Seltoplasmid Plus Revascularization for Diabetic Infrapopliteal Chronic Limb-Threatening Ischemia

Phase 4Not Yet RecruitingNCT07827521

First Affiliated Hospital of Wenzhou Medical University180 enrolled

Overview

The goal of this clinical trial is to learn whether Seltoplasmid Injection can improve outcomes after lower-extremity revascularization. Revascularization is a procedure used to restore blood flow to the leg. The study will include adults with type 2 diabetes, a foot ulcer caused by poor blood flow, and disease mainly affecting the arteries below the knee. The main questions are: * Does adding Seltoplasmid lower the risk of major amputation, another procedure to restore blood flow, or death? * What medical problems occur after treatment with Seltoplasmid? About 180 participants will undergo standard lower-extremity revascularization. After the procedure, eligible participants will be assigned by chance to one of two groups. One group will receive Seltoplasmid plus standard care. The other group will receive standard care alone. Participants in the Seltoplasmid group will receive injections into the muscles of the affected lower leg. The injections will be given on Day 0, Day 14, and Day 28. Participants will be followed for 12 months. Researchers will also assess wound healing, survival without amputation, heart and blood vessel problems, pain, and blood flow in the affected leg.

Chronic limb-threatening ischemia in patients with diabetes is commonly associated with diffuse, calcified, and multilevel infrapopliteal arterial disease. In patients with ischemic diabetic foot ulcers, revascularization is recommended to restore blood flow, support wound healing, and reduce the risk of limb loss. However, restoration of patency in the main arteries does not always result in adequate perfusion of the distal tissue. Persistent microvascular dysfunction, impaired collateral formation, endothelial dysfunction, inflammation, infection, neuropathy, and abnormal wound-repair responses may continue after technically successful revascularization. Restenosis, repeat revascularization, delayed wound healing, major amputation, cardiovascular events, and death therefore remain important residual risks. Seltoplasmid Injection is a plasmid-based gene therapy designed to produce local expression of two human hepatocyte growth factor isoforms. Hepatocyte growth factor activates c-Met-dependent signaling pathways involved in endothelial-cell survival, migration, angiogenesis, collateral-vessel development, microvascular repair, and tissue regeneration. Previous clinical studies in patients with severe lower-extremity ischemia have shown a potential benefit for ischemic ulcer healing. However, those studies primarily involved patients who were unsuitable for revascularization or in whom revascularization had produced an inadequate result. Revascularization and Seltoplasmid Injection may have complementary biological effects. Revascularization restores blood flow and perfusion pressure through the main arterial pathway, whereas locally expressed hepatocyte growth factor may support distal collateral formation, microvascular perfusion, endothelial repair, and wound healing. This combined strategy is intended to address both macroscopic arterial obstruction and persistent impairment of distal tissue perfusion. Nevertheless, the clinical benefit and safety of administering Seltoplasmid Injection after revascularization have not been established in an adequately controlled randomized study. This investigator-initiated trial is designed to evaluate the benefit-risk profile of this combined strategy in a high-risk population with diabetes, Rutherford category 5 chronic limb-threatening ischemia, ischemic foot ulceration, and predominantly infrapopliteal arterial disease. Randomization will occur only after completion of the index revascularization procedure and postoperative confirmation of eligibility and safety. This design ensures that treatment assignment cannot influence the revascularization procedure and excludes participants who cannot complete the procedure or do not meet the prespecified postoperative safety conditions. The trial is open-label because the experimental group receives multiple intramuscular injections and the control group does not receive placebo injections. To reduce potential assessment bias, suspected primary endpoint events will be adjudicated by an independent clinical event committee whose members are blinded to treatment assignment. Standardized definitions will be used for major amputation, clinically driven target-limb revascularization, ulcer healing, cardiovascular events, and other clinical outcomes. Wound assessments and photographs, vascular examinations, and tissue-perfusion measurements will be performed using prespecified procedures whenever possible. Seltoplasmid use after completed revascularization is outside its currently approved indication in China. Participants will be specifically informed of this off-label use, the uncertainty regarding additional benefit, the possibility of unknown risks, and the potential for increased injection-site bleeding or hematoma during antiplatelet or other antithrombotic treatment. Safety will be monitored throughout the study. An independent Data Monitoring Committee will periodically review accumulating safety information and may recommend continuation, modification, temporary suspension, or termination of the study in accordance with its charter. The study is intended to determine whether adding Seltoplasmid Injection to contemporary revascularization and standardized background care can improve clinically meaningful limb and survival outcomes, wound healing, pain, and distal tissue perfusion without introducing unacceptable safety risks. The findings may provide evidence regarding a combined treatment strategy that targets both large-vessel blood flow and persistent microvascular impairment after infrapopliteal revascularization.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Male or female, aged 18 years or older at the time of signing informed consent * Clinical diagnosis of type 2 diabetes mellitus with a diabetic foot ulcer and chronic limb-threatening ischemia classified as Rutherford category 5. The target limb must have an ischemic foot ulcer corresponding to WIfI wound grade 1 or 2. After at least 2 weeks of optimal standard wound care, including debridement, offloading, and infection control as clinically indicated, the ulcer must show no clear healing tendency, defined as a reduction in area of less than 30%, and infrapopliteal revascularization must be considered necessary to improve perfusion and promote wound healing. * Color duplex ultrasonography, computed tomography angiography (CTA), or digital subtraction angiography (DSA) demonstrates at least 70% stenosis or occlusion in one or more infrapopliteal arteries, the anterior tibial, posterior tibial, or peroneal artery, and the investigator considers this disease to be the principal cause of ischemia in the target limb. * No severe stenosis in the supra-popliteal inflow arteries, including the iliac, femoral, and popliteal arteries, defined as less than 70% stenosis; alternatively, any severe inflow stenosis can be treated during the index procedure. The infrapopliteal lesion or lesions must remain the principal revascularization target. * Objective evidence of severe limb ischemia meeting at least one of the following criteria: ankle-brachial index (ABI) ≤0.50; ankle systolic pressure measured at the dorsalis pedis or posterior tibial artery ≤70 mmHg; or transcutaneous oxygen pressure (TcPO₂) \<30 mmHg. If ABI is \>1.30 or otherwise considered unreliable because of arterial incompressibility, eligibility will be determined using toe-brachial index (TBI), toe pressure where available, and/or TcPO₂. * Willing and able to comply with study procedures and complete all scheduled follow-up assessments. * Provides written informed consent voluntarily before any study-specific procedure. Exclusion Criteria: * Unable or unwilling to undergo lower-extremity arterial revascularization. * WIfI foot-infection grade 3, including systemic infection or severe local infection requiring urgent surgical debridement. A potential participant may be reassessed after adequate antimicrobial and surgical management if the infection has improved to WIfI infection grade 1 or 2, systemic infection has resolved, and relevant infection indicators have returned to an acceptable range. * Gangrene or tissue destruction of the target limb for which above-ankle major amputation is considered immediately necessary or unavoidable. * Any contraindication to seltoplasmid injection according to the current prescribing information. * Acute myocardial infarction, stroke, intracranial hemorrhage, or unstable angina within 3 months before randomization. * Acute limb ischemia or acute exacerbation of chronic limb ischemia within 3 months before randomization. * New York Heart Association class IV heart failure. * Severe hepatic impairment, including decompensated cirrhosis, jaundice, ascites, or variceal bleeding. * Severe renal impairment, defined as serum creatinine \>2.5 times the upper limit of normal or estimated glomerular filtration rate \<30 mL/min/1.73 m², or current dialysis. * Coagulation disorder, defined as platelet count \<75 × 10⁹/L or international normalized ratio \>1.5 that cannot be corrected. * Hemoglobin \<80 g/L or white blood cell count \<3.0 × 10⁹/L. * Alanine aminotransferase or aspartate aminotransferase \>3 times the upper limit of normal. * Poorly controlled diabetes mellitus, defined as glycated hemoglobin \>10%. * Active malignant tumor or a history of malignant tumor within 5 years before enrollment. Any broader malignancy-related contraindication in the current seltoplasmid prescribing information will take precedence. * Pregnant or breastfeeding woman, or woman of childbearing potential unwilling to use effective contraception during the protocol-defined period. Pregnancy testing and contraceptive requirements will follow the protocol and current prescribing information. * Life expectancy \<12 months or, in the investigator's judgment, inability to complete follow-up. * Participation in another interventional clinical study within 30 days before enrollment. * Positive human immunodeficiency virus antibody; positive hepatitis C virus antibody; or positive hepatitis B surface antigen together with detectable peripheral-blood hepatitis B virus DNA when, in the investigator's judgment, active chronic hepatitis B may increase participant risk. * Current treatment with immunosuppressive therapy, radiotherapy, or chemotherapy. * Any serious comorbidity that may interfere with assessment of study outcomes, or any psychological or social circumstance that may materially prevent optimal participation in the study, in the investigator's judgment. * Any other condition that, in the investigator's judgment and with the reason documented, makes participation inappropriate or exposes the participant to unacceptable risk.

