A 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 recommended phase-2 dose of AUP1602-C in two dosing frequencies as a topical treatment for non-healing neuro-ischemic diabetic foot ulcers

Trial ID: 2022-502048-10-00
Protocol: AT-W-CLI-2022-04
Sponsor: Aurealis Oy

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Diseases & Conditions

Diabetic foot

Objectives

The primary objective of this clinical study is to investigate the **safety** and **tolerability** of the recommended Phase 2 Dose (RP2D) of AUP1602-C, administered as a topical treatment, in patients with non-healing neuro-ischemic **diabetic foot ulcers** (DFU). This includes evaluating both local and systemic safety profiles, as well as the proportion of patients achieving total wound closure with two dosing frequencies of AUP1602-C compared to a placebo control arm. The clinical relevance of this objective lies in its potential to establish a safe and effective treatment regimen for DFU, a condition that poses significant morbidity risks and healthcare challenges.

Secondary objectives include:

Evaluating the effect size of efficacy parameters for selected dosing schedules of AUP1602-C and placebo in DFU patients.
Assessing the impact on the percentage of wound area reduction, wound volume, wound depth, time to complete wound closure, long-term healing, and ulcer recurrence.
Investigating the impact on quality of life (QoL) and pain perception.
Assessing the effect on periwound skin maceration, local wound infections, local surgical procedures, and amputation rate.
Evaluating the number of hospital visits, patient-days of antibiotic therapy, and hospitalization due to target ulcer complications.

Participants

The clinical trial focuses on patients with **diabetic foot ulcers**. The study population includes both male and female participants aged 18 years and above. Participants are required to have a diagnosis of diabetes mellitus, either type 1 or type 2, with a glycosylated hemoglobin (HbA1c) level of ≤ 11.0% at randomization. The trial involves individuals who have at least one non-healing target ulcer, which must meet specific criteria regarding size, location, and duration. Participants must be willing to comply with study procedures, including the use of off-loading footwear. The trial includes a vulnerable population, and both genders are represented. However, the sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is a **phase-2**, multi-centre, prospective, randomized, standard-of-care plus placebo-controlled, patient and central evaluator blinded, parallel arm study. It aims to evaluate the safety, tolerability, and efficacy of the recommended phase-2 dose of AUP1602-C in two dosing frequencies as a topical treatment for non-healing neuro-ischemic **diabetic foot ulcers**. The trial is expected to last until September 2025, with recruitment having started in April 2023. Participants will be involved for a maximum of 20 weeks, with the possibility of early termination if they experience adverse events or fail to comply with study procedures.

The trial design includes a screening visit to assess eligibility based on specific inclusion criteria, such as age, diabetes status, and ulcer characteristics. Following successful screening, participants will be randomized to receive either the investigational product AUP1602-C or a placebo. The primary endpoints include the incidence of adverse events and the proportion of patients achieving complete wound closure within 20 weeks. Secondary endpoints focus on wound area reduction, time to wound closure, and quality of life assessments.

Study visits are scheduled at baseline, followed by regular follow-up visits at weeks 4, 8, 12, 16, and 20 to monitor progress and collect data on wound healing and safety. The end-of-study visit will occur at week 20 or upon early termination. Participants are required to adhere to study protocols, including the use of off-loading footwear and contraceptive measures for those of childbearing potential. The trial's rigorous design ensures that data collected will provide valuable insights into the treatment's efficacy and safety profile.

Treatment

The clinical trial involves the evaluation of **AUP1602-C**, a cell suspension for topical administration, as an experimental treatment. **AUP1602-C** is a genetically modified organism (GMO) derived from **Lactococcus lactis subsp. cremoris** cells, containing genes of interest such as **FGF-2**, **IL-4**, and **CSF-1**. The pharmaceutical form is a cell suspension, and it is applied topically to the ulcer site. The recommended Phase 2 Dose (RP2D) is 2.5 x 10⁸ colony-forming units (CFU) per square centimeter of ulcer size. The maximum daily dose is 2.5 billion CFU, with a total maximum dose of 60 billion CFU over a treatment period of up to 12 weeks. The treatment is administered in two dosing frequencies, and participant compliance is monitored throughout the study.

The trial also includes a placebo control arm, which utilizes a reconstitution solution containing 5% dextrose, 2.5% sodium chloride, and 1.6% sodium acetate in sterile water, with a pH range of 6.0-6.5. This solution serves as the placebo and is administered topically in a manner identical to the experimental treatment. The placebo is designed to mimic the physical characteristics of the experimental treatment without containing the active substance. The study is conducted in a blinded manner, ensuring that both patients and central evaluators are unaware of the treatment assignments to maintain the integrity of the trial results.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the incidence of adverse events and the proportion of patients achieving complete wound closure within 20 weeks after the first administration of the investigational medicinal product (IMP), either AUP1602-C or placebo. Secondary endpoints will evaluate various aspects of wound healing and patient outcomes, such as the percentage of wound area reduction at specified intervals (4, 8, 12, 16, and 20 weeks), time to complete wound closure, and time to achieve more than 50% and 75% wound area reduction within the same timeframe.

Additional secondary endpoints include the proportion of patients with complete wound closure and those with significant wound area reductions at the specified weeks, as well as the recurrence of the target ulcer. The study will also assess changes in health-related quality of life using the EuroQol-5D (EQ-5D) visual analogue scale (VAS), the EQ-5D utility index, and the Dermatology Life Quality Index (DLQI) score. Patient-reported outcomes will be collected to evaluate changes in pain intensity using a numerical rating scale. The incidence and prevalence of periwound skin maceration, local wound infection events, surgical procedures, and amputation events related to the target ulcer will be monitored throughout the study period.

Data collection will occur at multiple timepoints, including during the run-in period and at weeks 4, 8, 12, 16, and 20 after the first IMP administration, as well as 6 and 12 months post-treatment. The number of hospital visits, patient-days of antibiotic therapy, and hospitalization due to complications related to the target ulcer will also be recorded. These efficacy parameters will be analyzed to determine the overall effectiveness of AUP1602-C as a treatment for non-healing neuro-ischemic diabetic foot ulcers.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female patients aged 18 years and above, depending on the Investigator’s assessment of physical and psychological wellbeing of the patient to comply with study procedures and follow-up.
Patients with diabetes mellitus (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 (results up to 3 months prior to signing ICF accepted) undergoing therapy for glycaemic control using available diabetes drugs including insulin.
Patients with at least one DFU that fulfils all of 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 semipermeable 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 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.

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Exclusion Criteria

Current or previous (within 2 weeks prior to start of run-in period) treatment with another investigational drug and/or medical device or participation in another clinical study.
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.