Intravascular Ultrasound-Guided Intervention for Venous Leg Ulcers
Phase: NA
Conditions: Venous Ulcer of Leg
Sponsor: Philips Clinical & Medical Affairs Global

 
Clinical Investigation Protocol 
 
Document 
ID: 
200202 
Intravascular Ultrasound-Guided Intervention for  
Venous Leg Ulcers (IGuideU) 
Classification: 
For internal use 
Clinical Investigation Protocol - ISO 14155 
Modified: 
13 Jan 2022 
21
Author: 
Kelly O’Connell 
Version: 
4.0 
User Tool ID: 
16.2.6UserTool0001 
Status: 
Final 
User Tool Version Date: 
08JUL2019 
Page: 
4 of 57 
 
 
 
 
Protocol Synopsis 
Study Title & 
ID 
Intravascular Ultrasound-Guided Intervention for Venous Leg Ulcers (IGuideU) 
 
Protocol ID: 200202 
Objectives 
The primary objective of this study is to determine whether the interrogation of the deep venous 
system (iliac-common femoral veins) for deep venous obstruction (DVO) by multiplanar 
venography (MPV) plus intravascular ultrasound (IVUS), with subsequent interventional 
treatment determined and guided by IVUS (interrogation group), results in improved clinical 
outcomes when compared to deferred interrogation of the deep venous system (deferred-
interrogation group).  
 
The secondary objectives are to assess changes in treatment decision parameters made with  
MPV after further investigation with IVUS and to assess the long-term clinical and economic 
impact of IVUS-guided interventional treatment for venous leg ulcers compared to the deferred-
interrogation group. 
Study Design 
Global, prospective, multi-center, randomized controlled trial. After signing a written informed 
consent, patients will be randomized 1:1 to either a deferred-interrogation group or to an 
interrogation group in which patients will be first evaluated with MPV imaging during iliac-
common femoral vein assessment for possible endovascular intervention and then further 
interrogated with IVUS imaging. The treatment plan derived from venography alone will be 
compared to the treatment plan created with the addition of the IVUS information and any 
differences in treatment plan will be documented. Confirmation of whether or not the threshold 
of stenosis/occlusion required for endovenous stenting has been met will be determined by the 
IVUS imaging obtained. Any patients determined to require venous stenting will be stented 
according to the on-label manufacturer’s instructions for the use of IVUS in guiding stent sizing 
and placement.  
 
This study will employ an independent core laboratory to evaluate, review and adjudicate all 
scheduled and unscheduled de-identified wound, MPV, and IVUS images. The study will also 
utilize a medical monitor to review and adjudicate peri-procedural serious adverse events (SAE). 
Endpoints 
Primary Clinical Endpoint 
The primary clinical endpoint is the difference in complete ulcer healing between the interrogation 
group and the deferred-interrogation group at 3 months. Complete ulcer healing is defined as 
100% epithelialization of the venous ulcer. Healing will not be assumed for any area of the wound 
where a scab is present. 
 
Diagnostic Endpoint 
The diagnostic endpoint is a composite of the difference in DVO detection and the subsequent 
changes in treatment plan created based on the IVUS information in combination with MPV 
information versus the initial treatment plan created using the information from MPV alone. DVO 
is defined as ≥50% diameter reduction in the deep venous system when assessed by MPV 
or ≥50% reduction in cross-sectional area (CSA) of the deep venous system when assessed by 
IVUS.  
 
Changes in the following parameters will be considered a changed in treatment plan: 
1. Location of the IVC confluence (common iliac vein/confluence interface) relative to 
vertebral bodies 
2. Presence of significant disease (≥50% reduction in diameter and/or cross-sectional area) 
3. Location of the disease 

 
Clinical Investigation Protocol 
 
Document 
ID: 
200202 
Intravascular Ultrasound-Guided Intervention for  
Venous Leg Ulcers (IGuideU) 
Classification: 
For internal use 
Clinical Investigation Protocol - ISO 14155 
Modified: 
13 Jan 2022 
21
Author: 
Kelly O’Connell 
Version: 
4.0 
User Tool ID: 
16.2.6UserTool0001 
Status: 
Final 
User Tool Version Date: 
08JUL2019 
Page: 
5 of 57 
 
 
4. Percentage (%) of obstruction/compression (compression or residual lumen diameter 
divided by reference vessel diameter) 
5. Reference vessel and associated diameter/CSA 
6. Length of disease (mm) 
7. Decision to stent 
8. Decision to pre- and/or post-dilate the occlusion 
9. Number of stents to be used 
10. Length(s) and Diameter(s) of stents to be used 
11. Manufacturer and model of stent(s) to be used 
12. Desired landing zones for stent placement 
13. Diagnosis of PTS, NIVL, or other 
 
Secondary Endpoints 
The following are secondary endpoints:  
1. Rate of ulcer healing measured between groups at 3, 6, 12, 18 and 24 months.  
2. Rate of ulcer healing for stented PTS and NIVL patients at 3, 6, 12, 18 and 24 months. 
3. Recurring ulcers in both arms from 3 months out to follow-up visit 24 months provided 
each arm has at least 30 subjects. The choice of 30 is based on central limit theorem in 
order to have normally distributed data for descriptive summary statistics. 
4. Recurring ulcers between PTS and NIVL sub-groups. 
5. Change in QoL using EQ5D and SF-36 forms. 
6. Change in clinical score will be assessed using the VCSS and CEAP scoring systems. 
7. Medical resource utilization (MRU) and health economic analysis between the 
interrogation and deferred-interrogation arms.  
 
*Note: Every effort will be made to balance the enrollment of PTS and NIVL patients. 
Subject 
Population 
In order to have 212 evaluable subjects with a 20% projected attrition rate, up to 266 evaluable 
subjects will be enrolled and randomized. 
 
Inclusion Criteria: 
1. Be ≥ 18 and ≤ 85 years of age. 
2. Able and willing to participate and comply with the protocol, including the defined follow-
up schedule, by signing an IRB or Ethics Committee approved informed consent form. 
3. Active venous leg ulcer (CEAP C6). 
4. Previously completed treatment for clinically significant reflux in the superficial and/or 
perforator venous system of the target limb ≥ 3 months prior to enrollment, if clinically 
indicated. 
5. Completed at least 3 months of prescribed compression therapy after any ablation. 
6. Palpable dorsalis pedis or posterior tibial artery (DP/PT) pulses at ipsilateral foot or ABI 
≥0.8. 
7. Be able to ambulate unassisted or with non-motorized assistive devices. 
8. Current VLU present ≤ 48 months. 
 
Exclusion Criteria: 
1. Patient is known pregnant or breast-feeding or planning to become pregnant in the 
following year.  
2. If antiplatelet and anticoagulation therapy cannot be tolerated.  
3. Previous venous stent implantation involving the target limb, target lesion, or inferior 
vena cava.  
4. Previous venovenous bypass surgery involving the target limb. 
5. Previous endovascular recanalization of the target lesion segment 
6. Known metal allergy precluding stent implantation.  

 
Clinical Investigation Protocol 
 
Document 
ID: 
200202 
Intravascular Ultrasound-Guided Intervention for  
Venous Leg Ulcers (IGuideU) 
Classification: 
For internal use 
Clinical Investigation Protocol - ISO 14155 
Modified: 
13 Jan 2022 
21
Author: 
Kelly O’Connell 
Version: 
4.0 
User Tool ID: 
16.2.6UserTool0001 
Status: 
Final 
User Tool Version Date: 
08JUL2019 
Page: 
6 of 57 
 
 
7. Known or suspected to have inadequate inflow to support stent patency in the target 
limb.  
8. Active cancer diagnosis.  
9. Known positive test for COVID-19 (Sars-CoV-2) within the last 2 weeks and actively 
symptomatic. 
10. Known or suspected venous outflow obstruction caused by tumor 
compression/encasement with or without thrombus. 
11. Known allergy to contrast media that cannot adequately be pre-medicated prior to 
study procedure.  
12. Known Renal dysfunction (defined as eGFR <30 mL/min/1.73m2) that would preclude 
adequate contrast usage.  
13. Diagnosed with right heart failure/pulmonary hypertension. 
14. Has known clinically significant abnormal platelet count outside laboratory reference 
ranges. 
15. Has known clinically significant abnormal WBC, fever, sepsis or positive blood culture.  
16. Organ transplant requiring immunosuppressant therapy.  
17. Unstable angina pectoris, or myocardial infarction within 30 days and/or hemorrhagic 
stroke within 3 months.  
18. Subjects with an active diagnosis of osteomyelitis of the ipsilateral limb. 
19. Previous or planned surgical or catheter-based procedure on index leg within 30 days 
before or 30 days after the index procedure.  
20. Active participation in another investigational drug or device study. 
21. Subject has any condition, which, in the opinion of the investigator, precludes the 
subject from participation. 
Test Groups 
 
Deferred-Interrogation Group: See guidelines below. 
 
Interrogation Group: Compression therapy plus endovascular imaging (MPV+IVUS) with or 
without intervention (stenting).  
 
The deferred-interrogation group will continue to receive non-invasive therapies consisting 
primarily of compression therapy/stockings that would have otherwise been continued outside of 
this research protocol. Listed below are the protocol guidelines for deferred-interrogation 
therapies: 
Mandate 
 
Continued compression therapy/dressing as prescribed. 
Allow 
 
Periodic leg elevation. 
 
Sclerotherapy under ulcer bed. 
 
Recommend mechanical debridement as needed. 
 
Wound biopsy if evidence of infection. 
 
Systemic antibiotics if patient is diagnosed with an infection, avoid prophylactic 
prescription. 
 
Pain management medication (Pentoxifylline/Trental) allowed but not recommended 
 
Topical antimicrobial as needed.  
Prohibit 
 
Negative pressure systems. 
 
Artificial and/or autologous skin grafting within first 3 months after randomization and 
within the first 3 months for subjects that crossover from the deferred-interrogation 
group to the interrogation group. 
 
Skin substitutes and tissue-based therapies within first 3 months after randomization 
and within the first 3 months for subjects that crossover from the deferred-
interrogation group to the interrogation group. 
 
Experimental topical creams and lotions. 

 
Clinical Investigation Protocol 
 
Document 
ID: 
200202 
Intravascular Ultrasound-Guided Intervention for  
Venous Leg Ulcers (IGuideU) 
Classification: 
For internal use 
Clinical Investigation Protocol - ISO 14155 
Modified: 
13 Jan 2022 
21
Author: 
Kelly O’Connell 
Version: 
4.0 
User Tool ID: 
16.2.6UserTool0001 
Status: 
Final 
User Tool Version Date: 
08JUL2019 
Page: 
7 of 57 
 
 
 
Growth factors within first 3 months after randomization and within the first 3 months 
for subjects that crossover from the deferred-interrogation group to the interrogation 
group. 
Schedule of 
Assessments 
There are 6 in-person 
visits planned for this 
clinical study, including 
the screening visit. The 
study is anticipated to last 
a total of 24 months for 
each enrolled study 
Screening Visit 
Baseline Visit/Index 
Procedure 
1 Month (30 days) 
3 Months (90 days) 
6 Months (180 days) 
12 Months (365 days) 
18 Months (545 days) 
24 Months (720 days) 
Early Termination 
Visit* 
Unscheduled Visit* 
Re-intervention 
Procedure* 
Visit Window 
-30 to 
0 days 0 days ±14 
days 
±14 
days 
±30 
days 
±30 
days 
±30 
days 
±30 
days 
NA 
NA 
NA 
Visit Type 
Office Hospital
/OBL Office Office Office Office Phone 
Call 
Phone 
Call 
Office/ 
Hospital/
OBL 
Office/ 
Hospital
/OBL 
Hospital
/OBL 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility/Inclusion and 
Exclusion Criteria  
X 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testa  
 
X 
 
 
 
 
 
 
 
 
 
Enrollment and 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
Duplex Ultrasoundb 
 
 
X 
X 
X 
X 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
X 
X 
 
 
X 
X 
 
Anticoagulant and 
Antiplatelet 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
Xh 
Xh 
Clinical Laboratory Testsc 
 
X 
 
 
 
 
 
 
 
 
 
Venous Ulcer Assessment  
X 
X 
X 
X 
X 
X 
 
 
Xh 
Xh 
Xh 
Venous Ulcer Imaging  
 
X 
X 
X 
X 
X 
 
 
Xh 
Xh 
Xh 
CEAP Clinical Category 
X 
X 
X 
X 
X 
X 
 
 
Xh 
Xh 
Xh 
VCSS Category 
X 
X 
X 
X 
X 
X 
 
 
Xh 
Xh 
Xh 
Study Visit Questionnaire 
 
 
X 
X 
X 
X 
 
 
Xh 
Xh 
Xh 
Wound Care Management 
Educationd 
 
X 
X 
X 
X 
X 
 
 
 
 
 
SF-36 
 
X 
 
 
 
 
 
 
Xh 
Xh 
Xh 
EQ5D Questionnaire 
 
X 
 
 
 
 
 
 
Xh 
Xh 
Xh 
Phone Call Questionnaire 
 
 
 
 
 
 
X 
X 
 
 
 
MPV Imaginge 
 
X 
 
 
 
 
 
 
 
 
 

 
Clinical Investigation Protocol 
 
Document 
ID: 
200202 
Intravascular Ultrasound-Guided Intervention for  
Venous Leg Ulcers (IGuideU) 
Classification: 
For internal use 
Clinical Investigation Protocol - ISO 14155 
Modified: 
13 Jan 2022 
21
Author: 
Kelly O’Connell 
Version: 
4.0 
User Tool ID: 
16.2.6UserTool0001 
Status: 
Final 
User Tool Version Date: 
08JUL2019 
Page: 
8 of 57 
 
 
 
Abbreviations: CEAP - Clinical Etiology Anatomy Pathology, EQ5D – EuroQol 5 Dimensions; IVUS – intravascular 
ultrasound, MPV – multi- planar venography, SF-36 – Short form 36; VCSS – Venous Clinical Severity Score. 
*Note: While an attempt should be made to collect all non-invasive testing at unscheduled visits, early termination visits, 
or re-interventions, a protocol deviation will not be required if all assessments are not completed. 
aUrine pregnancy test shall be taken on all females of childbearing prior to the index procedure.  
bIn all follow-up visits, DUS will be performed on the patients who received a stent implantation as part of the index 
procedure to assess stent patency and position.  
cClinical laboratory tests include: Serum creatinine and eGFR. These laboratory tests must be performed within 30 
days of the index procedure. 
dStudy personnel will provide guidance on wound care management best practices according to the site/facility 
guidelines. 
eMPV and IVUS imaging will only be performed on patients receiving an index-procedure per the study protocol. 
fAdverse Event reporting is for peri-procedural events and IVUS-related adverse events (<48 after index-procedure). 
gSubjects will be provided with a diary at the baseline visit. The diary is designed to be completed on a monthly basis, 
as well as following any contact with the health care system related to treatment of his/her venous leg ulcer. The diary 
will be used to track major events, such as compliance to compression therapy and other notes related to the index 
ulcer. The diary also requires completion of the quality-of-life questionnaires (EQ-5D, SF-36). The diary will be reviewed 
at each office visit after the initial receipt. After the last in-person study visit, any hard-copy diaries will be sent to the 
study site coordinator on a monthly basis until the 24-month study completion.  
hFor early termination, unscheduled follow-up visits, and/or re-intervention procedures every attempt should be made 
to obtain the following assessments: Antiplatelet and Anticoagulant use; Study Visit Questionnaire; Venous Ulcer 
Assessment including venous ulcer imaging; CEAP clinical category, VCSS category, and the SF-36 and EQ5D 
Questionnaires.  
I Questionnaires should be completed in the diary.  If not completed in the diary, the subject should complete the 
questionnaires at the time of the visit.  
j Screening and baseline visits can be combined 
IVUS Imaginge 
 
X 
 
 
 
 
 
 
 
 
 
Adverse Eventsf 
 
X 
 
 
 
 
 
 
 
 
 
Patient-completed Diaryg 
SF-36 Questionnairei 
EQ5D Questionnairei 
Completed monthly for study duration, through 24 months 
At-Home 
Subject 
Procedures 
 
 
Diary of compliance with standard of care procedures, wound care management, quality 
of life questionnaires, and medical resource use questions. 
 
Follow-up phone call at 18 and 24 months. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Clinical Investigation Protocol 
 
Document 
ID: 
200202 
Intravascular Ultrasound-Guided Intervention for  
Venous Leg Ulcers (IGuideU) 
Classification: 
For internal use 
Clinical Investigation Protocol - ISO 14155 
Modified: 
13 Jan 2022 
21
Author: 
Kelly O’Connell 
Version: 
4.0 
User Tool ID: 
16.2.6UserTool0001 
Status: 
Final 
User Tool Version Date: 
08JUL2019 
Page: 
9 of 57 
 
 
Study Schematic 
The following diagram illustrates the sequence of evaluations and follow-up visits for study 
participants: