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

• ClinicalTrials.gov Identifier: NCT02479620
• Recruitment Status: Active, not recruiting
• First Posted: June 24, 2015
• Last Update Posted: February 19, 2020
• Sponsor: Mercator MedSystems, Inc.
• Information provided by (Responsible Party): Mercator MedSystems, Inc.

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Chronic Limb Ischemia	Drug: Dexamethasone Sodium Phosphate Injection, USP, 4 mg/mL	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: LIMBO-ATX: Lower-Limb Adventitial Infusion of DexaMethasone Via Bullfrog to Reduce Occurrence of Restenosis After Atherectomy (ATX)-Based Revascularization
• Actual Study Start Date: June 2016
• Actual Primary Completion Date: November 2019
• Estimated Study Completion Date: March 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Dexamethasone Delivery; 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; 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.
No Intervention: Control; 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.

Outcome Measures

Primary Outcome Measures :

1. Freedom from MALE [ Time Frame: Up to 6 Months following the procedure ]
   Freedom from major adverse limb event (MALE) within 6 months.
2. Freedom from CD-TLR [ Time Frame: Up to 6 Months following the procedure ]
   Freedom from clinically driven target lesion revascularization (CD-TLR) within 6 months.
3. Composite clinical safety by freedom from adverse events including death, MALE, major unplanned amputation, or CD-TLR. [ Time Frame: Up to 6 Months following the procedure ]
   Freedom from composite of death within 30 days from the index procedure, MALE, major unplanned amputation or CD-TLR within 6 months.
4. TVAL% change from post-procedure [ Time Frame: 6 Months following the 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

Secondary Outcome Measures :

1. Composite clinical safety by freedom from adverse events including death, unplanned amputation, CD-TLR, SAE or MALE. [ Time Frame: Up to 12 months following the procedure ]
   Freedom from composite of death, unplanned amputation and CD-TLR, serious adverse events (SAE) and MALE.
2. Event-free survival [ Time Frame: 12 months following the procedure ]
   Proportion of patients reaching 12-month endpoint without a composite clinical safety event.
3. QVA change from post-procedure [ Time Frame: 6 months following the 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).
4. IVUS change from post-procedure [ Time Frame: 6 months following the procedure ]
   Improvement in intravascular ultrasound (IVUS) result with in the TL (subgroup analysis).
5. Amputation-free survival [ Time Frame: 30 days, 6 and 12 months following the procedure ]
   Percentage of patients reaching the endpoints without major or minor amputation.
6. Major and minor amputations and amputation level [ Time Frame: 30 days, 6 and 12 months following the procedure ]
   Percentage of patients requiring amputation (major: above ankle, minor: below ankle), categorized by level on the foot, ankle, or leg.
7. Change in foot wounds versus baseline [ Time Frame: 30 days, 6 and 12 Months following the procedure ]
   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.
8. Resolved CLI death [ Time Frame: 30 days, 6 and 12 months following the procedure ]
   The rate of deaths in patients who had a resolution of their critical limb ischemia (CLI).
9. CD-TLR [ Time Frame: 30 days, 6 and 12 months following the procedure ]
10. Primary sustained clinical improvement versus baseline [ Time Frame: 30 days, 6 and 12 months following the procedure ]
    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.
11. Secondary sustained clinical improvement versus baseline [ Time Frame: 30 days, 6 and 12 months following the procedure ]
    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.
12. SVS WIfI score versus baseline [ Time Frame: 30 days, 6 and 12 months following the procedure ]
13. EQ5D versus baseline [ Time Frame: 30 days, 6 and 12 months following the procedure ]
14. Walking capacity assessment versus baseline [ Time Frame: 30 days, 6 and 12 months following the procedure ]
15. SAE/MALE assessment [ Time Frame: 30 days, 6 and 12 months following the procedure ]
16. Inflammatory biomarker changes from baseline [ Time Frame: 24 hours and 30 days ]
17. Healthcare economic analysis [ Time Frame: From baseline to 24 months ]
    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.
18. Infustion technical success [ Time Frame: Intra-procedural ]
    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.
19. Revascularization success [ Time Frame: Intra-procedural ]
    Establishment of antegrade flow with residual stenosis <30% by angiogram.

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, Arkansas

Arkansas Heart Hospital

Little Rock, Arkansas, United States, 72211

United States, Colorado

Denver Veterans Administration Hospital

Denver, Colorado, United States, 80220

United States, Michigan

Mid-Michigan Heart & Vascular

Saginaw, Michigan, United States, 48604

United States, Mississippi

Hattiesburg Clinic

Hattiesburg, Mississippi, United States, 39401

United States, Missouri

St.Louis University Hospital

Saint Louis, Missouri, United States, 63110

United States, New Jersey

Holy Name Medical Center

Teaneck, New Jersey, United States, 07666

United States, North Carolina

UNC Health Care - Rex Hospital

Raleigh, North Carolina, United States, 27607

United States, South Dakota

Sanford Research

Sioux Falls, South Dakota, United States, 57101

United States, Tennessee

Tennova - Turkey Creek Medical Center

Knoxville, Tennessee, United States, 37934

United States, Texas

Mission Research Institute (New Braunfels Cardiology - GRMC)

New Braunfels, Texas, United States, 78130

Sponsors and Collaborators

Mercator MedSystems, Inc.

Investigators

• Principal Investigator: George Adams, MD; REX Hospital, University of North Carolina Healthcare
• Principal Investigator: Donald Jacobs, MD; Saint Louis University Hospital

More Information

• Responsible Party: Mercator MedSystems, Inc.
• ClinicalTrials.gov Identifier: NCT02479620
• Other Study ID Numbers: CIP0173
• First Posted: June 24, 2015
• Last Update Posted: February 19, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Additional relevant MeSH terms:

Ischemia; Pathologic Processes; Dexamethasone; Dexamethasone acetate; Dexamethasone 21-phosphate; BB 1101; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action