Evaluation of Paclitaxel in Patients With CLI (Critical Limb Ischemia) and Femoropopliteal Occlusive Disease Treated With DCB Angioplasty
Phase: NA
Conditions: Ischemia
Sponsor: Rabih A. Chaer

 
 
 
 
 
 
 
 
Tissue Paclitaxel and Outcomes of Patients with Rutherford Class 5/6 Ischemia Treated with DCB Angioplasty 
 
Rabih A. Chaer1*, MD, Patrick Cherfan1, MD, Adham N. Abou Ali1, MD, Othman M. Abdul-Malak1, MD, Sina 
Asaadi1, MD, Mohammad H. Eslami1, MD, Efthymios D. Avgerinos1, MD, Karim M. Salem1, MD, Georges Al-
Khoury1, MD, Michel S. Makaroun1, MD, Maria E Romero2, MD, Renu Virmani2, MD 
 
1Division of Vascular Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa. 
2CVPath Institute, Inc, Gaithersburg, Md. 
 
*Corresponding Author:      
Rabih A. Chaer, MD, MSc 
200 Lothrop Street 
Pittsburgh, Pa 15213 
E-mail address: chaerra@upmc.edu 
 
 
NCT Number: NCT02758847 
 
 
 
 
 
Document Date: 03/19/2019 

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Study Title 
Evaluation of paclitaxel in patients with CLI 
(critical limb ischemia) and femoropopliteal 
occlusive disease treated with DCB (drug coated 
balloon) angioplasty 
Protocol Number 
PRO- PRO15120093 
Sponsor 
Funded by Department  
Study Design 
Prospective, single center, non-randomized, 
single arm clinical trial 
Study Objective 
To evaluate the paclitaxel level in debrided 
tissue following DCB (drug coated balloon) 
angioplasty for femoropopliteal occlusive 
disease in patients with CLI (critical limb 
ischemia) and tissue loss to see if it impacts 
wound healing 
Primary Study Endpoint 
Primary Study Endpoints: 
-wound healing rate 
-amputation free survival 
-amputation free and wound healing 
-primary sustained clinical improvement 
 
Major adverse events (MAE) 
     -Death of any cause 
     -Major amputation of target limb  
Secondary Study Endpoints 
Secondary Study Endpoints: 
-Primary patency at 1,3,6 and 12 months 
-secondary patency at 1,3,6 and 12 months 
-rate of sever >50% restenosis measured by  
  duplex ultrasound 
-rate of reinterventions 
Subject Population 
Patients age 40 years to 95 years identified with 
CLI (critical limb ischemia) and tissue loss with a 
Rutherford category of 5 or 6 
Number of Subjects 
50  
Device to be Used 
(FDA approved/commercially available) 
Medtronic Admiral Balloon  OR 
Bard Lutonix Balloon  
Expected Time to Complete Enrollment 
48 months 
Schedule of Events 
Baseline/Procedure 

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  -Inclusion/exclusion criteria review 
  -Informed consent 
  -medical history review 
  -concomitant medication review 
  -office visit 
  -arterial Doppler (ABI/PVR/Toe pressures) 
  -Rutherford Category 
  -Angiogram 
  -ballooning (Admiral or Lutonix) 
  -stenting (if indicated) 
  -wound debridement/toe amputation 
  -histological analysis 
  -pregnancy test (women of child-bearing age) 
 
1,3,and 6 month follow-up visits 
  -concomitant medication review 
  -office visit 
  -arterial Doppler (ABI/PVR/Toe pressures) 
  -wound debridement 
  -histological analysis 
  -AE assessment 
 
12 month visit 
  -office visit 
  -arterial Doppler (ABI/PVR/Toe pressures) 
  -AE assessment 
  -study exit 
Study Principal Investigator 
Rabih A. Chaer, MD 
Contact Information 
412-802-3333 or email chaerra@upmc.edu  
 

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◦Background and Objective 
The use of DCB in patients with CLI and tissue loss has recently raised some concerns after the IN PACT 
deep trial using paclitaxel coated balloon angioplasty in the tibial arteries was terminated.  Paclitaxel 
(also known as Abraxane) is classified as an antineoplastic drug.   
In this trial, there were stronger trends toward a higher rate of major amputation (8.8% vs 3.6%; P = 
.080) and a lower rate of major amputation-free survival (81.1% vs 89.2%; P = .057) in the DEB arm at 
12 months, despite the presence of longer lesions and deeper wounds in the patients who underwent 
standard balloon angioplasty. Wound healing was similar in the 2 groups, but overall procedural 
complications were more common with the DEB (9.7% vs 3.4%; P = .035). 
Our objective is to evaluate the paclitaxel level in debrided tissue following DCB (drug coated balloon) 
angioplasty for femoropopliteal occlusive disease in patients with CLI (critical limb ischemia) and tissue 
loss to see if it impacts wound healing. 
◦Question 
Although the association between the DCB therapy and limb outcomes could not be clearly linked to 
the use of antiproliferative agents, the findings of paclitaxel crystals downstream of the treated lesions, 
although in small amounts, has raised concerns about the safety of such therapy in patients with CLI 
and tissue loss. 
These concerns, however, may not translate to patients with femoropopliteal occlusive disease as the 
amount of paclitaxel reaching the foot may be even smaller after being filtered by the calf 
musculature. 
Since the use of DCB angioplasty in the SFA and popliteal has been shown to deliver significantly more 
durable outcomes compared to standard angioplasty alone, with reported primary patency rates of 
almost 90% at one year, this therapy may even be more needed in patients with tissue loss where 
prolonged patency is essential for wound healing. 
We hypothesize that DCB angioplasty of femoropopliteal occlusive disease using a 4, 5 or 6mm 
diameter InPact balloon is safe and effective in patients with CLI and tissue loss with negligible 
paclitaxel levels in debrided wounds (Rutherford 5,6). 
◦Patient Population 
Inclusion criteria: 
Ages Eligible for Study:   40 Years to 95 Years 
Genders Eligible for Study:  Both 
Patient population: all patients with CLI and tissue loss scheduled for endovascular intervention 
for fem pop occlusive or multilevel disease. 

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Patient or patient's legal representative have been informed of the nature of the study, agrees 
to participate and has signed an Ethical Committee approved consent form 
Patient has documented chronic Critical Limb Ischemia (CLI) in the target limb prior to the study 
procedure with Rutherford Category 5 or 6 
General Angiographic Inclusion Criteria 
Single or multiple lesions with ≥70% diameter stenosis (DS) of different lengths in the SFA 
and/or popliteal arteries. 
Iliac inflow or Tibial outflow interventions can be done at the discretion of the investigator with 
standard balloon PTA  
All subjects with CLI (critical limb ischemia) intended to be treated with a drug coated balloon 
Exclusion criteria: 
Patient unwilling or unlikely to comply with Follow-Up schedule 
*Since paclitaxel can be harmful to an unborn child, participants (male and female) of childbearing age 
will be required to have a blood and/or urine test before participating in this study.  A discussion 
related to Planned Parenthood will be held with participants of childbearing age.  Any participant that 
is pregnant or believes that they might be pregnant will be withdrawn from the study immediately.  At 
the completion of the study, the investigator will discuss with the participant when it might be safe to 
become pregnant or become a new father." 
◦Proposed Study Design 
Research design 
50 patients with documented chronic Critical Limb Ischemia (CLI) in the target limb prior to the study 
procedure with Rutherford Category 5 or 6 will be enrolled and followed for at least one year. 
Hemodynamic vascular lab testing with arterial Doppler (ABI, PVR, toe pressures) and arterial duplex 
imaging of the affected leg will be performed in an accredited vascular lab pre-enrollment as well as at 
12 months post intervention. 
Only patient with severe femoropopliteal occlusive disease (with or without multilevel disease 
including iliac inflow or tibial outflow disease) requiring intervention will be enrolled. The use of DCB 
angioplasty will be restricted to the fem pop segment. Patients with multilevel disease also requiring 
iliac inflow and/or tibial outflow intervention to establish in line flow to the foot will be treated with 
standard balloon angioplasty/stenting as per the standard of practice in the USA. 

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Procedures will be done in an operating room angiography suite, and patients with tissue loss will 
undergo concomitant wound debridement or planned toe amputation/debridement as per the 
standard of practice. The tissue obtained will be sent for histological analysis. 
Wound care will be provided per standard of practice on a weekly or bi-weekly basis, and tissue 
obtained from further debridement/amputation done in the office setting or operating room will also 
be obtained from analysis. 
From the obtained tissue specimen, the arterioles per each histologic section will be examined for any 
foreign material, paclitaxel crystals medial arterial wall inflammation, foreign-body reaction, emboli, 
and medial necrosis. Changes will be characterized as single or clusters of multiple small vessels 
(predominately arterioles) with varying degrees of eosinophilic fibrinoid necrosis, SMC apoptosis and 
loss, and adventitial inflammation or vasculitis consisting primarily of lymphocytes. The number of 
arterioles with findings will be expressed as a percentage of the total number of arterioles evaluated. 
Treatment: 
Patients that meet all of the inclusion and none of the exclusion criteria will be consented for the 
study.  Each participant will receive angiogram with DCB (drug coated balloon)/stenting with wound 
debridement.  Paclitaxel® coated balloons will be used for patients.   For the study, 50% of the study 
population will receive the Bard Lutonix balloon. The other 50% will receive the Medtronic Admiral 
balloon. Both FDA approved devices contain the drug paclitaxel. Tissue samples will be sent to 
pathology for specific staining to evaluate trace evidence of the drug paclitaxel.  Patients will be asked 
to return at 1 month, 3 months, 6 months and 12 months post procedure.  If indicated, patients with 
tissue loss may have an in-office wound debridement.  Tissue samples from these procedures will also 
be sent to pathology  to evaluate for wound healing.  
Primary Outcome Measures:  
.Wound healing. Rate of Wound Healing [Time Frame: 12 months] 
Percentage of participants with wound healing defined as > 50% area/volume reduction of baseline 
ulcer(s) in the treated leg at 1 year. 
.Amputation Free Survival [Time Frame: 12 months] 
Percentage of participants with a 1 year amputation free survival. 
.Amputation Free Survival and Wound Healing [Time Frame: 12 months] 
Percentage of participants with a 1 year amputation free survival and wound healing. Wound healing is 
defined as > 50% area/volume reduction of baseline ulcer(s) in the treated leg at a specified time point. 
 
 

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•MAE (Major Adverse Events) [Time Frame: 12 months] 
Percentage of participants with a MAE (Major Adverse Events) at 1 year. Major Adverse Events, 
defined as Death of any Cause, Major Amputation of target limb. 
Secondary Outcome Measures 
.Primary patency at 12 months as measured by duplex ultrasound 
◦Relevance to Drug Coated Balloon Therapies in Patients with CLT and Tissue Loss 
The findings of this study will determine the tissue levels of paclitaxel in debrided tissue in patients 
with CLI, and establish the safety and efficacy of DCB for femoropopliteal occlusive disease in those 
patients. I will reinforce the use of both Medtronic’s Admiral DCB and the Bard Lutonix DCB in this 
patient population by alleviating physician concern about increased limb loss secondary to Paclitaxel in 
patients with tissue loss. 
Statistical Analysis 
Data analysis was carried out using the Statistical Package for the Social Sciences, version 26 (IBM Corp, 
Armonk, NY) and all tests were two-sided with statistical significance defined at P0.05. Continuous 
variables were reported as mean ± SD, and categorical variables were reported as frequency (%). Chi-
square tests were used to compare categorical variables between the study groups. Kaplan-Meier (KM) 
survival analysis was used to estimate stent primary patency and survival rates. Multivariate logistic 
regression analysis was used to determine factors associated with major adverse limb events (MALE); 
odds ratios (OR) and their corresponding 95% confidence intervals were reported as measures of 
associated factors.