E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
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 |
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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 |
PHASE 1 PRIMARY OBJECTIVES -To determine local and systemic safety and tolerability of single and repeated topical administrations of AUP1602-C of safety (2.5 x 105 colony-forming unit [CFU]/cm2 ulcer size), low (2.5 x 106 CFU/cm2 ulcer size), medium (2.5 x 107 CFU/cm2 ulcer size), and high dose (2.5 x 108 CFU/cm2 ulcer size) in patients with chronic DFUs -To determine the recommended phase 2 dose (RP2D) of AUP1602-C and the treatment schedule to be applied in phase 2A of the study
PHASE 2A PRIMARY OBJECTIVES -To confirm local and systemic safety and tolerability of the RP2D and selected treatment schedule of AUP1602-C in DFU patients -To assess the efficacy of the RP2D and selected treatment schedule of AUP1602-C in DFU patients compared to a placebo control arm |
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E.2.2 | Secondary objectives of the trial |
PHASE 1 & 2A SECONDARY OBJECTIVES -To assess the efficacy of multiple administrations of AUP1602-C in DFU patients (for phase 1 only as being primary objective in phase 2A) -To determine the effect of AUP1602-C treatment on wound volume and depth reduction, time to complete wound closure, long-term healing and ulcer recurrence -To determine the effect of AUP1602-C treatment on local wound infections, local surgical procedures, and amputation rate -To determine the effect of AUP1602-C treatment on patient’s quality of life and pain perception -To determine the effect of AUP1602-C treatment on vital signs, electrocardiography (ECG), echocardiogram, ophthalmoscopy, physical examination, and clinical laboratory -To determine the presence of AUP1602-C (plasmid) in the systemic circulation, urine and faeces |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The study population are patients with chronic, non-healing DFU in phase 1, and DFU and optionally VLU for phase 2A part. The protocol will be amended in such case. The patients have to meet all of the following criteria to be eligible to enter the study: 1. Male or female patients aged 18 to 80 years 2. Patients with DM of type 1 or 2 having glycosylated haemoglobin (HbA1c) of ≤11% and a serum creatinine level of ≤1.5 times the upper limit of normal (ULN) 3. Patients with at least one ulcer that fulfills all of the following criteria at screening and at baseline (prior to treatment start) -Present for ≥1 month -Located either in the plantar or on the dorsum of foot, or in the distal part of the leg, around the malleolar area to be accessible for administration of AUP1602-C/placebo and to be completely covered by the primary and secondary dressings -Partial- or full-thickness, not involving bone, tendon, or joints, i.e. University of Texas classification Grade 1A, 1C, 2A or 2C -No clinical signs of active infection or osteomyelitis -Size of the target ulcer for DFU must be between 1-9 cm2 after debridement -Chronic target ulcer, defined as <30% reduction in size in response to SoC during the 2-week screening period -Target ulcer appropriately debrided (<10% black and at least 50% of red/pink on a colorimetric scale) -Ulcer and periwound tissue suitable to using film dressings (i.e. no contraindications [e.g.: excessive exudation, maceration] 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 cm healthy tissue but only one target ulcer will be selected for the investigational treatment (based on investigator decision) 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 mmHg (or ankle systolic pressure of at least 70 mmHg, if toe-pressure in not measured) on the foot with the target ulcer that do not require urgent vascular surgical referral 6. Patients with an assessment of the baseline level of neuropathy of the foot using 5.07 Semmes-Weinstein 10g monofilaments 7. Patients must adhere to wear therapeutic shoes or off-loading footwear if indicated 8. A female patient of childbearing potential must have a negative serum pregnancy test at the time of Screening 9. Patients must use a highly effective contraceptive measure (methods that can achieve a failure rate of less than 1% per year when used consistently and correctly), like hormonal contraception (oral pills, implantable device, or skin patch), intrauterine device, bilateral tubal occlusion, or double barrier throughout the study 10. 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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E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will not be permitted to enter the study: 2. Current or previous (within 2 weeks prior to start of screening/run-in period) treatment with another investigational drug and/or medical device or participation in another clinical study 3. Current or previous (within 30 days prior to start of screening/run-in period) treatment with a biologic agent, growth factors or skin equivalents (e.g. Regranex®, Apligraf®, or Dermagraft®) 4. Current or previous (within 1 week prior to first study drug dosing) treatment with active wound care agents (e.g. local and systemic antibiotics or silver dressings) 5. Current or previous (within 2 weeks prior to first study drug dosing) use of corticosteroids and immunosuppressants 6. Known hypersensitivity to any of the investigational drug or vehicle components 7. Ulcer of University of Texas Grade ≥3, with deep abscess, or gangrene 8. 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 study drug dosing 9. Target ulcer positive for MRSA 10. Target ulcer other than chronic non-healing DFU (e.g. pressure ulcers, burn wounds) 11. Prior radiation therapy (within 6 weeks prior to first study drug dosing) of any part of the foot/leg bearing the target ulcer under study 12. Sickle-cell anemia, Reynaud’s, or other peripheral vascular disease including venous leg ulcers 13. Infective endocarditis or increased risk for infective endocarditis, which includes, but is not limited to, prosthetic cardiac valve or prosthetic material used for cardiac valve repair, previous infective endocarditis, congenital heart disease, and cardiac transplantation recipients who develop clinically significant cardiac valvulopathy, history of rheumatic fever or rheumatic heart disease diagnosed by echocardiogram, or history (within 10 years prior to enrollment) of IV drug abuse 14. Active Charcot deformity of the study foot (i.e. foot is erythematous, warm, edematous, and is actively remodeling) 15. Patients with other reasons for wound healing disturbances: e.g. bleeding disorders, vitamin K deficiency, hypocalcemia, major immune deficiencies 16. 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, was treated and is currently disease-free and not on active treatment with an immune-suppressive therapy at least for 3 months, may be considered for study entry 17. Pregnant or lactating woman 18. Haemoglobin of less than 8.5 g/dL 19. Transaminase levels greater than 3 times ULN 20. Patients receiving haemodialysis or chronic ambulatory peritoneal dialysis (CAPD) therapy 21. Positive for hepatitis B or C virus (HBV, HCV), or human immunodeficiency virus (HIV); serology test results not older than 3 months are accepted 22. Planned surgery during the study period 23. Known abuse of alcohol, drugs, or medical products. Tobacco use will be allowed 24. Previous participation in this clinical study 25. Any diagnosed unstable condition that could interfere with compliance, such as psychiatric disorder 26. Myocardial infarction diagnosed within last 3 months prior to start of screening/run-in period 27. Confirmed or suspected COVID-19 infection |
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E.5 End points |
E.5.1 | Primary end point(s) |
PHASE 1 PRIMARY ENDPOINTS -Incidence of adverse events (AEs) and potential dose-limiting toxicities (DLTs) for safety, low, medium, and high dose cohorts of single and repeatedly administered AUP1602-C
PHASE 2A PRIMARY ENDPOINTS -Incidence of AEs in each treatment arm (including overall AEs, AEs of special interest (local tolerability), AEs related to AUP1602-C, study-ulcer-associated AEs, serious adverse events (SAEs), and AEs leading to discontinuation (systemic tolerability) -Proportion of patients with a target ulcer achieving complete wound closure during the treatment period and up to 1, 2, 3, 4, 6, 8, and 12 weeks (3 months) after last study drug administration -Percentage of wound size reduction during the treatment period and at Weeks 1, 2, 3, 4, 6, 8, 12, (Month 3) and 24 (Month 6) after last study drug administration |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
AE, SAE, wound size: throughout the study |
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E.5.2 | Secondary end point(s) |
PHASE 1 & 2A SECONDARY ENDPOINTS -Percentage of wound size reduction during the treatment period and at Weeks 1, 2, 3, 4, 6, 8, 12 (Month 3), and 24 (Month 6) after last study drug administration (phase 1 only) -Proportion of patients with a target ulcer achieving complete wound closure during the treatment period and up to 1, 2, 3, 4, 6, 8, and 12 weeks (3 months) after last study drug administration (phase 1 only) -Percentage of wound volume and depth reduction during the treatment period and at Weeks 1, 2, 3, 4, 6, 8, 12 (Month 3), and 24 (Month 6) after last study drug administration -Time to complete wound closure -Percentage of patients with complete wound closure at Week 24 (Month 6) after last study drug administration -Proportion of patients with ulcer recurrence after 6, 12 (Month 3), and 24 (Month 6) weeks post wound closure -Proportion of patients with local wound infections related to the target ulcer during the treatment period and at Weeks 6, 12 (Month 3) and 24 (Month 6) after last study drug administration -Proportion of patients with local surgical procedures during the treatment period and at Weeks 6, 12 (Month 3) and 24 (Month 6) after last study drug administration -Proportion of patients with amputations (minor or major) related to the target ulcer during the treatment period and at Weeks 6, 12 (Month 3) and 24 (Month 6) after last study drug administration -Change from baseline in health-related quality of life using EuroQol-5D (EQ-5D) visual analog scale (VAS), EQ-5D utility index, and Dermatology Life Quality Index (DLQI) score -Change from baseline in patient’s pain intensity using a numerical rating scale (ranging from 0 = no pain to 10 = worst imaginable pain) -Incidence of abnormal vital signs values, ECG data, echocardiogram data, ophthalmoscopy data, physical examination findings, laboratory data -Assessment of biodistribution of AUP1602-C (plasmid) in the blood by AUP- quantitative polymerase chain reaction (qPCR) -Assessment of shedding of AUP1602-C (plasmid) in urine and faeces by AUP-qPCR |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Wound size: throughout the study Local wound infections, patients with amputations: throughout the study Quality of life, pain, vital signs:SV-1, SV-2, V4,7,10,13,16,FU-V1,2,3,4,5,6. ECG data, echocardiogram data: SV-2, FU-V1,4, FU-V7. ECG also FU-V8. Ophthalmoscopy data: SV-2, FU-V1,4, FU-V7,8. physical examination findings: S-V1, V1, V4,7,10,13,16,FU-V1,2,3,4,5,6. Laboratory data: S-V1, V1, V7, V18, FU-V1,4,7,8. |
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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 | 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) | 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 | 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 | 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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
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 | 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |