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    Clinical Trial Results:
    An interventional, single arm, multicenter, phase I/IIa clinical trial to investigate the efficacy and safety of allo-APZ2-CVU on wound healing of chronic venous ulcer (CVU).

    Summary
    EudraCT number
    		 2017-000233-31
    Trial protocol
    		 DE  
    Global end of trial date
    30 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2021
    First version publication date
    20 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    allo-APZ2-CVU-II-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03257098
    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, 49 6221718330, office@rheacell.com
    Scientific contact
    Information Office, 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
    30 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this clinical trial was to investigate the efficacy (by monitoring the wound size reduction of chronic venous ulcers [CVUs]) and safety (by monitoring adverse events [AEs]) of two doses of allo-APZ2-CVU topically administered on wounds of patients with CVU.
    Protection of trial subjects
    The clinical trial was conducted in accordance with the Declaration of Helsinki in its current revision and the International Conference on Harmonisation (ICH) Guideline for 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. The COVID-19 pandemic did impact the conduct of the trial (e.g. delay of follow-up visits and examinations, delay of data entry/cleaning activities, change/delay of monitoring activities). The situation in this clinical trial was continuously monitored to ensure the safety of patients and to reduce the delays in collection and verification of data. The sponsor was informed and updated with short interval reports on critical issues in the trial, and on measures taken to control them. Investigators received a sponsor statement on handling patient visits and were informed about recruitment stop.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Nov 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: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    6
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of the 58 patients enrolled and screened at 9 centers, 27 patients were screening failures, and 31 patients were treated.

    Pre-assignment
    Screening details
    		 Patients who met each of the 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-CVU
    Arm description
    		 Patients treated with the investigational medicinal product (IMP), allo-APZ2-II-CVU.
    Arm type
    		 Experimental

    Investigational medicinal product name
    allo-APZ2-CVU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cutaneous suspension
    Routes of administration
    Topical use
    Dosage and administration details
    One (for patients enrolled under protocol Version 2.0) or 2 (for patients enrolled under protocol Version 3.0 or higher) topical applications of 1x10^6 cells/cm² of allo-APZ2-CVU cells were applied on the surface of the target ulcer with a syringe. Non-target wounds were treated as per standard of care.

    Number of subjects in period 1
    		allo-APZ2-CVU
    Started
    31
    Completed
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment and follow-up
    Reporting group description
    		 Patients were treated with 1x10^6 skin-derived ABCB5-positive mesenchymal stem cells/cm², which were topically applied under local anesthesia on the wound surface of a target CVU.

    Reporting group values
    		 Treatment and follow-up Total
    Number of subjects
    		 31 31
    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)
    		 6 6
        From 65-84 years
    		 25 25
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 75.0 (36 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 15 15
        Male
    		 16 16
    Subject analysis sets

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients who signed the informed consent form and who received allo-APZ2-CVU at least once.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients included in the safety analysis set who had a wound size assessment at Baseline (Visit 3, Day 0) and on at least one post-baseline visit.

    Subject analysis set title
    Modified full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients of the full analysis set except for patients with major protocol deviations affecting efficacy assessments. The modified full analysis set was used as sensitivity analysis set for efficacy analyses concerning wound assessments and contained all except 4 patients belonging to the full analysis set.

    Subject analysis sets values
    		 Safety analysis set Full analysis set Modified full analysis set
    Number of subjects
    31
    31
    27
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    6
    6
    5
        From 65-84 years
    25
    25
    22
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    75.0 (36 to 82)
    75.0 (36 to 82)
    75.0 (36 to 82)
    Gender categorical
    Units: Subjects
        Female
    15
    15
    14
        Male
    16
    16
    13

    End points

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    End points reporting groups
    Reporting group title
    allo-APZ2-CVU
    Reporting group description
    		 Patients treated with the investigational medicinal product (IMP), allo-APZ2-II-CVU.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients who signed the informed consent form and who received allo-APZ2-CVU at least once.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients included in the safety analysis set who had a wound size assessment at Baseline (Visit 3, Day 0) and on at least one post-baseline visit.

