| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Venous Leg Ulcer
Diabetic Foot Ulcer |
|
| E.1.1.1 | Medical condition in easily understood language |
Leg Ulcer
Diabetic Foot Ulcer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066677 |
| E.1.2 | Term | Chronic leg ulcer |
| E.1.2 | System Organ Class | 100000004858 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012664 |
| E.1.2 | Term | Diabetic foot ulcer |
| E.1.2 | System Organ Class | 100000004858 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess the safety and tolerability of multiple ascending doses of Aurase Wound Gel when administered cutaneously (topically) to participants with Venous Leg Ulcers (VLU)
To assess the safety and tolerability of multiple ascending doses of Aurase Wound Gel when administered cutaneously (topically) to participants with Diabetic Foot Ulcers (DFU) |
|
| E.2.2 | Secondary objectives of the trial |
To assess the rate and extent of wound debridement after cutaneous administration of Aurase Wound Gel at multiple ascending dose levels.
To assess the number of participants achieving full debridement after cutaneous administration of Aurase Wound Gel every 2-3 days in cohorts 1-5 and 7 for up to 4 weeks and every 3-4 days in cohort 6
To assess wound healing trajectory (wound size and extent of granulation tissue) after cutaneous administration of Aurase Wound Gel
To assess whether effective concentrations of Aurase Wound Gel in VLU also debride DFU wounds
To characterize the systemic absorption (pharmacokinetic profile) of the Aurase enzyme when administered cutaneously in gel form to VLU at multiple ascending dose levels.
To assess the immunogenicity (Anti-Drug Antibody [ADA] activity) of Aurase enzyme when administered cutaneously in gel form at multiple ascending dose levels.
To assess the impact of Aurase Wound Gel on systemic blood clotting factors. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
CORE INCLUSION CRITERIA
1) Male or female participants aged 18 years and older at screening
2) Willing and able to attend and comply with study visits and study related activities
3) Provide a signed and dated written informed consent form
4) Presence of slough within the reference ulcer suitable for debridement therapy
5) Good general state of physical and mental health as assessed by the Investigator
a) Stable chronic treated conditions such as diabetes or raised blood pressure are permissible, provided under good control, and on stable doses of medication where appropriate, with no admission for any acute hospital-based treatments in the last 3 months.
b) Laboratory parameters and vital signs at screening must be within the normal age-adjusted and comorbidity-adjusted ranges (one retest permitted if results are outside of range and re-performed within the 14-day screening period)
VLU SPECIFIC INCLUSION CRITERIA
6) Participants with at least one defined VLU suitable for treatment that is no smaller than 2 cm2 but no larger than 50cm2 and is confirmed as venous in origin by clinical assessments, by Ankle Brachial Pressure Index (ABPI) ≥ 0.8 and/or toe systolic BP pressure > 70mm Hg
7) Confirmed, clinically diagnosed VLU (ulceration of the lower limb, 30 days or more, with no other mechanistic explanation) which has been present for ≤ 2 years, defined by patient reporting or clinical records.
8) Participants with more than one VLU on the target leg can be included, provided other ulcers are at least 1 cm away from the reference ulcer identified for treatment. Selection of the reference ulcer will be at the investigator's discretion, provided it meets all other inclusion/exclusion criteria
DFU SPECIFIC INCLUSION CRITERIA
9) Participants with at least one defined DFU suitable for treatment that is no smaller than 2cm2 but no larger than 10cm2 and which has persisted for at least 6 weeks. Participants with more than one DFU can be included, provided ulcers are at least 1cm away from the reference ulcer identified for treatment. Selection of the reference ulcer will be at the investigator’s discretion, provided it meets all other inclusion / exclusion criteria.
10) Diagnosis of Diabetes Mellitus type I or II (according to WHO criteria) with an HbA1c ≤ 108 mmol/mol at screening
11) Participants with at least one full thickness ulcer (below the ankle) that is a non-interdigital wound located either on the heel, in the plantar or on the dorsum of the foot,
12) Has no undermining, with no exposed muscle, tendon or bone (University of Texas Diabetic Foot Ulcer Classification System Grade 1 A and 1C).
13) Accessible for administration of IMP and possible to completely cover by the primary and secondary dressings |
|
| E.4 | Principal exclusion criteria |
CORE EXCLUSION CRITERIA
A patient who meets any of the following criteria will be excluded from the study:
1) Significant hepatic impairment as defined by screening LFTs of AST and ALT >3 times upper limit of normal (1 retest allowed)
2) Significant cardiovascular disease including myocardial infarction, unstable angina, history of stroke, transient ischemic attacks or cerebral hemorrhage less than 6 months prior to screening.
3) Uncontrolled screening hypertension defined as SBP > 160 mmHg, DBP > 90mmHg
4) Temperature of the patient is ≥ 38.0°C
5) Uncontrolled screening anemia defined as hemoglobin < 10 g/dL in women, < 12g/dL in men.
