| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
In diabetic patients, impaired wound healing represents a major health
problem, leading eventually to a painful non healing wound at the foot
called diabetic foot ulcer (DFU). |
|
| 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 | 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 determine dose-response for clinical efficacy of APO-2 multiple dose administration in patients with diabetic foot ulcer at three different dose levels compared to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate safety and tolerability of APO-2 at three different doses
- To generate data on additional clinical endpoints
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is between 18 and 80 years of age
2. Patients with Type I or Type II diabetes with a glycosylated hemoglobin (HbA1c) of ≤ 12%, obtained at enrollment or within 30 days prior to study enrollment
3. Patients who have a wound defined as diabetic foot ulcer present for ≥ 4 weeks
4. Foot ulcer Wagner grade I– II or ARMSTRONG grade I-A (superficial, non-infected, non-ischemic wound not involving tendon, capsules, or bone) or II-A (non-infected, non-ischemic wound penetrating to tendon or capsule but not to the bone or joint)
5. Estimated foot ulcer surface area between ≥ 1 cm2 and ≤ 8 cm2 as measured at day of randomization assessed using the eKARE imaging and measurement device
6. A patient with more than one diabetic foot ulcer may be included in the study but only one ulcer will be selected for the investigational treatment based on Investigator judgment as far as the ulcer meets the inclusion criteria (the largest ulcer fitting the inclusion criteria will be selected as index ulcer)
7. Wound area has not changed by more than 30 % between screening visit and randomization visit (at least 14 days)
8. Adequate arterial blood perfusion (ABI [ankle brachial index] between 0.7 and 1.3 [the highest ABI measured value will be used as reference], or toe pressure > 50 mmHg, or tcPO2 > 40 mmHg) within the past 6 months
9. Patient must adhere to off-loading of the ulcer area (in mobile patients adherence to off-loading footwear during the study is mandatory)
10. Patient is able to give written informed consent prior to study start and to comply with the study requirements
11. Women of childbearing potential agree using adequate birth control methods during the study |
|
| E.4 | Principal exclusion criteria |
1. History of anaphylaxis, known hypersensitivity to sodium alginate, propylene glycol, methylene-blue or chicken-egg
2. Target ulcer is over a deformity (such as Charcot deformity) that interferes with off-loading based on investigator's opinion
3. Index wound duration of > 52 weeks without intermittent healing
4. Clinical evidence of ulcer bed infection or patients requiring intravenous (IV) antibiotics to treat the index wound infection at time of randomization
5. Current evidence of osteomyelitis, cellulitis, or other evidence of infection including pus drainage from the wound site, or documented history of osteomyelitis at the target wound location during the 6 months preceding the screening visit
6. Major uncontrolled medical disorder(s) such as severe uncontrolled leg edema, concurrent medication, or other issue that renders the patient unsuitable for participation in the study, including but not limited to: comorbid condition with an estimated life expectancy of ≤ 12 months, hemoglobin A1c (Hba1c) > 12% at screening, patients on dialysis, patients with severe pulmonary (requiring home oxygen, uncontrolled COPD Gold III/ IV) or cardiovascular conditions (heart failure NYHA IV, uncontrolled hypertension systolic BP by repeated measurement > 180mmHg)
7. Raynaud disease or any other severe peripheral microvascular disease, current diagnosis of vasculitis, or current diagnosis of claudication
8. Dermatologic comorbid disease (e.g. pyoderma gangrenosum, vasculopathy or vasculitic ulcers), history of Systemic Lupus Erythematosus with elevated anti-DNA antibody titers, Buerger’s disease (thromboangiitis obliterans)
9. Patient currently treated for an active malignant disease or prior diagnosis of an active malignant disease who is disease free for less than 1 year. Treatment with anticancer therapy (chemotherapy, immunotherapy, radiotherapy, targeted therapy or gene therapy) within 3 months before the first administration of investigational product or at any time during the study.
10. Patient with history of malignancy within the wound; history of radiation therapy to the wound region
11. Patients who have undergone wound treatments with growth factors, dermal substitutes, or other biological therapies within the last 30 days or during the study
12. Patients who received oral or parenteral corticosteroids, immunosuppressants, or cytotoxic agents within 30 days preceding the first study drug administration, or plan to use these medications during the study period
13. Patients who are pregnant or breastfeeding
14. Mental condition rendering the patient (or the patient’s legally acceptable representative[s]) unable to understand the nature, scope and possible consequences of the study
15. Patients who are incarcerated, including prisoners or patients compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
16. Therapy with another investigational agent within thirty days of screening, or during the study
17. Patients who are considered by the investigator to have a significant disease, which can impact the study; patients who are considered not suitable for the study by the investigator
18. Employee at the study site, spouse/partner or relative of any study staff (e.g. investigator, sub-investigators, or study nurse) or relationship to the sponsor |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Evaluation after 4 weeks treatment with APO-2 (Visit 14 = end of treatment visit) |
|
| E.5.2 | Secondary end point(s) |
1. >50 % reduction in wound area
2. Wound size
3. Proportion of patients with complete wound closure (100% re-epithelialization of the wound surface with the absence of drainage)
4. Time to complete wound closure
5. Recurrence rate of the ulcer
6. Clinical assessment of peripheral neuropathy
7. Number of patients with local adverse events or serious adverse events (SAEs) with causal relationship to study medication
8. Evaluation of wound pain by visual analogue scale (VAS)
9. Evaluation of Quality of Life using Wound QoL questionnaire |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the study (baseline until day 84)
1. after 4 weeks (binary outcome; Visit 14 = end of treatment visit)
2. at baseline, and 1, 2, 3, 4, 6, 8 and 12 weeks after first application of IMP (Investigational Medicinal Product)
3. during 12-week follow-up period
4. throughout the study (baseline until day 84)
5. during 12-week follow-up period
6. at baseline, 4, and 12 weeks after first application of IMP
7. throughout the study (baseline until day 84)
8. at baseline, at every treatment visit and 4, 6, 8 and 12 weeks after first application of IMP
9. at baseline, 4, and 12 weeks after first application of IMP |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The study will be considered completed when the visit 17 of the last randomized patient is reached or the study is terminated early based on recommendation of the DSMB. |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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