Unfractionated heparin, porcine, conjugated with human serum albumin for Peripheral arterial occlusive disease | Chronic limb-threatening ischemia

Inclusion criteria

• {"criterion_text":"- Parts A1, B1, and B2: 1. Males aged 45-85 years and postmenopausal females (i.e. no menstrual periods for 12 months without an alternative medical cause) up to 85 years.\n- Part A2: 2. Diagnosed with: a. PAOD classification Fontaine stage IIa and IIb; b. not prescheduled for endovascular revascularization within 90 days of first APAC administration.\n- Part A2: 3. CTA/MRA/DSA with contrast agent performed within 3 months prior to study enrolment.\n- Part A2: 4. Moderate to severe arterial disease, ABI < 0.7\n- Part A2: 5. Patients should be capable of performing evaluable treadmill exercise test.\n- Part A2: 6. Patients should be treated with antithrombotic medication either acetylsalicylic acid (up to 100 mg QD) or clopidogrel (up to 75 mg QD) for at least the preceding five days before the first APAC administration.\n- Part A2: 7. Adequate lipid lowering therapy, as evaluated by the investigator.\n- Part A2: 8. Capability and willingness to provide valid, voluntary written informed consent for the study.\n- Part A2: 9. Males must be willing to use a condom and their female partners of childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile hysterectomy, bilateral salpingectomy and bilateral oophorectomy) must be willing to use highly effective contraception while on study treatment. Highly effective methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); Intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; and sexual abstinence.\n- Part A2: 10. Males must refrain from sperm donation while on study treatment.\n- Parts A1, B1, and B2: 2. Diagnosed with: a. PAOD classification Fontaine stage III or IV; b. the total length of the treatment-targeted arterial segment ≥ 5 cm below the knee lesion(s) based on contrast-enhanced computed tomography angiography (CTA)/magnetic resonance angiography (MRA)/digital subtraction angiography (DSA) (Part B1 and B2); c. superficial forefoot wounds without overt infection and bone invasion (WIfI 0-1 and 2 limited to digits and WIfI infection 0-1)Mills et al. 2014 allowed; d.undergoing endovascular intervention. (In Part A1, if prescheduled endovascular intervention would take place before the D8 study visit, patient is not to be enrolled.)\n- Parts A1, B1, and B2: 3. CTA/MRA/DSA with contrast agent performed within 3 months prior to study enrolment as part of diagnostics of PAOD, with results available in the patient’s medical records.\n- Parts A1, B1, and B2: 4. Patients should be treated with antithrombotic medication either acetylsalicylic acid (up to 100 mg QD) or clopidogrel (up to 75 mg QD) for at least the preceding five days before the first APAC administration.\n- Parts A1, B1, and B2: 5. Adequate lipid lowering therapy, as evaluated by the investigator.\n- Parts A1, B1, and B2: 6. Capability and willingness to provide valid, voluntary written informed consent for the study.\n- Parts A1, B1, and B2: 7. Males must be willing to use a condom and their female partners of childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile hysterectomy, bilateral salpingectomy and bilateral oophorectomy) must be willing to use highly effective contraception while on study treatment. Highly effective methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); Intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; and sexual abstinence.\n- Parts A1, B1, and B2: 8. Males must refrain from sperm donation while on study treatment.\n- Part A2: 1.\tMales aged 45-85 years and postmenopausal females (i.e. no menstrual periods for 12 months without an alternative medical cause) up to 85 years."}

