Clinical trial NCT02217501
Conditions: Peripheral Arterial Disease
Keywords: peripheral arterial disease, antiplatelet therapy
Sponsor: University of Texas Southwestern Medical Center
Start date: 2015-11-01; Completion date: 2020-01-30
Enrollment: 159 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate whether clopidogrel 75 mg daily on a background of aspirin 75-100 mg/d for clinically indicated duration or for an additional 12 months will lead to an increased rate of primary patency, limb salvage, non-fatal myocardial infarction (MI), ischemic stroke, and survival, in patients receiving endovascular treatment of PAD at end of study treatment.

Detailed description:
Peripheral arterial disease (PAD) is extremely prevalent worldwide and affects over 206 million people. Over 36 million patients with PAD are estimated to be present in the United States. Percutaneous revascularization therapies have evolved dramatically, yet the long-term success of these therapies remains modest and the morbidity and mortality associated with PAD remains high, with up to 30% mortality risk at 5 years. Nearly, 3.2 million endovascular procedures are performed annually. Though, this exceeds interventional procedures performed for coronary artery disease (CAD), the current PAD guidelines are silent regarding the need and optimal duration of antiplatelet therapy (APT) for patients following an endovascular procedure for claudication or critical limb ischemia (CLI). The lack of data and clinical studies is by far the greatest impediment to the formulation of such guideline recommendations critically needed by providers and patients alike, especially given the current limited durability of lower extremity endovascular procedures.

The objective of this trial is to evaluate whether clopidogrel 75 mg QD on a background of ASA 75-100 mg/d for clinically indicated duration or for an additional 12 months will lead to an increased rate of primary patency, limb salvage, non-fatal myocardial infarction (MI), ischemic stroke, and survival, in patients receiving endovascular treatment of PAD at end of study treatment.

The investigators hypothesize that dual antiplatelet therapy (DAPT) with ASA and clopidogrel administered for an additional 12 months following iliac, femoropopliteal or below the knee endovascular intervention will improve primary patency, limb salvage, freedom from ischemic stroke and survival, in patients with symptomatic PAD.

Clinical endpoints will be analyzed in all subjects who are enrolled, regardless of whether the trial treatment administered successfully completed for the desired duration. A subject will be considered enrolled in the trial when he/she is randomized to one of the treatment arms of the study. All endpoints are subject-based unless otherwise specified.

The primary endpoint is subject-based of the longer of a 12-month or end of study treatment endpoint of the first occurrence of index limb arterial occlusion, surgical intervention, endovascular intervention, amputation of the affected limb (primary patency and limb salvage), MI, ischemic stroke or death (survival).

The secondary endpoints are subject-based on the longer of a 12 month or end of study treatment endpoints that include: (a) the first occurrence of any individual component of the primary endpoint, (b) the first occurrence of the following during follow-up: cardiovascular death, or MI, or ischemic stroke, or any amputation above the ankle and (c) severe bleeding defined according to the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) classification.

The tertiary endpoint is based on the longer of a 12-month or end of study moderate bleeding according to the GUSTO classification.

Arms: arm 1: Clopidogrel 75 mg daily and Acetylsalicylic acid (ASA) 75-100 mg daily for clinically indicated duration plus an additional 12 months arm 2: Clopidogrel 75 mg daily and Acetylsalicylic acid (ASA) 75-100 mg daily for clinically indicated duration with a minimum of 30 days
Interventions: intervention 1: Clopidogrel intervention 2: Acetylsalicylic acid (ASA)
Intervention descriptions: intervention 1: Clopidogrel 75 mg once daily for clinically indicated duration or for clinically indication duration + 12 months intervention 2: Acetylsalicylic acid (ASA) 75-100 mg once daily for clinically indicated duration or for clinically indication duration + 12 months

Protocol documents:
Prot_SAP_000.pdf: 
Official title: Antiplatelet Strategy for Peripheral Arterial Interventions for 
Revascularization of Lower Extremities  
 
 NCT number: NCT02217501 
 
Document date: February 23, 2018, Version A1.5 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
ASPiRE 
Antiplatelet Strategy for Peripheral Arterial Interventions for 
Revascularization of Lower Extremities 
Principal investigator: 
Subhash Banerjee, MD  
Primary institution:         University of Texas Southwestern Medical Center 
1801 Inwood Rd, 
Dallas, TX 75235 
 
Trial Monitoring: 
Preeti Kamath, MHA 
4500 S Lancaster Road 
151/3S 
Dallas, TX 75216 
Coordinating  
Investigators: 
Principal Investigator 
4500 S Lancaster Road 
111a Dallas, TX 75216 
 
Trial Centers: 
See the trial Manual of Operations for a list 
of trial centers  
Date of Issue: 
Feb 23 2018 
Version A1.5 
Date(s) of Amendment(s): Version A.1: Jan 1, 2014  ; Version A1.2 Mar 30, 2016                                                
                                                  Version A 1.3: Mar 13,2017 ;Version A 1.4: May 11 2017 
 
 
 
 
 
Do not copy or distribute without written permission. 
 
 
 
 
 
 
 
 
 
 
This protocol contains confidential information for use by the Investigators and their designated 
representatives participating in this clinical investigation. It should be held confidential and 
maintained in a secure location. 
 
THESE DOCUMENTS ARE THE PROPERTY OF THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER. AND SHALL 
NOT BE REPRODUCED, DISTRIBUTED, DISCLOSED OR USED FOR MANUFACTURE OR SALE OF APPARATUS WITHOUT THE 
EXPRESS WRITTEN CONSENT OF   THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
 
 
Investigator’s signature page 
 
ASPiRE 
Antiplatelet Strategy for Peripheral Arterial Interventions for 
Revascularization of Lower Extremities 
 
 
TRIALCENTER:         ______________________________________ 
 
 
 
 
Print Name of Trial Center) 
 
I, the undersigned, have read and understand the protocol specified above and agree on its 
content. I agree to perform and conduct the trial as described in the protocol and according to 
GCP and other applicable regulatory requirements. In addition, when applicable, I agree to enlist 
sub-investigators who also agree to perform and conduct the trial as described in the protocol. 
 
 
 
___________________________ 
__________________          _________ 
Principal Investigator Print name:  
 
Signature 
 
 
Date 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
 
Protocol Synopsis 
 
ASPiRE 
Antiplatelet Strategy for Peripheral Arterial Interventions for 
Revascularization of Lower Extremities 
 
 
 
PI 
Name: Subhash Banerjee, MD 
 
Phone number: 214-857-1608 
 
Email: Subhash.banerjee@utsouthwestern.edu  
 
TRIAL OBJECTIVE 
Primary Objective 
To evaluate whether clopidogrel 75 mg daily on a background of 
aspirin 81 mg/d for U.S. sites (75-100 mg/d for international sites) for 
clinically indicated duration or an additional 12 months will lead to 
an increased rate of primary patency, limb salvage, non-fatal 
myocardial infarction (MI), ischemic stroke, and survival, in patients 
receiving endovascular treatment of PAD at end of study treatment 
 
Control Arm 
clopidogrel 75 mg daily on a background of aspirin 81 mg/d for U.S. 
sites (75-100 mg/d for international sites) for clinically indicated 
duration with a minimum of 30 days. 
 