    Subject analysis set title
    Modified full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients of the full analysis set except for patients with major protocol deviations affecting efficacy assessments. The modified full analysis set was used as sensitivity analysis set for efficacy analyses concerning wound assessments and contained all except 4 patients belonging to the full analysis set.

    Primary: Percentage of wound size reduction at Week 12, or last available post-baseline measurement if the Week 12 measurement was missing (last observation carried forward [LOCF])

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    End point title
    		 Percentage of wound size reduction at Week 12, or last available post-baseline measurement if the Week 12 measurement was missing (last observation carried forward [LOCF]) [1]
    End point description
    The percentage of wound size reduction in comparison to the size at the day of allo-APZ2-CVU application was assessed by standardized photography.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 12, or last available post-baseline measurement if the Week 12 measurement was missing (LOCF)
    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: No statistical analyses were done in this phase I/II trial.
    End point values
    		 Full analysis set Modified full analysis set
    Number of subjects analysed
    31 [2]
    27 [3]
    Units: Target wound size reduction [%]
        median (full range (min-max))
    75.60 (-278.9 to 100.0)
    78.40 (-27.4 to 100.0)
    Notes
    [2] - At some visits, less than 31 patients were investigated.
    [3] - At some visits, less than 27 patients were investigated.
    No statistical analyses for this end point

    Secondary: Percentage of wound size reduction at Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10 and 12 (without LOCF)

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    End point title
    		 Percentage of wound size reduction at Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10 and 12 (without LOCF)
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline to Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10 and 12
    End point values
    		 Full analysis set Modified full analysis set
    Number of subjects analysed
    31 [4]
    27 [5]
    Units: Target wound size reduction [%]
    median (full range (min-max))
        Week 2
    28.70 (-8.6 to 75.9)
    28.70 (-8.6 to 75.9)
        Week 3
    39.50 (-10.8 to 100.0)
    39.65 (-10.8 to 100.0)
        Week 4
    47.20 (-61.0 to 100.0)
    49.90 (-11.0 to 100.0)
        Week 6
    53.25 (-147.5 to 100.0)
    59.00 (-12.8 to 100.0)
        Week 6.1
    36.95 (-187.9 to 95.1)
    42.80 (-23.0 to 95.1)
        Week 6.2
    36.75 (-64.2 to 90.4)
    41.50 (-13.2 to 90.4)
        Week 8
    58.30 (-136.0 to 100.0)
    58.70 (-24.5 to 100.0)
        Week 10
    68.70 (-84.3 to 100.0)
    69.60 (-23.4 to 100.0)
        Week 12
    76.85 (-278.9 to 100.0)
    78.40 (-27.4 to 100.0)
    Notes
    [4] - At some visits, less than 31 patients were investigated.
    [5] - At some visits, less than 27 patients were investigated.
    No statistical analyses for this end point

    Secondary: Absolute wound size reduction at Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12

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    End point title
    		 Absolute wound size reduction at Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline to Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12
    End point values
    		 Full analysis set Modified full analysis set
    Number of subjects analysed
    31 [6]
    27 [7]
    Units: Wound size reduction [cm²]
    median (full range (min-max))
        Week 2
    1.18 (-3.38 to 15.06)
    1.18 (-3.38 to 15.06)
        Week 3
    1.89 (-4.25 to 15.93)
    1.90 (-4.25 to 15.93)
        Week 4
    2.39 (-4.31 to 16.94)
    2.39 (-4.31 to 16.94)
        Week 6
    2.08 (-8.12 to 19.95)
    2.11 (-5.03 to 19.95)
        Week 6.1
    2.51 (-10.34 to 20.21)
    2.52 (-2.20 to 20.21)
        Week 6.2
    2.72 (-3.53 to 23.38)
    2.77 (-2.75 to 23.38)
        Week 8
    2.91 (-9.62 to 19.55)
    2.94 (-9.62 to 19.55)
        Week 10
    3.19 (-9.19 to 19.87)
    3.37 (-9.19 to 19.87)
        Week 12
    2.69 (-62.79 to 21.74)
    3.16 (-10.76 to 21.74)
    Notes
    [6] - At some visits, less than 31 patients were investigated.
    [7] - At some visits, less than 27 patients were investigated.
    No statistical analyses for this end point