Exclusion criteria

• {"criterion_text":"- 1.\tAny ischemic lesions of the heel and midfoot and lesions (wounds or gangrene) invading bones, joints, or tendons at metatarsophalangeal joints or more proximal sites.\n- 10.\tPatients with clinically significant acute infection, as judged by the investigator.\n- 11.\tUse of non-steroidal anti-inflammatory medications within 2 weeks prior to the first dose of APAC or during the treatment period. If medication for pain is required, paracetamol or tramadol (e.g. an opioid patch) may be used.\n- 12.\tUse of selective serotonin reuptake inhibitor (SSRI) medication within 2 weeks prior to the first dose of APAC or during the treatment period.\n- 13.\tPeroral use of glycosaminoglycans or omega 3 or related products within 28 days before IMP treatment.\n- 14.\tMajor surgery, major trauma or any endovascular intervention within the past 90 days or organ biopsy prior to the screening visit or scheduled for such an intervention during the study.\n- 15.\tUncontrolled arterial hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg).\n- 16.\tBlood hemoglobin concentration <120 g/L or > 170 g/L (men) and <110 g/L or >160 g/L (women) at screening.\n- 17.\tBlood platelet count <150 x 109/L or > 450 x109/L and/or leukocyte count in the lower reference range or not above >12 x 109/L.\n- 18.\tClinically significantly prolonged plasma PT (> 1.2-fold) or a value of less than 50% (when normal reference range is 70-130%).\n- 19.\tAPTT above the upper limit of the reference range.\n- 2.\tAcute limb-threatening ischemia (e.g., thromboembolic disease).\n- 20.\tPatients with a medical history of heparin-induced thrombocytopenia.\n- 21.\tPatients with known significant liver disease, incl. an alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) level > 2.5 x the upper limit of normal (ULN) at screening.\n- 22.\tA diagnosis of severe chronic kidney disease, defined as having an eGFR category 4 or 5 (eGFR < 30 mL/min/1.73 m2 as per calculation of Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) or albuminuria stage A3 (uACR >300 mg/g).\n- 23.\tPatients with an active malignancy, or who have received treatment for any malignancy including bone marrow transplantation within 5 years before the screening visit, except for localized basal cell or squamous cell skin cancer that has been cured at least 90 days before screening.\n- 24.\tPrevious treatment with APAC.\n- 25.\tPatients with known allergy or hypersensitivity to heparin, or heparin products, APAC, and/or antiplatelet agents (e.g., aspirin or clopidogrel), and protamine sulphate, the reversal agent for APAC.\n- 26.\tParticipation in an investigational drug or device study within 90 days prior to screening.\n- 27.\tPatients who have ever received treatment with a gene therapy.\n- 28.\tPatients with known antiphospholipid antibody syndrome or other known significant thrombophilia (homozygosity for FV Leiden or FIIG20210A mutation, or phospholipid antibody syndrome, deficiency of antithrombin, protein C or protein S or combined thrombophilias).\n- 29.\tAny concomitant disease or condition or treatment that could interfere with, or the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the patient in this study as judged by the investigator.\n- 3.\tMedical history of, or an existing aneurysm.\n- 30.\tPatients with severe comorbidities and limited life expectancy as judged by the investigator.\n- 31.\tPatients unable or unwilling to comply with the protocol or to cooperate fully with the investigator or site personnel.\n- 32.\tPatients with current and/or history of drug abuse (defined as illicit drug use) or alcohol abuse (defined as daily consumption of more than 23-24 and 12-16 alcoholic drinks per week in males and femals, respectively\n- 4.\tEndovascular revascularization intervention is done from the contralateral side using cross-over access (Part B1 and B2).\n- 5.\tMedical history of, or condition known to be associated with impaired hemostasis, i.e., increased intracranial bleeding risk e.g., previous history of intracranial hemorrhage, subarachnoidal bleeding, hemorrhagic stroke, thrombotic or thromboembolic stroke, gastrointestinal bleeding within 6 months of enrolment, or retroperitoneal bleeding any time, or any inherited or acquired bleeding disorder, i.e., von Willebrand disease or hemophilia or other relevant diagnosis causing impaired hemostasis.\n- 6.\tCurrent use of therapeutic dose of anticoagulation (warfarin, apixaban, rivaroxaban, dabigatran, edoxaban, fondaparinux, or any heparin derivative) for any medical reason. (Use of dual pathway inhibition [= acetylsalicylic acid 100 mg + rivaroxabahn 2.5 mg x 2] is not a contraindication, but will be temporarily halted for the day of intervention and day of repeating dosing.)\n- 7.\tPatients treated with combined antiplatelet agents: aspirin + P2Y12 antagonist (clopidogrel, ticagrelor, prasugrel).\n- 8.\tDiagnosis of autoimmune diabetes mellitus (Type 1 diabetes, or latent autoimmune diabetes in adults [LADA]) vasculitis, rheumatoid arthritis, inflammatory bowel diseases, or other general autoimmune diseases.\n- 9.\tBody mass index > 35 kg/m2."}

Primary endpoints

• {"endpoint_text":"- Part A: Occurrence and severity of treatment-emergent adverse events (TEAEs) from baseline to D29 (Part A1) and D90 (Part A2) after the first dose of APAC. Other safety and tolerability endpoints: •\tphysical examination findings •\tvital signs •\tclinical laboratory data •\tbleeding events (International Society on Thrombosis and Haemostasis (ISTH) bleeding score","definition_or_measurement_approach":"Occurrence and severity of TEAEs recorded from baseline to D29 (Part A1) and D90 (Part A2). Other safety measures include physical examination findings, vital signs, clinical laboratory data, and bleeding events assessed using ISTH bleeding score."}
• {"endpoint_text":"- Part B: Occurrence and severity of TEAEs from baseline to D90 after the first dose of APAC Other safety and tolerability endpoints: •\tphysical examination findings •\tvital signs •\tclinical laboratory data •\tbleeding events (ISTH bleeding score) •\tsurgical AEs, collected according to the Clavien-Dindo classification","definition_or_measurement_approach":"Occurrence and severity of TEAEs recorded from baseline to D90. Safety measures include physical examinations, vital signs, labs, bleeding events assessed by ISTH bleeding score, and surgical adverse events collected per Clavien-Dindo classification."}

