A Multicenter, Randomized, Open-Label, Controlled Trial to Evaluate the Safety and Efficacy of Seltoplasmid Injection Combined With Revascularization for Chronic Limb-Threatening Ischemia Caused by Infrapopliteal Artery Disease in Patients With Diabetes
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 入组人数
- 180
- 试验地点
- 6
- 主要终点
- Time to First Clinically Driven MALE or All-Cause Death
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
Participants, care providers, and site investigators are not masked because the experimental group receives multiple intramuscular injections and the control group does not receive placebo injections. Members of the independent clinical event committee who adjudicate suspected primary endpoint events will remain blinded to treatment assignment. Event documentation submitted for adjudication will be prepared to minimize disclosure of treatment allocation.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •The target limb must have an ischemic foot ulcer corresponding to WIfI wound grade 1 or
- •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.
排除标准
- •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.
研究组 & 干预措施
Seltoplasmid Plus Revascularization
Following completion of the index lower-extremity revascularization procedure, participants will receive Seltoplasmid Injection in addition to protocol-defined standard care. Seltoplasmid will be administered at a total dose of 8 mg by intramuscular injection at 32 sites in the affected lower leg on Day 0, Day 14 (±3 days), and Day 28 (±3 days), provided that the prespecified safety conditions are met. Standard care includes wound care, offloading, glycemic control, treatment of infection, antiplatelet therapy, lipid-lowering therapy, and other clinically indicated treatment.
干预措施: Lower-Extremity Revascularization (Procedure)
Revascularization
Following completion of the index lower-extremity revascularization procedure, participants will receive protocol-defined standard care without Seltoplasmid Injection or placebo injections. Standard care includes wound care, offloading, glycemic control, treatment of infection, antiplatelet therapy, lipid-lowering therapy, and other clinically indicated treatment. Participants will be followed according to the same visit schedule and outcome-assessment procedures as those in the experimental group.
干预措施: Lower-Extremity Revascularization (Procedure)
Seltoplasmid Plus Revascularization
Following completion of the index lower-extremity revascularization procedure, participants will receive Seltoplasmid Injection in addition to protocol-defined standard care. Seltoplasmid will be administered at a total dose of 8 mg by intramuscular injection at 32 sites in the affected lower leg on Day 0, Day 14 (±3 days), and Day 28 (±3 days), provided that the prespecified safety conditions are met. Standard care includes wound care, offloading, glycemic control, treatment of infection, antiplatelet therapy, lipid-lowering therapy, and other clinically indicated treatment.
干预措施: Donaperminogene Seltoplasmid (Genetic)
结局指标
主要结局
Time to First Clinically Driven MALE or All-Cause Death
时间窗: From randomization through Day 360 (±14 days)
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.
次要结局
- Incidence of Treatment-Emergent Adverse Events and Serious Adverse Events(From randomization through Day 360 (±14 days))
- Incidence of Clinically Driven Target-Lesion Revascularization(From randomization through Day 360 (±14 days))
- Amputation-Free Survival(From randomization through Day 360 (±14 days))
- Proportion of Participants With Confirmed Complete Ulcer Healing(From randomization through Day 360 (±14 days))
- Time to Confirmed Complete Ulcer Healing(Baseline and scheduled assessments through Day 360 (±14 days))
- Change From Baseline in Target-Limb Rest Pain Score(Baseline and scheduled assessments through Day 360 (±14 days))
- Change From Baseline in Target-Limb Transcutaneous Oxygen Pressure(Baseline and scheduled assessments through Day 360 (±14 days))
- Change From Baseline in Target-Limb Ankle-Brachial Index(Baseline and scheduled assessments through Day 360 (±14 days))
- Incidence of Major Adverse Cardiovascular Events(From randomization through Day 360 (±14 days))
研究者
jingyong huang
Director, Department of Vascular Surgery; Principal Investigator
First Affiliated Hospital of Wenzhou Medical University