    Secondary: Number of patients achieving complete wound closure at Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, 12, and at any time point

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    End point title
    		 Number of patients achieving complete wound closure at Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, 12, and at any time point
    End point description
    Complete wound closure was defined as 95% to 100% epithelialization of the wound.
    End point type
    Secondary
    End point timeframe
    From Baseline to Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, 12, and at any time point
    End point values
    		 Full analysis set Modified full analysis set
    Number of subjects analysed
    31 [8]
    27 [9]
    Units: Number of patients
        Day 1-3
    0
    0
        Day 8
    0
    0
        Week 2
    0
    0
        Week 3
    1
    1
        Week 4
    1
    1
        Week 6
    2
    2
        Week 6.1
    1
    1
        Week 6.2
    0
    0
        Week 8
    3
    3
        Week 10
    3
    3
        Week 12
    6
    6
        Any time up to Week 12
    7
    7
    Notes
    [8] - At some visits, less than 31 patients were investigated.
    [9] - At some visits, less than 27 patients were investigated.
    No statistical analyses for this end point

    Secondary: Time to first complete wound closure

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    End point title
    		 Time to first complete wound closure
    End point description
    Complete wound closure was defined as 95% to 100% epithelialization of the wound. Not all patients had a complete wound closure during the trial, thus, it was not possible to calculate the median time to wound closure. Instead, a Kaplan-Meier analysis was done to calculate product-limit survival estimates for the time to wound closure.
    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
    31 [10]
    27 [11]
    Units: days to ≥50% probability of closure
        number (confidence interval 95%)
    91.0 (85.00 to 91.00)
    91.0 (85.00 to 91.00)
    Notes
    [10] - At some visits, less than 31 patients were analyzed.
    [11] - At some visits, less than 27 patients were analyzed.
    No statistical analyses for this end point

    Secondary: Number of patients achieving an at least 30% wound size reduction at Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, 12, and at any time point

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    End point title
    		 Number of patients achieving an at least 30% wound size reduction at Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, 12, and at any time point
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline to Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, 12, and at any time point
    End point values
    		 Full analysis set Modified full analysis set
    Number of subjects analysed
    31 [12]
    27 [13]
    Units: Patients
        Day 1-3
    2
    2
        Day 8
    7
    7
        Week 2
    14
    13
        Week 3
    20
    18
        Week 4
    20
    19
        Week 6
    21
    19
        Week 6.1
    12
    11
        Week 6.2
    15
    14
        Week 8
    21
    20
        Week 10
    20
    19
        Week 12/end of treatment
    21
    21
        Week 12
    21
    21
        Week 12 (LOCF)
    21
    21
        Any time up to Week 12
    26
    24
    Notes
    [12] - At some visits, less than 31 patients were investigated.
    [13] - At some visits, less than 27 patients were investigated.
    No statistical analyses for this end point

    Secondary: Time to first 30% wound size reduction

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    End point title
    		 Time to first 30% wound size reduction
    End point description
    The time (days) from Baseline until a probabilty of at least 50% for a wound size reduction of at least 30% was calculated.
    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
    31
    27
    Units: days to ≥50% probability
        number (confidence interval 95%)
    21.0 (12.00 to 27.00)
    15.0 (9.00 to 27.00)
    No statistical analyses for this end point

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

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    End point title
    		 Number of patients whose wound reopened after wound closure within the 12-week efficacy follow-up
    End point description
    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
    31
    27
    Units: Patients
    1
    1
    No statistical analyses for this end point

    Secondary: Epithelialization at Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12

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    End point title
    		 Epithelialization at Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12
    End point description
    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
    31 [14]
    27 [15]
    Units: % of wound area
    median (full range (min-max))
        Day 0
    0.0 (0 to 30)
    0.0 (0 to 30)
        Day 1 - 3
    0.0 (0 to 60)
    1.0 (0 to 60)
        Day 8
    10.0 (0 to 50)
    10.0 (0 to 50)
        Week 2
    20.0 (0 to 80)
    20.0 (0 to 80)
        Week 3
    20.0 (0 to 100)
    20.0 (0 to 100)
        Week 4
    30.0 (0 to 100)
    30.0 (0 to 100)
        Week 6
    40.0 (0 to 100)
    40.0 (0 to 100)
        Week 6.1
    30.5 (0 to 95)
    30.0 (0 to 95)
        Week 6.2
    40.0 (0 to 88)
    40.0 (0 to 88)
        Week 8
    40.0 (0 to 100)
    40.0 (0 to 100)
        Week 10
    42.5 (0 to 100)
    56.0 (0 to 100)
        Week 12
    40.0 (0 to 100)
    45.0 (0 to 100)
    Notes
    [14] - At some visits, less than 31 patients were investigated.
    [15] - At some visits, less than 27 patients were investigated.
    No statistical analyses for this end point

    Secondary: Formation of granulation tissue before IMP applications (Visit 3, Visit 10) and at each follow-up visit (Days 1-3 and 8, Weeks 2, 3, 4, 6, 6.2, 8, 10, and 12)

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    End point title
    		 Formation of granulation tissue before IMP applications (Visit 3, Visit 10) and at each follow-up visit (Days 1-3 and 8, Weeks 2, 3, 4, 6, 6.2, 8, 10, and 12)
    End point description
    End point type
    Secondary
    End point timeframe
    From Day 0 (before allo-APZ2-CVU application) to Week 12
    End point values
    		 Full analysis set Modified full analysis set
    Number of subjects analysed
    31 [16]
    27 [17]
    Units: % of wound area
    median (full range (min-max))
        Day 0
    70.0 (0 to 100)
    65.0 (0 to 100)
        Day 1 - 3
    65.0 (0 to 100)
    60.0 (0 to 100)
        Day 8
    50.0 (0 to 95)
    50.0 (0 to 95)
        Week 2
    50.0 (5 to 95)
    50.0 (5 to 95)
        Week 3
    50.0 (0 to 80)
    50.0 (0 to 80)
        Week 4
    50.0 (0 to 95)
    50.0 (0 to 95)
        Week 6
    50.0 (0 to 95)
    50.0 (0 to 95)
        Week 6.1
    60.0 (5 to 100)
    60.0 (5 to 100)
        Week 6.2
    53.0 (10 to 100)
    50.0 (10 to 100)
        Week 8
    50.0 (0 to 95)
    50.0 (0 to 95)
        Week 10
    30.0 (0 to 95)
    25.0 (0 to 95)
        Week 12
    30.0 (0 to 95)
    22.0 (0 to 95)
    Notes
    [16] - At some visits, less than 31 patients were investigated.
    [17] - At some visits, less than 27 patients were investigated.
    No statistical analyses for this end point

    Secondary: Further wound healing parameters: formation of wound exudation before IMP applications (Visit 3, Visit 10) and at each follow-up visit (Days 1-3 and 8, Weeks 2, 3, 4, 6, 6.2, 8, 10, and 12)

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    End point title
    		 Further wound healing parameters: formation of wound exudation before IMP applications (Visit 3, Visit 10) and at each follow-up visit (Days 1-3 and 8, Weeks 2, 3, 4, 6, 6.2, 8, 10, and 12)
    End point description
    The number (%) of patients with low, moderate, and high wound exudation was reported.
    End point type
    Secondary
    End point timeframe
    From Day 0 (before allo-APZ2-CVU application) to Week 12
    End point values
    		 Full analysis set Modified full analysis set
    Number of subjects analysed
    31 [18]
    27 [19]
    Units: Patients
        low at Day 0
    14
    11
        moderate at Day 0
    15
    14
        high at Day 0
    2
    2
        low at Week 6.1
    14
    11
        moderate at Week 6.1
    8
    8
        high at Week 6.1
    0
    0
        low at Week 12
    18
    16
        moderate at Week 12
    10
    10
        high at Week 12
    1
    0
    Notes
    [18] - At Weekt 6.1, 22 patients and at Week 12, 30 patients (including 1 with missing data) were analyzed.
    [19] - At Weekt 6.1, 19 patients were analyzed; Week 12 includes 1 patient with missing data.
    No statistical analyses for this end point

    Secondary: Change from Baseline in pain assessment as per numerical rating scale (NRS) at Days 1-3 and 8, Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12

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    End point title
    		 Change from Baseline in pain assessment as per numerical rating scale (NRS) at Days 1-3 and 8, Weeks 2, 3, 4, 6, 6.1, 6.2, 8, 10, and 12
    End point description
    The pain perceived was rated on an NRS ranging from score 0 (no pain) to score 10 (strongest pain perceivable). The median (full range) pain score at Baseline was 3.0 (0 - 9).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    		 Full analysis set
    Number of subjects analysed
    31 [20]
    Units: score (change from Baseline)
    median (full range (min-max))
        Day 1 - 3
    0.0 (-3 to 6)
        Day 8
    0.0 (-3 to 6)
        Week 2
    1.0 (-3 to 9)
        Week 3
    1.0 (-2 to 9)
        Week 4
    1.9 (-4 to 8)
        Week 6
    1.0 (-3 to 9)
        Week 6.1
    1.0 (-2 to 9)
        Week 6.2
    1.0 (-2 to 9)
        Week 8
    1.0 (-4 to 9)
        Week 10
    1.0 (-6 to 9)
        Week 12
    0.5 (-4 to 9)
    Notes
    [20] - At some visits, less than 31 patients were investigated.
    No statistical analyses for this end point

    Secondary: Change from Baseline in assessment of Quality of Life (QoL) using the short form 36 (SF-36) questionnaire at Week 12/end of treatment

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    End point title
    		 Change from Baseline in assessment of Quality of Life (QoL) using the short form 36 (SF-36) questionnaire at Week 12/end of treatment
    End point description
    Quality of life was assessed using the short form 36 (SF-36) questionnaire. Changes from Baseline at Week 12/end of treatment 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: 45.00 (0.0 - 100.0) Limitations in role activities due to problems in physical health: 25.00 (0.0 - 100.0) Bodily pain: 51.00 (0.0 - 100.0) General health: 52.0 (25.0 - 95.0) Vitality (fatigue and energy): 45.00 (15.0 - 100.0) Limitations in social functioning due to physical or emotional problems: 75.00 (25.0; 100.0) Limitations in usual role due to emotional problems: 100.00 (0.0; 100.0) Mental health (depressed or happy): 64.0 (36.0; 100.0) Health transition: 3.00 (1.0 - 5.0)
    End point type
    Secondary
    End point timeframe
    Day 0 to Week 12/end of treatment
    End point values
    		 Full analysis set
    Number of subjects analysed
    31 [21]
    Units: subscore (change from Baseline)
    median (full range (min-max))
        Limitations in physical functioning
    2.50 (-30.0 to 35.0)
        Limit. in role act. due to probl. in phys. health
    0.00 (-100.0 to 100.0)
        Bodily pain
    0.00 (-31.0 to 51.0)
        General health
    0.00 (-25.0 to 37.0)
        Vitality (fatigue and energy)
    0.00 (-50.0 to 30.0)
        Limit. in soc. funct. due to phys. or emot. probl.
    0.00 (-37.5 to 62.5)
        Limit. in usual role due to emot. probl.
    0.00 (-100.0 to 100.0)
        Mental health (depressed or happy)
    -4.00 (-40.0 to 28.0)
        Health transition
    0.00 (-2.0 to 2.0)
    Notes
    [21] - At some visits, less than 31 patients were investigated.
    No statistical analyses for this end point

    Secondary: Change from Baseline in dermatology-specific quality of life based on the Dermatology Life Quality Index (DLQI) questionnaire at Weeks 4, 8 and 12 (summary score)

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    End point title
    		 Change from Baseline in dermatology-specific quality of life based on the Dermatology Life Quality Index (DLQI) questionnaire at Weeks 4, 8 and 12 (summary score)
    End point description
    At Baseline, the median (full range) dermatology-specific quality of life summary score was 9.5 (0 - 23).
    End point type
    Secondary
    End point timeframe
    From Day 0 (Baseline) to Week 12
    End point values
    		 Full analysis set
    Number of subjects analysed
    31 [22]
    Units: Score (change from Baseline)
    median (full range (min-max))
        Week 4
    -1.0 (-20 to 3)
        Week 8
    -1.0 (-15 to 4)
        Week 12
    -3.0 (-15 to 10)
    Notes
    [22] - At some visits, less than 31 patients were analyzed.
    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 first allo-APZ2-CVU application (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
    Treated patients
    Reporting group description
    		 All patients who were treated with allo-APZ2-CVU at least once.

    Serious adverse events
    		 Treated patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 31 (22.58%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    2
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    General disorders and administration site conditions
    Malaise
    Additional description: The event recovered with sequelae.
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Skin and subcutaneous tissue disorders
    Skin ulcer
    Additional description: One event resolved without sequelae, one event resolved with sequelae.
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal amyloidosis
    Additional description: The event recovered with sequelae.
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot deformity
    Additional description: The event recovered with sequelae.
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
    Additional description: The event recovered without sequelae.
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
    Additional description: The event recovered without sequelae.
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treated patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 31 (87.10%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Skin pressure mark
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Traumatic haematoma
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    3 / 31 (9.68%)
         occurrences all number
    3
    Oedema peripheral
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2
    Application site erosion
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Dysphonia
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Pleural effusion
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    2
    Dermatitis allergic
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2
    Dermatitis contact
         subjects affected / exposed
    4 / 31 (12.90%)
         occurrences all number
    5
    Dermatitis psoriasiform
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2
    Erythema
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Hyperkeratosis
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Intertrigo
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Mechanical urticaria
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2
    Skin ulcer
         subjects affected / exposed
    11 / 31 (35.48%)
         occurrences all number
    15
    Stasis dermatitis
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2
    Venous ulcer pain
         subjects affected / exposed
    5 / 31 (16.13%)
         occurrences all number
    7
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 31 (9.68%)
         occurrences all number
    3
    Wound infection
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Erysipelas
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Superinfection bacterial
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1
    Wound infection bacterial
         subjects affected / exposed
    1 / 31 (3.23%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Mar 2018
    Main changes from protocol version 1.0 (03-Feb-2017) to 2.0 (21-Mar-2018) included: - Inclusion criterion #1 was changed from "Male or female patients aged 45 to 85 years" to "Male or female patients aged 35 to 85 years" - Inclusion criterion #6 was changed from "Body mass index (BMI) between 20 and 40 kg/m²" to "Body mass index (BMI) between 20 and 45 kg/m²" - Wound dressing treatment changed from "For further wound dressing Mepilex® or Biatain® plaster must be used until Week 12" to "For further wound dressing Mepilex® or Biatain® or Cutimed® Sorbact® plaster must be used until Week 12".
    18 May 2018
    Main changes from protocol version 2.0 (21-Mar-2018) to 3.0 (18-May-2018) included: - A second IMP application after 6 weeks, at Visit (V)10 - Section 9.4: Due to the inclusion of two new visits (Visit 10 and Visit 11) that were required for the second IMP application, Week 6.1 and Week 6.2 were supplemented as secondary efficacy endpoints for determining: o Percentage and absolute wound size reduction, o Proportion of patients achieving 30% wound closure, o Epithelialization, formation of granulation tissue and wound exudation, o Pain assessment, o Secondary safety endpoints for determining physical examination and vital signs at Week 6.1 and Week 12.
    27 Apr 2020
    Main changes from protocol version 3.0 (18-May-2018) to 4.0 (27-Apr-2020) included: - Due to the COVID-19 pandemic and the already reached target of responders (at least 14 of 18 patients with 30% wound size reduction), the trial was completed on 30-Jun-2020 - The possibility to treat non-target wounds was removed (Section 13.1).

    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.
    None reported
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