Test Arm (as applicable) clopidogrel 75 mg daily on a background of aspirin 81 mg/d for U.S. 
sites (75-100 mg/d for international sites)  for clinically indicated 
duration + 12 months 
 
Endovascular 
interventions included 
Iliac  
Femoropoliteal 
Below-the knee 
 
TRIAL DESIGN 
Trial Design 
Prospective, two-arm, multicenter randomized clinical trial. 
 
Planned Number of 
Subjects 
202 subjects will be enrolled in each arm (total subjects = 404) 
Clinically indicated dual 
antiplatelet therapy 
(DAPT) duration 
Clinically indicated DAPT duration will be based on the longest pre-
discharge following an index peripheral intervention procedure, 
DAPT duration. This will be determined based on: peripheral 
intervention device IFUs, preceding coronary intervention, acute 
coronary syndrome or other guideline-based clinical or device 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
specific DAPT durations.   
 
Planned Number of Sites 
/ Countries 
Approximately 18 investigational centers in the U.S.. are expected 
to participate. 
 
No center will be allowed to enroll more than 40% of planned total 
enrollment. 
Primary Endpoint 
Primary Endpoint (subject-based): 
The first occurrence of index limb arterial occlusion, surgical 
intervention, endovascular intervention, amputation of the 
affected limb (vessel occlusion or failure), MI, ischemic stroke 
or death at 12 months from index procedure or end of study 
treatment, whichever is longer 
 
Secondary Endpoints 
Secondary Endpoints through end of study treatment: 
 
The first occurrence of any individual component of the 
primary endpoint 
 
First occurrence of the following during follow-up: 
cardiovascular death, or MI, or ischemic stroke, or any 
amputation above the ankle. 
 
Severe bleeding defined according to the Global Utilization 
of Streptokinase and Tissue plasminogen activator for 
Occluded coronary arteries (GUSTO) classification 
 
Tertiary Endpoints 
 Moderate bleeding defined according to the Global Utilization of 
Streptokinase and Tissue plasminogen activator for Occluded 
coronary arteries (GUSTO) classification 
 
Randomization 
• 
Patients scheduled for a planned discharge will be randomized 
on a 1: 1 basis using a computerized central randomization 
portal available through RedCap® to either of the following 
treatment groups: 
• 
ASA (81 mg U.S. sites; 75-100 mg international 
sites) + clopidogrel: for clinically indicated 
duration (control arm)  
• 
ASA (81 mg U.S. sites; 75-100 mg international 
sites) + Clopidogrel 75mg: for clinically indicated 
duration +12m (treatment arm)  
Randomization will be performed at the within 2 weeks of an eligible 
procedure 
 
Follow-up schedule 
All potential subjects will be evaluated for enrollment after the index 
procedure pre-discharge or within 14 days of the procedure. Follow-
up schedule will include patient visits at 30 days and q6 months till 
the end of study treatment The trial will be considered complete with 
regard to the primary endpoint after all enrolled subjects have 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
completed a 12-month or end of study treatment follow-up 
evaluation, have died, have a documented premature 
discontinuation, or whose follow-up window  has closed. Follow-
up window is +7 days for the 30-day visit and +15 days for all other 
visits. 
 
Key Inclusion Criteria 
General: 
 
Signed informed consent 
 
At least 18 years old 
 
Documented symptomatic iliac, femoropopliteal (FP) or 
below-the knee artery (BTK) atherosclerotic disease 
(Rutherford/Becker category 2, 3 or ≥4) 
 
Undergone clinically indicated uncomplicated endovascular 
intervention to one or more locations of the iliac, 
femoropopliteal below-the knee arteries 
 
Estimated survival ≥1 year in the judgment of the primary 
operator 
 
Pre-index procedure use of ASA, clopidogrel or both at any dose 
 
Angiographic: 
 
De novo or restenotic lesions in the common and/or external 
iliac artery, superficial femoral artery (SFA), popliteal artery, 
tibio-peroneal (TP) trunk, anterior tibial (AT) artery, peroneal 
artery (PA) or posterior tibial (PT) artery (applies to all target 
lesions if multiple) 
 
Subjects with multiple planned procedures can be enrolled after the 
completion of the last planned procedure. 
 
Key Exclusion Criteria 
General: 
 
Complicated qualifying procedure (perforation, flow limiting 
dissection, distal embolization requiring re-intervention, need 
for repeat endovascular, surgical revascularization, amputation 
or blood transfusion prior to hospital discharge following index 
procedure 
 
Extended hospital stay >7 days following the index procedure 
 
Allergy to aspirin or clopidogrel 
 
Life expectancy less than 12 months due to other medical co-
morbid condition(s) that could limit the subject’s ability to 
participate in the trial, limit the subject’s compliance with the 
follow-up requirements, or impact the scientific integrity of the 
trial 
 
Known hypersensitivity or contraindication to contrast 
dye that, in the opinion of the investigator, cannot be 
adequately pre-medicated. 
 
Intolerance to antiplatelet, anticoagulant, or thrombolytic 
medications 
 
Platelet count <90,000 mm3 or >600,000 mm3 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
 
Serum creatinine >2.5 mg/dL 
 
Dialysis-dependent end stage renal disease 
 
Pregnancy 
 
Current participation in another drug or device trial that requires 
interruption of dual-antiplatelet therapy with aspirin or 
clopidogrel for  the duration of this study  
 
Planned surgeries, endovascular or other non-vascular or cardiac 
procedures 
 
Warfarin or other chronic oral anticoagulant use 
 
Contraindication(s) to the use of antithrombin or antiplatelet 
agents (history of intra-cerebral bleed, presence of intracerebral 
mass, recent or <6 weeks gastrointestinal bleed, blood 
transfusion within the last 6 weeks, any trauma requiring surgery 
or blood transfusion within the last 4 weeks or any surgical 
procedure within the last 4 weeks. 
 
Angiographic: 
 
Endovascular intervention to iliac, FB or BTK 
artery bypass graft 
 
Persistent, intraluminal thrombus of the 
proposed target lesion at the completion of 
the index procedure 
 
Perforated vessel as evidenced by extravasation of contrast media 
 
Vascular graft, aneurysm or postsurgical stenosis of the target 
vessel 
Multiple Interventions 
During Index Procedure 
Multiple interventions during an index procedure will be allowed as 
long as the procedure is deemed successful and uncomplicated by the 
primary operator and no additional procedures are planned 
 
Statistical Methods 
Sample size parameters 
• 
The occurrence of the primary endpoint is expected 
to be approximately 49% at 12 months in the 
control group17 
• 
A 30% relative risk reduction in the incidence of primary 
endpoint would be clinically important 
• 
To detect a 30% relative reduction in the 1-year primary 
event rate from 49% to  34.0%17 with 80% power at the 
two-sided, .05 significance level, assuming a 12-month 
recruitment period and a 1 0 % dropout rate at 1 year, a total 
of 404 (368+36) patients will be randomized (202 in each 
group) and followed-up for endpoints for 12 months or until 
end of study treatment, whichever is longer  
 
Statistical analysis 
• 
Continuous variables will be summarized as mean±standard 
deviation and compared using the t-test or the Wilcoxon rank-
sum test, as appropriate 
• 
Discrete variables will be presented as frequencies and 
group percentages and compared using the chi-square 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
test 
• 
For all comparisons a two-sided probability of <0.05 will be 
considered statistically significant 
• 
All analyses were performed using the SAS 9.1 or recent 
version (SAS Institute Inc., Cary, North Carolina) 
• 
Primary endpoint will be assessed as per an intention-to treat 
principle 
• 
Subsequent analysis will also be performed based on as treated 
groups 
• 
Pre-specified subgroup analyses will include: 
• 
Stent vs. non-stent groups 
• 
DES vs. BMS 
• 
Above and below-the knee treatment 
• 
Claudication vs. CLI groups 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table of Contents 
Investigator’s Signature Page .......................................................................... 2 
Protocol Synopsis .............................................................................................. 3 
Table of Content ................................................................................................ 8 
Introduction and Rationale ............................................................................. 10 
Clinical outcomes following lower extremity endovascular interventions ... 10 
Antiplatelet agents following lower extremity endovascular intervention .... 10 
Trial objective ................................................................................................. 12 
Trial hypothesis ............................................................................................... 12 
Trial endpoints ................................................................................................ 12 
Trial Design ................................................................................................... 14 
Justification for the Trial Design ................................................................... 14 
Method of Assigning Subjects to Treatments ................................................ 15 
Trial Population (inclusion/exclusion criteria) ............................................... 15 
Withdrawal and Replacement of Subjects ..................................................... 17 
Trial Procedures .............................................................................................. 18 
Written Informed Consent ............................................................................ 19 
Sample Size Estimate ...................................................................................... 19 
Control of Systematic Error/Bias ................................................................... 19 
Eligibility of Subjects, Exclusions, and Missing Data .................................. 20 
Analysis Sets ................................................................................................... 20 
Availability of aspirin and clopidogrel ........................................................... 20 
Statistical Analysis .......................................................................................... 20 
Postprocedure Endpoints ................................................................................ 21 
Data Management ......................................................................................... 22 


 
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Monitoring Procedures .................................................................................. 22 
Adverse Events ............................................................................................... 23 
Risk Benefit Analysis ..................................................................................... 25 
Ethical Considerations .................................................................................... 27 
Appendices .................................................................................................... 30 
References…………………………………………………………………..31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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1. Introduction and Rationale 
Peripheral arterial disease (PAD) is extremely prevalent worldwide and affects over 206 
million people.1 Over 36 million patients with PAD are estimated to be present in the 
United States. Percutaneous revascularization therapies have evolved dramatically, yet the 
long-term success of these therapies remains modest and the morbidity and mortality 
associated with PAD remains high, with up to 30% mortality risk at 5 years 2. Nearly, 3.2 
million endovascular procedures are performed annually.3, 4 Though, this exceeds 
interventional procedures performed for coronary artery disease (CAD), the current PAD 
guidelines are silent regarding the need and optimal duration of antiplatelet therapy (APT) 
for patients following an endovascular procedure for claudication or critical limb ischemia 
(CLI). 5 The lack of data and clinical studies is by far the greatest impediment to the 
formulation of such guideline recommendations critically needed by providers and patients 
alike, especially given the current limited durability of lower extremity endovascular 
procedures.6 
 
2. Clinical outcomes following lower extremity endovascular 
interventions 
Endovascular or surgical revascularization procedures are performed on individuals with 
lifestyle-limiting claudication or CLI.7 Percutaneous transluminal angioplasty (PTA) is a well- 
established endovascular technique for revascularizing obstructed lower limb arteries. This 
technique is associated with good patency in iliac artery interventions; however with dismal 
patency rates for infra-inguinal interventions.8 Stents have improved patency of lower 
extremity arterial interventions, mainly applied at the aortic bifurcation or in iliac segments.9 
Until recently stents in the femoropopliteal district were associated with a higher risk of re-
occlusion because of the smaller diameter of these vessels.6 However, the new generation of 
self-expanding nitinol stents or paclitaxel-coated balloons have yielded better results than those 
obtained with standard balloons at the femoropopliteal level.10 Compared to surgical 
procedures, endovascular techniques are less invasive and are associated with lower morbidity 
and mortality and shorter recovery time.11 The main disadvantage of endovascular intervention 
is the low rates of long-term success, with relatively frequent clinical deterioration and 
restenosis during follow-up. Thus, reintervention is often necessary in patients treated with 
endovascular intervention for symptomatic with PAD.12 In addition to the type of intervention, 
early studies have demonstrated the impact of clopidogrel discontinuation on acute thrombotic 
occlusion of the limb post- endovascular intervention.13 In addition clopidogrel use in patients 
with PAD has been associated with improved mortality and non-fatal myocardial infarction 
(MI) events.14 
 
3. Antiplatelet agents following lower extremity endovascular 
intervention 
It has been shown that dual antiplatelet therapy is a very important factor for short- and long-
term success in coronary interventions. Thus, based on the results of randomized clinical trials, 


 
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current guidelines recommend dual antiplatelet therapy consisting of clopidogrel and aspirin 
for 12 months after percutaneous coronary intervention (PCI) for acute coronary syndromes 
and/or use of drug-eluting stents.15 
After peripheral artery interventions, there is still some uncertainty regarding the optimal peri-  
and post-interventional antiplatelet treatment of clopidogrel and/or aspirin 
.6 The results of the Management of peripheral arterial interventions with mono or dual 
antiplatelet therapy  (MIRROR) study showed that patients treated with clopidogrel+aspirin 
compared to aspirin alone had significantly lower target lesion revascularization (TLR) rates at 
6 months.17 Nevertheless, the duration of dual antiplatelet therapy remains unknown and not 
been addressed by well-powered randomized clinical trials. The investigators of the MIRROR 
study therefore conducted an additional clinical follow-up of MIRROR patients at 12 months to 
evaluate the persistence or extinction of the clinical advantage of dual antiplatelet therapy.18 At 
6 months, clopidogrel patients had significantly lower rates of TLR compared to placebo 
patients [2 (5%) vs. 8 (20%), p=0.04]. None of the TLR was due to thrombotic occlusion 
of previously recanalized arteries. There were no significant differences in the rate of 
binary restenosis at 6 months. After stopping clopidogrel/placebo, the significant 
difference in TLR disappeared [9 (25%) clopidogrel vs. 12 (32.4%) placebo (p=0.35)]. 
Thus in contrast to the first report of a reduction in the TLR at 6 months in the MIRROR 
study, this advantage of dual antiplatelet therapy does not persist after stopping 
clopidogrel. The investigators concluded that prolonged dual therapy (>6 months) should 
be considered in patients who are at high risk for restenosis. 
 
