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    Clinical Trial Results:
    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)

    Summary
    EudraCT number
    2017-000234-57
    Trial protocol
    DE  
    Global end of trial date
    29 Jun 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Jul 2021
    First version publication date
    01 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    allo-APZ2-DFU-II-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    RHEACELL GmbH & Co. KG
    Sponsor organisation address
    Im Neuenheimer Feld 517, Heidelberg, Germany, 69120
    Public contact
    Information Office, RHEACELL GmbH & Co. KG, RHEACELL GmbH & Co. KG, +49 6221718330, office@rheacell.com
    Scientific contact
    Information Office, RHEACELL GmbH & Co. KG, RHEACELL GmbH & Co. KG, +49 6221718330, office@rheacell.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy (by monitoring the wound surface area reduction of diabetic foot ulcers [DFUs]) and safety (by monitoring adverse events [AEs]) of 2 doses of the investigational medicinal product (IMP) allo-APZ2-DFU topically administered to the wound matrix of patients with DFU.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation (of Technical Requirements for Pharmaceuticals for Human Use) Good Clinical Practice (GCP, CPMP/ICH/135/95). All national and local regulatory requirements were followed. The investigator ensured that the patient was fully informed about the objectives, procedures, potential risks, any discomforts, and expected benefits of the trial. Based on the available data, a starting dose of 2x10^6 allogeneic skin-derived ATP-binding cassette sub-family B member 5 (ABCB5)-positive cells/cm², if administered topically on DFU wounds (1 to 50 cm²), was considered to be safe (196-fold safety margin) and expected to be beneficial for patients with DFU.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    13
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Of the 63 patients screened at 8 centers, 40 patients were screening failures; 23 patients met the eligibility criteria, were treated with allo-APZ2-DFU, and were included in the safety analysis set (SAF).

    Pre-assignment
    Screening details
    Patients who met all inclusion and none of the exclusion criteria were eligible to participate in the trial.

    Period 1
    Period 1 title
    Treatment and follow-up (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    allo-APZ2-DFU
    Arm description
    Patients treated with the IMP, allo-APZ2-DFU
    Arm type
    Experimental

    Investigational medicinal product name
    allo-APZ2-DFU
    Investigational medicinal product code
    Other name
    ABCB5-positive mesenchymal stem cells
    Pharmaceutical forms
    Cutaneous suspension
    Routes of administration
    Topical use
    Dosage and administration details
    Up to 2 topical applications of 2x10^6 cells/cm², applied in 200 μL Human Serum Albumin/Ringer-Lactate/Glucose solution with a syringe on the wound surface of patients with DFU and optionally covered with fibrin gel after 15-30 minutes.

    Number of subjects in period 1
    allo-APZ2-DFU
    Started
    23
    Completed
    22
    Not completed
    1
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment and follow-up
    Reporting group description
    Patients treated with allo-APZ2-DFU

    Reporting group values
    Treatment and follow-up Total
    Number of subjects
    23 23
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    13 13
        From 65-84 years
    10 10
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    20 20

    End points

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    End points reporting groups
    Reporting group title
    allo-APZ2-DFU
    Reporting group description
    Patients treated with the IMP, allo-APZ2-DFU

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The SAF included all patients who were treated with allo-APZ2-DFU at least once.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis set (FAS) included all patients of the SAF with wound surface area assessments at Day 0 (Baseline) and at least one post-baseline visit.

    Subject analysis set title
    Modified full analysis set
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The modified FAS (mFAS) included all patients of the FAS except for 3 patients with major protocol deviations affecting efficacy assessments.

