Temsirolimus Adventitial Delivery to Improve ANGioplasty and/or Atherectomy Revascularization Outcomes Below the Knee

Study Overview
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Brief Summary
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A multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of Temsirolimus Perivascular Injection 0.1 mg/mL on the incidence of ischemia-driven major amputation, clinically driven target lesion revascularization, and clinically relevant target lesion occlusion after revascularization of lesions below the knee in patients with symptomatic Rutherford 3-5 peripheral artery disease. The primary safety endpoint will be gathered at 1-month post-index procedure. The primary efficacy endpoint will be gathered at 6 months post-index procedure. Participants will be followed for up to 5 years post-index procedure.

Detailed Description
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After completion of revascularization therapy and any decision to place stents, participants will be qualified for final enrollment in the study and will be randomized 1:1 and treated with the investigational drug or placebo. Any stents will be placed only after randomization, assignment, and adventitial drug therapy, although any stenting decisions (other than for treatment of AEs) must be made prior to randomization and adventitial drug delivery in order to avoid bias toward or against stenting.

Official Title
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Temsirolimus Adventitial Delivery to Improve ANGioplasty and/or Atherectomy Revascularization Outcomes Below the Knee: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Temsirolimus Perivascular Injection 0.1 mg/mL on the Incidence of Ischemia-Driven Major Amputation, Clinically Driven Target Lesion Revascularization, and Clinically Relevant Target Lesion Occlusion After Revascularization of Lesions Below the Knee in Patients With Symptomatic Rutherford 3-5 Peripheral Artery Disease

Conditions
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Peripheral Artery Disease, Critical Limb Ischemia

Intervention / Treatment
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* Drug: Temsirolimus
* Drug: Saline placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age ≥18 years and <90 years Patient has documented severe claudication (Rutherford 3) or chronic Critical Limb Ischemia (CLI) (Rutherford 4-5) in the target limb due to arterial stenosis between the knee joint space and the ankle joint prior to the study procedure Life expectancy >1 year in the Investigator's opinion Patient has been informed of the nature of the study, agrees to participate, agrees to the follow-up schedule, and has signed an IRB approved consent form Female patients of childbearing potential have a negative pregnancy test ≤7 days before the procedure and are willing to use a highly effective method of birth control for one month preceding and 12 months following study treatment Exclusion Criteria Patient is already enrolled in another clinical study of systemic drug therapy or another device study that has not completed its primary endpoint, including prior enrollment in this study Patient is unwilling or unlikely to comply with visit schedule Patient is incapable of providing consent and/or incapable of understanding the nature, significance and implications of the clinical trial Patient is already receiving or planned to receive systemic immunotherapy or chemotherapy Patient is at high risk of thrombosis and taking systemic anticoagulant therapy that is unable to be withheld during the procedure Patient has a CNS tumor or elevated risk for intracerebral bleeding and is receiving chronic anticoagulation therapy e.g. warfarin or oral anticoagulant (note: chronic antiplatelet therapy, e.g. aspirin and clopidogrel, and procedural anticoagulation therapy, e.g. heparin or bivalirudin, are allowed) Recent (<30 days prior to study procedure) myocardial infarction Cerebrovascular accident <60 days prior to the study procedure or any history of intracerebral hemorrhage Any surgical or endovascular procedure performed within 14 days prior to the index procedure or planned within 30 days post index procedure is exclusionary; allowable exceptions to this exclusion include the following: concurrent procedures during the index procedure prior staged revascularization in the target limb, e.g. for inflow revascularization within 14 days of and prior to the index procedure Planned major (above the ankle) target limb amputation Active foot infection, including osteomyelitis of the metatarsal or more proximal region; allowable exceptions to this exclusion include the following: osteomyelitis in the toes mild cellulitis around the perimeter of gangrene small ulcers (<25mm largest diameter) Inability to receive temsirolimus or iodinated contrast medium due to labeled contra-indications or known sensitivity reactions Stage 3 (per SVS WIfI classification) or worse heel ulcers or heel ulcers that are determined to be primarily neuropathic in nature or non-ischemic in origin Risk of amputation based on WIfI clinical staging = HIGH Patient has active viral infection of SARS-CoV-2 or active disease diagnosis of COVID-19 (must be determined within 7 days of index procedure) Patient has a bilirubin level of >1.5xULN Estimated glomerular filtration rate (eGFR, calculated from serum creatinine using an isotope dilution mass spectrometry (IDMS)-traceable equation) less than 30 mL/min, except for patients with end stage renal disease on chronic hemodialysis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Block randomization will be stratified for Rutherford 3 and for Rutherford 4/5 participants such that each strata will be randomized 1:1. Block randomization will also be stratified by site such that each site will be assigned a 1:1 randomization.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Temsirolimus<br>Temsirolimus delivered to adventitia and perivascular tissue after primary revascularization | Drug: Temsirolimus<br>* 0.1 mg/mL temsirolimus, including contrast medium with approximately 75 mg iodine per mL. The dosage will be delivered in a volume of 0.50 mL per cm of target lesion length, up to 30 cm, with +50% allowance for anatomical considerations; for a total volume of up to 22.5 mL and a total dose of up to 2.25 mg in participants assigned to treatment. The same volumes of comparator agent will be delivered in control participants.<br>|
| Placebo Comparator: Placebo<br>Saline placebo delivered to adventitia and perivascular tissue after primary revascularization | Drug: Saline placebo<br>* Saline placebo, including contrast medium with approximately 75 mg iodine per mL. The dosage will be delivered in a volume of 0.50 mL per cm of target lesion length, up to 30 cm, with +50% allowance for anatomical considerations; for a total volume of up to 22.5 mL and a total dose of up to 2.25 mg in participants assigned to treatment. The same volumes of comparator agent will be delivered in control participants.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom from Cinical Relevant Target Lesion Failure | Superiority of treatment vs. control group in the composite freedom from the following: Clinically Relevant Target Lesion Occlusion Clinically Driven Target Lesion Revascularization Ischemia-Driven Major Amputation of the Target Limb | 6 Months | 
| MALE + POD | Noninferiority of treatment vs. control groups in the composite freedom from Major Adverse Limb Event (MALE) in the target limb or Perioperative Death (POD) | 30 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom from Target Lesion Failure | Superiority of treatment vs. control group in the composite freedom from the following: Target Lesion Occlusion Clinically Driven Target Lesion Revascularization Ischemia-Driven Major Amputation of the target limb | 6 Months | 
| To determine non-inferiority in long-term mortality rate | Death at the following time points | 12, 24, 36, 48, 60 months | 
| To determine non-inferiority in freedom from all-cause death or major adverse limb event. | Composite of all-cause death or MALE of the target limb | 30 days, 6, 12 months | 
| To determine non-inferiority in amputation-free survival. | Freedom from death and ischemia-driven major amputation of the target limb | 30 days, 6, 12, 24 months | 
| Safety and tolerability will be assessed from overall rate of adverse events (subclassified as major, serious, non-serious, unanticipated, revascularization procedure-related, device-related and drug-related). | AEs/ARs will be categorized into one of the following: MALE of the target limb Non-MALE target limb SAE/SAR Other SAE/SAR Non-serious AE/AR AEs/ARs will further be classified as: Expected UADE SUSAR AEs/ARs will also be classified for relatedness (definitely, probably, possibly or not) to the following: Revascularization procedure Use of the Bullfrog device The study drug | 30 days, 6, 12, 24 months | 
| Change of the individual components of the primary and secondary endpoints (ischemia-driven major amputation, clinically driven target lesion revascularization, clinically relevant target lesion occlusion or all target lesion occlusion) | Taken individually: Ischemia-driven major amputation of the target limb CD-TLR Clinically relevant target lesion occlusion Any target lesion occlusion | 6, 12, 24 months | 
| Freedom from major adverse limb events | MALE of the target limb | 30 days, 6, 12, 24 months | 
| Composite of the following wound healing measures | Total size of foot wounds on the target limb, percent and absolute change from baseline Status of foot wounds on the target limb Unassisted wound healing | 30 days, 6, 12 months | 
| Reduction in unplanned minor amputations | Unplanned minor amputation rate, overall and by level (forefoot, midfoot, hindfoot) | 30 days, 6, 12 months | 
| Rutherford score improvement | Rutherford category and change from baseline | 30 days, 6, 12, 24 months | 
| WIfI score improvement | WIfI category and change from baseline | 30 days, 6, 12, 24 months | 
| Composite of hemodynamic improvement measures (ABI, TBI and toe pressure) | Ankle-brachial index and change from baseline Toe-brachial index and change from baseline Toe pressure and change from baseline | 30 days, 6, 12, 24 months | 
| Patient reported quality of life benefits (VascuQoL) | VascuQoL results and change from baseline | 30 days, 6, 12, 24 months | 
| Patient reported outcomes (walking impairment questionnaire) benefits | WIQ results and change from baseline | 30 days, 6, 12, 24 months | 
| Primary and primary assisted patency rates | Primary patency rate Primary assisted patency rate | 30 days, 6, 12, 24 months | 
| Primary and secondary sustained clinical improvement rates | Primary sustained clinical improvement rate Secondary sustained clinical improvement rate | 30 days, 6, 12, 24 months |