6) A clinical history of bleeding disorder including hemophilia, purpura, or thrombocytopenia
7) Current or history of use of anti-thrombotic therapy less than 7 days prior to screening. Low dose single antiplatelet agents (aspirin, ticlopidine, clopidogrel, prasugrel, ticagrelor) are permitted.
8) Stage 4 or 5 chronic kidney disease, defined as eGFR of ≤30 mL/min
9) Reference ulcer has active infection or florid oedema at screening determined by the investigator using clinical criteria.
10) Oral or IV antibiotics for any indication within 72 hours of screening
11) Reference ulcer has exposed tendons, ligaments, muscle, or bone
12) Reference ulcer with high levels of exudate, which in the opinion of the investigator, would render the proposed trial management protocol unsuitable.
13) Active osteomyelitis, cellulitis or gangrene in either leg.
14) Currently active malignancy or history of any malignancy in the target leg within 5 years prior to screening (other than successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma).
15) Currently receiving or has received radiation, immunosuppression or chemotherapy within 3 months of screening.
16) Planned vascular surgery, angioplasty, or thrombolysis procedures within the study period, or 4 weeks before screening.
17) Prior skin graft, negative pressure therapy, ultrasound therapy, systemic or cutaneously applied growth factor, other enzymatic debriding agents (e.g. Collagenase, Nexobrid) or live maggot therapy applied to the reference ulcer within 2 weeks before screening.
18) Currently enrolled or has been enrolled in the last 30 days in another investigational device or drug study.
19) Known allergy or hypersensitivity to any component of the investigational product, medication or surgical dressings to be used in the study.
20) Participants who, in the opinion of the study Investigator, have significant ongoing psychiatric disorders (including depression with psychosis, bipolar disease and schizophrenia), which may interfere with the study procedures, assessments and/or visits.
21) Participants lacking capacity to provide informed consent.
22) Pregnant or breastfeeding women.
23) Women of child-bearing potential (WoCBP) who are unwilling to practice highly effective contraception or undergo pregnancy tests at screening, during the study if necessary, and on the last study visit.
VLU SPECIFIC EXCLUSION CRITERIA:
1) HbA1c >69 mmol/mol at screening
2) Participants with amputation above a trans metatarsal amputation (TMA) in the target leg.
DFU SPECIFIC EXCLUSION CRITERIA:
3) Active Charcot deformity of the study foot (i.e. foot is erythematous, warm, edematous, and is actively remodeling).
4) Has undergone a change in their treatment for diabetes during the last 4 weeks
5) Has evidence of dermatological disorders as a cause of ulceration (e.g. pyoderma gangrenosum or epidermolysis bullosa) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Adverse Events and Serious Adverse Event type and frequency
Assessments of pain and itch made by the participant prior to dressing removal, at each visit to assess general pain and itch between visits
Assessments of pain, made by the participant on application of the Aurase Wound Gel or vehicle to the reference ulcer
Clinical assessment of tolerability at the wound site (i.e. clinical signs of wound inflammation) made by the investigator including erythema, oedema, exudate, induration, bleeding and wound infection |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary endpoint assessments will be made over the 29 day duration of the study |
|
| E.5.2 | Secondary end point(s) |
Reference ulcer debridement trajectory (surface area of wound and devitalized tissue) at visits 4, 7, 10 and 14 [cohorts 1-5 and 7] and at visits 3,5,7 and 10 in cohort 6 assessed by an investigator or a delegated research nurse based on a digital photo tracing and /or clinical observations compared to baseline (visit 2 – pre-treatment).
Number of participants achieving 100% debridement by visits 4, 7, 10 and 14 [cohorts 1-5 and 7] and visits 3,5,7 and 10 in cohort 6 assessed by an investigator or a delegated research nurse based on a digital photo tracing and/or clinical observations.
Reference ulcer healing trajectory (surface area of wound and granulation tissue), based on digital photo tracing and/or clinical assessment by an investigator or delegated research nurse, at visits 4, 7, 10 and 14 [cohorts 1-5 and 7] and at visits 3,5,7, and 10 in cohort 6 compared to baseline.
Reference ulcer debridement trajectory (surface area of wound and devitalized tissue) may be assessed by an independent external reader and/or by digital image analysis based on standardized photographs of wounds
Anti-drug antibody measurement at baseline and at the last study visit
Pharmacokinetics (absorption kinetics): prior to dosing and at 5 ± 1 min, 10 ± 1 min, 15 ± 1 min, and 60 ± 10 mins post dosing after 1st and last application of IMP (Day 1 [Visit 2] and Day 26 [Visit 13 cohorts 1-5 and 7; visit 9 cohort 6]
Systemic clotting factors including plasma fibrinogen concentrations at visits 1, 2, 5 and 14 in cohorts 1-5 and 7 and at visits 1,2,4 and 10 in cohort 6 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Time points out to Day 29 of the Study [Visit 14 in cohorts 1-5 and 7; Visit 10 in cohort 6] |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Dose concentration of Aurase Wound Gel compared to vehicle |
|
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last Patient Last Visit (LPLV) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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