Temsirolimus Adventitial Delivery to Improve ANGiographic Outcomes Below the Knee

Abstract

Background: Current endovascular treatments of below the knee (BTK) popliteal or tibial/peroneal arteries including investigational drug-coated balloons have limited long-term efficacy.

Objectives: This Phase 2 trial assessed the feasibility of adventitial deposition of temsirolimus to reduce neointimal hyperplasia and clinically relevant target lesion failure (CR-TLF) 6 months after BTK arterial revascularization.

Methods: This prospective, multicenter, double-blinded, comparative, dose-escalation trial enrolled 61 patients with Rutherford 3 to 5 symptoms undergoing endovascular revascularization of ≥1 angiographically significant BTK lesions. Perivascular infusion after completion of arterial revascularization was randomized into control (saline) vs low-dose (0.1 mg/mL) temsirolimus groups for the first 30 patients. In the second part of the trial, patients were randomized to control versus high-dose (0.4 mg/mL) temsirolimus groups. Primary and secondary efficacy endpoints were target lesion (TL) transverse-view vessel area loss percentage (TVAL%) and CR-TLF at 6 months, respectively. CR-TLF was defined as a composite of ischemia-driven major amputation of the target limb, clinically driven target lesion revascularization (CD-TLR), and clinically relevant TL occlusion. The primary safety endpoint was freedom from major adverse limb events or perioperative death (MALE+POD) at 30 days.

Results: There was no discernable difference in effect between temsirolimus doses; therefore, the low- and high-dose cohorts were pooled for the analyses. The principal analysis on the per protocol (PP) group of 53 patients revealed superior primary efficacy of the treatment arm, with reduction in TVAL% of 13.9% absolute (37.3% relative) and the rate of CR-TLF reduced by 27.1% absolute (51.3% relative), at 6 months. Subgroup analysis of all Trans-Atlantic Inter-Society Consensus (TASC) B to D lesions (N=36) revealed TVAL% reduction of 22.3% absolute (48.3% relative) and the rate of CR-TLF reduced by 39.2% absolute (56.6% relative). Freedom from 30-day MALE+POD was 100% in all groups.

Conclusions: This hypothesis-generating trial suggests that adventitial infusion of temsirolimus in BTK arteries improves TVAL% and CR-TLF with no adverse safety signals through 6 months, supporting the move to a Phase 3 trial.

Clinical impact: There remain gaps in the endovascular treatment of patients with atherosclerotic lesions of below-the-knee (BTK) arteries. The TANGO trial evaluated the use of sub-adventitial temsirolimus with the Bullfrog micro-infusion device during BTK interventions. The therapy was safe and effective. Compared with controls, vessel lumen area patency was improved, and target lesion failure was less frequent. The effects were most appreciable in subjects with higher baseline TASC lesions (B, C, or D). Sub-adventitial temsirolimus offers the potential to improve the results of BTK interventions in this challenging patient population.

Keywords: endovascular; ischemia; neointimal hyperplasia; revascularization.

Figure 1.

Bullfrog micro-infusion device and method of study drug administration. Diagram of the Bullfrog Micro-infusion device and its method of action. The Bullfrog device is introduced into the artery while fully deflated, with the balloon walls sheathing and protecting the microneedle. When the target is reached, the balloon is inflated to extrude the microneedle through the arterial wall for drug delivery to the adventitia and perivascular tissue.

Figure 2.

Schematic of subject flow.

Figure 3.

Kaplan-Meier—Freedom from CR-TLF—All PP subjects. The presence of CR-TLF was measured for 360 days after index procedure across treatment and control groups. Treatment groups were infused with temsirolimus and the control group was given saline after arterial revascularization. By follow-up Day 240, the difference of freedom from CR-TLF between treatment (74.4%) and control (47.2%) groups was 27.2% as indicated by the red arrow. CR-TLF, clinically relevant target lesion failure.

Figure 4.

Kaplan-Meier—Freedom from CR-TLF—All PP TASC B to D subjects. The presence of CR-TLF was measured for 360 days after index procedure across treatment and control groups with the subgroup PP-TASC B to D patients. By follow-up Day 240, the difference of freedom from CR-TLF between treatment (70.2%) and control (31.0%) groups was 39.2%. CR-TLF, clinically relevant target lesion failure; PP, per protocol; TASC, Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease.