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

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

• Male or female patients aged 18 and above
• 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
• 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).
• 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.
• 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.
• Revascularized patients with an ulcer fulfilling the inclusion criteria can be included 3.0 months after the procedure.
• Patients with an assessment of the baseline level of neuropathy in the lower limb where the target ulcer is located.
• Patients must be willing to wear off-loading footwear, while ambulating, for the period requested by the Investigator.
• 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).
• 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.
• 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

• 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.
• 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.
• 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.
• 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.
• Known hypersensitivity to any of the components of AUP1602-C or placebo
• Ulcer of University of Texas Grade ≥ 3, with deep abscess, sinus track, necrosis or gangrene that cannot be removed by debridement.
• Target ulcers with excessive exudation requiring more than one dressing change within 24-hrs.
• Target ulcers with clinically significant periwound skin maceration.
• 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.
• Target ulcers requiring urgent vascular surgical interventions.
• Target ulcer other than non-healing DFU fulfilling inclusion criteria (e.g., including, but not limited to, pressure ulcers, burn wounds).
• Serum creatinine level of > 3.0 times the upper limit of normal (ULN).
• 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.
• 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.
• Active or unstable Charcot deformity of the study foot (i.e., foot is erythematous, warm, oedematous, and is actively remodelling).
• Patients with other reasons for wound healing disturbances: e.g., bleeding disorders, vitamin K deficiency, hypocalcaemia, major immune deficiencies.
• 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.
• Haemoglobin of less than 8.5 g/dL
• Liver transaminase & total bilirubin levels greater than 3 times ULN.
• Patients receiving haemodialysis or continuous ambulatory peritoneal dialysis (CAPD) therapy.
• 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).
• Patients with confirmed active infection with SARS-CoV-2 and related disease (COVID-19) at Baseline (V1) prior to first administration of trial medication.
• Planned major surgery during the run-in, treatment and post-treatment efficacy and safety follow-up period of the study.
• Known abuse of alcohol, drugs, or medical products. Tobacco use will be allowed.
• Previous treatment with AUP1602-C.
• Any diagnosed unstable psychological or physical condition including major organ failure that could interfere with compliance.
• Myocardial infarction diagnosed within 1 month prior to start of run-in period.
• White Blood Cells (WBC) < 3.0 X 109 cells/L；> 12.0 X 109 cells/L
• Albumin < 2.5 g/dL (or total protein < 4.0 g/dl).
• The patient has any other factor/reason which may, in the opinion of the Investigator, compromise participation and/or follow-up in the study.
• Pregnant or lactating woman at the time of signing the informed consent and prior to first IMP (AUP1602-C or placebo) dosing.
• 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.
• Patients who are institutionalized because of legal or regulatory order.