β 
3For Visit 3 Post-Op, Research & Clinical Labs must be drawn POD #1-7 
4Clinical labs for Visit 1 include Serum chemistry, CBC, lipid panel, coagulation studies 
5eGFR only 
6For subjects randomized to DEX 
7For subjects randomized to POBA (formerly PTX) 
8Perform research MRI, if >30 days since last study MRI 
(Continued) 
VISIT 1 
VISIT 2 
VISIT 3 
VISIT 4 
VISIT 5 
VISIT 6 
VISIT 7 
VISIT 8 
UV 
 
S & B 
PROCEDURE POST-OP 
MONTH 1 
MONTH 6 
MONTH 12 
MONTH 24 
(BY PHONE) 
MONTH 36 
(BY PHONE) 
 
 (-30 days) 
(Day 0) 
(Day 1-7) 
(Day 30±7) 
(Day 180±14) 
(Day 365±30) 
(Day 730±30) 
(Day 1095±30) 
 
Procedural Inclusion & 
Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
Primary 
Revascularization 
 
X 
 
 
 
 
 
 
 
Treated Segment 
Registration 
 
 
 
 
 
 
 
 
 
Randomization 
(after successful 
angioplasty) 
 
X 
 
 
 
 
 
 
 
DEX Infusion6 or  
POBA7 
 
X 
 
 
 
 
 
 
 
Telephone follow-up 
 
 
 
 
 
 
X 
X 
 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
 


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11 EVALUATIONS BY VISIT  
11.1 Visit 1: Screening & Baseline (Day -30 to Day -1) 
1. Review the study with the subject and obtain written informed consent and HIPAA 
authorization and assent, if appropriate 
2. Assign the subject a unique study ID number 
3. Evaluate Inclusion & Exclusion Criteria 
4. Assess childbearing potential of female patients, administer serum βHCG pregnancy test 
if indicated 
5. Record demographics data 
6. Record medical history 
7. Record concomitant medications 
8. Perform and record vital signs 
9. Perform a general physical examination 
10. Perform a focused vascular exam including Ankle-Brachial Index & Rutherford 
Categorization 
11. Collect blood for research laboratory tests (CRP, MCP-1, IL-1β) 
12. Record results from standard-of-care clinical laboratory tests (results obtained within 30 
days may be recorded): serum chemistry, CBC, lipid panel, coagulation studies 
13. Administer Walking Impairment Questionnaire (WIQ) 
14. Schedule baseline research MRI prior to procedure (up to -30 days allowed) 
11.2 Visit 2: Procedure (Day 0) 
1. Define index lesion after initial angiogram. Using Glow ‘N Tell tape, starting at the medical 
tibial spine, the index lesion is registered according to its location and length. 
2. If subject is eligible, perform Primary Revascularization (angioplasty of index lesion) 
3. Register the treated segment, location and length using Glow ‘N Tell tape.  
4. Assess Procedural Inclusion/Exclusion Criteria 
5. Randomize subject (see Sec. 9.7” Randomization” & Sec. 16.4 “Sample Size and 
Randomization”) 
6. For subjects Randomized to DEX, infuse dexamethasone 
7. For subjects Randomized to POBA (formerly PTX), perform no further treatment 
8. Perform provisional stenting if indicated clinically 
9. Record any procedural Adverse Events 
10. Record any interim Adverse Events 
11.3 Visit 3: Post-Operative Assessments (Day 1-7) 
1. Obtain research labs (CRP, MCP-1, IL-1β) on Post-Operative Day #1 (POD #1)  
2. Obtain clinical labs (eGFR only) on Post-Operative Day #1 (POD #1) 
3. Record any changes to medications 
4. Record vital signs 
5. Perform physical exam 