Peripheral catheter interventions are performed under local anesthesia allowing early and full 
mobilization. However, as a result of this intervention, atherosclerotic plaques are ruptured and 
platelets aggregate at the site of injury.19 Extensive vessel wall damage coupled with low shear 
stress and poor infrapopliteal outflow are mostly responsible for the occurrence of 
reocclusion.20 
Additionally, in the initial phase after catheter intervention, a hypercoagulable state prevails, as 
parameters of activated coagulation, including thrombin-antithrombin complexes (TAT), D- 
Dimer and Fibrinopeptide A (Fa) become elevated in the plasma.21 This activated coagulation 
system produces conditions favorable for early thrombotic occlusion, where ‘early’ is usually 
defined as a period covering the first four weeks after the intervention. Subsequently, intimal 
hyperplasia may follow which is responsible for intermediate and late-term restenosis and 
reocclusion. Intimal hyperplasia occurs as a result of denudation (tearing off of the inner lining)   
of the endothelium caused by manipulation of the vessel wall with the catheter. Reported rates 
of arterial reocclusion or symptomatic restenosis following femoropopliteal PTA are between 
five and twenty-five per cent for early events and about 40% one year.6 The five year patency 
rate was reported to be 83% for iliac and 58% for femoropopliteal PTA, whilst patients with 
stenoses or occlusions of less than 3 cm had a favorable long-term patency rate of 74%.22 
Patients with CLI or those subjected to local thrombolysis show higher incidences of 
reocclusion.23 The implantation of drug-eluting or nitinol stents, or treatment by intravascular 
brachytherapy following PTA are considered as interventions with the capacity of reducing the 
occurrence of intimal hyperplasia, however may be associated with delayed endothelialization 


 
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and increased risk of thrombosis. 
Drug interventions with antiplatelet agents to prevent thrombosis and/or reocclusion of the 
treated segments would make an important contribution to the sustained success of 
endovascular treatment, along with its contribution towards reducing overall mortality in 
patients with PAD. Current peri-interventional treatment strategies mostly include aspirin 
intake before and after PTA, initial administration of either unfractionated heparin (Ellis 
1989) followed mostly by antiplatelet drugs or anticoagulants on a long-term basis (Do 
1994; Hess 1985; Shammas 2003b; Watson 2000). However, these practices have never 
been tested in the setting of an adequately powered randomize controlled trial. 
The Swedish trial on aspirin (50 mg daily) use after PTA was a negative study, whereas the 
study by Heiss et al showed greater patency and a dose effect favoring a higher dose of aspirin 
(100- 300 mg daily).24 At time points three and 12 months there were 798 and 575 patients 
included with OR 1.38 (95% CI 0.85 to 2.23) and 0.98 (95% CI 0.64 to 1.48), respectively, for 
primary occlusion. In fact, one clinical trial called CAMPER (Clopidogrel and Aspirin in the 
Management of Peripheral Endovascular Revascularization) (CAMPER) was started in the 
USA evaluating clopidogrel combined with ASA versus ASA after femoropopliteal 
angioplasty. Unfortunately, this study had to be stopped due to insufficient randomization 
numbers after one year. 
 
4. Trial Objectives 
To evaluate whether clopidogrel 75 mg QD on a background of ASA 81 mg/d for U.S. sites 
(75-100 mg/d for international sites)  for clinically indicated duration with a minimum of 
30 days or an additional 12 months will lead to an increased rate of primary patency, limb 
salvage, freedom form ischemic stroke and survival, in patients receiving endovascular 
treatment of PAD. 
 
5. Trial hypothesis 
We hypothesize that DAPT with ASA and clopidogrel administered for an additional 12 
months after a clinically indicated duration following iliac, FP or BTK endovascular 
intervention will improve primary patency, limb salvage, freedom form ischemic stroke and 
survival, in patients with symptomatic PAD. 
 
6. Trial endpoints 
Clinical endpoints will be analyzed in all subjects who are enrolled, regardless of whether the 
trial treatment administered successfully completed for the desired duration. A subject will be 
considered enrolled in the trial when he/she is randomized to one of the treatment arms of the 
study. All endpoints are subject-based unless otherwise specified. 
 
The primary endpoint is  subject-based of the longer of a 12-month or end of study treatment 
endpoint of the first occurrence of index limb arterial occlusion, surgical intervention, 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
endovascular intervention, amputation of the affected limb (primary patency and limb salvage), 
MI, ischemic stroke or death (survival) 
The secondary endpoints are subject-based  on the longer of a 12-month  or end of study 
treatment endpoints that include: (a) the first occurrence of any individual component of the 
primary endpoint, (b) the first occurrence of the following during follow-up: cardiovascular 
death, or MI, or ischemic stroke, or any amputation above the ankle and (c) severe bleeding 
defined according to the Global Utilization of Streptokinase and Tissue plasminogen activator 
for Occluded coronary arteries (GUSTO) classification 
The tertiary endpoint is based on the longer of a12-month  or end of study treatment moderate 
bleeding according to the GUSTO classification 
 
Clinically indicated DAPT duration will be based on the longest pre-discharge following 
index peripheral intervention procedure DAPT duration. This will be determined based 
on: peripheral intervention device IFUs, preceding coronary intervention, acute coronary 
syndrome or other guideline-based clinical or device specific DAPT duration.   
Study treatment will be discontinued at the first occurrence of a primary endpoint as 
defined in the table below. Patients, however, can resume taking aspirin, Clopidogrel, 
or both based on their provider’s clinical decision.  
 
Primary endpoint definition(s) 
Secondary/Tertiary  endpoint  definition(s) 
Occlusion of the target limb documented by 
any imaging procedure performed clinically  
 
Any surgical or endovascular 
revascularization procedure on the index 
limb 
 
Amputation above the ankle of the index 
limb Death from any cause 
 
Ischemic stroke: An episode of neurological 
dysfunction caused by focal cerebral, spinal, 
or retinal infarction confirmed by a 
neurologist 
 
MI: Detection of a rise in cardiac troponin 
(cTn) with at least one value 3x above the 
99th percentile upper reference limit (URL) 
and with at least 1 of the following: 
 Symptoms of ischemia 
 New or presumed new significant (≥1 
mm) ST- segment–T wave (ST–T) 
changes or new left bundle branch 
block (LBBB) 
As described in section 6, except for: 
GUSTO bleeding criteria: 
1. Severe or Life-threatening: Intracerebral 
hemorrhage resulting in substantial 
hemodynamic compromise requiring 
treatment 
2. Moderate: Requiring blood transfusion 
but not resulting in hemodynamic 
compromise 
3. Mild: Bleeding that does not meet above 
criteria 


 
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 Development of pathological Q 
waves in the ECG 
 
 
 
7. Trial design 
This is a prospective, multi-center, two-arm randomized clinical trial to evaluate whether 
clopidogrel 75 mg QD on a background of ASA 81 mg for U.S. sites (75-100 mg/d for 
international sites)  for clinically indicated duration with a minimum of 30 days or an 
additional 12 months will lead to an increased rate of primary patency, limb salvage and 
survival, in patients receiving endovascular treatment of PAD. 
Up to 404 subjects at approximately 18 centers in the United States are planned. Assuming 
10% attrition at 12 months, enrollment of a minimum of 404 would yield at least   368 
evaluable subjects for the longer of a12-month or end of study treatment endpoint. No center 
will be allowed to enroll more than 40% of the subjects. 
 
A schematic of the trial design is provided in Figure 1.  
 
Figure 1: Trial design 
 
 
 
Patients following 
Iliac, FP, BTK 
Endovascular intervention 
 
 
 
 
 
 
 
 
 
 
 
 
8. Justification of trial design 
A multitude of clinical studies and analyses have attempted to address the question of 
optimal DAPT duration following endovascular peripheral arterial intervention for 
symptomatic PAD and have either not been adequately powered or have been 
abandoned. This study needs to be undertaken as a randomized controlled trial to try 
and conclusively answer the question in an unbiased fashion. This modification will 
facilitate recruitment and make the study consistent with current clinical practice. The 
relevance of the study results will is significantly elevated. 
ASA + Clopidogrel 
For clinically 
indicated duration (at 
least 30 days) 
12-month f/u 
or end of study 
treatment, 
whichever is 
longer (q6m 
f/u 
Randomized 1: 1 
ASA + Clopidogrel 
For clinically 
indicated duration + 
12m  


 
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9. Method of assigning subjects to treatment 
Patients scheduled for a planned discharge will be randomized on a 1: 1 basis using a central 
computerized randomization portal available through RedCap® to either of the following 
treatment groups: 
ASA (81 mg/d for U.S. sites; 75-100 mg for international sites) + clopidogrel:for clinically 
indicated duration with a minimum of 30 days (control arm) 
ASA (81 mg/d for U.S. sites; 75-100 mg for international sites) + clopidogrel 75 mg: for  
clinically indicated duration + 12m (treatment arm) 
An inclusion and exclusion checklist needs to be completed via computerized 
randomization portal available through RedCap® prior to randomization of the subject. 
 
10. 
Trial population 
Table 1 on the following pages outlines the specific inclusion and exclusion criteria for the 
trial, according to general and angiographic categories. Before enrollment in the trial, a subject 
must meet all of the inclusion and none of the exclusion criteria. 
 
Key Inclusion Criteria 
General: 
 Signed informed consent 
 At least 18 years old 
 Documented symptomatic iliac, 
femoropopliteal (FP) or below-the 
knee artery (BTK) atherosclerotic 
disease (Rutherford/Becker 
category 2, 3 or ≥4) 
 Undergone clinically indicated 
uncomplicated endovascular 
intervention to one or more 
locations of the iliac, 
femoropopliteal below-the knee 
arteries 
 Estimated survival ≥1 year in the 
judgment of the primary operator 
 Pre-index procedure use of ASA, 
clopidogrel or both at any dose 
 
Angiographic: 
 De novo or restenotic lesions in the 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
common and/or external iliac artery, 
superficial femoral artery (SFA), popliteal 
artery, tibio-peroneal (TP) trunk, anterior 
tibial (AT) artery, peroneal artery (PA) or 
posterior tibial (PT) artery (applies to all 
target lesions if multiple) 
 Subjects with multiple planned procedures 
can be enrolled after the completion of the 
last planned procedure. 
 
Key Exclusion Criteria 
General: 
 Complicated qualifying procedure 
(perforation, flow limiting dissection, 
distal embolization requiring re-
intervention, need for repeat endovascular, 
surgical revascularization, amputation or 
blood transfusion prior to hospital 
discharge following an index procedure 
 Extended hospital stay >7 days following 
the index procedure 
 Allergy to aspirin or clopidogrel 
 Life expectancy less than 12 months due 
to other medical co-morbid condition(s) 
that could limit the subject’s ability to 
participate in the trial, limit the subject’s 
compliance with the follow-up 
requirements, or impact the scientific 
integrity of the trial 
 Known hypersensitivity or 
contraindication to contrast dye that, in 
the opinion of the investigator, cannot 
be adequately pre-medicated. 
 Intolerance to antiplatelet, 
anticoagulant, or thrombolytic 
medications 
 Platelet count <90,000 mm3 or 
>600,000 mm3 
 Serum creatinine >2.5 mg/dL 
 Dialysis-dependent end stage renal 
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 Pregnancy 
 Current participation in another drug or 
device trial that requires interruption of 
dual-antiplatelet therapy with aspirin 
or clopidogrel for the duration of the 
study 
 Planned surgeries, endovascular or 
other non-vascular or cardiac 
procedures 
 Concurrent warfarin or other chronic 
oral anticoagulant therapy 
 Contraindication(s) to the use of AT 
(history of intra-cerebral bleed, 
presence of intracerebral mass, recent 
or <6 weeks gastrointestinal bleed, 
blood transfusion within the last 6 
weeks, any trauma requiring surgery or 
blood transfusion within the last 4 
weeks or any surgical procedure 
within the last 4 weeks. 
 
Angiographic: 
 Endovascular intervention to iliac, FB or 
BTK artery bypass graft 
 Persistent, intraluminal thrombus of the 
proposed target lesion at the completion of 
the index procedure 
 Perforated vessel as evidenced by 
extravasation of contrast media 
 Vascular graft, aneurysm or postsurgical 
stenosis of the target vessel 
 
 
11. 
Withdrawal and replacement of subjects 
 
While trial withdrawal is discouraged, subjects may withdraw from the trial at any 
time, with or without reason and without prejudice to further treatment. Withdrawn 
subjects will not undergo any additional follow-up, nor will they be replaced (the 
justified sample size considers an estimated allowance for attrition). 
Potential reasons for subject discontinuation are as follows: 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
I. 
Withdrawal of consent 
II. 
Secondary to an Adverse Event 
III. 
A Principal Investigator, IRB or a regulatory body deemed safety concern 
IV. 
Lost to follow-up 
 
12. Trial procedures 
The schedule of observations and assessments to take place during the trial are listed in Table 
2. 
Table 2: Trial Event Schedule 
 
 
enrollment 30day (±7days) 
6m4,5 (± 15 days) 
12m and q6m till 
end of study 
treatment 3, 4,5 (±15 
days) 
Informed consent 
+ 
 
 
 
Inclusion/Exclusion 
+ 
 
 
 
Physical Examination 1 
+ 
+ 
+ 
+ 
Rutherford Classification 
+ 
+ 
+ 
+ 
ABI 
+ 
+ 
+ 
+ 
TASC classification 
+ 
 
 
 
Serum creatinine 
+ 
+ 
+ 
+ 
Hemoglobin 
+ 
+ 
+ 
+ 
Platelet count 
+ 
+ 
+ 
+ 
Recommended Anti-
Coagulant Therapy 
Assessment 
+ 
+ 
+ 
+ 
WIQ (section 1) 
+ 
+ 
+ 
+ 
AE assessment 2 
 
+ 
+ 
+ 
Concomitant medications 
+ 
+ 
+ 
+ 
1. Physical examination includes gross assessment of standard organ systems (e.g., cardiac, 
pulmonary, etc).  
2. AE assessments and reporting include AE, SAE and MAE. 
3. End of study treatment visit will be performed when patient completes duration of assigned 
study treatment. This visit may fall between q6m visit schedule for some patients. 
4. Phone visits can be done if patients refuse in-clinic visit during the follow up period, or 
who are do not show up to their follow up visits. Labs and ABIs will be collected and 


 
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documented, if available in their medical records during the follow up period. Study 
team should document 2 attempts to schedule in-clnic visits before phone visits are 
completed during follow-up 
5. Patients who do not complete their follow up visits in -clinic will not be provided a refill 
of aspirin and Plavix (if randomized to the long arm) They will remain on the study as 
ITT and phone follow-up may be completed to collect data. Prescriptions may be 
renewed when patients complete an in-clinic visit. 
 
13. Informed consent 
All subjects who are potential trial candidates must provide written informed consent before 
enrollment. 
Subjects must sign the trial-specific, most recent version of the Institutional Review Board 
(IRB) approved Informed Consent form before any trial-specific interventions. Trial 
personnel should explain to the subject that even if a he or she agrees to participate in the 
trial and signs an Informed Consent form, careful assessment of inclusion/exclusion criteria 
may demonstrate that the subject is not a suitable candidate for the trial, and, therefore, the 
subject will not be allowed to participate. 
Trial Center personnel will maintain a Screening/Enrollment Log to document enrolled 
subjects and select information about candidates who fail to meet the general or angiographic 
entry criteria. 
 
14. Sample size estimate 
The occurrence of the primary endpoint is expected to be approximately 49% in the control 
group, derived on the basis of current literature review and preliminary data form XLPAD 
registry.18 
A 30% relative risk reduction in the incidence of primary endpoint would be clinically 
important. To detect a 30% relative reduction in the primary event rate from 49% to34% 17 
with 80% power at the two-sided, 0.05 significance level, assuming a 12-month recruitment 
period and a 10% dropout rate at 1 year, a total of 404 patients will be randomized (202in 
each group) and followed-up for endpoints for longer of a 12-month or end of study 
treatment period. 
 
15. Control of systematic bias/errors 
In determining subject eligibility for the trial, the Investigator or his/her designee’s 
assessment of inclusion/exclusion parameters will be used.  
An independent Clinical Events Committee (CEC) will review clinical events that occur 
during the trial. The CEC will be blinded to the trial center and subject identification to the 
extent possible. An independent Data Safety Monitoring Board (DSMB) will review adverse 
events that occur during the trial. 
 


 
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16. Eligibility of subjects, exclusions and missing data 
 
All subjects who are enrolled will be eligible for evaluation, regardless if they receive the 
control or active arm drug treatments for the assigned durations or not. Sensitivity analyses 
to account for missing data will be performed and may include imputation of missing data if 
deemed appropriate. The distribution of prognostic factors between subjects with and 
without data will be examined. Statistical models that account for censored data will be 
employed in appropriate circumstances, e.g., for time-to-event outcomes. Outlier values will 
be evaluated for their validity. All data will be included unless judged to be invalid. The 
robustness of the primary endpoint conclusion will be assessed based on these analyses. 
 
17. Analysis set 
The primary endpoint will be analyzed on an intent-to-treat basis and on a per-protocol basis 
analysis will also be performed. For intent-to-treat analysis, all subjects who sign the IRB/EC- 
approved written Informed Consent form and are enrolled into the trial will be included in the 
analysis, regardless of whether they receive the control or active arm drug treatments for the 
assigned durations or not. For per-protocol analysis, only subjects who receive the control or 
active arm drug treatments for the assigned durations will be included in the analysis. 
The primary analysis set for testing of the primary endpoint is the intent-to-treat analysis set. No 
formal interim analyses are planned for the purpose of stopping this trial early for efficacy. 
 
18. Availability of aspirin and clopidogrel 
As both these drugs are approved worldwide and used routinely in post endovascular 
interventions, they would be used on the basis of use as per routine clinical practice and as 
per local/regional drug procurement and dispensing practices. 
 
19. Statistical analysis 
Continuous variables will be summarized as mean±standard deviation and compared 
using the t-test or the Wilcoxon rank-sum test, as appropriate. Discrete variables will be 
presented as frequencies and group percentages and compared using the chi-square test. 
For all comparisons a two-sided probability of <0.05 will be considered statistically 
significant. All analyses were performed using the SAS 9.4 or recent version (SAS 
Institute Inc., Cary, North Carolina). Primary endpoint will be assessed as per an intention-
to treat principle. 
Subsequent analysis will also be performed based on per-protocol basis. Pre-specified 
subgroup analyses will include: 
1. Stent vs. non-stent groups 
2. DES vs. BMS 
3. Above and below-the knee intervention 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
4. Claudication vs. CLI groups 
 
20. Post‐procedure endpoints 
Post-procedure information will be collected at regularly scheduled follow-up examinations, as 
detailed in the clinical trial schedule, and will be summarized using the descriptive statistics 
described above. 
 
Primary Endpoint 
 
For the primary endpoint of 12-month composite of primary patency, limb salvage, MI, 
ischemic stroke and survival, with 95% confidence bounds will be calculated in the 
active arm and compared to control treatment duration. If this bound is less than that of 
control, then the primary endpoint will be considered met. All enrolled subjects are to be 
assessed for adverse events at follow-up visits. Assuming a maximum of 10% attrition 
due to non-compliance, loss to follow-up or death or non-compliance with follow-up, a 
minimum of 184 subjects in each arm are expected to be evaluable for the primary 
endpoint. 
Secondary Endpoints 
Secondary endpoints will be summarized at the specified time points using the descriptive 
statistics described above, individually or in comparison between the treatment groups. 
Statistical analyses of the following secondary endpoints will be summarized for descriptive 
purposes and without adjustments for multiplicity: 
 Changes in ABI from baseline to hospital discharge, 30 days, 6 months and 12 
months post-procedure will be analyzed using paired two-sided Student t-tests. 
 Changes in Walking Impairment Questionnaire scores from baseline to 30 days, 
6 month, and 12 months post-procedure will be analyzed using paired two-sided 
Student t-tests. 
 Freedom from Target Lesion Revascularization Kaplan-Meier estimates and plots 
will be presented to 12 months post-procedure 
Pooling Across Institutions 
Analyses will be performed using data pooled across institutions. Analyses to justify pooling 
will include the following: 
 The primary endpoint presented by institution. 
 An assessment of the ‘poolability’ of the institutions using a 2-by-(number of 
institutions) contingency table of outcome versus institution. Fisher’s Exact Test will be 
used to assess homogeneity. Institutions with fewer than five subjects will be combined 
based on geographic region if possible. 
 If the institutions are found to be significantly heterogeneous with respect to the 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
primary endpoint, additional analyses will be conducted to assess differences between 
institutions in baseline and procedural variables that might explain differences in 
primary outcome. 
 
Other Analysis Methods 
Kaplan-Meier plots of time-to-event variables will be constructed for clinical outcomes. 
 
 
21. Data management 
 
Data collection and processing 
 
Subject data will be collected in a secure electronic data capture (EDC) system via the 
Internet.  The Principal Investigator or Sub-investigator must ensure the accuracy and 
completeness of the recorded data entered into the EDC and also by providing his/her 
electronic signature on the appropriate paper Case Report Forms (CRF). The 
Investigator’s signature for specific CRF will be documented in compliance with local 
regulations. 
Changes to data previously submitted to the sponsor will require a new signature by the 
Investigator to acknowledge and approve the changes. The coordinating or primary 
study site team will compare the data entered into EDC and paper CRF for discrepancy 
and require a response from the site PI/Sub-I. 
Audits may be performed for quality assurance of data handling against source 
documents 
Visual and/or computer data review will be performed to identify possible data 
discrepancies. Manual and/or automatic queries will be created in the EDC system and 
will be issued to the site for appropriate response. The trial center will be responsible 
for resolving all queries in the database in a timely manner. 
 
22. Monitoring 
Monitoring of trial centers will be made periodically during the trial, as outlined in the 
trial monitoring plan, to ensure that all aspects of the current, approved 
protocol/amendment(s) are followed. 
Original source documents will be reviewed for verification of data in the electronic 
database. The Investigator/institution guarantees direct access to original source 
documents, including electronic medical records, if applicable, by monitoring 
personnel, their designees, and appropriate regulatory authorities. In the event that the 
original medical records cannot be obtained for a subject that is seen by a non-trial 
physician at a non-trial institution, photocopies of the original source documents must 
be made available for review. In the event such records cannot be released, the study 
site will allow verification of the source data by passive viewing of the source electronic 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
medical record screen handled exclusively by the site coordinator/investigator(s). 
The trial also may be audited for quality assurance by monitors or its designees, as well 
as inspected by appropriate regulatory authorities. 
It is important that the Investigator and relevant trial personnel are available during 
monitoring visits, audits and inspections, and that sufficient time is devoted to the 
process. 
Monitoring plan 
Designated monitor(s) funded and supported by the PI will undertake site monitoring. 
Such monitoring visits will be conducted for. sites on a six monthly basis  
 
23. Adverse Events 
All Adverse Events (AE) and Serious Adverse Events (SAE) will be reported through 
EDC and analyzed through study follow-up period. 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a 
subject. This definition does not imply 
that there is a relationship between the 
adverse event and the treatment under 
investigation. 
Note 1: In addition, the definition of AE 
applies to any event with an onset post-
randomization procedure or to any 
underlying diseases, present at baseline, 
that exacerbate in severity post-
randomization procedure. Therefore, any 
underlying disease that was present at the 
time of enrollment is not to be reported as 
an AE, but any increase in the severity in 
the underlying disease is to be reported as 
an AE. This definition includes events 
occurring in the follow-up period. 
Serious Adverse Event (SAE) 
 
An adverse event that: 
• led to death; 
• led to a serious deterioration in the 
health of the subject that: 
 resulted in a life-threatening illness 
or injury, 
 resulted in a permanent 
impairment of a body structure or 
a body function, 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
 required in-hospitalization or 
prolongation of existing 
hospitalization, 
 resulted in medical or surgical 
intervention to prevent 
permanent impairment to body 
structure or a body function 
 
 
Clinical events to be considered and reported as expected SAE include, but are not limited 
to: 
 MAE (see definitions) 
 Stent Thrombosis 
 Bleeding complication as per GUSTO definition 
 Vascular event requiring target limb surgical or 
endovascular intervention or amputation 
 Any hospitalization 
Relationship 
The Investigator must assess the relationship of the adverse event to the participation in the 
study and use of antiplatelet drugs using the following criteria categories and definitions: 
 Unrelated: The adverse event is determined to be due to a concurrent illness or 
effect of another device/drug and is not related to the study related drugs 
 Possible: The adverse event is determined to be potentially related to the study 
related drugs, and an alternative etiology is equally or less likely compared to the 
potential relationship to the study related drug 
 Probable: There is a strong relationship to study related drug or recurs on re- 
challenge, and another etiology is unlikely 
 Highly Probable: There is no other reasonable medical explanation for the event 
The Investigator must assess the relationship of the adverse event to the study related drug 
using the following categories and definitions: 
 Unrelated – The adverse event is determined to be due to a concurrent illness or 
effect of a device/drug and is not related to the study related drug use 
 Possible – The adverse event is determined to be potentially related to the index 
procedure, and an alternative etiology is equally or less likely compared to the 
potential relationship to study related drug use 
 Probably – There is a strong relationship to index procedure, or recurs on re-
challenge, and another etiology is unlikely 
 Highly Probable – There is no other reasonable medical explanation for the event 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
 
Outcome 
The Investigator must document the outcome of the AE using the following categories: 
 Resolved without residual effects 
 Resolved with residual effects 
 Recovering/Resolving 
 Not Recovered/Not Resolved 
 Death 
 Unknown 
 
Reporting Requirements 
Trial personnel must report to the study PI’s office any SAE or MAE by fax within 24 
hours of learning of the event. When faxing in notification of an event, a fax confirmation 
report must be retained at the site as adequate documentation of timely event reporting. 
Source documentation should record when the site became aware of the event. Trial 
personnel must forward follow-up information and the completed adverse event CRF to 
the as the event continues and/or resolves. 
All adverse events will be recorded in the electronic database managed by the primary 
study team at the primary institution and report them at each DSMB meeting. A 
description of the event, including the start date, resolution date, action taken, assessment, 
and outcome should be provided, along with the Investigator’s assessment of the 
relationship between the AE and the trial treatment. All adverse events also need to be 
reported to the local IRB within 24 hours of knowledge of the study team. 
 
24. Risk-benefit analysis 
Based on review of the scientific literature, outcomes of design verification, the results of 
preclinical studies, and known adverse drug effects, the benefit of treatment with the 
aspirin and clopidogrel post-iliac, FP and BTK endovascular intervention outweighs the 
risks. However, the effect of unknown factors accounting for unanticipated side effects 
cannot be completely excluded, therefore observation and follow-up of subjects is 
required as outlined in the protocol. 
 
Risks associated with aspirin and clopidogrel drug therapy may include: 
a. Allergic reaction 
b. Amputation 
c. Aneurysm 
d. Angina/coronary ischemia 
e. Arrhythmia 
f. Arteriovenous fistula 
g. Death 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
h. Drug-drug interactions 
i. GI bleeding 
j. Hemorrhage/hematoma 
k. Hypotension / Hypertension 
l. Myocardial infarction (MI) 
m. Need for urgent intervention or surgery 
n. Pseudoaneurysm 
o. Renal insufficiency or failure 
p. Restenosis of stented artery 
q. Rupture of the retroperitoneum or other organ 
r. Stroke 
s. Thrombosis / Thrombus 
t. Tissue ischemia/necrosis 
u. Vasospasm 
v. Vessel injury, examples include perforation, dissection, intimal tear, rupture 
w. Vessel occlusion 
 
Risk minimization 
The risks associated with the aspirin and clopidogrel use are relatively well established, and 
the preceding risks represent the most up-to-date understanding of risks associated. The 
study team will employ measures throughout the course of this investigation, to minimize 
these risks to subjects choosing to participate. In general, efforts will be made to 
minimize these risks by: 
i. Selecting Investigators who are experienced and skilled clinicians and 
expert in endovascular procedures 
ii. Clearly defining inclusion/exclusion criteria to ensure only appropriate 
subjects are enrolled 
iii. Ensuring that the treatment and follow-up of the subjects are consistent 
with current medical practices 
 
Specifically, every subject participating in this trial will undergo the following: 
a. Medical history, physical examination, and laboratory assessment prior to the 
procedure to identify factors which may increase risk 
b. Required review of anti-coagulant and anti-platelet medication before and after 
enrolment into the trial 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
Data safety monitoring board (DSMB) 
A DSMB will meet every 6 months as scheduled or sooner based on reported AE and 
review all adverse events at these meetings and make recommendations to the study 
executive committee regarding the conduct and continuation of the trial, with/without 
recommendations for the study team(s) and or the executive committee/PI. The 
DSMB will include 5 members with a chair and all decisions will be adopted by a 
clear majority and all proceeding minutes recorded and stored with the primary study 
team/PI’s office. A minimum of 3 members will be required to conduct the 
proceedings of the DSMB. 
 
Clinical events committee (CEC) 
A Clinical Events Committee with pertinent expertise that reviews and adjudicates 
important endpoints and relevant adverse events reported by trial Investigators. 
Committee membership will include practitioners of peripheral endovascular 
procedures, as well as other experts with the necessary therapeutic and subject matter 
expertise, to adjudicate the event categories outlined above. CEC responsibilities, 
qualifications, membership, and committee procedures are outlined in the CEC charter. 
The CEC will adjudicate the following events: 
 All Deaths 
 Myocardial infarction (MI) that occurs during index hospitalization 
 Target lesion revascularization (TLR), surgical or endovascular 
 Target vessel revascularization (TVR), surgical or endovascular 
 Target limb/extremity revascularization (TER), surgical or endovascular 
 Amputation of index limb or any amputation 
 Stent Thrombosis or target iliac, FP or BTK vessel occlusion 
 Any urgent limb/extremity revascularization surgical or endovascular procedure 
 Bleeding events 
 Any stroke 
 
25. Ethical considerations 
 
Declaration of Helsinki 
The Investigator will ensure that this trial is conducted in full conformity with the 
recognized version of the Declaration of Helsinki per country regulation, and with the 
regulations and guidelines of the Food and Drug Administration (FDA) and all 
country/state/local regulations; whichever affords the greater protection to the subject. 
 
 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
Institutional Review Board 
A copy of the protocol, proposed Informed Consent form, other written subject information, 
and any proposed advertising material must be submitted to the IRB for written approval. 
A copy of the written IRB approval of the protocol and Informed Consent form and a copy 
of the Investigator Signature Page must be received by primary study site/team before 
recruitment of subjects into the trial. 
The Investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the Informed Consent form. The 
Investigator must notify the IRB of deviations from the protocol or MAE (i.e. death, MI, 
TLR, or amputation) and stent thrombosis occurring at their site, and other AE/SAE 
reports. 
The Investigator is responsible for obtaining annual IRB approval and renewal throughout 
the duration of the trial. Copies of the Investigator’s reports and the IRB continuance of 
approval must be sent to primary study coordinating site/team. 
 
Amending the Protocol and/or Informed Consent 
This protocol is to be followed exactly, and can be altered only by written amendments. 
Administrative changes that do not affect the subject benefit/risk ratio (e.g., editorial 
changes for clarity) may be made without any further approvals. Any change that would 
require alteration of the Informed Consent form must receive approval from appropriate 
coordinating site/PI’s office personnel and from the IRB prior to implementation. 
Following approval, protocol amendment(s) will be distributed to all protocol recipients 
with instructions to append them to the protocol. 
 
Emergency Actions 
Study coordinating site/PI accepts the right of the Investigator to deviate from the protocol 
in an emergency when necessary to safeguard the life or physical well-being of a trial 
subject. The Investigator must give notice of any emergency deviation, and justification for 
the deviation, to the study coordinating site/PI and the IRB as quickly as possible, no later 
than 24 hours after the emergency. 
 
Protocol Adherence 
Prior to beginning the trial, the Investigator must sign the Investigator Agreement and 
Signature page documenting his/her agreement to conduct the trial in accordance with the 
protocol. An Investigator must not make any changes or deviate from this protocol, except 
to protect the life and physical well-being of a subject in an emergency. Each deviation 
from the protocol must be documented with the date and reason for the deviation and 
reported to the study coordinating site/PI and to the IRB, per local guidelines and 
government regulations. 
 


 
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ASPIRE Trial Protocol; Version A1.5: 2‐23‐18 
Trial Administration 
Investigators are required to conduct the trial in accordance with Good Clinical Practice 
(GCP) and other applicable regulatory requirements. 
 
Record Retention 
The Investigator/study coordinating site/PI’s office will maintain all essential trial 
documents and source documentation, in original format, that support the data collected 
on the trial subjects in compliance with the GCP guidelines. Documents must be retained 
for at least 2 years after completion of the study, unless extended by the coordinating site 
IRB. 
 
Criteria for Terminating Trial 
Study coordinating site/PI reserves the right to terminate the trial, but intends only to 
exercise this right for valid scientific or administrative reasons and reasons related to the 
protection of subjects. Investigators and associated IRB will be notified in writing in the 
event of termination. 
 
Criteria for Suspending/Terminating a Trial Center 
Study coordinating site/PI reserves the right to stop the enrollment of subjects at a trial 
center at any time after the trial initiation visit if no subjects have been enrolled or if the 
center has systemic or major protocol non-compliance without justification or fails to 
follow remedial actions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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1. Appendix: 
 
 
Walking impairment score 
Patients will be asked to complete a walking impairment questionnaire (score range: 0 to 
14,080) at baseline, and then every 6 months for 12 months or until the end of study 
treatment visit depending on the randomization arm. A patient with a total score of 0 on 
question 2 would not be able to walk indoors around his/her home without claudication, 
while a maximum score of 14,080 would be achieved by a patient who can walk 5 blocks 
(1,500 feet) without claudication. The questionnaire will exclude patients with bilateral 
superficial femoral artery interventions, to minimize patient bias resulting from partial 
symptomatic improvements following successful intervention of one extremity, later 
followed by treatment of the contra- lateral superficial femoral artery. 
All , clinical adjudication and adverse events monitoring will be performed by an 
independent data oversight and safety monitoring board. 
 
 
 
 
 
 
 
 
Reference: 
1. Hirsch AT, Duval S. Lancet. 2013 Oct 19;382(9901):1312-4. 
2. Parikh SV, Saya S, Divanji P, Banerjee S, Selzer F, Abbott JD, Naidu SS, Wilensky 
RL, Faxon DP, Jacobs AK, Holper EM. Risk of death and myocardial infarction in 
patients with peripheral arterial disease undergoing percutaneous coronary 
intervention (from the National Heart, Lung and Blood Institute Dynamic 
Registry). Am J Cardiol. 2011 Apr 1;107(7):959-64. 
3. Diehm C, Schuster A, Allenberg JR, et al. High prevalence of peripheral arterial 
disease and co-morbidity in 6880 primary care patients: cross-sectional study. 
Atherosclerosis.  2004;172:95–105. 
4. Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral arterial 
disease. JAMA. 2006;295:547–53. 
5. ACC/AHA Guidelines for the Management of Peripheral Artery Disease. 
ACC/AHA Task Force on Practice Guidelines. J Vasc Interv Radiol. 2006 
Sep;17(9):1383-97. 
6. Banerjee S, Das TS, Abu-Fadel MS, Dippel EJ, Shammas NW, Tran DL, Zankar A, 
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revascularization of peripheral arterial segments: the COBRA trial. J Am Coll 
Cardiol. 2012 Oct 9;60(15):1352-9. 
7. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice Guidelines for 
the management of patients with peripheral arterial disease (lower extremity, renal, 
mesenteric, and abdominal aortic): a collaborative report from the American 
Association for Vascular Surgery/ Society for Vascular Surgery, Society for 
Cardiovascular Angiography and Interventions, Society for Vascular Medicine and 
Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on 
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