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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Aurealis Oy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

21 Jul 2023 → 9 Oct 2025

Decision date (initial)

2023-05-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Others

To investigate local and systemic safety and tolerability of the recommended Phase 2 Dose (RP2D) (2.5 x 108 CFU/cm2 ulcer size) and selected treatment schedules of AUP1602-C and of the placebo control arm, in patients with DFU fulfilling inclusion criteria.

To evaluate the proportion of patients achieving total wound closure with the 2 dosing frequencies of AUP1602-C and placebo treatment.

Secondary objectives 6

1. To evaluate the effect size of the efficacy parameters for the selected dosing schedules of the RP2D of AUP1602-C and placebo control arm in DFU patients
2. To evaluate the effect of the RP2D and selected treatment schedules of AUP1602-C compared to a placebo control arm, and among the selected dosing frequency subgroups, on the percentage of wound area reduction in DFU patients
3. To evaluate the effect of the RP2D and selected treatment schedules of AUP1602-C compared to a placebo control arm, and among the selected dosing frequency subgroups, on wound area, wound volume and wound depth reduction, time to complete wound closure, long-term healing, and ulcer recurrence in DFU patients
4. To evaluate the impact of the RP2D and selected treatment schedules of AUP1602-C compared to a placebo control arm, and among the selected dosing frequency subgroups, on QoL and pain perception in DFU patients
5. To assess the impact of the RP2D and selected treatment schedules of AUP1602 C compared to a placebo control arm, and among the selected dosing frequency subgroups, on target ulcer related periwound skin maceration, local wound infections, local surgical procedures, and amputation rate in DFU patients
6. To evaluate the effect of the RP2D and selected treatment schedules of AUP1602C compared to a placebo control arm, and among the selected dosing frequency subgroups, on number of target ulcer related hospital visits, patient-days of antibiotic therapy, and patient-days of hospitalisation, due to target ulcer complications in DFU patients

Conditions and MedDRA coding

diabetic foot ulcers

Regulatory references

Scientific advice from competent authorities

Finnish Medicines Agency, Paul Ehrlich Institute, Paul Ehrlich Institute, Medicines And Healthcare Products Regulatory Agency, Paul Ehrlich Institute, Medicines And Healthcare Products Regulatory Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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.
2. 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.
3. 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).
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 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 33

1. 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.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Incidence of adverse events (AEs)
2. Proportion of patients, receiving the RP2D of AUP1602-C in one of both dosing frequencies, and placebo achieving complete wound closure within 20 weeks after first IMP (i.e., either AUP1602-C or placebo) administration

Secondary endpoints 18

1. Percentage of wound area reduction at 4, 8, 12, 16 and 20 weeks after first IMP (AUP1602-C or placebo) administration
2. Time to complete wound closure (Timeframe: within 20 weeks after first IMP (AUP1602-C or placebo) administration)
3. Time to >50% wound area reduction (Timeframe: within 20 weeks after first IMP (AUP1602-C or placebo) administration)
4. Time to >75% wound area reduction (Timeframe: within 20 weeks after first IMP (AUP1602-C or placebo) administration)
5. Proportion of patients with complete wound closure (Timeframe: Weeks 4, 8, 12, 16 and 20 after first IMP (AUP1602-C or placebo) administration)
6. Proportion of patients with a >50% wound area reduction (Timeframe: Weeks 4, 8, 12, 16 and 20 after first IMP (AUP1602-C or placebo) administration)
7. Proportion of patients with a >75% wound area reduction (Timeframe: Weeks 4, 8, 12, 16 and 20 after first IMP (AUP1602-C or placebo) administration)
8. Proportion of patients with a target ulcer recurrence (Timeframe: Weeks 8, 12, 16 and 20 after first AUP1602-C/placebo administration, and 6 and 12 Months after last IMP (AUP1602-C or placebo) administration)
9. Percentage of wound volume and depth reduction (Timeframe: Weeks 4, 8, 12, 16 and 20 after first IMP (AUP1602-C or placebo) administration)
10. Change from baseline in health-related QoL using the EuroQol-5D (EQ-5D) visual analogue scale (VAS), the EQ-5D utility index, and the Dermatology Life Quality Index (DLQI) score (Timeframe: Weeks 4, 8, 12, 16 and 20 after first IMP (AUP1602-C or placebo) administration)
11. Change from baseline in patient’s pain intensity using a numerical rating scale (NRS, ranging from 0 = no pain to 10 = worst imaginable pain) (Timeframe: Weeks 4, 8, 12, 16 and 20 after first IMP (AUP1602-C or placebo) administration)
12. Incidence and prevalence of target ulcer related periwound skin maceration events (Timeframe: during run-in period, and Weeks 4, 8, 12, 16 and 20 after first IMP (AUP1602-C or placebo) administration)
13. Incidence and prevalence of target ulcer related local wound infection events (Timeframe: during run-in period, Weeks 4, 8, 12, 16 and 20 after first IMP (AUP1602-C or placebo) administration, and 6 and 12 Months after last IMP (AUP1602-C or placebo) administration)
14. Incidence of surgical procedures related to the target ulcer (Timeframe: during run-in period, Weeks 4, 8, 12, 16 and 20 after first IMP (AUP1602-C or placebo) administration, and 6 and 12 Months after last IMP (AUP1602-C or placebo) administration
15. Incidence of target ulcer related amputation events (Timeframe: during run-in period, Weeks 4, 8, 12, 16 and 20 after first IMP (AUP1602-C or placebo) administration, and 6 and 12 Months after last IMP (AUP1602-C or placebo) administration)
16. Number of target ulcer related hospital visits during run-in, treatment and post-treatment efficacy and safety follow-up periods
17. Number of patient-days of target ulcer related antibiotic therapy during run-in, treatment and post-treatment efficacy and safety follow-up periods
18. Number of patient-days of hospitalization due to complications related to target ulcer during run-in, treatment and post-treatment efficacy and safety follow-up periods

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Aurealis Oy

Sponsor organisation

Aurealis Oy

Address

Microkatu 1

City

Kuopio

Postcode

70210

Country

Finland

Scientific contact point

Organisation

Aurealis Oy

Contact name

CMO

Public contact point

Organisation

Aurealis Oy

Contact name

CMO

Third parties 14

Locations

3 EU/EEA countries · 9 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 56 files

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

Application history

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