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6. Perform vascular exam including Ankle-Brachial Index & Rutherford Categorization 
7. Perform research MRI (up to POD #7 allowed)  
8. Record any interim Adverse Events 
11.4 Visit 4: 1 Month Follow-up (Day 30±7) 
1. Record any changes to medications 
2. Record vital signs 
3. Perform physical exam 
4. Perform vascular exam including Ankle-Brachial Index & Rutherford Categorization 
5. Obtain research labs (CRP, MCP-1, IL-1β) 
6. Obtain clinical labs (eGFR only) 
7. Administer Walking Impairment Questionnaire 
8. Perform research MRI 
9. Record results of clinical ultrasound 
10. Record any interim Adverse Events 
11.5 Visit 5: 6 Month Follow-up (Day 180±14) 
1. Record any changes to medications 
2. Record vital signs 
3. Perform physical exam 
4. Perform vascular exam including Ankle-Brachial Index & Rutherford Categorization 
5. Obtain clinical labs (eGFR only) 
6. Administer Walking Impairment Questionnaire 
7. Perform research MRI 
8. Record results of clinical ultrasound  
9. Record any interim Adverse Events 
11.6 Visit 6: 12 Month Follow-up (Day 365±30) 
1. Record any changes to medications 
2. Record vital signs 
3. Perform physical exam 
4. Perform vascular exam including Ankle-Brachial Index & Rutherford Categorization 
5. Obtain research labs (CRP, MCP-1, IL-1β) 
6. Administer Walking Impairment Questionnaire 
7. Perform research MRI 
8. Record results of clinical ultrasound  
9. Record any interim Adverse Events 
11.7 Visit 7: 24 Month Telephone Follow-up (Day 730±30) 
10. Record any changes to medications 
11. Record any interim Adverse Events 


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11.8 Visit 8: 36 Month Telephone Follow-up (Day 1095±30) 
12. Record any changes to medications 
13. Record any interim Adverse Events 
11.9 Early Withdrawal Visit  
In the event of early withdrawal, the Principal Investigator or Co-Investigator will contact the 
subject and arrange a follow-up clinical appointment. If the subject is unable or unwilling to 
return, the investigator may perform a telephone interview. 
The following information will be recorded at a final clinical appointment: 
1. Record changes to concomitant medications 
2. Perform vascular exam including Ankle-Brachial Index & Rutherford Categorization 
3. Collect blood for research laboratory tests (CRP, MCP-1, IL-1β) and safety (eGFR) 
4. Record any interim Adverse Events 
 
The following steps will be performed during a telephone interview: 
1. Record any interim Adverse Events 
2. Arrange for release of records from outside hospitals/providers 
3. Record reason for withdrawal 
11.10 Unplanned Visit for Index Leg Reintervention 
If the investigator determines that a subject requires reintervention of the index leg, a study visit 
will be performed prior to the reintervention.  
If the need for reintervention is determined within the window of a study visit, all procedures for 
that study visit will be performed. 
If the need for reintervention is determined outside of a study visit window, the following will be 
performed: 
1. Record any changes to medications 
2. Record vital signs 
3. Perform physical exam 
4. Perform vascular exam including Ankle-Brachial Index & Rutherford Categorization 
5. Obtain clinical labs (eGFR only) 
6. Administer Walking Impairment Questionnaire 
7. Perform research MRI, if >30 days since last study MRI 
8. Record results of clinical ultrasound 
9. Record procedural details of the reintervention 
10. Record any interim Adverse Events 
 
 
If subject is receiving reintervention on <75% of the treated segment, please continue to follow 
subject until they have completed the study. For further specifics on study completion, please 
see section 11.11 Study Completion.   


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11.11 Study Completion 
For subject to complete their participation in this study they must:   
1. Undergo follow-up for 36-month period after index procedure, completing all 
assessments in the Schedule of Assessments.  
 
