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Sonodynamic Therapy Manipulates Atherosclerosis Regression Trial on Patients With PAD and Claudication (SMART-PAD)

Primary Purpose

Peripheral Arterial Disease, Atherosclerosis, Cardiovascular Diseases

Status
Completed
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
OMC and pseudo-SDT
OMC and SDT
Sponsored by
First Affiliated Hospital of Harbin Medical University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Peripheral Arterial Disease

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 1. Patients with atherosclerotic peripheral artery disease with symptoms of moderate to severe intermittent claudication (defined as ability to walk at least 2, but not more than 11 minutes on a graded treadmill test using the Gardner protocol)
  • 2. Aged ≥40 years
  • 3. Resting ABI < 0.9 or ABI decreases > 0.15 after treadmill test regardless of the ABI at rest
  • 4. Presence of atherosclerotic plaque in femoropopliteal arteries including the common femoral artery, superficial femoral artery and popliteal artery as determined by: Duplex ultrasound imaging OR lower extremity computed Tomography Angiography (CTA) OR lower extremity magnetic resonance angiography (MRA) OR lower extremity catheter-based contrast arteriography. Each of these noninvasive and invasive anatomic assessments will identify patients with at least a 50% stenosis in the affected segment
  • 5. Stable use of low to moderate dose statin and the permitted statin drugs/ doses: atorvastatin 20 mg, simvastatin 40 mg, rosuvastatin 10 mg, pravastatin, 40 mg, fluvastatin 80 mg or lovastatin 40 mg for at least 6 weeks prior to screening
  • 6. Written informed consent

Exclusion Criteria:

  • 1. Critical limb ischemia or other comorbid conditions that limit walking ability (claudication must be the consistent primary exercise limitation)
  • 2. Inability to complete treadmill testing per protocol requirements
  • 3. Two treadmill tests are completed at baseline to confirm reproducibility of results; those who deviates >25% are excluded
  • 4. Severe aorto-iliac arteries stenosis or occlusion documented by noninvasive and invasive anatomic assessments
  • 5. Active systemic inflammatory disease or have an infectious disease within 1 month prior to enrollment
  • 6. Allergic to DVDMS
  • 7. Diagnosis of porphyria
  • 8. Pregnant women and nursing mothers
  • 9. Contraindications of PET/CT
  • 10. Concurrent enrollment in another clinical trial
  • 11. Presence of any clinical condition that in the opinion of the principal investigator makes the patient not suitable to participate in the trial

Sites / Locations

  • The First Affiliated Hospital of Harbin Medical University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

OMC and pseudo-SDT

OMC and SDT

Arm Description

Optimal medical care (OMC) and pseudo-SDT are administrated in this arm. OMC is established according to the standards established by the 2016 ACC-AHA Guidelines for the Management of Patients with Peripheral Artery Disease in order to promote best practices for risk factor management.

OMC and SDT are administrated in this arm.

Outcomes

Primary Outcome Measures

Change in MDS TBR
The primary efficacy endpoint is the change of target-to-background ratio (TBR) within the most diseased segment (MDS) of index-leg artery at 30-day follow-up after treatment, defined as ratio of the standardized uptake value (SUV) in artery wall to background venous activity within the MDS of index- leg artery assessed by PET/CT.

Secondary Outcome Measures

AS TBR change, (%)
Change from baseline to 30-day in active slice (AS) assessed by PET/CT. The mean max AS TBR is defined as average mean maximal TBR of only slices with TBR >1.6 from index-leg at baseline.
WV TBR change, (%)
Change from baseline to 30-day in whole vessel (WV) TBR assessed by PET/CT. The mean max WV TBR is defined as a single whole vessel average mean maximal TBR of all the slices that compose the index vessel.
PWT change, s
Change from baseline peak walking time (PWT) at 1 month is assessed by graded treadmill test (Gardner protocol). The patient continues the test until walking can no longer be tolerated because of claudication symptoms.
COT change, s
Change from baseline claudication onset time (COT) at 1 month is assessed by graded treadmill test (Gardner protocol). The patient continues the test until calf muscle discomfort is first noticed.
Pre-exercise ABI
Ankle-Brachial Index (ABI) is the ratio of the blood pressure at the ankle to the blood pressure of the upper arm. Pre- exercise ABI is collected routinely with the patient supine immediately prior to a treadmill test.
Diameter stenosis, (%)
Estimation of the maximum diameter stenosis of the affected segments by doppler ultrasound.
WIQ score
The Walking Impairment Questionnaire (WIQ) assesses the severity of the subjective walking impairment on distance, speed, and stair climbing scales. It is administered as a self report. Range: Minimum score is 0.2, maximum 100.
SF-36 score
The patient reported SF-36 data assesses subjective physical limitations, leg symptoms, social function, treatment satisfaction, and quality of life. It is administered as a self report. Higher scores are indicative of better outcome. The summary scores is compiled by taking the mean of five subscales generated from the original questions. Range: Minimum score is 11.1, maximum 85.

Full Information

First Posted
March 1, 2018
Last Updated
July 23, 2019
Sponsor
First Affiliated Hospital of Harbin Medical University
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1. Study Identification

Unique Protocol Identification Number
NCT03457662
Brief Title
Sonodynamic Therapy Manipulates Atherosclerosis Regression Trial on Patients With PAD and Claudication
Acronym
SMART-PAD
Official Title
Sonodynamic Therapy Manipulates Atherosclerosis Regression Trial on Patients With PAD and Claudication
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
March 15, 2018 (Actual)
Primary Completion Date
December 18, 2018 (Actual)
Study Completion Date
April 11, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
First Affiliated Hospital of Harbin Medical University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this trial is to evaluate the safety and efficacy of sonodynamic therapy (SDT) on reducing atherosclerotic plaques inflammation among patients with symptomatic femoropopliteal peripheral artery disease.
Detailed Description
Atherosclerotic lower extremity PAD affects more than 202 million people in the worldwide. PAD is associated with a major decline in walking functional status and claudication is the most frequent symptom. Current claudication therapies are associated with significant limitations. Pharmacotherapy cilostazol and supervised exercise are recommended in 2016 AHA/ACC Guideline on the management of lower extremity PAD patients with claudication, but cilostazol may not achieve an ideal response rate, and supervised exercise efficacy may be limited by co-morbidities and medicare reimburse. Furthermore endovascular procedure may not be feasible, durable or cost-effective, especially in femoropopliteal arteries. SDT is a novel anti-inflammatory regimen to atherosclerosis with non-invasive, plaque-based, macrophage-targeted characteristics. We hypothesize that reducing local arterial inflammation of affected limb will ameliorate claudication symptom in patients with PAD. The main objectives of this trial are to evaluate the efficacy and safety of SDT in patients with symptomatic femoropopliteal PAD. Thirty-two eligible participants will be randomly assigned to SDT or sham-control groups. Results of PET/CT are the prespecified primary endpoint.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Peripheral Arterial Disease, Atherosclerosis, Cardiovascular Diseases