    Primary: Percentage of wound surface area reduction at Week 12

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    End point title
    Percentage of wound surface area reduction at Week 12 [1]
    End point description
    The wound surface area was assessed using digital photographs and digital planimetry software.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: In a posthoc analysis the precent reduction in wound surface area was evaluated with a Wilcoxon signed rank test. H0 tested was median = 0. The 2-sided p was <0.0001 in both the FAS and mFAS.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23
    20
    Units: Percentage
        median (full range (min-max))
    59.00 (-56.0 to 100.0)
    63.50 (-56.0 to 100.0)
    No statistical analyses for this end point

    Secondary: Percentage of wound surface area reduction at Weeks 2, 4, 6, 8 and 12 (without last observation carried forward [LOCF])

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    End point title
    Percentage of wound surface area reduction at Weeks 2, 4, 6, 8 and 12 (without last observation carried forward [LOCF])
    End point description
    The wound surface area was assessed using digital photographs and digital planimetry software.
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23 [2]
    20 [3]
    Units: Percentage
    median (full range (min-max))
        Week 2
    30.85 (-24.1 to 83.1)
    30.85 (-24.1 to 83.1)
        Week 4
    44.10 (-315.3 to 99.8)
    47.55 (-315.3 to 99.8)
        Week 6
    28.90 (-98.5 to 100.0)
    42.05 (-98.5 to 100.0)
        Week 8
    48.25 (-123.2 to 100.0)
    52.70 (-123.2 to 100.0)
        Week 12
    59.00 (-56.0 to 100.0)
    63.50 (-56.0 to 100.0)
    Notes
    [2] - At some visits, less than 23 patients were investigated.
    [3] - At some visits, less than 20 patients were investigated.
    No statistical analyses for this end point

    Secondary: Percentage of visible wound surface area reduction at Weeks 2, 4, 6, 8 and 12 (without LOCF)

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    End point title
    Percentage of visible wound surface area reduction at Weeks 2, 4, 6, 8 and 12 (without LOCF)
    End point description
    The wound surface area was assessed using digital photographs and digital planimetry software.
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23 [4]
    20 [5]
    Units: Percentage
    median (full range (min-max))
        Week 2
    30.85 (-1.6 to 83.1)
    30.85 (0.2 to 83.1)
        Week 4
    44.10 (-105.5 to 99.8)
    47.55 (-105.5 to 99.8)
        Week 6
    28.90 (-98.5 to 100.0)
    42.05 (-98.5 to 100.0)
        Week 8
    48.25 (-123.2 to 100.0)
    52.70 (-123.2 to 100.0)
        Week 12
    58.35 (-56.0 to 100.0)
    60.40 (-56.0 to 100.0)
    Notes
    [4] - At some visits, less than 23 patients were investigated.
    [5] - At some visits, less than 20 patients were investigated.
    No statistical analyses for this end point

    Secondary: Absolute target wound surface area reduction at Weeks 2, 4, 6, 8 and 12 (without LOCF)

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    End point title
    Absolute target wound surface area reduction at Weeks 2, 4, 6, 8 and 12 (without LOCF)
    End point description
    The wound surface area was assessed using digital photographs and digital planimetry software. At Baseline, the median size of the wound was 2.58 cm² (range: 1.03 - 15.20) in the FAS and 3.08 cm² (range: 1.13 - 15.20) in the mFAS.
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23 [6]
    20 [7]
    Units: cm²
    median (full range (min-max))
        Week 2
    1.07 (-0.50 to 4.08)
    1.18 (-0.50 to 4.08)
        Week 4
    1.13 (-6.58 to 5.16)
    1.56 (-6.58 to 5.16)
        Week 6
    1.09 (-1.49 to 4.39)
    1.40 (-1.49 to 4.39)
        Week 8
    1.76 (-1.75 to 6.92)
    1.99 (-1.75 to 6.92)
        Week 12
    1.71 (-3.62 to 7.83)
    2.00 (-3.62 to 7.83)
    Notes
    [6] - At some visits, less than 23 patients were investigated.
    [7] - At some visits, less than 20 patients were investigated.
    No statistical analyses for this end point

    Secondary: Median time to first complete target wound closure

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    End point title
    Median time to first complete target wound closure
    End point description
    The wound surface area was assessed using digital photographs and digital planimetry software. Complete wound closure was defined as 95% to 100% epithelialization of the wound.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23
    20
    Units: Days
    89
    89
    No statistical analyses for this end point

    Secondary: Number of patients achieving complete target wound closure at Weeks 2, 4, 6, 8 and 12, and at any timepoint

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    End point title
    Number of patients achieving complete target wound closure at Weeks 2, 4, 6, 8 and 12, and at any timepoint
    End point description
    The wound surface area was assessed using digital photographs and digital planimetry software. Complete wound closure was defined as 95% to 100% epithelialization of the wound.
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23 [8]
    20 [9]
    Units: Patients
        Week 2
    0
    0
        Week 4
    1
    1
        Week 6
    2
    2
        Week 6.1
    0
    0
        Week 8
    1
    1
        Week 12
    6
    6
        Any time up to Week 12
    6
    6
    Notes
    [8] - At some visits, less than 23 patients were investigated.
    [9] - At some visits, less than 20 patients were investigated.
    No statistical analyses for this end point

    Secondary: Time to first 30% reduction of target wound surface area

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    End point title
    Time to first 30% reduction of target wound surface area
    End point description
    The wound surface area was assessed using digital photographs and digital planimetry software.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23
    20
    Units: Days
        median (confidence interval 95%)
    27 (14 to 30)
    22 (14 to 30)
    No statistical analyses for this end point

    Secondary: Number of patients achieving at least 30% reduction of target wound surface area at Weeks 2, 4, 6, 8 and 12, and at any timepoint

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    End point title
    Number of patients achieving at least 30% reduction of target wound surface area at Weeks 2, 4, 6, 8 and 12, and at any timepoint
    End point description
    The wound surface area was assessed using digital photographs and digital planimetry software.
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23 [10]
    20 [11]
    Units: Patients
        Week 2
    11
    10
        Week 4
    13
    13
        Week 6
    9
    9
        Week 8
    15
    14
        Week 12
    17
    17
        Any time up to Week 12
    19
    18
    Notes
    [10] - At some visits, less than 23 patients were investigated.
    [11] - At some visits, less than 20 patients were investigated.
    No statistical analyses for this end point

    Secondary: Number of patients whose target wound reopened after wound closure within the 12-week efficacy follow-up

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    End point title
    Number of patients whose target wound reopened after wound closure within the 12-week efficacy follow-up
    End point description
    The wound surface area was assessed using digital photographs and digital planimetry software. Complete wound closure was defined as 95% to 100% epithelialization of the wound.
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23
    20
    Units: Patients
    0
    0
    No statistical analyses for this end point

    Secondary: Assessment of target wound exudation at Day 0 and Week 6.1 prior to IMP application, and at Week 12

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    End point title
    Assessment of target wound exudation at Day 0 and Week 6.1 prior to IMP application, and at Week 12
    End point description
    Wound exudation was classified by the investigator using the following scores: High: small amounts of fluid or free fluids are visible when the dressing is removed; dressing is extensively marked or wet. Moderate: Small amounts of fluid are visible when dressing is removed; wound bed may appear glossy; primary dressing may be lightly marked. Low: Wound bed is dry; there is no visible moisture; primary dressing is unmarked; dressing may be adherent to wound. Wound exudation was assessed at all visits, representative results for 3 visits are reported below.
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23 [12]
    20 [13]
    Units: Patients
        Low at Day 0
    10
    7
        Moderate at Day 0
    11
    11
        High at Day 0
    2
    2
        Low at Week 6.1
    8
    6
        Moderate at Week 6.1
    7
    6
        High at Week 6.1
    1
    1
        Low at Week 12
    12
    10
        Moderate at Week 12
    10
    9
        High at Week 12
    1
    1
    Notes
    [12] - At Week 6.1, 16 patients were investigated.
    [13] - At Week 6.1, 13 patients were investigated.
    No statistical analyses for this end point

    Secondary: Assessment of target wound epithelialization at Day 0 and Week 6.1 prior to IMP application, and at Week 12

