Evaluation of AUP12602-C as New Topical Treatment for DFUs (DIAMEND STUDY)

Phase-2, Multi-centre, Prospective, Randomized, Standard-of-care Plus Placebo-controlled, Patient and Central Evaluator Blinded, Parallel Arm, Clinical Study to Evaluate Safety, Tolerability and Efficacy of the AUP1602-C as Treatment for Non-healing Neuro-ischemic DFU

This is a phase 2 study performed in diabetic foot ulcer (DFU) patients with chronic non-healing, neuro-ischemic wounds to investigate the safety, tolerability and efficacy of AUP1602-C.

This is a phase 2 multi-centre, parallel arm, patient and central evaluator-blinded, randomized, SoC plus placebo-controlled study of the RP2D of AUP1602-C performed in DFU patients with non-healing wounds. The RP2D of AUP1602-C derived from phase 1 study is 2.5 x 10E8 CFU/cm2 ulcer area and is used in this study.

Inclusion Criteria:

1. Male or female patients aged 18 and above

2. Patients with DM of type 1 or 2 having a glycosylated haemoglobin (HbA1c) of ≤ 11.0% OR 97.0 mmol/mol OR 14.9 mmol/l at randomization undergoing therapy for glycaemic control using available diabetes drugs including insulin

3. Patients with at least one DFU that fulfils all the following criteria:

   • Non-healing target ulcer defined as ≤ 20.0% reduction in area in response to SoC during the 2-weeks run-in period,
   • Duration: ≥ 4 weeks and ≤ 12 months at screening visit 1,
   • Located either in the plantar or on the dorsum of foot, or at or below the ankle,
   • Ulcer is accessible for administration of IMP and can be completely covered by the primary and secondary dressings,
   • Full-thickness, not involving bone or joints (i.e., University of Texas classification Grade 1A, 1C, 2A, 2C)(5),
   • No clinical signs of active wound infection defined by IDSA/IWGDF criteria(6) or clinical evidence osteomyelitis at randomization (V1),
   • Area of the target ulcer between 1.0-10.0 cm2 after debridement at randomization (V1)
   • Ulcer and periwound tissue suitable for application of film dressings (i.e., no contraindications and sufficient periwound space to hold the dressing).

4. Patients with more than one ulcer will be included if ulcers are separated by a minimum of 2.0 cm healthy tissue. The largest ulcer fulfilling the inclusion criteria will be selected for the investigational treatment.

5. Patients with either an ankle brachial index (ABI) ≥ 0.7 OR a toe-brachial index (TBI) ≥ 0.5, AND a toe systolic pressure of at least 50.0 mmHg (or ankle systolic pressure of at least 70.0 mmHg if toe-pressure is not measured) on the foot with the target ulcer.

6. Revascularized patients with an ulcer fulfilling the inclusion criteria can be included 3.0 months after the procedure.

7. Patients with an assessment of the baseline level of neuropathy in the lower limb where the target ulcer is located.

8. Patients must be willing to wear off-loading footwear, while ambulating, for the period requested by the Investigator.

9. A woman of childbearing potential (WOCBP) must have a negative serum pregnancy test at the time of screening after sign the informed consent and a negative pregnancy dip-stick test at baseline (before starting treatment).

10. Females of childbearing potential must agree to use a highly effective contraceptive measure (methods that can achieve a failure rate of less than 1% per year when used consistently and correctly) , throughout the study. / Male patients who are biologically capable of having children must agree to apply at least two methods of contraception including male barrier protection throughout the study.

11. Patients who understand and are willing to comply with study procedures and give written informed consent prior to enrolment in the study or initiation of study procedures.

Exclusion Criteria:

1. Participating in another clinical study or treatment with another investigational product and/or medical device in the 30 days prior to inclusion in the study or within the 5 half-lives of the investigational product, whichever is longer.
2. Current or previous (within 30 days prior to start of run-in period) treatment of target ulcer with a treatment that could interfere with wound healing/IMP such as biological agents, growth factors, skin equivalents/substitutes (e.g., Regranex®, Apligraf®, or Dermagraft®), keratinocytes, platelet-rich-plasma, collagen products, blood products, placental products, oxygen therapy, topical steroids.
3. Current or previous (within 1 week prior to first IMP (AUP1602-C or placebo) dosing) treatment with active wound care agents (e.g., local/topical antibiotics OR antibacterials such as silver, iodine, chlorhexidine) OR systemic antibiotics for any indication.
4. Current or previous (within 2 weeks prior to first IMP (AUP1602-C or placebo) dosing) use of corticosteroids and immunosuppressants. Treatment with immunosuppressive agents with known therapeutic effects longer than 2 weeks may be considered as exclusion and should be consulted with Medical Monitor/Sponsor.
5. Known hypersensitivity to any of the components of AUP1602-C or placebo
6. Ulcer of University of Texas Grade ≥ 3, with deep abscess, sinus track, necrosis or gangrene that cannot be removed by debridement.
7. Target ulcers with excessive exudation requiring more than one dressing change within 24-hrs.
8. Target ulcers with clinically significant periwound skin maceration.
9. Target ulcer with known or suspected active infection, which requires antimicrobials. Any antibiotic therapy must be completed or discontinued within 1 week prior to first IMP (AUP1602-C or placebo) dosing.
10. Target ulcers requiring urgent vascular surgical interventions.
11. Target ulcer other than non-healing DFU fulfilling inclusion criteria (e.g., including, but not limited to, pressure ulcers, burn wounds).
12. Serum creatinine level of > 3.0 times the upper limit of normal (ULN).
13. Prior radiation therapy (within 6 weeks prior to first IMP (AUP1602-C or placebo) dosing) of any part of the foot/leg bearing the target ulcer under study or total body irradiation.
14. Sickle-cell diseases, Reynaud's, or other peripheral vascular disease including venous leg ulcers or any vasculitic ulcer irrespective of the cause will be excluded.
15. Active or unstable Charcot deformity of the study foot (i.e., foot is erythematous, warm, oedematous, and is actively remodelling).
16. Patients with other reasons for wound healing disturbances: e.g., bleeding disorders, vitamin K deficiency, hypocalcaemia, major immune deficiencies.
17. Active malignant disease of any kind except for basal cell carcinoma (of the skin) not co-located with the target ulcer. A patient, who has had a malignant disease in the past, completed treatment and is currently disease-free and not on active treatment for at least 3 months, may be considered for study entry. Cancer therapies with known therapeutic effects longer than 3 months may be considered as exclusion and should be consulted with Medical Monitor/Sponsor.
18. Haemoglobin of less than 8.5 g/dL
19. Liver transaminase & total bilirubin levels greater than 3 times ULN.
20. Patients receiving haemodialysis or continuous ambulatory peritoneal dialysis (CAPD) therapy.
21. Positive for hepatitis B or C virus (HBV, HCV), or human immunodeficiency virus (HIV) (serology test results up to 3 months prior signing ICF accepted).
22. Patients with confirmed active infection with SARS-CoV-2 and related disease (COVID-19) at Baseline (V1) prior to first administration of trial medication.
23. Planned major surgery during the run-in, treatment and post-treatment efficacy and safety follow-up period of the study.
24. Known abuse of alcohol, drugs, or medical products. Tobacco use will be allowed.
25. Previous treatment with AUP1602-C.
26. Any diagnosed unstable psychological or physical condition including major organ failure that could interfere with compliance.
27. Myocardial infarction diagnosed within 1 month prior to start of run-in period.
28. White Blood Cells (WBC) < 3.0 X 109 cells/L；> 12.0 X 109 cells/L
29. Albumin < 2.5 g/dL (or total protein < 4.0 g/dl).
30. The patient has any other factor/reason which may, in the opinion of the Investigator, compromise participation and/or follow-up in the study.
31. Pregnant or lactating woman at the time of signing the informed consent and prior to first IMP (AUP1602-C or placebo) dosing.
32. Close affiliation with the Investigator (e.g., a close relative, financially dependent on the investigational site) or patient who is an employee of the Sponsor's company.
33. Patients who are institutionalized because of legal or regulatory order.