Ultrasound Cavitation Therapy for Peripheral Arterial Disease

Overseen By Jonathan Lindner, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Virginia

Disqualifiers: Severe heart failure, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 18 days

30 Participants Needed

Trial Summary

What is the purpose of this trial?

In this study, we will explore how ultrasound exposure of ultrasound contrast agents, which produces beneficial shear-mediated bioeffects, can be used to treat patients with severe non-healing ulcers secondary to peripheral arterial disease (PAD). The primary outcome measure is whether ultrasound exposure to microbubble contrast agents in the inflow artery and at the wound site can accelerate wound healing. A secondary outcome measure is whether cavitation-related changes occur in tissue perfusion in the treated limb and wound measured by ultrasound perfusion imaging and skin flow.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Ultrasound Cavitation Therapy for Peripheral Arterial Disease?

Research shows that ultrasound treatment can improve blood flow and circulation in patients with atherosclerotic lesions in the legs. Additionally, ultrasound combined with other agents has been effective in breaking down blood clots in animal models, suggesting potential benefits for similar conditions. ^{1 2 3 4 5}

How is Ultrasound Cavitation Therapy different from other treatments for Peripheral Arterial Disease?

Ultrasound Cavitation Therapy is unique because it uses sound waves to create tiny bubbles that help improve blood flow in the affected areas, unlike traditional treatments that often rely on drugs or surgery. This method can enhance circulation without the bleeding risks associated with standard thrombolytic (clot-dissolving) therapies. ^{1 2 6 7 8}

Eligibility Criteria

This trial is for people with severe non-healing ulcers due to Peripheral Arterial Disease (PAD), specifically those who have not seen any improvement in the past 3 months. Participants must have a confirmed PAD diagnosis and be classified as having Critical Limb Ischemia. Those with major illnesses affecting the limb, pregnant or breastfeeding women, allergies to ultrasound contrast agents or PEG, unstable blood pressure, or upcoming amputation are excluded.

Inclusion Criteria

I have severe leg artery disease with a non-healing wound for over 3 months.

I have been diagnosed with PAD due to low ankle-brachial index or non-compressible vessels.

Exclusion Criteria

You are allergic to ultrasound contrast agents or polyethylene glycol.

I am expected to undergo amputation or a procedure to restore blood flow within the next month.

Pregnant or lactating females

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ultrasound cavitation therapy to treat non-healing ulcers

18 days

Follow-up

Participants are monitored for changes in wound granulation and tissue perfusion

4 weeks

Treatment Details

Interventions

• Ultrasound Cavitation Therapy

Trial Overview The study tests if using ultrasound to shake microbubble contrast agents can help heal severe ulcers caused by poor blood flow in PAD patients. It looks at whether this treatment speeds up healing and improves blood flow in the affected limb compared to usual care without these ultrasound effects.

Participant Groups

Group I: Cavitation therapy Experimental Treatment 1 Intervention

Subjects treated with cavitation energy

Group II: Control Active Control 1 Intervention

Control subjects not treated with cavitation energy

Ultrasound Cavitation Therapy is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Ultrasonic Cavitation for:

• Body contouring
• Fat reduction
• Cellulite treatment

Approved in United States as Ultrasonic Cavitation for:

• Body contouring
• Fat reduction
• Cellulite treatment

Approved in Canada as Ultrasonic Cavitation for:

• Body contouring
• Fat reduction
• Cellulite treatment

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Findings from Research

In a study involving 40 patients with atherosclerotic lesions, low-dose ultrasound treatment applied locally to ischemic leg tissues resulted in improved peripheral circulation and microcirculation.

The treatment also positively affected hemocoagulation, suggesting that low-dose ultrasound may enhance blood flow and clotting factors in patients with vascular issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The ultrasonic therapy of patients with arteriosclerosis obliterans of the vessels of the lower extremities]. Vashkevich, DL.[2006]

The study explores a new approach to treating acute peripheral arterial thrombosis using contrast-enhanced sonothrombolysis, which combines ultrasound, ultrasound contrast agents (UCAs), and fibrinolytic agents, potentially improving thrombus dissolution compared to standard methods.

Using a porcine model, the research aims to enhance the effectiveness of thrombolytic therapy while addressing safety concerns, such as the risk of severe allergic reactions to UCAs, which could lead to better outcomes for patients with arterial occlusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contrast-enhanced sonothrombolysis in a porcine model of acute peripheral arterial thrombosis and prevention of anaphylactic shock. Nederhoed, JH., Slikkerveer, J., Meyer, KW., et al.[2014]

The study found that using percutaneous catheter-delivered ultrasound energy combined with local paclitaxel delivery resulted in a significantly lower rate of restenosis (3.6%) and no target lesion revascularization (0%) at 6 months in patients with critical limb ischemia, compared to the control group which had a 21.4% restenosis rate and 10.7% TLR.

