The efficacy of biologic therapies in critical limb ischemia (CLI) remains elusive, in part, due to limitations in trial design and patient selection. Using a novel design, we examined the impact of complementing revascularization therapy with intramuscular JVS-100 – a non-viral gene therapy that activates endogenous regenerative repair pathways. In this double-blind, placebo-controlled, Phase 2B trial, we randomized 109 patients with CLI (Rutherford class V or VI) to 8 mg or 16 mg intramuscular injections of placebo versus JVS-100. Patients were eligible if they persistently had reduced forefoot perfusion, by toe–brachial index (TBI) or skin perfusion pressure (SPP), following successful revascularization with angiographic demonstration of tibial arterial flow to the ankle. The primary efficacy end point was a 3-month wound healing score assessed by an independent wound core laboratory. The primary safety end point was major adverse limb events (MALE). Patients’ mean age was 71 years, 33% were women, 79% had diabetes, and 8% had end-stage renal disease. TBI after revascularization was 0.26, 0.27, and 0.26 among the three groups (placebo, 8 mg, and 16 mg injections, respectively). Only 26% of wounds completely healed at 3 months, without any differences between the three groups (26.5%, 26.5%, and 25%, respectively). Similarly, there were no significant changes in TBI at 3 months. Three (2.8%) patients died and two (1.8%) had major amputations. Rates of MALE at 3 months were 8.8%, 20%, and 8.3%, respectively. While safe, JVS-100 failed to improve wound healing or hemodynamic measures at 3 months. Only one-quarter of CLI wounds healed at 3 months despite successful revascularization, highlighting the need for additional research in therapies that can improve microcirculation in these patients. ClinicalTrials.gov Identifier: NCT02544204.
Bibliographical noteFunding Information:
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this study was funded by Juventas Therapeutics. The authors are responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and final contents.
Patients underwent randomization in a 2:1 ratio in a double-blinded fashion to receive 8 mg (8 × 1 mg/mL) or 16 mg (16 × 1 mg/mL) of JVS-100 or matching placebo intramuscular injections in the index leg and foot in a pattern shown in supplementary Appendix Figure 1. Randomization was performed with the use of an Interactive Web Response System (IWRS) and stratified by presence of diabetes and end-stage renal disease (ESRD). This study was approved by the United States Food and Drug Administration (FDA) and the Institutional Review Board of the participating centers. All participants provided written informed consent prior to enrollment and randomization (http://www.clinical trials.gov; registration number: NCT02544204).
© The Author(s) 2019.
- biological therapies
- critical limb ischemia (CLI)
- lower extremity wound (ulcer)
- peripheral artery disease (PAD)
- randomized controlled trials (RCT)
- toe–brachial index (TBI)
PubMed: MeSH publication types
- Clinical Trial, Phase II
- Journal Article
- Multicenter Study
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't