Lower-Limb Adventitial Infusion of DexaMethasone Via Bullfrog to Reduce Occurrence of Restenosis After Percutaneous Transluminal Angioplasty Revascularization

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multi-center, randomized pilot study to document the effects of adventitial delivery of dexamethasone after balloon angioplasty 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 sodium phosphate injection (4 mg/mL) after balloon angioplasty 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 Europe and the United States. 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-PTA: Lower-Limb Adventitial Infusion of DexaMethasone Via Bullfrog to Reduce Occurrence of Restenosis After Percutaneous Transluminal Angioplasty 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 a failure to successfully treat and obtain a <30% residual stenosis Index lesion length is >30 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-index lesions) >50 cm Lesions revascularized during the index case but untreated by Bullfrog Use of alternative therapy, e.g. atherectomy, laser, or 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: Treatment Group: Dexamethasone Delivery<br>Up to 60 angioplasty procedures at up to 30 sites in Europe and in the United States. Patients will be randomized 1:1 to receive either the active treatment or control therapy. Treatment Group: Standard endovascular revascularization therapy consisting of angioplasty followed by Dexamethasondihydrogenphosphat-dinatrium (Ph.Eur.) 4 mg/mL Injektionslösung and with or without stent placement. The drug is diluted to 3.2 mg/mL and administered to the adventitia per Bullfrog Instructions for Use in a dose of 0.8 mg dexamethasone (0.25 mL) per cm of desired vessel treatment length, up to 30 cm. | Drug: Dexamethasone sodium phosphate injection, USP, 4 mg/mL<br>* Post-balloon angioplasty revascularization, the unblinded Pharmacist will prepare a sterile 20 mL syringe (Luer locking) with 16 mL of investigational drug or placebo per assignment. The unblinded Pharmacist provides syringe to investigator. Syringe shall only be labeled with the study number, patient number, randomization number and Investigational Drug. Investigational Drug will be administered via Bullfrog Micro-Infusion Device.<br>|
| No Intervention: Control Group<br>Up to 60 angioplasty procedures at up to 30 sites in Europe and in the United States. Patients will be randomized 1:1 to receive either the active treatment or control therapy. Control Group: Standard endovascular revascularization therapy consisting of angioplasty with or without stent placement. No specific distribution of gender regarding enrollment or randomization is intended. There will also be a separate randomization of patients with Rutherford 6 score to a maximum of 20 enrolled patients. | |

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 post-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 post-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 post-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 post-procedure | 
| CD-TLR |  | 30 days, 6 and 12 months post-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 post-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 post-procedure | 
| SVS WIfI score versus baseline |  | 30 days, 6 and 12 months post-procedure | 
| EQ5D versus baseline | Quality of life assessment. | 30 days, 6 and 12 months post-procedure | 
| Walking capacity assessment versus baseline |  | 30 days, 6 and 12 months post-procedure | 
| SAE/MALE assessment |  | 30 days, 6 and 12 months post-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 | 
| Infusion 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 |