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    EudraCT Number:2017-000234-57
    Sponsor's Protocol Code Number:allo-APZ2-DFU-II-01
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-03-13
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2017-000234-57
    A.3Full title of the trial
    An interventional, multicenter, single arm, phase I/IIa clinical trial to investigate the efficacy and safety of allo-APZ2-DFU on wound healing of diabetic neuropathic ulcer (DFU).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to investigate the efficacy and safety of allo-APZ2-DFU on wound healing of diabetic neuropathic ulcer.
    A.4.1Sponsor's protocol code numberallo-APZ2-DFU-II-01
    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 SponsorRHEACELL GmbH & Co. KG
    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 supportRHEACELL GmbH & Co. KG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRHEACELL GmbH & Co. KG
    B.5.2Functional name of contact pointInformation Office
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 517
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.4Telephone number+496221718330
    B.5.5Fax number+4962217183329
    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 nameallo-APZ2-DFU
    D.3.2Product code allo-APZ2-DFU
    D.3.4Pharmaceutical form Cutaneous suspension
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPCutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeT202-3
    D.3.9.3Other descriptive nameAllogeneic skin-derived ABCB5-positive mesenchymal stem cells
    D.3.10 Strength
    D.3.10.1Concentration unit million organisms/ml million organisms/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product Yes
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 No
    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 neuropathic ulcer (DFU)
    E.1.1.1Medical 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.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    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
    The aim of this clinical trial is to investigate the efficacy (by monitoring the wound size reduction of DFUs) and safety (by monitoring adverse events) of two doses of allo-APZ2-DFU topically administered to the wound matrix of patients with diabetic neuropathic ulcer.
    E.2.2Secondary objectives of the trial
    Not applicable.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients aged 18 to 85 years;
    2. Patients with an existing diagnosis of diabetic mellitus Type 2, evaluated by blood test [HbA1c] < 11%) at the Screening visit (Visit 1). The HbA1c value at Visit 1 should not vary more than 1.5% (absolute range) compared to a HbA1c value that was previously measured 1 to 6 months before visit 1;
    3. The presence of diabetic neuropathic ulcers “malum perforans” (Grade I and II according to Wagner) at plantar side of the foot diagnosed by ABI ≥0.7, without claudication, or TcPO2 >40 mmHg or doppler ultrasonography (at the discretion of the investigator) to exclude significant arterial diseases and critical limb ischemia, and a diabetic neuropathy test using a 128 Hz vibration tuning fork according to Rydel-Seiffer (as described by Guideline ”Nationale Versorgungsleitlinie - Neuropathie bei Diabetes im Erwachsenenalter”). If the ABI is >1.3, an additional doppler ultrasonography must be performed to exclude a PAOD masked by media sclerosis;
    4. At Screening Visit 1 and 2 the wound surface area of the target ulcer should be between 1 and 50 cm² measured by using a scaled measuring sensor in combination with digital image analysis;
    5. The ulcer’s surface area should be (mostly) free from callus or necrotic tissue;
    6. If patients are suffering from two or more ulcers at the same extremity, the target ulcer has to be separated by a minimum bridge of 1 cm of healthy tissue from other ulcers;
    7. Patients are willing and able to wear therapeutic shoes that are especially designed for patients with a diabetic neuropathic foot;
    8. Body mass index (BMI) between 20 and 45 kg/m²;
    9. Patients understand the nature of the procedure and are providing written informed consent prior to any clinical trial procedure;
    10. Women of childbearing potential must have a negative blood pregnancy test at Visit 1;
    11. Women of childbearing potential must be willing to use highly effective contraceptive methods during the course of the clinical trial.
    E.4Principal exclusion criteria
    1. Presence of acute Charcot foot;
    2. Clinical signs of active osteomyelitis in the last three months;
    3. Active wet gangrenous tissue;
    4. Infection of the target ulcer requiring treatment as judged clinically;
    5. Presence of an ulcer Grade ≥3 according to Wagner on the same foot as target ulcer;
    6. Patients who are currently receiving dialysis;
    7. Peripheral arterial occlusive disease (PAOD) including claudication with need of treatment;
    8. Ulcers due to non-diabetic etiology;
    9. Prior surgical procedures such as bypass or mesh-graft treatment within 2 months prior to IMP application;
    10. Acute deep vein thrombosis (maximum 30 days from diagnosis) or a still untreated deep vein thrombosis;
    11. Any chronic dermatological disorders diagnosed at the investigator’s discretion;
    12. Skin disorders, unrelated to the ulcer, that are present adjacent to the target wound;
    13. Treatment of target wound with active wound care agents (e.g. iruxol, local antibiotics or silver dressings), which have not been stopped 14 days before IMP application;
    14. Any malignancy within the past 5 years, excluding successfully treated carcinoma in situ, basal cell carcinoma or squamous cell carcinoma of the skin without evidence of metastases;
    15. Current use of steroid medication above Cushing threshold dose (>7.5 mg/d prednisone or equivalent);
    16. Known abuse of alcohol, drugs, or medicinal products;
    17. Patients anticipated to be unwilling or unable to comply with the requirements of the protocol;
    18. Pregnant or lactating women;
    19. Patients infected with the human immunodeficiency virus (HIV 1&2);
    20. Any known allergies to components of the IMP or concomitant medication;
    21. Current or previous (within 30 days of enrollment) treatment with another IMP, or participation and/or under follow-up in another clinical trial;
    22. Evidence of any other medical conditions (such as psychiatric illness, physical examination, or laboratory findings) that may interfere with the planned treatment, affect the patient’s compliance, or place the patient at high risk of complications related to the treatment;
    23. Employees of the sponsor, or employees or relatives of the investigator.
    E.5 End points
    E.5.1Primary end point(s)
    1. Primary efficacy endpoint: Percentage of wound surface area reduction at Week 12, or last available post-baseline measurement of Weeks 4, 6 or 8, if the Week 12 measurement is missing (last observation carried forward [LOCF]).
    2. Primary safety endpoint: Adverse events.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Week 12, or last available post-baseline measurement of Weeks 4, 6 or 8, if the Week 12 measurement is missing.
    2. During all patient visits except screening.
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints:
    1. Percentage of wound surface area reduction;
    2. Percentage of invisible and visible wound surface area reduction;
    3. Absolute wound surface area reduction;
    4. Absolute invisible and visible wound surface area reduction
    5. Assessment of wound infection;
    6. Time to first complete wound closure;
    7. Proportion of patients achieving complete wound closure;
    8. Time to first 30% reduction of wound surface area;
    9. Proportion of patients achieving 30% reduction of wound surface area;
    10. Assessment of wound exudation, epithelialization and formation of granulation tissue;
    11. Time to amputation at target leg until Week 12;
    12. Pain assessment as per numerical rating scale (NRS);
    13. Assessment of Quality of life (QoL) using the short form 36 (SF-36) questionnaire;
    14. Assessment of Dermatology-specific QoL based on the Dermatology Life Quality Index (DLQI) questionnaire.

    Secondary safety endpoints:
    15. Physical examination and vital signs at Week 6.1 and Week 12;
    16. Time to amputation of target leg until Month 12.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Weeks 2, 4, 6, 8, 12, w/o LOCF;
    2. Weeks 2, 4, 6, 8, 12, w/o LOCF;
    3. Weeks 2, 4, 6, 8, 12, w/o LOCF;
    4. Weeks 2, 4, 6, 8, 12, w/o LOCF;
    5. Days 1 and 2, Weeks 1, 2, 4, 6, 6.1, 6.2, 6.3, 8, 12;
    6. A priori specification not possible; between baseline and week 12;
    7. Weeks 2, 4, 6, 8, 12;
    8. A priori specification not possible; between baseline and week 12;
    9. Weeks 2, 4, 6, 8, 12;
    10. Day 0 and Week 6.1 prior IMP-application, Weeks 1, 2, 4, 6, 8, 12;
    11. A priori specification not possible; between baseline and month 12;
    12. Both Screening Visits, Days 0, 1, 2 and Weeks 1, 2, 4, 6, 6.1, 6.2, 6.3, 8, 12;
    13. Screening V1, V3, Weeks 4 and 12;
    14. Screening V1, V3, Weeks 4 and 12.
    15. Weeks 6.1 and 12;
    16. A priori specification not possible; between baseline and month 12.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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 Yes
    E. trial type description
    Safety and efficacy in patients
    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 No
    E.8.1.1Randomised No
    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 No
    E.8.2.3Other No
    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 concerned3
    E.8.5The trial involves multiple Member States No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 27
    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 state37
    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)
    After withdrawal patients will receive standard medical care according to individual needs.
    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 Decision2017-08-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-06-29
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