Sonodynamic Therapy on Patients With Femoropopliteal PAD and Claudication

Phase 1

Withdrawn

Conditions: Cardiovascular Diseases
Atherosclerosis
Peripheral Arterial Disease

Interventions: Drug: Optimal Medical Care
Combination Product: Sonodynamic therapy

Registration Number: NCT03318484

Lead Sponsor: First Affiliated Hospital of Harbin Medical University

Brief Summary: The purpose of this trial is to evaluate the safety and efficacy of sonodynamic therapy (SDT) in reducing atherosclerotic plaques inflammation and increasing peak walking time (PWT) among peripheral artery disease (PAD) patients with symptom of intermittent claudication.

Detailed Description: Atherosclerotic lower extremity PAD affects more than 20 million people in the world. PAD is associated with a major decline in 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.

The aim of this trial is to test the hypothesis that SDT improves PWT by inhibiting atherosclerotic plaques inflammation in femoropopliteal arteries PAD patients compared to optimal medical care (OMC) within 6 month. An estimated 80 eligible patients will be randomly divided into tow groups: OMC and SDT combined with OMC. Recruitment will be performed over 6 months and patients will be followed for 6 months; the anticipated total study duration will be 2 years.

Finally, this trial investigate the safety and efficacy of SDT in PAD patients with intermittent claudication and explore new end-points to evaluate therapeutic effects using PET-CT imaging as well as traditional endpoints.

Recruitment & Eligibility

Status: WITHDRAWN

Sex: All

Target Recruitment: Not specified

Inclusion Criteria

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)
Aged ≥40 years
Resting ABI < 0.9 or ABI decreases > 0.15 after treadmill test regardless of the ABI at rest
Presence of significant stenosis but not occlusion of 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
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
Written informed consent

Exclusion Criteria

Critical limb ischemia or other comorbid conditions that limit walking ability (claudication must be the consistent primary exercise limitation)
Inability to complete treadmill testing per protocol requirements
Two treadmill tests are completed at baseline to confirm reproducibility of results; those who deviates >25% are excluded
Severe aorto-iliac arteries stenosis or occlusion documented by noninvasive and invasive anatomic assessments
Allergic to DVDMS
Diagnosis of porphyria
Pregnant women and nursing mothers
Contraindications of PET/CT
Concurrent enrollment in another clinical trial
Presence of any clinical condition that in the opinion of the principal Investigator or the sponsor makes the patient not suitable to participate in the trial

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Optimal Medical Care and SDT	Sonodynamic therapy	OMC and sonodynamic therapy (SDT) are administrated in this arm.
Optimal Medical Care	Optimal Medical Care	Optimal medical care (OMC) only is 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.
Optimal Medical Care and SDT	Optimal Medical Care	OMC and sonodynamic therapy (SDT) are administrated in this arm.

Primary Outcome Measures

Name	Time	Method
MDS TBR change, (%)	Measured at baseline, 1 and 3 months.	Change from baseline most disease segments (MDS) at 3 months is assessed by 18FDG-PET imaging. Uptake of FDG by the common and superficial femoral artery is expressed as the target, vessel wall to background, lumen ratio (TBR). The mean max MDS TBR is defined as the arterial segment centered on the slice of artery demonstrating the highest FDG uptake at baseline within the index vessel, and calculated as a mean of maximum TBR values derived from three contiguous axial segments.
PWT change, mins	Measured at baseline, 1, 3 and 6 months.	Change from baseline peak walking time (PWT) at 6 months is assessed by graded treadmill test (Gardner protocol). The patient continues the test until walking can no longer be tolerated because of claudication symptoms.

Secondary Outcome Measures

Name	Time	Method
COT change, mins	Measured at baseline, 1, 3, and 6 months.	Change from baseline claudication onset time (COT) at 6 months is assessed by graded treadmill test (Gardner protocol). The patient continues the test until calf muscle discomfort is first noticed.
Peak flow velocity, (cm/s)	Measured at baseline, 1, 3, and 6 months.	Estimation of the systolic and diastolic peak flow velocity of the affected segments by doppler ultrasound.
Serum inflammation cytokine level	Measured at baseline, 1, 3, and 6 months.	Including Interleukin-6, Interleukin-1β, and high-sensitivity C-reactive protein (hs-CRP) level in serum
Post-exercise ABI	Measured at baseline, 1, 3, and 6 months.	Ankle-Brachial Index (ABI) is the ratio of the blood pressure at the ankle to the blood pressure of the upper arm. Post-exercise ABI is collected routinely with the patient supine immediately following a treadmill test.
AS TBR change, (%)	Measured at baseline, 1 and 3 months.	Change from baseline active slice (AS) at 3 months is assessed by 18FDG-PET imaging. Uptake of FDG by the common and superficial femoral artery is expressed as the target, vessel wall to background, lumen ratio (TBR). The mean max AS TBR is defined as average mean maximal TBR of only slices with TBR \>1.6 from index vessel at baseline.
WV TBR change, (%)	Measured at baseline, 1 and 3 months.	Change from baseline whole vessel (WV) TBR at 3 months is assessed by 18FDG-PET imaging. Uptake of FDG by the common and superficial femoral artery is expressed as the target, vessel wall to background, lumen ratio (TBR). 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.
Pre-exercise ABI	Measured at baseline, 1, 3, and 6 months.	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.
Vessels' diameter, (mm)	Measured at baseline, 1, 3, and 6 months.	Estimation of the vessels' diameter for common femoral artery by doppler ultrasound.
Diameter stenosis, (%)	Measured at baseline, 1, 3, and 6 months.	Estimation of the maximum diameter stenosis of the affected segments by doppler ultrasound.
WIQ score	Measured at baseline, 1, 3, and 6 months.	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.
Intimal-medial thickness, (mm)	Measured at baseline, 1, 3, and 6 months.	Estimation of the intimal-medial thickness for common femoral artery by doppler ultrasound.
SF-36 score	Measured at baseline, 1, 3, and 6 months	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.