APAC (antiplatelet, anticoagulant) antithrombotic treatment for limb-threatening impairment of blood flow (HEALING-study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Aplagon Oy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

29 Jan 2026 → ongoing

Decision date (initial)

2025-09-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Aplagon Oy

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Pharmacokinetic, Pharmacogenetic, Others, Pharmacodynamic, Therapy, Safety

Part A: To evaluate safety and tolerability of i.v. APAC for single infusion and weekly dosing.;
Part B: To establish the safety of the selected dose(s) and dosing frequency of periprocedural i.a. and weekly i.v. APAC administration in patients undergoing endovascular revascularization.

Secondary objectives 6

1. Part A: To evaluate the effects of i.v. APAC on the clinical status of PAOD from baseline until D29 (Part A1) and D90 (Part A2) after the first dose of APAC.
2. Part A: To assess the PD and PK of i.v. APAC and other biomarkers of blood coagulation from baseline until D29 (Part A1) and D90 (Part A2).
3. Part A: To evaluate the effects of i.v. APAC on MALE and MACE-free survival and quality of life at D29 (Part A1), D90 (Part A1 and A2), and D180 (Part A2).
4. Part B: To establish the dosing regimen (single vs. multiple dosing) and preliminary efficacy of APAC in patients undergoing endovascular revascularization.
5. Part B: To assess the PD and PK of APAC and other biomarkers of blood coagulation from baseline until D90.
6. Part B: To evaluate the effects of APAC on MALE and MACE-free survival and quality of life at D29 (Part A1), D90 (Part A1 and A2), and D180 (Part A2).

Conditions and MedDRA coding

Peripheral arterial occlusive disease (PAOD)

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

IPD plan description

IPD will not be shared publicly due to data protection considerations under the GDPR and ethical obligations to maintain participant confidentiality e.g. this is a study with small sample size. Additionally, the informed consent obtained from participants does not include provisions for public sharing of IPD

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. 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.
2. 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.)
3. 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.
4. 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.
5. Parts A1, B1, and B2: 5. Adequate lipid lowering therapy, as evaluated by the investigator.
6. Parts A1, B1, and B2: 6. Capability and willingness to provide valid, voluntary written informed consent for the study.
7. 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.
8. Parts A1, B1, and B2: 8. Males must refrain from sperm donation while on study treatment.
9. Part A2: 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.
10. 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.
11. Part A2: 3. CTA/MRA/DSA with contrast agent performed within 3 months prior to study enrolment.
12. Part A2: 4. Moderate to severe arterial disease, ABI < 0.7
13. Part A2: 5. Patients should be capable of performing evaluable treadmill exercise test.
14. 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.
15. Part A2: 7. Adequate lipid lowering therapy, as evaluated by the investigator.
16. Part A2: 8. Capability and willingness to provide valid, voluntary written informed consent for the study.
17. 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.
18. Part A2: 10. Males must refrain from sperm donation while on study treatment.

Exclusion criteria 32

1. 1. Any ischemic lesions of the heel and midfoot and lesions (wounds or gangrene) invading bones, joints, or tendons at metatarsophalangeal joints or more proximal sites.
2. 2. Acute limb-threatening ischemia (e.g., thromboembolic disease).
3. 3. Medical history of, or an existing aneurysm.
4. 4. Endovascular revascularization intervention is done from the contralateral side using cross-over access (Part B1 and B2).
5. 5. Medical 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.
6. 6. Current 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.)
7. 7. Patients treated with combined antiplatelet agents: aspirin + P2Y12 antagonist (clopidogrel, ticagrelor, prasugrel).
8. 8. Diagnosis 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.
9. 9. Body mass index > 35 kg/m2.
10. 10. Patients with clinically significant acute infection, as judged by the investigator.
11. 11. Use 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.
12. 12. Use of selective serotonin reuptake inhibitor (SSRI) medication within 2 weeks prior to the first dose of APAC or during the treatment period.
13. 13. Peroral use of glycosaminoglycans or omega 3 or related products within 28 days before IMP treatment.
14. 14. Major 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.
15. 15. Uncontrolled arterial hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg).
16. 16. Blood hemoglobin concentration <120 g/L or > 170 g/L (men) and <110 g/L or >160 g/L (women) at screening.
17. 17. Blood 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.
18. 18. Clinically significantly prolonged plasma PT (> 1.2-fold) or a value of less than 50% (when normal reference range is 70-130%).
19. 19. APTT above the upper limit of the reference range.
20. 20. Patients with a medical history of heparin-induced thrombocytopenia.
21. 21. Patients 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.
22. 22. A 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).
23. 23. Patients 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.
24. 24. Previous treatment with APAC.
25. 25. Patients 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.
26. 26. Participation in an investigational drug or device study within 90 days prior to screening.
27. 27. Patients who have ever received treatment with a gene therapy.
28. 28. Patients 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).
29. 29. Any 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.
30. 30. Patients with severe comorbidities and limited life expectancy as judged by the investigator.
31. 31. Patients unable or unwilling to comply with the protocol or to cooperate fully with the investigator or site personnel.
32. 32. Patients 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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: • physical examination findings • vital signs • clinical laboratory data • bleeding events (International Society on Thrombosis and Haemostasis (ISTH) bleeding score
2. Part B: Occurrence and severity of TEAEs from baseline to D90 after the first dose of APAC Other safety and tolerability endpoints: • physical examination findings • vital signs • clinical laboratory data • bleeding events (ISTH bleeding score) • surgical AEs, collected according to the Clavien-Dindo classification

Secondary endpoints 6

1. Part A: 1. Changes in the clinical status of PAOD a. Fontaine classification, b. Wound Ischemia foot Infection (WIfI) scoring, c. hemodynamics (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. in Part A2, maximal walking distance in a treadmill exercise test (3.2 km/h, 10% incline).
2. Part A: 2. Changes in PD and PK of selected biomarkers
3. Part A: 3. MALE 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).
4. Part B: 1. Changes in the clinical status of PAOD a. Fontaine classification, b. WIfI scoring, c. outcome of recanalization (hemodynamics; TBI and ABI) at rest.
5. Part B: 2. Changes in PD and PK of selected biomarkers
6. Part B: 3. MALE 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).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Aplagon Oy

Sponsor organisation

Aplagon Oy

Address

Tukholmankatu 8 A

City

Helsinki

Postcode

00290

Country

Finland

Scientific contact point

Organisation

Aplagon Oy

Contact name

Chief Scientific and Medical Officer

Public contact point

Organisation

Aplagon Oy

Contact name

CEO

Third parties 7

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications