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    Summary
    EudraCT Number:2018-003415-22
    Sponsor's Protocol Code Number:AP-W-CLI-2018-8
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-10-02
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2018-003415-22
    A.3Full title of the trial
    A Phase 1/2A clinical study to evaluate the safety, tolerability and efficacy of single and repeated doses of AUP1602-C as topical treatment of diabetic foot ulcers
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the safety, tolerability and efficacy of AUP1602-C product for diabetic foot ulcers
    A.4.1Sponsor's protocol code numberAP-W-CLI-2018-8
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAurealis Oy
    B.1.3.4CountryFinland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAurealis Oy
    B.4.2CountryFinland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAurealis Oy
    B.5.2Functional name of contact pointThomas Wirth
    B.5.3 Address:
    B.5.3.1Street AddressMicrokatu 1
    B.5.3.2Town/ cityKuopio
    B.5.3.3Post code70211
    B.5.3.4CountryFinland
    B.5.4Telephone number+358401587765
    B.5.6E-mailthomas@aurealistherapeutics.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAUP1602-C
    D.3.2Product code AUP1602-C
    D.3.4Pharmaceutical form Cutaneous suspension
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTopical use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAUP1602-C
    D.3.9.2Current sponsor codeAUP1602-C
    D.3.9.3Other descriptive nameAUP1602-C
    D.3.10 Strength
    D.3.10.1Concentration unit CFU/ml colony forming unit(s)/millilitre
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number10000000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Diabetic foot ulcers
    E.1.1.1Medical condition in easily understood language
    Diabetic foot ulcers
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10012664
    E.1.2Term Diabetic foot ulcer
    E.1.2System Organ Class 100000004858
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    E.4Principal 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
    E.5 End points
    E.5.1Primary 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
    E.5.1.1Timepoint(s) of evaluation of this end point
    AE, SAE, wound size: throughout the study
    E.5.2Secondary 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
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 75
    F.4.2.2In the whole clinical trial 75
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    No plans for treatment after the study. The study subjects will receive the expected normal treatment on Diabetic foot ulcers from their treating doctor.

    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-03-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-11
    P. End of Trial
    P.End of Trial StatusOngoing
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