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
OMC and pseudo-SDT
Arm Type
Active Comparator
Arm Description
Optimal medical care (OMC) and pseudo-SDT are administrated in this arm. OMC is established according to the standards established by the 2016 ACC-AHA Guidelines for the Management of Patients with Peripheral Artery Disease in order to promote best practices for risk factor management.
Arm Title
OMC and SDT
Arm Type
Experimental
Arm Description
OMC and SDT are administrated in this arm.
Intervention Type
Combination Product
Intervention Name(s)
OMC and pseudo-SDT
Intervention Description
OMC is established according to the 2016 ACC-AHA Guidelines for the Management of Patients with PAD. Pseudo-SDT combines saline injection and obstructed ultrasound exposure on targeted lesions to simulate real SDT progression.
Intervention Type
Combination Product
Intervention Name(s)
OMC and SDT
Intervention Description
OMC is established according to the 2016 ACC-AHA Guidelines for the Management of Patients with PAD. SDT treatment is the combination of sonosensitizer administration and target atherosclerotic lesions ultrasound exposure. Sinoporphyrin sodium (DVDMS) as sonosensitizer, is dissolved in 0.9% sodium solution for following skin test and intravenous injection. 0.01mg/ml DVDMS solution (0.1ml) is prepared for skin test followed by 0.04 mg/ml.DVDMS solution intravenous injection (0.2mg/kg). The target atherosclerotic lesions are marked on the corresponding skin with ultrasound guidance and underwent ultrasound exposure after 4 hours incubation. The therapeutic ultrasonic transducer is fixed to the marked skin site of each lesion.
Primary Outcome Measure Information:
Title
Change in MDS TBR
Description
The primary efficacy endpoint is the change of target-to-background ratio (TBR) within the most diseased segment (MDS) of index-leg artery at 30-day follow-up after treatment, defined as ratio of the standardized uptake value (SUV) in artery wall to background venous activity within the MDS of index- leg artery assessed by PET/CT.
Time Frame
Measured at baseline, 1month.
Secondary Outcome Measure Information:
Title
AS TBR change, (%)
Description
Change from baseline to 30-day in active slice (AS) assessed by PET/CT. The mean max AS TBR is defined as average mean maximal TBR of only slices with TBR >1.6 from index-leg at baseline.
Time Frame
Measured at baseline, 1month.
Title
WV TBR change, (%)
Description
Change from baseline to 30-day in whole vessel (WV) TBR assessed by PET/CT. The mean max WV TBR is defined as a single whole vessel average mean maximal TBR of all the slices that compose the index vessel.
Time Frame
Measured at baseline, 1month.
Title
PWT change, s
Description
Change from baseline peak walking time (PWT) at 1 month is assessed by graded treadmill test (Gardner protocol). The patient continues the test until walking can no longer be tolerated because of claudication symptoms.
Time Frame
Measured at baseline, 1month.
Title
COT change, s
Description
Change from baseline claudication onset time (COT) at 1 month is assessed by graded treadmill test (Gardner protocol). The patient continues the test until calf muscle discomfort is first noticed.
Time Frame
Measured at baseline, 1month.
Title
Pre-exercise ABI
Description
Ankle-Brachial Index (ABI) is the ratio of the blood pressure at the ankle to the blood pressure of the upper arm. Pre- exercise ABI is collected routinely with the patient supine immediately prior to a treadmill test.
Time Frame
Measured at baseline, 1month.
Title
Diameter stenosis, (%)
Description
Estimation of the maximum diameter stenosis of the affected segments by doppler ultrasound.
Time Frame
Measured at baseline, 1month.
Title
WIQ score
Description
The Walking Impairment Questionnaire (WIQ) assesses the severity of the subjective walking impairment on distance, speed, and stair climbing scales. It is administered as a self report. Range: Minimum score is 0.2, maximum 100.
Time Frame
Measured at baseline, 1month.
Title
SF-36 score
Description
The patient reported SF-36 data assesses subjective physical limitations, leg symptoms, social function, treatment satisfaction, and quality of life. It is administered as a self report. Higher scores are indicative of better outcome. The summary scores is compiled by taking the mean of five subscales generated from the original questions. Range: Minimum score is 11.1, maximum 85.
Time Frame
Measured at baseline, 1month.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 1. Patients with atherosclerotic peripheral artery disease with symptoms of moderate to severe intermittent claudication (defined as ability to walk at least 2, but not more than 11 minutes on a graded treadmill test using the Gardner protocol) 2. Aged ≥40 years 3. Resting ABI < 0.9 or ABI decreases > 0.15 after treadmill test regardless of the ABI at rest 4. Presence of atherosclerotic plaque in femoropopliteal arteries including the common femoral artery, superficial femoral artery and popliteal artery as determined by: Duplex ultrasound imaging OR lower extremity computed Tomography Angiography (CTA) OR lower extremity magnetic resonance angiography (MRA) OR lower extremity catheter-based contrast arteriography. Each of these noninvasive and invasive anatomic assessments will identify patients with at least a 50% stenosis in the affected segment 5. Stable use of low to moderate dose statin and the permitted statin drugs/ doses: atorvastatin 20 mg, simvastatin 40 mg, rosuvastatin 10 mg, pravastatin, 40 mg, fluvastatin 80 mg or lovastatin 40 mg for at least 6 weeks prior to screening 6. Written informed consent Exclusion Criteria: 1. Critical limb ischemia or other comorbid conditions that limit walking ability (claudication must be the consistent primary exercise limitation) 2. Inability to complete treadmill testing per protocol requirements 3. Two treadmill tests are completed at baseline to confirm reproducibility of results; those who deviates >25% are excluded 4. Severe aorto-iliac arteries stenosis or occlusion documented by noninvasive and invasive anatomic assessments 5. Active systemic inflammatory disease or have an infectious disease within 1 month prior to enrollment 6. Allergic to DVDMS 7. Diagnosis of porphyria 8. Pregnant women and nursing mothers 9. Contraindications of PET/CT 10. Concurrent enrollment in another clinical trial 11. Presence of any clinical condition that in the opinion of the principal investigator makes the patient not suitable to participate in the trial
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
YE TIAN, MD, PhD
Organizational Affiliation
First Affiliated Hospital of Harbin Medical University
Official's Role
Study Chair
Facility Information:
Facility Name
The First Affiliated Hospital of Harbin Medical University
City
Harbin
State/Province
Heilongjiang
ZIP/Postal Code
150000
Country
China

12. IPD Sharing Statement

Citations:
PubMed Identifier
32966832
Citation
Jiang Y, Fan J, Li Y, Wu G, Wang Y, Yang J, Wang M, Cao Z, Li Q, Wang H, Zhang Z, Wang Y, Li B, Sun F, Zhang H, Zhang Z, Li K, Tian Y. Rapid reduction in plaque inflammation by sonodynamic therapy inpatients with symptomatic femoropopliteal peripheral artery disease:A randomized controlled trial. Int J Cardiol. 2021 Feb 15;325:132-139. doi: 10.1016/j.ijcard.2020.09.035. Epub 2020 Sep 20.
Results Reference
derived

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Sonodynamic Therapy Manipulates Atherosclerosis Regression Trial on Patients With PAD and Claudication

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