Outcomes

Primary Outcomes

Time to First Clinically Driven MALE or All-Cause Death

Time from randomization to the first occurrence of a clinically driven major adverse limb event (MALE) or all-cause death, whichever occurs first. MALE is defined as target-limb major amputation (amputation at or above the ankle) or clinically driven target-limb revascularization. Participants without an event will be censored at the date of their last available assessment. All suspected endpoint events will be adjudicated by an independent clinical event committee blinded to treatment assignment.

Time frame: From randomization through Day 360 (±14 days)

Secondary Outcomes

Incidence of Treatment-Emergent Adverse Events and Serious Adverse Events

Number and percentage of participants with treatment-emergent adverse events, serious adverse events, adverse reactions, adverse events leading to treatment discontinuation, and deaths. Events will be coded using MedDRA and graded according to the protocol-specified version of the Common Terminology Criteria for Adverse Events.

Time frame: From randomization through Day 360 (±14 days)

Incidence of Clinically Driven Target-Lesion Revascularization

Cumulative incidence of clinically driven target-lesion revascularization (CD-TLR) in the target limb. CD-TLR is defined as repeat endovascular or surgical treatment of the index target lesion prompted by recurrent or worsening clinical symptoms, wound deterioration, or objective evidence of impaired perfusion. Death and target-limb major amputation will be treated as competing events.

Time frame: From randomization through Day 360 (±14 days)

Amputation-Free Survival

Time from randomization to the first occurrence of target-limb major amputation or all-cause death, whichever occurs first. Major amputation is defined as amputation at or above the ankle. Participants without an event will be censored at the date of their last available assessment.

Time frame: From randomization through Day 360 (±14 days)

Proportion of Participants With Confirmed Complete Ulcer Healing

Proportion of participants with complete healing of the target ulcer, defined as complete epithelialization without drainage or the need for a dressing, confirmed at two consecutive scheduled assessments. Healing assessments will be supported by standardized wound measurement and photography.

Time frame: From randomization through Day 360 (±14 days)

Time to Confirmed Complete Ulcer Healing

Change from baseline in target-limb rest pain measured using an 11-point numerical rating scale ranging from 0 to 10, where 0 indicates no pain and 10 indicates the worst imaginable pain. A decrease from baseline indicates improvement.

Time frame: Baseline and scheduled assessments through Day 360 (±14 days)

Change From Baseline in Target-Limb Rest Pain Score

Time frame: Baseline and scheduled assessments through Day 360 (±14 days)

Change From Baseline in Target-Limb Transcutaneous Oxygen Pressure

Transcutaneous oxygen pressure (TcPO₂) will be measured in mmHg under standardized conditions at a prespecified, reproducible site near the target wound. The same device, probe location, participant position, and measurement conditions should be used whenever possible. An increase from baseline indicates improved tissue oxygenation and microcirculatory perfusion.

Time frame: Baseline and scheduled assessments through Day 360 (±14 days)

Change From Baseline in Target-Limb Ankle-Brachial Index

Change from baseline in the ankle-brachial index (ABI) of the target limb at each scheduled assessment. ABI will be calculated as the higher target-ankle systolic pressure divided by the higher brachial systolic pressure, using a standardized measurement procedure. An increase from baseline generally indicates improved limb perfusion. ABI will be interpreted cautiously in participants with noncompressible arteries.

Time frame: Baseline and scheduled assessments through Day 360 (±14 days)

Incidence of Major Adverse Cardiovascular Events

Cumulative incidence of the first major adverse cardiovascular event (MACE), defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Only the first qualifying event will be counted in the time-to-first-event analysis.

Time frame: From randomization through Day 360 (±14 days)

Seltoplasmid Plus Revascularization for Diabetic Infrapopliteal Chronic Limb-Threatening Ischemia

Overview

Conditions

Interventions

Eligibility

Locations (6)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts