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

Phase 4

• Conditions: Peripheral Artery Disease; Vascular Disease; Critical Limb Ischemia
• Interventions: Drug: Dexamethasone infusion; Device: Drug coated balloon; Device: Plain balloon angioplasty

• Registration Number: NCT02807779
• Lead Sponsor: University of California, San Francisco

Brief Summary

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

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.

Study Timeline

• Study Start: 2016-02-10
• Study First Submitted: 2016-04-01
• Study First Submitted QC: 2016-06-16
• Study First Posted: 2016-06-21
• Primary Completion: 2020-10-31
• Status Verified: 2021-11
• Last Update Submitted: 2021-11-02
• Last Update Posted: 2021-11-10
• Study Completion: 2022-10

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 33

Inclusion Criteria

Screening:

1. Male or non-pregnant female ≥ 35 years of age
2. Atherosclerotic, infrainguinal PAD
3. Rutherford Clinical Category 2-6
4. Stenosis detected by radiology that in the clinician's opinion is the reason for the PAD symptoms
5. Patient is willing to provide informed consent and comply with the required follow up visits, testing schedule, and medication regimen
6. Estimated Glomerular Filtration Rate (eGFR) ≥ 30 and/or threshold established by the local Institutional Review Board or Committee of Human Research

Procedural Criteria:

1. De novo atherosclerotic lesion qualifying for angioplasty
2. 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.
3. >50% diameter stenosis of the superficial femoral artery and/or popliteal artery (between the profunda and tibioperoneal trunk)
4. Reference vessel diameter ≥3 mm and ≤ 8mm
5. Successful wire crossing of lesion
6. 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:

1. Any contraindication to receiving an MRI
2. Pregnant, nursing, or planning on becoming pregnant in < 2yrs
3. Life expectancy of < 1 yr
4. History of solid organ transplantation
5. Patient actively participating in another investigational device or drug study
6. History of hemorrhagic stroke within 3 months of index procedure
7. Previous or planned surgical or interventional procedure within 30 days of index procedure
8. Chronic renal insufficiency with eGFR < 30
9. Prior bypass surgery, stenting, atherectomy or angioplasty of the index lesion
10. Inability to take required study medications
11. Contra-indication or known hypersensitivity to dexamethasone sodium phosphate, contrast media, gadolinium, aspirin or Plavix
12. Systemic fungal infection
13. Acute limb ischemia
14. Prior participation of the index limb in the current study (contralateral treatment is allowed)
15. Patient is being treated with long-term steroids (not including treatment of a bronchial condition with inhaled steroids)

Procedural Criteria:

1. 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.
2. 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
3. Inadequate distal outflow defined as no patent tibial arteries (>50% stenosis). The outflow vessel can be established at the time of primary treatment
4. Use of adjunctive therapies other than angioplasty. Chocolate balloons and/or scoring balloons are allowed, if used below reference diameter.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dexamethasone	Dexamethasone infusion	Participants randomized to the Dexamethasone group will receive dexamethasone infusion to the adventitia of the artery following plain-old-balloon-angioplasty (POBA).
Drug Coated Balloon	Drug coated balloon	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.
Plain Balloon Angioplasty	Plain balloon angioplasty	Participants randomized to the Plain Balloon Angioplasty will receive balloon angioplasty (POBA) only. They will not receive adventital dexamethasone or paclitaxel.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Change in wall volume (WV) without a change in total vessel volume (TVV)	From Post-Operative Day One to 12 Months	As measured by MRI
Change in perioperative inflammatory profile (MCP-1)	From Post-Operative Day One to 12 Months	As measured by serum MCP-1
Change in perioperative inflammatory profile (CRP)	From Post-Operative Day One to 12 Months	As measured by serum CRP
Change in perioperative inflammatory profile (IL-1beta)	From Post-Operative Day One to 12 Months	As measured by serum IL-1beta
Change in ktrans	From 1 Month to 6 Months	As measured by MRI
Percentage of subjects with clinically significant restenosis that undergo reintervention of greater than or equal to 75% of the treated segment	From Post-Operative Day One to 12 Months	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 .
Change in lumen volume (LV) relative to total vessel volume (TVV)	From Post-Operative Day One to 12 Months	As measured by MRI

Trial Locations

Locations (2)

San Francisco VA Medical Center; 🇺🇸 San Francisco, California, United States

University of Washington; 🇺🇸 Seattle, Washington, United States