Lower-Limb Adventitial Infusion of DexaMethasone Via Bullfrog to Reduce Occurrence of Restenosis After Atherectomy (ATX)-Based Revascularization

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multi-center, randomized pilot study to document the effects of adventitial delivery of dexamethasone after atherectomy-based revascularizations of lesions below the knee in symptomatic patients with critical limb ischemia (CLI).

Detailed Description
-----------------
This is a prospective, multi-center, randomized pilot study to document the effects of adventitial delivery of dexamethasone after atherectomy-based revascularizations of lesions below the knee in symptomatic patients with critical limb ischemia (CLI). Up to 120 patients (60 treatment and 60 control), including up to 20 Rutherford 6 patients (10 treatment and 10 control) at up to 30 sites in the United States and Europe. This study will assess the safety and effectiveness of Bullfrog Micro-Infusion Device adventitial deposition of dexamethasone in reducing inflammation and restenosis in patients with clinical evidence of chronic critical limb ischemia with an angiographically significant lesion in the infrapopliteal crural vessels.

Official Title
-----------------
LIMBO-ATX: Lower-Limb Adventitial Infusion of DexaMethasone Via Bullfrog to Reduce Occurrence of Restenosis After Atherectomy (ATX)-Based Revascularization

Conditions
-----------------
Chronic Limb Ischemia

Intervention / Treatment
-----------------
* Drug: Dexamethasone Sodium Phosphate Injection, USP, 4 mg/mL


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Screening Criteria: Age ≥18 years Patient or patient's legal representative have been informed of the nature of the study, agrees to participate and has signed an IRB/EC approved consent form Female patients of childbearing potential have a negative pregnancy test ≤7 days before the procedure and are willing to use a reliable method of birth control for the duration of study participation Patient has documented chronic Critical Limb Ischemia (CLI) in the target limb from the popliteal artery to the ankle joint prior to the study procedure with Rutherford Category 4, 5 or 6 Life expectancy >1 year in the Investigator's opinion Angiographic Criteria: Successful revascularization of the TL with less than 30% residual stenosis, run-off down to the foot and direct in-line flow to any foot wound Reference vessel(s) diameter ≥2 mm Single or multiple atherosclerotic lesion ≥70% in at least one infrapopliteal crural target vessel including the tibioperoneal trunk that totals up to 30 cm in length (with no greater than 5 cm length of contiguous intervening normal artery), with possible extension into the popliteal artery distal to the center of the knee joint space (the P3 segment) Exclusion Criteria: Screening Criteria: Patient unwilling or unlikely to comply with visit schedule Planned major index limb amputation Active foot infection; however, osteomyelitis in the toes or mild cellulitis around the perimeter of gangrene or small ulcers are not exclusions, but osteomyelitis of the metatarsal or more proximal region would be exclusionary Inability to receive study medications Estimated glomerular filtration rate (eGFR) less than 30 mL/min, except for patients with end stage renal disease on chronic hemodialysis Stage 3 (per SVS WIfI classification) or worse heel ulcers or heel ulcers that are determined to be primarily neuropathic in nature Angiographic/Procedural Criteria: Hemodynamically significant inflow lesion (≥50% DS) or occlusion in the ipsilateral iliac, SFA, or popliteal arteries in which there is failure to successfully treat and obtain a <30% residual stenosis Target lesion length is >25 cm as measured from proximal normal vessel to distal normal vessel Total length of lesions treated during the case (including target lesion, inflow lesions, and other non-target lesions) >25 cm Lesions revascularized during the index case but untreated by Bullfrog Use of alternative therapy, e.g. radiation therapy, as part of the index lesion treatment, or use of any drug eluting stents (DES) or drug-eluting balloon/drug-coated balloons (DEB/DCB) for treatment of any infra-inguinal lesions during the study procedure or during the initial six-month follow up period Previously implanted stent in the TL(s) Aneurysm in the target vessel Acute thrombus in the target limb Failure to cross the TL with a guide wire; however, subintimal wire crossing is allowed Heavy eccentric or concentric calcification at index lesion, which in the judgment of the investigator would prevent penetration of the Micro-Infusion Device needle through the vessel wall

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dexamethasone Delivery<br>Up to 60 atherectomy-based revascularization procedures at up to 30 sites in the United States and Europe. For Subjects randomized into the Dexamethasone Delivery arm, this protocol will utilize a 4 mg/mL preparation of Dexamethasone Sodium Phosphate Injection, USP. Each milliliter of the solution contains 4.37 mg of dexamethasone sodium phosphate equivalent to 4 mg of dexamethasone phosphate or 3.33 mg of dexamethasone. The total dose of Dexamethasone Sodium Phosphate Injection, USP will be diluted by 20% prior to infusion. This will result in a final concentration of 3.2 mg dexamethasone phosphate (3.5 mg dexamethasone sodium phosphate, or 2.67 mg dexamethasone) in each milliliter of solution. | Drug: Dexamethasone Sodium Phosphate Injection, USP, 4 mg/mL<br>* Following atherecomy-based revascularization, Investigators will be unblinded to assignment and will treat only patients assigned to the treatment arm with the Bullfrog delivery of dexamethasone.<br>|
| No Intervention: Control<br>Up to 60 atherectomy-based revascularization procedures at up to 30 sites in the United States and Europe. Standard endovascular revascularization therapy consisting of atherectomy with or without angioplasty and with or without stent placement. No additional drug will be given to Subjects randomized to Control. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom from MALE | Freedom from major adverse limb event (MALE) within 6 months. | Up to 6 Months following the procedure | 
| Freedom from CD-TLR | Freedom from clinically driven target lesion revascularization (CD-TLR) within 6 months. | Up to 6 Months following the procedure | 
| Composite clinical safety by freedom from adverse events including death, MALE, major unplanned amputation, or CD-TLR. | Freedom from composite of death within 30 days from the index procedure, MALE, major unplanned amputation or CD-TLR within 6 months. | Up to 6 Months following the procedure | 
| TVAL% change from post-procedure | Transverse-view vessel area loss percentage (TVAL%) of the target lesion at 6 months by quantitative vascular angiography (QVA) or prior to any CD-TLR of the target lesion before 6 months | 6 Months following the procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite clinical safety by freedom from adverse events including death, unplanned amputation, CD-TLR, SAE or MALE. | Freedom from composite of death, unplanned amputation and CD-TLR, serious adverse events (SAE) and MALE. | Up to 12 months following the procedure | 
| Event-free survival | Proportion of patients reaching 12-month endpoint without a composite clinical safety event. | 12 months following the procedure | 
| QVA change from post-procedure | Improvement in % diameter stenosis (%DSS) of the target lesion (TL) and the maximum late lumen loss for the lesion (LLL) will be assessed by quantitative vascular angiography (QVA). | 6 months following the procedure | 
| IVUS change from post-procedure | Improvement in intravascular ultrasound (IVUS) result with in the TL (subgroup analysis). | 6 months following the procedure | 
| Amputation-free survival | Percentage of patients reaching the endpoints without major or minor amputation. | 30 days, 6 and 12 months following the procedure | 
| Major and minor amputations and amputation level | Percentage of patients requiring amputation (major: above ankle, minor: below ankle), categorized by level on the foot, ankle, or leg. | 30 days, 6 and 12 months following the procedure | 
| Change in foot wounds versus baseline | The number and total size of foot wounds, reduction in number and size of baseline wounds, and occurrence of new wounds (number and size) will be measured against baseline. | 30 days, 6 and 12 Months following the procedure | 
| Resolved CLI death | The rate of deaths in patients who had a resolution of their critical limb ischemia (CLI). | 30 days, 6 and 12 months following the procedure | 
| CD-TLR |  | 30 days, 6 and 12 months following the procedure | 
| Primary sustained clinical improvement versus baseline | Sustained upward shift of at least 1 category on Rutherford classification as compared to baseline without the need for repeated TLR or surgical revascularization in amputation-free surviving subjects. | 30 days, 6 and 12 months following the procedure | 
| Secondary sustained clinical improvement versus baseline | Sustained upward shift of at least 1 category on Rutherford classification as compared to baseline including the need for repeated TLR or surgical revascularization in amputation-free surviving subjects. | 30 days, 6 and 12 months following the procedure | 
| SVS WIfI score versus baseline |  | 30 days, 6 and 12 months following the procedure | 
| EQ5D versus baseline |  | 30 days, 6 and 12 months following the procedure | 
| Walking capacity assessment versus baseline |  | 30 days, 6 and 12 months following the procedure | 
| SAE/MALE assessment |  | 30 days, 6 and 12 months following the procedure | 
| Inflammatory biomarker changes from baseline |  | 24 hours and 30 days | 
| Healthcare economic analysis | An analysis of the economics associated with the care of patients, including number of hospital days throughout the study, return visits and hospitalizations, time from index procedure to required revascularization and number of index-lesion-related readmissions. | From baseline to 24 months | 
| Infustion technical success | The grade of distribution (A-F) around infusion sites will be used as a qualitative measure of technical success of adventitial delivery of the drug. | Intra-procedural | 
| Revascularization success | Establishment of antegrade flow with residual stenosis <30% by angiogram. | Intra-procedural |