Secondary endpoints

• {"endpoint_text":"- Part A: 1. Changes in the clinical status of PAOD a.\tFontaine classification, b.\tWound Ischemia foot Infection (WIfI) scoring, c.\themodynamics (toe-brachial blood pressure index [TBI] and ankle-brachial systolic blood pressure index [ABI]) at rest and in Part A2 patients also after treadmill exercise test, and d.\tin Part A2, maximal walking distance in a treadmill exercise test (3.2 km/h, 10% incline).","definition_or_measurement_approach":"Clinical status changes assessed by Fontaine classification, WIfI scoring, hemodynamics (TBI and ABI) at rest and post-exercise (Part A2), and maximal walking distance on treadmill (3.2 km/h, 10% incline) for Part A2."}
• {"endpoint_text":"- Part A: 2.\tChanges in PD and PK of selected biomarkers","definition_or_measurement_approach":"Pharmacodynamic and pharmacokinetic measurements of selected biomarkers from baseline through D29/D90 as specified (assay details not provided in CTIS record)."}
• {"endpoint_text":"- Part A: 3.\tMALE and MACE-free survival and Quality of life (assessed using quality of life questionnaire EQ-5D-5L, ischemic pain using visual analog scale, and ischemic ulcers or gangrene and physical performance using tailored questionnaire).","definition_or_measurement_approach":"MALE and MACE-free survival tracked over specified follow-up visits; quality of life assessed with EQ-5D-5L, ischemic pain by visual analog scale, and physical performance by tailored questionnaire."}
• {"endpoint_text":"- Part B: 1.\tChanges in the clinical status of PAOD a.\tFontaine classification, b.\tWIfI scoring, c.\toutcome of recanalization (hemodynamics; TBI and ABI) at rest.","definition_or_measurement_approach":"Clinical status measured via Fontaine classification and WIfI scoring; recanalization outcome assessed by hemodynamics (TBI and ABI) at rest."}
• {"endpoint_text":"- Part B: 2. Changes in PD and PK of selected biomarkers","definition_or_measurement_approach":"Pharmacodynamic and pharmacokinetic biomarker assessments from baseline until D90 (assay specifics not provided)."}
• {"endpoint_text":"- Part B: 3.\tMALE and MACE-free survival and Quality of life (assessed using quality of life questionnaire EQ-5D-5L, ischemic pain using visual analog scale, ischemic ulcers or gangrene, and physical performance using tailored questionnaire).","definition_or_measurement_approach":"MALE and MACE-free survival tracked; QoL assessed via EQ-5D-5L, ischemic pain via VAS, and physical performance via tailored questionnaire."}

Finland

Earliest CTIS Part Ii Submission Date

28-08-2025

Latest Decision Or Authorization Date

15-09-2025

Processing Time Days

18

Number Of Sites

3

Number Of Participants

42

Primary sponsor

Full Name

Aplagon Oy

Organisation Type

Pharmaceutical company

Country Of Registered Address

Finland

Contract research organisations

Name

Link Medical GmbH

Responsibilities

[1,11,12,13,5,8]

Name

Link Medical Research AS

Responsibilities

[1,11,12,13,5,8]

Name

LINK Medical Research AB

Responsibilities

[1,11,12,13,5,8]

Name

CRST Helsinki Oy

Responsibilities

[1,11,12,13,5,8]

Third parties

• {"country":"Germany","full_name":"Link Medical GmbH","duties_or_roles":"[1,11,12,13,5,8]","organisation_type":"Pharmaceutical company"}
• {"country":"Norway","full_name":"Link Medical Research AS","duties_or_roles":"[1,11,12,13,5,8]","organisation_type":"Pharmaceutical company"}
• {"country":"Sweden","full_name":"LINK Medical Research AB","duties_or_roles":"[1,11,12,13,5,8]","organisation_type":"Pharmaceutical company"}
• {"country":"Finland","full_name":"EstiMates Oy","duties_or_roles":"[10,6]","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Good Biomarker Sciences","duties_or_roles":"[4]","organisation_type":"Industry"}
• {"country":"Sweden","full_name":"LINK Medical Research AB","duties_or_roles":"[1,11,12,13,5,8]","organisation_type":"Pharmaceutical company"}
• {"country":"Finland","full_name":"CRST Helsinki Oy","duties_or_roles":"[1,11,12,13,5,8]","organisation_type":"Pharmaceutical company"}