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    End point title
    Assessment of target wound epithelialization at Day 0 and Week 6.1 prior to IMP application, and at Week 12
    End point description
    Epithelialization (in % of wound area) was assessed by the investigator based on image analysis and is shown here for 3 selected visits.
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23 [14]
    20 [15]
    Units: Percentage of patients
    median (full range (min-max))
        Day 0
    0.0 (0 to 10)
    0.0 (0 to 10)
        Week 6.1
    0.0 (0 to 100)
    0.0 (0 to 90)
        Week 12
    50.0 (0 to 100)
    58.5 (0 to 100)
    Notes
    [14] - At Week 6.1, 9 patients were analyzed.
    [15] - At Week 6.1, 6 patients were analyzed.
    No statistical analyses for this end point

    Secondary: Assessment of target wound formation of granulation tissue at Day 0 and Week 6.1 prior to IMP application, and at Week 12

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    End point title
    Assessment of target wound formation of granulation tissue at Day 0 and Week 6.1 prior to IMP application, and at Week 12
    End point description
    Formation of granulation tissue was assessed by the investigator based on image analysis and is shown here for 3 seleted visits.
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23 [16]
    20 [17]
    Units: Percentage of granulation tissue
    median (full range (min-max))
        Day 0
    100.0 (0 to 100)
    100.0 (0 to 100)
        Week 6.1
    80.0 (0 to 100)
    77.5 (0 to 100)
        Week 12
    41.0 (0 to 100)
    35.0 (0 to 100)
    Notes
    [16] - At Week 6.1, 9 patients were investigated.
    [17] - At Week 6.1, 6 patients were investigated.
    No statistical analyses for this end point

    Secondary: Time to amputation at target leg until Week 12

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    End point title
    Time to amputation at target leg until Week 12
    End point description
    An amputation at the target leg until Week 12 was reported in only one patient.
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set Modified full analysis set
    Number of subjects analysed
    23
    20
    Units: Patients
        Day 42
    1
    1
    No statistical analyses for this end point

    Secondary: Pain assessment as per numerical rating scale (NRS) at Day 0, Week 6.1, and Week 12

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    End point title
    Pain assessment as per numerical rating scale (NRS) at Day 0, Week 6.1, and Week 12
    End point description
    Pain was assessed by the patient using an NRS ranging between no pain (0) and worst imaginable pain (10) and is shown here for 3 seleted visits.
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set
    Number of subjects analysed
    23 [18]
    Units: pain score
    median (full range (min-max))
        Day 0
    1.0 (0 to 9)
        Week 6.1
    0.0 (-1 to 3)
        Week 12
    0.0 (-1 to 7)
    Notes
    [18] - At Week 6.1, 16 patients were investigated.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Quality of life (QoL) as assessed with the short form 36 (SF-36) questionnaire at Week 12

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    End point title
    Change from Baseline in Quality of life (QoL) as assessed with the short form 36 (SF-36) questionnaire at Week 12
    End point description
    Quality of life was assessed using the short form 36 (SF-36) questionnaire. Changes from Baseline in the scores of 9 subscales were measured. A higher score corresponds to a more positive health status. Median (full range) values at Baseline were: Limitations in physical functioning: 50.00 (5.0 - 100.0) Limitations in role activities due to problems in physical health: 25.00 (0.0 - 100.0) Limitations in usual role due to emotional problems: 100.00 (0.0 - 100.0) Limitations in social functioning due to physical or emotional problems: 87.50 (0.0 - 100.0) Mental health (depressed or happy): 76.00 (0.0 - 100.0) Bodily pain: 74.00 (12.0 - 100.0) Vitality (fatigue and energy): 55.00 (0.0 - 85.0) General health: 55.00 (10.0 - 92.0) Health transition: 3.00 (2.0 - 5.0)
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set
    Number of subjects analysed
    23
    Units: Score (change from Baseline)
    median (full range (min-max))
        Limitations in physical functioning
    0.00 (-20.0 to 80.0)
        Limit. in role act. due to probl. in phys. health
    0.00 (-75.0 to 100.0)
        Limit. in usual role due to emotional probl.
    0.00 (-100.0 to 100.0)
        Limit. in soc. funct. due to phys. or emot. probl.
    0.00 (-37.5 to 50.0)
        Mental health (depressed or happy)
    0.00 (-24.0 to 52.0)
        Bodily pain
    0.00 (-40.0 to 62.0)
        Vitality (fatigue and energy)
    0.00 (-30.0 to 50.0)
        General health
    0.00 (-27.0 to 40.0)
        Health transition
    0.00 (-4.0 to 2.0)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Dermatology-specific QoL as assessed with the Dermatology Life Quality Index (DLQI) questionnaire at Weeks 4 and 12

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    End point title
    Change from Baseline in Dermatology-specific QoL as assessed with the Dermatology Life Quality Index (DLQI) questionnaire at Weeks 4 and 12
    End point description
    The DLQI consists of 10 questions concerning symptoms and feelings, daily activities, leisure, work, school, personal relationships, and treatment. Each question is answered by a tick box: ‘not at all’, ‘a little’, ‘a lot’, or ‘very much’. Each question is scored from 0 to 3 and the scores are summed, giving a range from 0 (no impairment of life quality) to 30 (maximum impairment). All questions relate to the previous week. At Baseline, the median DLQI summary score was 6.0 (range: 0 - 28).
    End point type
    Secondary
    End point timeframe
    As indicated in the end point title.
    End point values
    Full analysis set
    Number of subjects analysed
    23
    Units: Score (change from Baseline)
    median (full range (min-max))
        Week 4
    0.0 (-14 to 5)
        Week 12
    -1.0 (-17 to 11)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent AEs were reported from the application of allo-APZ2-DFU (Day 0) until the end of the safety follow-up (Month 12).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Safety analysis set
    Reporting group description
    -

    Serious adverse events
    Safety analysis set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 23 (43.48%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Safety analysis set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 23 (100.00%)
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    6 / 23 (26.09%)
         occurrences all number
    10
    Decubitus ulcer
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    3
    Skin ulcer
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    5
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    3
    Infections and infestations
    Wound infection
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    4
    Nasopharyngitis
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    4
    Localised infection
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    5
    Infected skin ulcer
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    5

