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.

Study Overview

• Status: Recruiting
• Conditions: Diabetic Foot Ulcer
• Intervention / Treatment: Biological: AUP1602-C; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Haritha Samaranayake, MD; Phone Number: +358504384996; Email: haritha@aurealistherapeutics.com

Study Locations

• Germany
  • Münster, Germany
    • Recruiting
    • Institut für Diabetesforschung Muenster GmbH
    • Contact: Dirk Lammers; Email: diabetesforschung@diabetes-muenster.de
  • Pirna, Germany
    • Recruiting
    • Hauärztliche und Diabetologische Praxis
    • Contact: Christine Kosch; Email: info@diabetologie-pirna.de
• Italy
  • Arezzo, Italy
    • Not yet recruiting
    • Ospedale San Donato
    • Contact: Alessia Scatena
  • Firenze, Italy
    • Not yet recruiting
    • Azienda Ospedaliero-Universitaria Careggi
    • Contact: Matteo Monami
  • Pisa, Italy
    • Not yet recruiting
    • AOU Pisana - Ospedale S. Chiara
    • Contact: Alberto Piaggesi; Email: pec-aoupisana@legalmail.it
  • Pistoia, Italy
    • Recruiting
    • Ospedale S. Jacopo Pistoia, Diabetologia e Diabetic foot unit Aziendale
    • Contact: Roberto Anichini
• Poland
  • Poznan, Poland
    • Not yet recruiting
    • Med-Polonia Sp. z o.o.
    • Contact: Malwina Grobelna
  • Warsaw, Poland
    • Recruiting
    • PODOS Klinika Leczenia Ran Podema sp. z o.o.
    • Contact: Marcin Malka; Email: przychodnia@podos.pl
  • Wrocław, Poland
    • Recruiting
    • Lecran Centrum Opieki Nad Ranami
    • Contact: Konrad Pańczak; Email: rejestracja@lecran.pl
  • Łódź, Poland
    • Recruiting
    • Mikomed
    • Contact: Jacek Mikosinski; Email: mikomed@mikomed.pl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AUP1602-C; AUP1602-C is administered topically during the treatment period.	Biological: AUP1602-C; AUP1602-C is topically applied on chronic wounds and covered by wound dressing.
Placebo Comparator: Placebo; Placebo is administered topically during the treatment period.	Other: Placebo; Placebo is topically applied on chronic wounds and covered by wound dressing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of local and systematic adverse events (AEs)	Incidence of local and systematic adverse events (AEs) for repeatedly administered AUP1602-C and of the placebo control arm.	6 weeks
Incidence of Wound Closure	Proportion of patients with a target ulcer achieving complete wound closure	20 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the effect size of the efficacy parameters for AUP1602-C and placebo control arm in DFU patients	Percentage of wound area reduction; Percentage of wound volume and depth reduction	20 weeks
To evaluate the effect size of the efficacy parameters for AUP1602-C and placebo control arm in DFU patients	Time to complete wound closure; Time to >50% wound area reduction; Time to >75% wound area reduction	20 weeks
To evaluate the effect size of the efficacy parameters for AUP1602-C and placebo control arm in DFU patients	Proportion of patients with complete wound closure; Proportion of patients with a >50% wound area reduction; Proportion of patients with a >75% wound area reduction; Proportion of patients with a target ulcer recurrence	20 weeks
To evaluate the effect of the RP2D and selected treatment schedules on the percentage of wound area reduction in DFU patients	• Percentage of wound area reduction	20 weeks
To evaluate the effect of the RP2D and selected treatment schedules on the percentage of wound area reduction in DFU patients	Time to complete wound closure; Time to >50% wound area reduction; Time to >75% wound area reduction	20 weeks
To evaluate the effect of the RP2D and selected treatment schedules on the percentage of wound area reduction in DFU patients	Proportion of patients with complete wound closure; Proportion of patients with a >50% wound area reduction; Proportion of patients with a >75% wound area reduction	20 weeks
To evaluate the effect of the RP2D and selected treatment schedules long-term healing in DFU patients	• Proportion of patients with complete wound closure	20 weeks
To evaluate the effect of the RP2D and selected treatment schedules ulcer recurrence in DFU patients	• Proportion of patients with a target ulcer recurrence	20 weeks
Changes in Quality of Life according to EQ-5D-5L	Change from baseline in health-related quality is assessed according to EuroQoL-5 Dimensions (EQ-5D-5L) patient quesionnaire. Five single-item dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) are assessed. Result of the questionnaire is scored from 0 (worst health imaginable) to 100 (best health imaginable).	20 weeks
Changes in Quality of Life according to DLQI	Change from baseline in health-related quality is assessed according to Dermatology Life Quality Index (DLQI). It consists of 10 questions, where each question is scored from 0 (not affected at all) to 3 (very much affected). The DLQI score will be calculated as the sum of the 10 individual question scores and ranges from 0 to 30, with lower scores indicating better quality of life.	20 weeks
Changes in pain assessment according to VAS	Change from baseline in patient's pain intensity according to a numerical Visual Analog Scale (VAS) ranging from 0 = no pain to 10= worst imaginable pain.	20 weeks
Incidence of target ulcer related hospital visits	Number of target ulcer related hospital visits; Number of patient-days of hospitalization due to complications related to target ulcer; Number of patient-days of target ulcer related antibiotic therapy	20 weeks

Collaborators and Investigators

• Sponsor: Aurealis Oy

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2023
• Primary Completion (Estimated): October 31, 2025
• Study Completion (Estimated): October 31, 2025

Study Registration Dates

• First Submitted: October 9, 2023
• First Submitted That Met QC Criteria: October 30, 2023
• First Posted (Actual): November 1, 2023

Study Record Updates

• Last Update Posted (Actual): November 1, 2023
• Last Update Submitted That Met QC Criteria: October 30, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Endocrine System Diseases; Diabetic Angiopathies; Leg Ulcer; Skin Ulcer; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Foot Diseases; Diabetic Foot; Foot Ulcer
• Other Study ID Numbers: AT-W-CLI-2022-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No