Intima Versus Adventitia Drug Delivery to Elucidate Mechanisms of Restenosis: Magnetic Resonance Imaging

Study Overview
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Brief Summary
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This is a prospective, multicenter, randomized trial to determine the mechanisms of vascular healing. The study will evaluate subjects with peripheral artery disease (PAD) who require an endovascular intervention of the femoro-popliteal (SFA) artery to restore blood flow to the leg.

Detailed Description
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Peripheral artery disease (PAD) affects at least 12 million Americans annually with more than half a million patients undergoing an endovascular or surgical revascularization procedure in order to treat the disease. Unfortunately, about two-thirds of patients still have blockages in the leg arteries, even after these procedures. Advances in Magnetic resonance imaging (MRI) offer promise for understanding the mechanism of failure through insights into vessel wall composition, remodeling, and inflammation. Restenosis has a known relationship to inflammation. Advances in micro-catheter technologies offer the ability to deliver anti-inflammatory medications such as Dexamethasone (DEX) directly to the adventitia and advances in drug delivery on balloon surfaces to deliver paclitaxel to the intima of the artery. This study aims to investigate if patient-specific parameters affect angioplasty outcomes, if DEX has a biological effect on the vessel wall, and if this effect is through the reduction of inflammation. In response to an FDA issued Letter to Healthcare Providers dated August 9, 2019 that reported the relative risk for increased mortality at 5 years was 1.57 (95% confidence interval 1.16 - 2.13), which corresponds to a 57% relative increase in mortality in patients treated with paclitaxel-coated devices, participant enrollment in the paclitaxel drug coated balloon arm was stopped and a plain balloon angioplasty arm was added to the protocol.

Official Title
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Intima Versus Adventitia Drug Delivery to Elucidate Mechanisms of Restenosis: Magnetic Resonance Imaging

Conditions
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Peripheral Artery Disease, Vascular Disease, Critical Limb Ischemia

Intervention / Treatment
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* Drug: Dexamethasone infusion
* Device: Drug coated balloon
* Device: Plain balloon angioplasty


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Screening: Male or non-pregnant female ≥ 35 years of age Atherosclerotic, infrainguinal PAD Rutherford Clinical Category 2-6 Stenosis detected by radiology that in the clinician's opinion is the reason for the PAD symptoms Patient is willing to provide informed consent and comply with the required follow up visits, testing schedule, and medication regimen Estimated Glomerular Filtration Rate (eGFR) ≥ 30 and/or threshold established by the local Institutional Review Board or Committee of Human Research Procedural Criteria: De novo atherosclerotic lesion qualifying for angioplasty A patent artery proximal to the index lesion. Concomitant inflow procedures, including open femoral artery endarterectomy and/or stenting of the iliac arteries, are permissible. >50% diameter stenosis of the superficial femoral artery and/or popliteal artery (between the profunda and tibioperoneal trunk) Reference vessel diameter ≥3 mm and ≤ 8mm Successful wire crossing of lesion Successful angioplasty of the index lesion or part of the index lesion, defined as ≤30% residual lumen stenosis compared with adjacent non-diseased lumen diameter, without flow-limiting dissection Exclusion Criteria: Screening Criteria: Any contraindication to receiving an MRI Pregnant, nursing, or planning on becoming pregnant in < 2yrs Life expectancy of < 1 yr History of solid organ transplantation Patient actively participating in another investigational device or drug study History of hemorrhagic stroke within 3 months of index procedure Previous or planned surgical or interventional procedure within 30 days of index procedure Chronic renal insufficiency with eGFR < 30 Prior bypass surgery, stenting, atherectomy or angioplasty of the index lesion Inability to take required study medications Contra-indication or known hypersensitivity to dexamethasone sodium phosphate, contrast media, gadolinium, aspirin or Plavix Systemic fungal infection Acute limb ischemia Prior participation of the index limb in the current study (contralateral treatment is allowed) Patient is being treated with long-term steroids (not including treatment of a bronchial condition with inhaled steroids) Procedural Criteria: Index lesions extending into the tibial trifurcation or above the profunda. Note: the outflow tibial artery can be treated concomitantly. Similarly, the common femoral artery can be treated concomitantly, either with open endarterectomy and patch angioplasty or with endovascular methods. However, the index lesion cannot be contiguous with either the CFA or the tibial trifurcation. Circumferential calcification at index lesion, which in the judgment of the investigator would prevent penetration of the Micro-Infusion catheter needle through the vessel wall Inadequate distal outflow defined as no patent tibial arteries (>50% stenosis). The outflow vessel can be established at the time of primary treatment Use of adjunctive therapies other than angioplasty. Chocolate balloons and/or scoring balloons are allowed, if used below reference diameter.

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexamethasone<br>Participants randomized to the Dexamethasone group will receive dexamethasone infusion to the adventitia of the artery following plain-old-balloon-angioplasty (POBA). | Drug: Dexamethasone infusion<br>* Participants will receive dexamethasone infusion following plain balloon angioplasty<br>* Other names: microinfusion catheter;|
| Active Comparator: Drug Coated Balloon<br>Participants randomized to the Drug Coated Balloon (DCB) group will not receive dexamethasone infusion to the adventitia of the artery following (POBA). They will receive additional angioplasty with a paclitaxel coated balloon. | Device: Drug coated balloon<br>* Participants will receive angioplasty with a drug-coated balloon following plain balloon angioplasty<br>|
| Active Comparator: Plain Balloon Angioplasty<br>Participants randomized to the Plain Balloon Angioplasty will receive balloon angioplasty (POBA) only. They will not receive adventital dexamethasone or paclitaxel. | Device: Plain balloon angioplasty<br>* Participants will receive plain balloon angioplasty only<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Percent Wall Volume (PWV) | Percent Wall Volume (PWV) of the treated segment of artery will be measured by MRI. | From Post-Operative Day One to 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in wall volume (WV) without a change in total vessel volume (TVV) | As measured by MRI | From Post-Operative Day One to 12 Months | 
| Change in perioperative inflammatory profile (MCP-1) | As measured by serum MCP-1 | From Post-Operative Day One to 12 Months | 
| Change in perioperative inflammatory profile (CRP) | As measured by serum CRP | From Post-Operative Day One to 12 Months | 
| Change in perioperative inflammatory profile (IL-1beta) | As measured by serum IL-1beta | From Post-Operative Day One to 12 Months | 
| Change in ktrans | As measured by MRI | From 1 Month to 6 Months | 
| Change in lumen volume (LV) relative to total vessel volume (TVV) | As measured by MRI | From Post-Operative Day One to 12 Months | 
| Percentage of subjects with clinically significant restenosis that undergo reintervention of greater than or equal to 75% of the treated segment | As the subject undergoes reintervention, any treatment that overlaps with greater than or equal to 75% of the segment initially treated by the index procedure (treated segment) may result in obfuscation of the primary outcome measure . | From Post-Operative Day One to 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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walking, angioplasty, peripheral artery disease, peripheral vascular disease, atherosclerosis, balloon angioplasty, dexamethasone, drug coated balloon, paclitaxel, claudication