2.  Subject develops restenosis after the 1-month study follow-up, requiring 
reintervention of 75% of treated segment.  
If subject does not complete the study following the above indications, please see section 13.1 
for specifics on Early Discontinuation/Withdrawals.  
If subject develops restenosis after the 1-month study follow-up, requiring reintervention of 
<75% of the treated segment, please see section 11.10 for specifics on recording Unplanned 
Visits for Index Leg Reintervention and continuing follow-up.  
12 ADVERSE EVENT REPORTING AND DOCUMENTATION 
12.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with the treatment.  An AE is therefore any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the administration 
of an investigational product, whether related to that investigational product or not.  An 
unexpected AE is one of a type not identified in nature, severity, or frequency in the current 
Investigator’s Brochure or of greater severity or frequency than expected based on the 
information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during 
each subject visit and record the information in the site’s source documents.  Adverse events 
will be recorded in the patient CRF.  Adverse events will be described by duration (start and 
stop dates and times), severity, outcome, treatment and relation to the index procedure, or if 
unrelated, the cause.  
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 3.0 should be used to assess and grade AE severity, including laboratory abnormalities 
judged to be clinically significant. The modified criteria can be found in the study manual.  If the 
experience is not covered in the modified criteria, the guidelines shown below, in Table 1, 
should be used to grade severity.  It should be pointed out that the term “severe” is a measure 
of intensity and that a severe AE is not necessarily serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of 
the sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 


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12.2 Serious Adverse Events (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
12.2.1 Serious Adverse Event Reporting 
Study sites will document and report all SAEs that occur (whether or not related to index 
procedure) within 5 business days of investigator awareness, as per UCSF IRB Guidelines.  
The collection period for all SAEs will begin after informed consent is obtained and end after 
procedures for the final study visit have been completed. 
 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs 
to the IRB/IEC.     
13 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
13.1 Early Discontinuation/Withdrawal 
A subject may be discontinued from study treatment at any time if the subject, the investigator, 
or the Sponsor feels that it is not in the subject’s best interest to continue.  The following is a list 
of possible reasons for study treatment discontinuation: 
• 
Subject withdrawal of consent (or assent) 
• 
Subject is not compliant with study procedures 
• 
Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment (i.e. treated segment restenosis/occlusion 
occurring between index procedure date and the 1-month study follow-up date) 
• 
Protocol violation requiring discontinuation of study treatment 
• 
Positive pregnancy test (females) 
• 
Lost to follow-up 
• 
Death 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed 
and treated by the Investigator until the abnormal parameter or symptom has resolved or 
stabilized.   
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as 
it occurred. This does not refer to an experience that 
hypothetically might have caused death if it were more severe. 


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All subjects who decide to withdraw or discontinue study treatment should come in for an early 
discontinuation visit as soon as possible. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents. 
  
13.2 Replacement of Subjects 
Subjects who withdraw from the study treatment will not be replaced.   
 
14 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fails to adhere to significant protocol 
requirements affecting the inclusion, exclusion, subject safety and primary endpoint criteria.  
Protocol violations for this study include, but are not limited to, the following: 
• 
Failure to meet inclusion/exclusion criteria 
• 
Use of a prohibited concomitant medication 
• 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Investigator will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by the 
Investigator. A copy of the form will be filed in the site’s regulatory binder and in the Sponsor’s 
files. 
 
15 DATA SAFETY MONITORING 
Since this is a multi-institutional study, a Data Monitoring Committee (DMC) comprised of the 
principal investigator, two co-investigators (Drs. Hatsukami and Gasper) will meet on a regular 
semi-annual basis to review the progress of the trial and address all safety issues. The minutes 
of the meetings will be submitted to the UCSF institutional review board.  
All Serious Adverse Events (SAEs) will be reported to the IRB within 5 business days of 
investigator awareness (or as per local IRB policy), followed to resolution and adjudicated. 
Adverse Events will also be grouped and analyzed in the following three distinct periods: 
1. From intervention through discharge from hospital; 
2. From hospital discharge until the 1-month evaluation; and 
3. Beyond the 1-month evaluation and through 36 months and completion of study 
participation. 
Adverse events will be documented on the AE Case Report Form. Those SAEs that are 
possibly related to the treatment (angioplasty, infusion or drug), the procedure (angiogram, 
access vessel, etc.), or the disease state being treated (PAD) may be reviewed and adjudicated 


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by an Independent Reviewer. All Serious Adverse Events and/or Unanticipated Adverse Device 
Effects will be reported to the IRB per the IRB’s specific policies and guidelines. 
16 STATISTICAL METHODS AND CONSIDERATIONS 
16.1 Data Sets Analyzed 
All eligible patients who are randomized into the study will be included in the safety analysis and 
descriptive statistics of the study population. 
Descriptive statistics will be used to characterize the parametric and nonparametric data with 
means and standard deviation or median and interquartile range where appropriate.  
Proportions will be used for categorical data.  
16.2 Analysis of Primary Endpoint 
The primary endpoint for this study will be PWV change of the treated segment from the post-
operative (1-7 days after intervention) MRI scan to 12 months between DEX treated and non-
DEX (PTX or POBA) treated patients. 
Statistical hypothesis 1a: Adventitial DEX infusion will result in reduced change in percent wall 
volume (PWV) within the treated segment. 
Statistical Methods: The primary analysis will be an intention-to-treat (ITT) comparison of 
observed change in mean ΔPWV between treatment groups at 12 months using a t-test. 
Because ΔPWV may be nonlinear in time, linear splines with knots at 24 hours, 1 month, 6 
months, and 12 months will be used to fit the model. Multivariable regression models will be 
constructed to determine independent variables associated with ΔPWV controlling for 
demographic and anatomical variables, statin use, inflammatory markers, and smoking. We will 
also investigate effects by treatment received by constructing generalized linear models 
controlling for demographic, clinical, and anatomic variables. Predictors of PWV will be 
evaluated via univariate and multivariate regression analysis. 
16.3 Analysis of Secondary Endpoints 
Statistical hypothesis 1b: Adventitial DEX infusion will result in improved vascular remodeling 
of the treated segment. 
Statistical Methods: ITT comparison of observed change in remodeling between treatment 
groups at 12 months using a t-test. Models will be constructed similar to ΔPWV with attention or 
hemodynamic descriptors, WSS and OSI, derived by CFD and plaque composition which have 
both been hypothesized to influence vessel remodeling. 
 
Statistical hypothesis 2a: Adventitial DEX infusion will result in reduced peri-operative 
inflammatory profile. 
Statistical Methods: Each biomarker will be tested for normality and log-transformed as 
necessary. Descriptive statistics will record the mean and standard deviation (or median and 
inter-quartile range) of each biomarker at each time point. Then, the area under the curve (AUC) 
will be calculated for each biomarker from baseline, 24 hours post-intervention, and the 1 month 
time point. ITT comparisons of the mean AUC between treatment assignments will be by a t-
test. 
 
 
 


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Statistical hypothesis 2b: Adventitial DEX infusion will result in less adventitial perfusion (a 
surrogate of inflammation) as measured by kinetic modeling of dynamic contrast-enhanced MRI. 
Statistical Methods: ITT Comparisons will be made between average Ktrans values of the two 
treatment groups using the Wilcoxon signed rank test. Spearman rank correlation coefficient will 
be determined between VP and Ktrans values, and other variables such as smoking status, statin 
use, plaque component, and biomarker levels. Ktrans will also be assessed at baseline MRI visit 
as a parameter of plaque inflammation for descriptive purposes. Ktrans will likely be difficult to 
assess in the freshly injured artery at the 24 hour MRI. 
 
Statistical hypothesis 2c: Peri-operative inflammatory profile will be associated with ΔPWV. 
Statistical Methods: Pearson correlation coefficients will be calculated between CRP, MCP-1, 
and IL-1β and confounding factors such as diabetes, foot ulcer, and treated segment length, 
etc. Multivariable linear regression models will be created with each inflammatory marker AUC 
as the dependent variable in order to determine the independent effect of inflammation on 
ΔPWV. 
 
Statistical hypothesis 3a:  Treated segment remodeling will be associated with the fibrous 
volume in the plaque. 
Statistical Methods:    Multi-contrast MRI will be used to determine the relative volumes of 
fibrous, calcification, and LRNC expressed as a percent of TVV for each treated segment in this 
study. Pearson’s correlation coefficient will be used to determine if patient-related factors or 
markers of inflammation are associated with plaque composition. Then multivariable regression 
equations will be generated to determine if fibrous tissue content is associated with remodeling. 
Models will be constructed with and without DEX to determine if DEX will change the β-
coefficient of the association between fibrous tissue content and remodeling. 
 
Statistical hypothesis 3b: Treated segment remodeling/ΔPWV will be associated with wall 
shear stress provided by MRI-determined, patient-specific, geometry and computational fluid 
dynamics 
Statistical Methods: Hemodynamic parameters WSS, WSSG, and OSI, derived from CFD will 
be calculated at each MRI time point. Multivariable regression models will be constructed to 
determine the independent contribution of these parameters on treated segment remodeling 
and ΔPWV. 
Interim analyses will be made prior to DMC meetings and in preparation of publications. 
16.4 Sample Size and Randomization 
The sample size for this study is based on Statistical Hypothesis 1a. While there are no 
predicate serial studies of PWV changes in femoral artery restenosis following PTA to estimate 
the sample size, previous work on the progression of de novo atherosclerosis in similar sized 
peripheral arteries (carotids) forms the basis of this estimation (please refer to Section 1.2 
reference numbers 70 and 71). Power calculations were performed based on an expected 
reproducibility variance of 8% (determined from evaluations performed on measurements 
performed on the untreated leg for studies at multiple time points).  An effect size of 6.3% or 7% 
was assumed based on data from pilot studies. Based on power calculations, we estimate the 
need for 22 subjects/treatment assignment to detect a 7% difference in PWV at a power level of 
80%. Assigning a 20% attrition rate due to loss to follow up or index lesion revascularization, 27 


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subjects will be enrolled per arm. Calculation is based on an unpaired t test at a 5% significance 
level. 
 
Overall sample size providing 80% power in 2-sided 5% tests 
Between-group 
difference  
Measurement error 
7% 
8% 
9% 
6.3% 
42 
54 
68 
7% 
34 
44 
54 
 
The Principal Investigator’s staff will develop and maintain a block randomizations scheme for 
each site. The scheme will be developed using Stata 12.1 (StataCorp, College Station, TX, 
USA) with a 1:2 allocation of DEX:POBA because the 9 or 10 subjects treated with DEX to this 
point will be carried forward in the analysis.  The block size will not be revealed to Investigators, 
to minimize bias. Allocation to treatment group will be tied to Randomization ID.  The 
Randomization ID will be assigned to a subject once the Procedural Inclusion/Exclusion Criteria 
are assessed.  Figure 6 illustrates the Study Enrollment and Randomization process. 
 
Figure 6: Enrollment and Randomization process 
 


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17 DATA COLLECTION, RETENTION AND MONITORING 
17.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed 
to record all observations and other pertinent data for each subject treated with the index 
procedure.   
Study personnel at each site will enter data from source documents corresponding to a subject’s 
visit into the protocol-specific electronic Case Report Form (eCRF) when the information 
corresponding to that visit is available.  Subjects will not be identified by name in the study 
database but will be identified by a subject number. 
If a correction is required for an eCRF, the time and date stamps track the person entering or 
updating eCRF data and creates an electronic audit trail. If a correction is made on a paper 
source form, the study staff member will line through the incorrect data, write in the correct data 
and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this study.  All 
data collected during the course of this study must be reviewed and verified for completeness 
and accuracy by the Investigator.  A copy of the CRF will remain at the Investigator’s site at the 
completion of the study pursuant to institutional record retention guidelines. 
17.2 Data Management Procedures 
The data will be entered into a validated database.  A staff member designated as the Data 
Manager will be responsible for data processing, in accordance with procedural documentation.  
Database lock will occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
Data will be shared with collaborating investigators and contract laboratories as appropriate for 
analyses. Data will be coded or deidentified, according to the matrix in Appendix III – Data 
Management. The code will be maintained and kept secure by the Data Manager. 
17.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. These checks will 
occur following the completion of each 10 study subjects. Ad hoc checks may be initiated by the 
Investigator. The study database will be updated in accordance with the resolved queries.  All 
changes to the study database will be documented. 
17.4 Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with any 
updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for 
analysis is locked and cleaned per established procedures. 
17.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) 
inspectors upon request.  A file for each subject must be maintained that includes the signed 


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Informed Consent, HIPAA Authorization and Assent Form and copies of all source 
documentation related to that subject.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) must be kept secured and retained according VA & UW IRB policies. 
17.6 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and subject 
initials will identify all study subjects on CRFs and other documentation submitted to the IRB 
and contract organizations.  
18 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be kept in a 
locked file cabinet and code sheets linking a patient’s name to a patient identification number 
will be stored separately in another locked file cabinet.  Clinical information will not be released 
without written permission of the subject, except as necessary for monitoring by the FDA.  The 
Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance 
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
18.1 Protocol Amendments 
Any amendment to the protocol will be written by the Investigator.  Protocol amendments cannot 
be implemented without prior written IRB/IEC approval except as necessary to eliminate 
immediate safety hazards to patients.  A protocol amendment intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, provided the IRBs are notified 
within five working days. 
18.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of causality 
will be reported to the IRB/IEC in accordance with the standard operating procedures and 
policies of the IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress 
of the study.  The Investigator will obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the study protocol 
and the informed consent form will be in the possession of the Investigator before the study is 
initiated.  The IRB/IECs unconditional approval statement will be transmitted by the Investigator 
to designee prior to the shipment of study supplies to the site.  This approval must refer to the 
study by exact protocol title and number and should identify the documents reviewed and the 
date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the patients 
or when the change(s) involves only logistical or administrative aspects of the study.  Such 


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modifications will be submitted to the IRB/IEC and written verification that the modification was 
submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with 
the standard operating procedures and policies of the IRB; new information that may affect 
adversely the safety of the patients of the conduct of the study; an annual update and/or request 
for re-approval; and when the study has been completed. 
18.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, 
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if 
applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization and 
provide the documents to the Sponsor or designee for approval prior to submission to the 
IRB/IEC.  The consent form generated by the Investigator must be acceptable to the Sponsor 
and be approved by the IRB/IEC.  The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will also 
comply with local regulations. The Investigator will send an IRB/IEC-approved copy of the 
Informed Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written form and 
subjects must be given ample opportunity to inquire about details of the study.  If appropriate 
and required by the local IRB/IEC, assent from the subject will also be obtained.  If a subject is 
unable to sign the informed consent form (ICF) and the HIPAA authorization, a legal 
representative may sign for the subject.   A copy of the signed consent form (and assent) will be 
given to the subject and the original will be maintained with the subject’s records. 
18.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results shall 
be in accordance with a process determined by mutual written agreement among the study 
Sponsor and participating institutions.  The publication or presentation of any study results shall 
comply with all applicable privacy laws, including, but not limited to, the Health Insurance 
Portability and Accountability Act of 1996.  
18.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. 
Conduct the study in accordance with the protocol and only make changes after notifying 
the Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. 
Personally conduct or supervise the study (or investigation). 
3. 
Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. 
Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. 
Ensure that all associates, colleagues and employees assisting in the conduct of the study 
are informed about their obligations in meeting the above commitments. 


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6. 
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee). 
7. 
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. 
Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to include 
amendments and IND safety reports). 
9. 
Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
 


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Protocol Template © CFFT TDN   Effective: 12 SEP 2007 
APPENDIX 1.  SAMPLE COLLECTION & PROCESSING GUIDELINES 
 
Tube Matrix 
Tube 
Volume 
(ml) 
Processing 
Centrifuge 
Aliquot to 
Storage 
Tiger Top SST 
10 
Allow to clot 30-
60 min 
4°C, 2800 RPM, 
10 min 
Serum, 4x2ml 
cryovials 
-80°C 
Lavender EDTA 
10 
Process 
immediately 
4°C, 2800 RPM, 
10 min 
Plasma, 4x2ml 
cryovials 
-80°C 
 
Assay Matrix 
Assay 
Obtained from 
CRP 
10 ml Tiger Top SST 
MCP-1 
10 ml Tiger Top SST 
IL-1β 
10 ml Lavender 
EDTA 
 
 
 


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Protocol Template © CFFT TDN   Effective: 12 SEP 2007 
APPENDIX 2.  DATA MANAGEMENT 
 
Individual/Institution 
Role 
Role 
Dataset 
Coded 
Deidentified 
David Saloner, PhD 
Principal-
investigator 
Analysis, manuscript 
preparation 
Full dataset 
As 
appropriate 
No 
Chun Yuan, PhD 
Co-investigator 
Analysis, manuscript 
preparation 
Full dataset 
As 
appropriate 
No 
Warren Gasper, MD 
Co-investigator 
Analysis, manuscript 
preparation 
Full dataset 
As 
appropriate 
No 
Thomas Hatsukami, MD 
Co-investigator 
Analysis, manuscript 
preparation 
Full dataset 
As 
appropriate 
No 
Michael Hope, MD 
Co-investigator 
Analysis, manuscript 
preparation 
Full dataset 
As 
appropriate 
No 
Balu Niranjan, PhD 
Co-investigator 
Analysis, manuscript 
preparation 
Full dataset 
As 
appropriate 
No 
Niten Singh, MD 
Co-investigator 
Analysis, manuscript 
preparation 
Full dataset 
As 
appropriate 
No 
DMC 
Safety monitoring 
Interim safety analyses 
 descriptive 
statistics, adverse 
event descriptions, 
prepared by DSMB 
coordinator 
AE 
descriptions 
may contain 
coded 
information 
No 
Children’s Hospital 
Boston: Dept. of 
Laboratory Medicine, 
CERLab 
Contract lab 
Inflammatory Marker 
analysis 
Manifests 
containing subject 
IDs 
Yes 
No 


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APPENDIX 3.  RESEARCH MRI ACQUISITION PARAMETERS 
 
 
 
 
Pre-post 
3D-
MERGE 
(3D Dash) 
MP-RAGE 
2D T1w 
2D T2w 
DCE 
CE-MRA 
PC-MRI 
Mode 
3D 
3D 
2D 
2D 
2D 
3D 
2D 
Acquisition  plane 
Coronal 
Coronal 
Axial 
Axial 
Axial 
Coronal 
Axial 
Black-blood prep 
MSDE 
(DANTE) 
 
MSDE 
MSDE 
 
 
 
Resolution, mm2 
1.0 (0.8) 
1.0 
0.7 
0.7 
0.7 
0.7 
0.5 
FOV, mm2 
300×360 
(324x370) 
300x360 
120x300 
(160x300) 
120x300 
(160x300) 
120x300 
300x360 
160x300 
Slice thickness , mm 
0.7 (0.8) 
0.7 
3 
3 
4 
0.7 
5 
# of slices 
150 (104) 
150 
16 
16 
8 
150 
2 
TR/TE, ms 
8/4 (7/3.4) 
8/5 
800/10 
4500/40 
8/4 
8/4 
5/3 
Flip angle, ° 
6 (8) 
11 
 
 
15 
 
20 
Turbo factor 
25 (100) 
100 
14 
10 
 
 
 
NSA 
1 
1 
2 
1 
1 
1 
1 
No of stations 
1 
1 
1 
1 
1 
1 
2 
Scan time (min) 
3.5  (4.5) 
4.5 
12 
6 
5 
2 
2 


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APPENDIX 4.  DEXAMETHASONE SODIUM PHOSPHATE MONOGRAPH 
APPENDIX 5.  BULLFROG MICRO-INFUSION CATHETER IFU 
APPENDIX 6. LUTONIX 035 DCB CATHETER IFU 
APPENDIX 7. INPACT ADMIRAL DCB CATHETER IFU 
APPENDIX 8. STELLAREX DCB CATHETER IFU 
APPENDIX 9. WALKING IMPAIRMENT QUESTIONNAIRE (WIQ)