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jul 2017
    o Inclusion criterion 3: ‘If the ABI is >1.3, an additional doppler ultrasonography must be performed to exclude a PAOD masked by media sclerosis’ was added o Wound debridement can also be carried out at Visit 1 o Definition of “best standard of care management” of the diabetic foot ulcer was added o New Inclusion Criterion 4 added: At Screening Visit (Visit 1) the target ulcer should exist for at least six weeks without complete wound healing despite receiving standard of care treatment as described in the study protocol, and the wound surface area should be between 1 and 50 cm² measured by using a scaled measuring sensor in combination with digital image analysis o New Inclusion Criterion 6 added: Patients suffering from two or more ulcers at the same extremity, as long as these ulcers are separated by a minimum bridge of 1 cm of healthy tissue o New Exclusion Criterion 8 added: Ulcers due to non-diabetic etiology.
    17 Aug 2017
    o Change of Inclusion Criterion 4: ‘At Screening visit (Visit 1) the target ulcer should exist for at least six weeks without complete wound healing despite receiving standard of care treatment as described in the study protocol, and the wound surface area should be between 1 and 50 cm² measured by using a scaled measuring sensor in combination with digital image analysis’ was changed to ‘At Screening Visit 1 and 2 the wound surface area should be between 1 and 50 cm² measured by using a scaled measuring sensor in combination with digital image analysis’ o Change of Exclusion Criterion 2: presence of osteomyelitis was changed to clinical signs of active osteomyelitis in the last three months o Change of Exclusion Criterion 14: ‘History of tumour disease or active tumour disease, systemic or local neoplasia or suspicion of any carcinomas or malignant tumour’ was changed to ‘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’ o Secondary efficacy endpoint ‘Percentage of invisible and visible wound surface area reduction at Weeks 2, 4, 8 and 12 (without LOCF)’ was added o Secondary efficacy endpoint ‘Absolute invisible and visible wound surface area reduction at Weeks 2, 4, 8 and 12 (without LOCF)’ was added o Secondary efficacy endpoints: assessments of QoL using the SF-36 questionnaire and of dermatology-specific QoL based on the DLQI were additionally to be done at Visit 3 o Visit 1 was moved from 1-7 days before Visit 2 to at least 6 weeks before Visit 2 o Wound debridement can also be carried out at Visit 3.
    09 Apr 2018
    o Change of Inclusion Criterion 8: allowed BMI was extended from a range between 20 and 40 kg/m² to a range of 20 and 45 kg/m² o Clarified that Tisseel application after IMP application is optional and should occur 15-30 minutes after IMP application o Specified that determination of the wound surface will be done at Visit 1 and Visit 2 (instead of only Visit 2) o Appendix 1, wound surface area calculation was updated.
    28 May 2018
    o A second IMP application was introduced (adding Visit 10, Week 6.1), including 1 additional visit before and 2 additional visits after the 2nd IMP application (Visit 9, Visit 11 and Visit 12 to be performed at Week 6, Week 6.2, and Week 6.3, respectively). Visit 9 was added to measure the wound size 1 to 3 days before the 2nd IMP application to calculate the required cell amount. All treatments and procedures related to the IMP application were to be repeated at Visit 10 (physical examination and vital signs, and optional wound debridement). The risk/benefit assessment was adapted for the inclusion of a 2nd IMP application. o Due to the inclusion of 4 new visits for the 2nd IMP application, new time points, i.e. Week 6, Week 6.1, Week 6.2, and Week 6.3, were added to the following secondary efficacy endpoints: − Percentage wound surface area reduction (Week 6 only) − Percentage of invisible and visible wound surface area reduction (Week 6 only) − Absolute wound surface area reduction (Week 6 only) − Absolute invisible and visible wound surface area reduction (Week 6 only) − Assessment of wound infection − Proportion of patients achieving 30% and complete wound closure (Week 6 only) − Wound exudation, epithelialization and formation of granulation tissue (Week 6 and Week 6.1), and − Pain assessment as per NRS. o Primary efficacy endpoint: Week 6 was added as an LOCF measurement in case of a missing wound surface area measurement at Week 12. o Safety endpoints: Week 6.1 was added to analyze data obtained by physical examination and the assessment of vital signs. o For Inclusion Criterion 4 clarified that the required wound surface area between 1 and 50 cm² applies for the target ulcer. o Inclusion Criterion 6 wording changes.
    07 Mar 2019
    o In Inclusion Criterion 2 the following: ‘…..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 3 months before visit 1’ changed to ‘….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.’ o In Inclusion Criterion 3 the following: ‘…..The presence of diabetic neuropathic ulcers “malum perforans” not involving subcutis (Grade I according to Wagner) at plantar side of the foot diagnosed by ABI ≥0.8, without claudication, or TcPO2 >40 mmHg…’ changed to ‘….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.’ o Exclusion Criterion 1 clarified that acute Charot foot is meant.
    12 Dec 2019
    o The procedure to transfer wound photographs to the sponsor added. o New SOP references added.
    27 Apr 2020
    o Specified that due to the COVID-19 pandemic and the already reached target of responders, it was planned to complete the trial on 30-Jun-2020. References to the respective trial stop were added and adjusted. o The possibility to treat non-target wounds was removed.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The trial was completed on 29-June-2020 (last patient last visit) due to the coronavirus disease-2019 (COVID-19) pandemic and the efficacy of allo-APZ2-DFU as specified in a protocol amendment.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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