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

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

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).

Study Overview

• Status: Unknown
• Conditions: Chronic Limb Ischemia
• Intervention / Treatment: Drug: Dexamethasone sodium phosphate injection, USP, 4 mg/mL

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.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kristen L. Poole, PhD; Phone Number: 818 510-564-7761; Email: kpoole@mercatormed.com

Study Locations

• Germany
  • Bad Krozingen, Germany, 79189
    • Recruiting
    • Universitäts-Herzzentrum Freiburg Bad Krozingen GmbH
  • Leipzig, Germany, 04103
    • Recruiting
    • Universitätsklinikum Leipzig AöR
  • Sonneberg, Germany, 96515
    • Recruiting
    • Medinos Kliniken des Landkreiss Sonneberg GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment Group: Dexamethasone Delivery; 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; 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.
No Intervention: Control Group; 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
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
Revascularization success	Establishment of antegrade flow with residual stenosis <30% by angiogram.	Intra-procedural
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
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

Collaborators and Investigators

• Sponsor: Mercator MedSystems, Inc.
• Investigators: Principal Investigator: Dierk Scheinert, MD, University Hospital Of Leipzig

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Anticipated): August 1, 2020
• Study Completion (Anticipated): August 1, 2020

Study Registration Dates

• First Submitted: June 15, 2015
• First Submitted That Met QC Criteria: June 19, 2015
• First Posted (Estimate): June 24, 2015

Study Record Updates

• Last Update Posted (Actual): February 20, 2020
• Last Update Submitted That Met QC Criteria: February 19, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Dexamethasone; Dexamethasone acetate; BB 1101; Dexamethasone 21-phosphate
• Other Study ID Numbers: CIP0169

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No