No adverse procedural events occurred in either group, indicating that the ultrasound and paclitaxel treatment is safe, with no myocardial infarctions, deaths, or amputations reported during the follow-up period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local Ultrasound to Enhance Paclitaxel Delivery After Femoral-Popliteal Treatment in Critical Limb Ischemia: The PACUS Trial. Gandini, R., Del Giudice, C.[2021]

In a study involving 9 pigs with induced thrombus, the use of targeted microbubbles carrying urokinase combined with ultrasound significantly improved arterial blood flow compared to urokinase alone, with 3 out of 5 pigs showing improvement in the microbubble group.

The targeted microbubble approach also resulted in a significantly lower thrombus weight, indicating a more effective thrombolysis without any observed adverse effects, suggesting a promising new method for treating acute peripheral arterial occlusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous Targeted Microbubbles Carrying Urokinase versus Urokinase Alone in Acute Peripheral Arterial Thrombosis in a Porcine Model. Nederhoed, JH., Ebben, HP., Slikkerveer, J., et al.[2018]

A review of ten studies on therapeutic ultrasound for lower limb musculoskeletal conditions found no high-quality evidence supporting its effectiveness, as most studies were of low quality.

None of the placebo-controlled trials demonstrated significant differences between actual ultrasound treatment and sham (fake) ultrasound, indicating that therapeutic ultrasound may not be an effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effectiveness of therapeutic ultrasound for musculoskeletal conditions of the lower limb: A literature review. Shanks, P., Curran, M., Fletcher, P., et al.[2011]

Low-intensity pulsed ultrasound (LIPUS) and SonoVue alone do not harm human renal glomerular endothelial cells (HRGECs), but when used together, they significantly reduce cell proliferation and increase cell death.

The combination of LIPUS and SonoVue works by suppressing the ERK1/2 signaling pathway, and blocking this pathway with an inhibitor prevents the harmful effects, suggesting a specific mechanism of action for the cytotoxicity observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-intensity pulsed ultrasound in combination with SonoVue induces cytotoxicity of human renal glomerular endothelial cells via repression of the ERK1/2 signaling pathway. Liu, X., Wang, B., Ding, H., et al.[2018]

In a pilot study involving 12 patients with critical limb ischemia, the use of low-frequency, high-intensity ultrasound followed by balloon angioplasty achieved a high primary patency rate of 95% at 6 months, indicating effective treatment for calcified infrapopliteal lesions.

The treatment was found to be safe, with no reported deaths, major amputations, or target vessel occlusions within 30 days, and complete ulcer healing was observed in all patients by the 6-month follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Six-Month Angiographic and Clinical Outcomes of Therapeutic Ultrasound Pretreatment Associated With Plain Balloon Angioplasty for Below-the-Knee Lesions in Patients With Critical Limb Ischemia: A Prospective, Single-Center Pilot Study. Del Giudice, C., Gandini, R.[2022]

In preclinical studies with mice, optimized ultrasound (US) conditions significantly increased blood flow in the treated limb, with the best results achieved using high line density and longer pulse durations, leading to a 3- to 4-fold increase in perfusion.

In a first-in-human study, the same optimized US conditions combined with intravenous microbubble contrast resulted in over a 2-fold increase in calf muscle blood flow in both healthy individuals and patients with peripheral artery disease (PAD), suggesting a potential new therapy for PAD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmentation of Tissue Perfusion in Patients With Peripheral Artery Disease Using Microbubble Cavitation. Mason, OR., Davidson, BP., Sheeran, P., et al.[2021]

References

1. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[The ultrasonic therapy of patients with arteriosclerosis obliterans of the vessels of the lower extremities]. [2006]

2. United States pubmed.ncbi.nlm.nih.gov

Contrast-enhanced sonothrombolysis in a porcine model of acute peripheral arterial thrombosis and prevention of anaphylactic shock. [2014]

3. United States pubmed.ncbi.nlm.nih.gov

Local Ultrasound to Enhance Paclitaxel Delivery After Femoral-Popliteal Treatment in Critical Limb Ischemia: The PACUS Trial. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Intravenous Targeted Microbubbles Carrying Urokinase versus Urokinase Alone in Acute Peripheral Arterial Thrombosis in a Porcine Model. [2018]

5. Scotland pubmed.ncbi.nlm.nih.gov

The effectiveness of therapeutic ultrasound for musculoskeletal conditions of the lower limb: A literature review. [2011]

6. England pubmed.ncbi.nlm.nih.gov

Low-intensity pulsed ultrasound in combination with SonoVue induces cytotoxicity of human renal glomerular endothelial cells via repression of the ERK1/2 signaling pathway. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Six-Month Angiographic and Clinical Outcomes of Therapeutic Ultrasound Pretreatment Associated With Plain Balloon Angioplasty for Below-the-Knee Lesions in Patients With Critical Limb Ischemia: A Prospective, Single-Center Pilot Study. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Augmentation of Tissue Perfusion in Patients With Peripheral Artery Disease Using Microbubble Cavitation. [2021]