Seltoplasmid Plus Revascularization for Diabetic Infrapopliteal Chronic Limb-Threatening Ischemia

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.