A Randomized Trial Comparing Drug-coated Balloon and Regular Balloon for Dialysis Access Stent Graft Restenosis
Phase: NA
Conditions: Hemodialysis Access Failure (Disorder), Stent-Graft Restenosis, Arteriovenous Graft, Drug-coated Balloon
Sponsor: National Taiwan University Hospital Hsin-Chu Branch

A Randomized Trial Comparing Drug-coated 
Balloon and Regular Balloon for Dialysis Access 
Stent Graft Restenosis
Mu-Yang Hsieh, MD1           Ren-Huei Wang, RN1           Lin Lin, MD1
Tsung-Yan Chen, MD1,2              Chih-Cheng Wu, MD1
Nov 25, 2017
1   Cardiovascular Center, National Taiwan University Hospital, Hsin-Chu Branch, 
Hsin-Chu, Taiwan
2   College of Medicine, National Taiwan University, Taipei, Taiwan
Corresponding Author: Mu-Yang Hsieh, No. 25, Lane 442, Sec. 1, Jingguo Rd., Hsin- 
Chu City 300, Taiwan; Email, drake1128@gmail.com; Phone, 886-35-326151, 
 
 ext:
 
  
2009,
2010
Manuscript type: clinical study
Key word: hemodialysis access, recurrent thrombosis, restenosis
Running title: drug-coated balloon versus regular balloon for stent graft restenosis
Total word count: 2553 words
Funding: no
Conflicting of interest: none
Acknowledgement: This study was supported by Grants from the National Taiwan 
University Hospital, Hsin-Chu Branch (HCH105-015-F). 

1    NTUH HC
2017 Research Protocol
English Title                    A Randomized Trial Comparing Drug-coated Balloon and
Regular Balloon for Dialysis Access Stent Graft Restenosis
Principal Investigator   Cardiology Division
Mu-Yang Hsieh (drake1128@gmail.com)
Title: Attending Physician MD, extension: 2009, 2010
Original protocol date: 2016-10-28
Revision for text: 2016-12
Translation to English version: 2017-10-31
Update for protocol number and text editing: 2017-11-25
Research 2017: Drug-coated Balloon for Dialysis Stent Graft 
NTUH-HC
1 of 21

Contents
1   NTUH HC
2017 Research Protocol                                                                                             1
2   Abstract                                                                                                                          4
3   Background                                                                                                                   5
3.1    Studies utilizing paclitaxel-coated balloon for dialysis access  .  .  .  .  .  .  .     6
3.2
Evidences suggested that DCB may be useful for dialysis access in-stent 
restenosis.
.  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .     6
3.3   Mechanisms of in-stent restenosis of AV grafts  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .     6
3.4   Mechanisms of balloon angioplasty- artery  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .     6
3.5   Mechanisms of balloon angioplasty- arterialized vein   .  .  .  .  .  .  .  .  .  .  .     6
3.
Mechanisms of luminal gain after balloon angioplasty for coronary in-
stent restenosis .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .
.
7
3.6.1    Intravascular Ultrasound  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .
.
7
3.6.2   Mechanisms of vessel dilatation after angioplasty to AV fistulae
.
7
3.6.3    Intravascular ultrasound (IVUS) as a sensitive study tool  .  .  .  .
.
7
3.6.4
Limitations of prior studies
. . . . . .
.
8
4   Purpose and goals                                                                                                       9
5 Materials and Methods
10
5.1    Randomization Process  .
. . . . . . . . . . . . . . . . . . . . . . . . . . .
13
5.1.1     Informed consent
. . . . . . . . . . . . . . . . . . . . . . . . . . .
13
5.1.2    Randomization .  .
. . . . . . . . . . . . . . . . . . . . . . . . . . .
13
5.2   Intravascular Ultrasound Evaluation .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .   13
5.2.1    Imaging Before and After Endovascuar Intervention .  .  .  .  .  .  .  .   13

6   Anticipated results                                                                                                  20

2    Abstract
Background
Prosthetic arteriovenous hemodialysis access graft (AVG) has high incidences of 
venous anastomotic stenosis and access failure. We can use stent graft in AVG with 
re- current venous anastomotic stenosis to improve long-term patency rate. However, 
after stent graft implementation, the effective treatment for restenosis of stent graft 
is still unknown. We thus design this study to investigate the efficacy and safety of 
drug- coated balloon versus regular balloon angioplasty in stent graft restenosis.

Methods
We designed a randomized trial to evaluate the efficacy and safety of drug-coated bal- 
loon versus regular balloon for in-stent restenosis in stent graft. We plan to enroll 40 
patients who presented with prosthetic AVG in-stent restenosis, and then to evaluate 
the restenosis lesions with intravascular ultrasound. Patients will be randomized into 
two groups of treatment: drug-coated  balloon angioplasty or regular balloon 
angioplasty.

3    Background
Recurrent arteriovenous graft (AVG) thrombosis decreases quality of life in end-stage 
renal disease patients and increases medical expenditure significantly. For recurrent 
venous anastomosis site restenosis, there was established evidence to use stent graft 
to improve  long-term  patency  rate.1 For hemodialysis  access  stenosis,  regular 
balloon, cutting balloon, and drug-eluting balloon have been proved to be safe in 
treatment of various morphology of stenosis.
In regard of regular balloon angioplasty to AVG, the 1-year primary patency rate is 
around  5%. Currently  some  data  suggested  that  drug-coated  balloon  (paclitaxel 
coated balloon) can lead to higher primary patency rate around 35%.  However, there 
is no established evidence to support use of drug-coated balloon for AVG stent graft 
restenosis.2
Purpose (for clinicaltrials.gov registration)
The purpose of this study is to determine whether drug-coated balloon is more 
effective than regular or common PTA balloon in graft stent patency.   The 
condition is for hemodialysis access intervention. The focused graft stent is that 
implanted for  hemodialysis  access. The  intervention  included  drug-coated  balloon 
(paclitaxel-coated balloon) versus regular or common balloon.
•  Study type: interventional
•  Study Design:
– Allocation: randomized
– Endpoint classification: efficacy study
– Intervention model: parallel
– Masking: single blind (outcomes assessor)
– Primary purpose: treatment
•  Official title: as the study project title

Literature Review
3.1 
Studies utilizing paclitaxel-coated balloon for dialysis 
access
Figure 2: Summary table of paclitaxel-coated balloon for dialysis access.
In 3 studies, the study populations were patients with AV fistulae.Katsanos2012, Patane2014, 
Lai2014. Only 1 study focused on AV grafts.Kitrou2015
In 3 studies, the study design involved randomization with comparison to plain 
balloon angioplasty, while one study had single arm in design.Patane2014
3.2 Evidences suggested that DCB may be useful for dialysis 
access in-stent restenosis.
This clinical implication mainly come from studies focusing on AVF (dialysis access)
and SFA in-stent restenosis studies.
3.3    Mechanisms of in-stent restenosis of AV grafts
3.4    Mechanisms of balloon angioplasty- artery
3.5    Mechanisms of balloon angioplasty- arterialized vein
•  Vessel wall and stent expansion.Higuchi2001

3.6 Mechanisms of luminal gain after balloon angioplasty for 
coronary in-stent restenosis
•  Neointimal tissue compression or extrusion out of the stent.Gordon1993, Mehran1996
•  Vessel wall and stent expansion.Mehran1996
•  Plaque redistribution.Mehran1996
•  Plaque fracture.
3.6.1   Intravascular Ultrasound
There are literatures discuss the IVUS use and stent graft use in hemodialysis access.Higuchi2001, 
Arbab-Z
3.6.2   Mechanisms of vessel dilatation after angioplasty to AV fistulae
Intravascular ultrasound imaging before and after angioplasty for steno- 
sis of arteriovenous fistulae in haemodialysis patients.  Dr. Higuchi demon- 
strated  that IVUS can  perform qualitative and  quantitative  studies of AVF after 
balloon angioplasty. They found that both stretching of vessel wall and plaque 
fractures contributed to luminal dilatation after balloon angiplasty.Higuchi2001
3.6.3   Intravascular ultrasound (IVUS) as a sensitive study tool
Hemodialysis access assessment with intravascular ultrasound.  Dr. Arbab- 
Zadeh reported that IVUS identified more lesions that angiography. And IVUS is a 
safe and feasible study tool for AVG lesions.Arbab-Zadeh2002
The use of  intravascular  ultrasound to assist angiography in diagnosis 
and  management  of hemodialysis  access.    Dr. Maursetter  reported  case 
experience in using IVUS to provide treatment guidance.Maursetter2011
Intravascular ultrasound-guided angioplasty of hemodialysis loop graft in 
a patient with contrast allergy.    Dr.  Casey reported that using IVUS can avoid 
contrast use in patient with contrast allergy.Casey2014

3.6.4   Limitations of prior studies
•  No IVUS data: not able to differentiate between intimal hyperplasia versus in-
situ thrombosis
•  Not aimed to AVG lesions.  However, the AVG has the worst thrombosis and 
restenosis rates in comparison to AVF.
•  No solution to stent graft stenosis available yet. However, the stent graft is the 
current treatment standard.
•  Case numbers

4    Purpose and goals
1. To evaluate the treatment efficacy of regular balloon versus drug-coated balloon 
in-stent restenosis in AVG.
2. To evaluate the primary patency rate and secondary patency rate.
3. To evaluate the changes in luminal parameters by IVUS.
4. To establish a research database.
5. To describe the anatomical distribution of in-stent restenosis of stent graft in AV
graft.

5    Materials and Methods
Investigational Plan
Table 2: Investigational Plan for Graft Stent Stenosis Study
IRB Number
Principal Investigator                  Mu-Yang Hsieh 
Co-Principal Investigator            Chih-Cheng Wu 
Angiography Core Laboratory
IVUS Core Laboratory 
Biomarker Core Laboratory 
Clinical Events Follo-wup
Study Design
This is a prospective, single-blind, single-center, randomized trial designed to assess 
the efficacy of  drug-coated  balloon angioplasty in  comparison  to regular balloon 
angioplasty in maintaining primary patency in patients with in-stent restenosis of 
stent graft placed for dialysis access dysfunction. The institutional review board in 
our hospital approved the study.
Background and Rationale
Null Hypothesis
The post-angioplasty primary patency rate is the same between drug-coated balloon 
angioplasty to regular balloon angioplasty in hemodialysis access stent graft 
restenosis.
Description of Devices
Study Population
The patients were eligible if they had end-stage renal disease and had graft stent at 
dial- ysis vascular access. Details of the inclusion and exclusion criteria are provided 
in table

1. The study flow chart was presented in Figure 3. The patients or legal representative 
provided written informed consent.

Eligibility
Patients visited our catheterization lab for shunt dysfunction. Patients age between 
20 years to 90 years. We do not accept healthy volunteers.
Inclusion Criteria
The patients will be enrolled if they meet the following criteria: 1. Age of 20 to 90 
years on regular hemodialysis at least 3 months, 2. had stent graft implemented at 
dialysis vascular access, 3. Angiographic evidence of stenosis within the stent graft or 
less then
2 cm from the stent graft edge, 4. clinical evidence of a hemodynamically significant 
stenosis or thrombosis, 5. patients ability to provide written informed consent.
Exclusion Criteria
The patient will be excluded from the study by the following criteria: Elbow fracture 
or any disease involve the elbow joint that prohibit the flexion maneuver. Target le- 
sion cannot be cross by the guide wire. Known hypersensitivity to heparin or contrast 
medium. Patients  have  bleeding  diathesis. Patients participating  in  another clinical 
tri- als with interfere with this trial in the past three months. Untreatable bleeding 
diathe- sis. Other diseases, such as cancer, liver disease, or cardiac insufficiency, 
which may lead to protocol violations or markedly shorten a patient’s life expectancy 
(less than three months). Patients unable or unwilling to participate this trial. 
Pregnancy, lac- tating woman, non-adult, criminals in sentence, psychiatric patients, 
research staffs or colleagues are prohibited from joining this study.
Sample Size Estimation
The required sample for analysis of covariance of change in patency rate of AVG to 
detect a 45% difference, controlling for baseline values with 80% power and type I 
error of 0.05 is 19 participants per group.   Allowing for a 15% drop-out rate, we 
aimed to recruit 21 participants per group.3
The sample size was estimated according to the following parameters: for a alpha of
0.05 and power of 0.90, the  restenosis  rate of AVG venous  anastomosis  site 49% 
versus
77%  at  6  months  in  groups  treated  with  stent  graft  versus  standard  balloon 
angioplasty, the sample size was calculated to be 114 patients.4

Because  the  estimated  sample  size  number  114  patients  will  require  3  years  to 
complete

the enrollment number, we plan to do a pilot study first, and the intended enrollment 
number in pilot study is 20 patients.
The study flow chart is presented in Figure 3.

5.1    Randomization Process
5.1.1   Informed consent
The patient or family has to sign all the investigational documents before enrollment.
5.1.2   Randomization
At the time  of  enrollment,  the  research assistant  will  use  computer  to  generate 
randomization allocation table with computer-based program (REDCap). REDCap 
(Research  Electronic  Data  Capture)  system  is  a  validated  and  mature  databank 
developed by Vanderbilt University. It is also extensively used in Stanford University. 
The randomization module in REDCap is computer-based  and excluded any 
manipulation process that can alter randomization result.
The  patient  will  be  randomized  into  drug-coated  balloon  group  or  into  regular 
balloon group.
Biomarkers
Patients will also receive blood sampling with target biomarkers measurements. The 
biomarkers to be focused in our study:  uremic toxins and miRNAs, or other novel 
markers, which are found to be associated with vascular access restenosis.
5.2    Intravascular Ultrasound Evaluation
5.2.1   Imaging Before and After Endovascuar Intervention
After obtaining vascular access, a 0.035-inch wire was used to traverse the occlusion 
or stenosis in the stent graft. The wire was then exchanged to a 0.014-inch wire by a 
bal- loon catheter. Intravascular ultrasound was then performed across the whole 
length of the stent graft (25 mm within the stent edge) and the lesion (5 mm of the 
lesion  margin). The parameters were collected as Table 6. Both angiography and 
IVUS parameters are to be collected.Stone2011
An  additional measurement  of luminal  area with  elbow  in  extension  or  flexion  was 
done  to obtain another parameter regarding mechanical  stress to the venous 
anastomosis junction.

Research 2017: Drug-coated Balloon for Dialysis Stent Graft 
NTUH-HC

Table 4: Study Protocol Checklist
Content
Confirmation
Enrollment
Evaluation
Cath room team
Randomization
By REDCap
Device and Equipment
IVUS
Angiography
IVUS set-up
QCA
with track
before and after angioplasty
IVUS
before and after lesion: 5
mm, before and after stent 
edge: 25 mm
Intravascular Ultrasound (IVUS) The interpretation of IVUS is performed by 
physician unaware of the group assignment. The minimal luminal area (MLA) has to 
be documented.5,6
IVUS procedures
1. A track use is mandatory. The IVUS pull-back speed is set to 1 mm/sec.
2. IVUS evaluation must include 2.5 cm beyond the stent edge. If the lesion 
extends beyond the stent edge, IVUS has to evaluate distal 0.5 cm further.
3. IVUS maximal depth: 8 mm.
4. IVUS must be performed before and after angioplasty in the index procedure.
Endovascular Intervention
Balloon used: Drug-coated balloon (Boston-Scientific), Regular balloon (Wanda). The 
size of balloon is determined by the operator.
Drug-coated balloon: inflation time 1 minute. Regular balloon: inflation determined 
by the operator.
1. Sequence of balloon angioplasty: DCB first, then cutting or high-pressure as 
indicated.
2. If DCB not enough in length, treat at least one lesion of in-stent restenosis. Note 
it within the study report.
15 of 21

Table 6: Study Protocol Case Report FormStone2011
Category                          Parameters                                                                                         Result
Angiography
Reference vessel diameter (mm)
Minimal luminal diameter (mm) 
Diameter stenosis (%)
Lesion length (mm)
IVUS (gray scale)
lesion: 5 mm; stent edge: 25 mm
Minimal lumen area (mm2) 
Minimal lumen area ≤4.0mm
External elastic membrane area (mm2) Plaque 
and media cross sectional area (mm2) Plaque 
burden (%)
Lesion length (mm)
Remodeling index (median [IQR]) Distance 
to the minimal lumen area (mm)
IVUS          
(radiofrequency)
Tissue composition (%, median [IQR]):
•  fibrous tissue
•  fibrofatty
•  dense calcium
•  necrotic core
Lesion classification:
•  pathological intimal thickening
•  thick-cap fibroatheroma
•  thin-cap fibroatheroma
•  fibrotic plaque
•  fibrocalcific plaque

For patients presented with acute shunt thrombolysis
This study will not use urokinase for acute thrombosis patient. Please arrange follow- 
up of patient after acute thrombosis treatment.

Outcomes measurement (for clinicaltrials.gov registration)
•  Primary outcome measures
– target lesion late luminal loss [time frame: 1 and 3 months] [designated as 
safety issue: no]
measure the difference of the MLD (minimal luminal diameter) by IVUS at
0 time and at 1, 3, and 6 months
•  Secondary outcome measures
– minimal luminal area and diameter (MLA and MLD) [time frame: 1 and 3 
months] [designated as safety issue: no]
measured MLA and MLD of target lesion at 1 and 3months
– Restenosis rate of target lesion [time frame: 1 and 3] [designated as safety 
issue: no]
>50% stenosis is designated as restenosis
– repeated intervention for AV shunt
– abandon of AV shunt
because of repeated non-salvageable occlusion, the arteriovenous shunt 
(including both fistula or grafts) was abandoned
– death
death of any cause
The other secondary end points were:  the primary patency rate, which was a 
composite of recurrent in-stent restenosis and shunt dysfunction  requiring 
endovascular treatment and acute thrombosis. Shunt acute thrombosis was defined 
as no thrills or pulsations and confirmation made by angiography, the luminal area 
documented by intra-vascular ultrasound study; the secondary patency rate; the rate 
of repeated endovascular intervention.
Safety assessments included the incidence of hematoma, vessel rupture, infection, 
and the pain scale rated by patients after recovering from treatment.
The patient will be followed at 30 days with angiography in the cath lab.
Statistical Analysis
We plan to enroll 20 patients as a pilot study.

Participants will be randomly assigned into two groups according to the use of drug- 
coated or regular balloons. These two groups will be compared in the following 
parameters: clinical data, laboratory data, intravascular  ultrasound parameters 
before and  after balloon angioplasty, post-interventional  lesion primary and 
secondary patency (PLP and PLS).
For patient with very long graft stent longer than the coverage of drug-coated balloon, 
there will be additional comparison of the lesion treated with drug-coated balloon 
and regular balloon in the same vessel.
Two-sample  student’s t  tests  will  be  used  for  the  comparisons  of  continuous 
variables.  Chi-square  test  will  be  used  to  detect  difference  between  categorical 
variables. For patients with recurrent thrombosis or stent graft stenosis, univariate 
correlation will be analyzed by the Spearman rank correlation test. Difference is 
considered statistically significant if P < 0.05. All statistics works were analyzed using 
the SPSS 17.0 software (Chicago, IL, USA), R software (Gimc packages).

6    Anticipated results
1. To provide results to support the use of DCB in AVG in-stent restenosis.
2. To decrease medical expenditure.

References
1.
Haskal ZJ, Trerotola S, Dolmatch B, et al. Stent graft versus balloon angioplasty 
for failing dialysis-access grafts. N Engl J Med 2010;362:494–503.
2.
Kitrou PM, Katsanos K, Spiliopoulos S, et al. Drug-eluting versus plain balloon an- 
gioplasty for the treatment of failing dialysis access: final results and cost-
effectiveness analysis from a prospective randomized controlled trial 
(NCT01174472). Eur. J. Radiol. 2015;84:418–423.
3.
Wu CC, Lin MC, Pu SY, et al. Comparison of cutting balloon versus high-pressure 
balloon angioplasty for resistant venous stenoses of native hemodialysis fistulas. 
J. Vasc. Interv. Radiol. 2008;19:877–883.
4.
Salman L and Asif A. Stent graft for nephrologists: concerns and consensus. Clin 
J Am Soc Nephrol 2010;5:1347–1352.
5.
Maursetter L and Yevzlin AS. The use of intravascular ultrasound to assist angiog- 
raphy in diagnosis and management of hemodialysis access. Semin Dial 
2011;24:89–
91.
6.
Arbab-Zadeh A, Mehta RL, Ziegler TW, et al. Hemodialysis access assessment 
with intravascular ultrasound. Am. J. Kidney Dis. 2002;39:813–823.