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    Clinical Trial Results:
    An Interventional, Single Arm, Phase I/IIa Clinical Trial to Investigate the Efficacy and Safety of APZ2 on Wound Healing of Chronic Venous Ulcer (CVU)

    Summary
    EudraCT number
    		 2015-000399-81
    Trial protocol
    		 DE  
    Global end of trial date
    15 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 May 2021
    First version publication date
    26 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APZ2-II-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02742844
    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
    15 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jan 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate the efficacy (by monitoring the wound size reduction of CVUs) and safety (by monitoring adverse events [AEs]) of one dose of the IMP APZ2 topically administered on wounds of patients with CVU.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and ICH 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 500,000 ABCB5+ cells/cm² administered topically on CVU wounds of a maximum size of 50 cm² (in the clinical Phase I/IIa trial) was considered to be safe and to provide benefit to the patients.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Aug 2016
    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: 11
    Worldwide total number of subjects
    11
    EEA total number of subjects
    11
    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)
    3
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of the 13 patients screened at one center, 11 patients were enrolled and 2 patients were screening failures. 9 patients were treated. 6 of whom met all eligibilty criteria and were, thus, included in the full analysis set.

    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
    Biopsy period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 APZ2
    Arm description
    		 Patients who underwent a skin biopsy in period 1.
    Arm type
    		 Biopsy collection & APZ2 production

    Investigational medicinal product name
    APZ2
    Investigational medicinal product code
    Other name
    ATP-binding cassette sub-family B member 5 (ABCB5)-positive dermal mesenchymal stem cells
    Pharmaceutical forms
    Cutaneous suspension
    Routes of administration
    Topical use
    Dosage and administration details
    One dose of APZ2 (500,000 autologous skin-derived ABCB5+ MSCs/50 μL/cm2) was topically administered on the wound surface of patients with CVU. In case of multiple wounds, one wound was selected as the target wound of APZ2 application.

    Number of subjects in period 1
    		APZ2
    Started
    11
    Biopsy (first visit in Biopsy period)
    11
    Completed
    9
    Not completed
    2
         IMP production not successful
    2
    Period 2
    Period 2 title
    Treatment and follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 APZ2
    Arm description
    		 Patients treated with APZ2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    APZ2
    Investigational medicinal product code
    Other name
    ATP-binding cassette sub-family B member 5 (ABCB5)-positive dermal mesenchymal stem cells
    Pharmaceutical forms
    Cutaneous suspension
    Routes of administration
    Topical use
    Dosage and administration details
    One dose of APZ2 (500,000 autologous skin-derived ABCB5+ MSCs/50 μL/cm2) was topically administered on the wound surface of patients with CVU. In case of multiple wounds, one wound was selected as the target wound of APZ2 application.

    Number of subjects in period 2
    		APZ2
    Started
    9
    IMP administration
    9
    Completed
    6
    Not completed
    3
         Protocol deviation
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    APZ2
    Reporting group description
    		 Patients who underwent a skin biopsy in period 1.

    Reporting group values
    		 APZ2 Total
    Number of subjects
    		 11 11
    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)
    		 3 3
        From 65-84 years
    		 8 8
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        male
    		 5 5
        female
    		 6 6
    Subject analysis sets

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients who were enrolled and who were treated with APZ2 cells.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set included all patients of the safety analysis set, who did not violate efficacy exclusion criteria 1 and 2 and had wound size assessments at Baseline and at least at one post-baseline visit.

    Subject analysis sets values
    		 Safety analysis set Full analysis set
    Number of subjects
    9
    6
    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)
    2
    1
        From 65-84 years
    7
    5
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        male
    3
    2
        female
    6
    4

    End points

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    End points reporting groups
    Reporting group title
    APZ2
    Reporting group description
    		 Patients who underwent a skin biopsy in period 1.
    Reporting group title
    APZ2
    Reporting group description
    		 Patients treated with APZ2.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients who were enrolled and who were treated with APZ2 cells.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set included all patients of the safety analysis set, who did not violate efficacy exclusion criteria 1 and 2 and had wound size assessments at Baseline and at least at one post-baseline visit.

    Primary: Percentage of wound size reduction at Week 12 or last available post-baseline measurement

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    End point title
    		 Percentage of wound size reduction at Week 12 or last available post-baseline measurement [1]
    End point description
    The percentage of wound size reduction in comparison to the size at the day of APZ2 application was assessed by standardized photography.
    End point type
    Primary
    End point timeframe
    Change from Baseline to Week 12 or last available post-baseline measurement if the Week 12 measurement was missing (last observation carried forward).
    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 formal hypothesis was statistically tested. All variables were analyzed descriptively.
    End point values
    		 Full analysis set
    Number of subjects analysed
    6
    Units: Target wound size reduction [%]
        median (full range (min-max))
    63.38 (32.11 to 100.00)
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of wound size reduction at Weeks 2, 3, 4, 6, 8, 10 and 12 (without LOCF)
    End point description
    The percentage of wound size reduction was assessed by standardized photography. The assessment of wound size reduction in comparison to the size at the day of APZ2 application started on the day of the first change of wound dressing (in general on Day 3).
    End point type
    Secondary
    End point timeframe
    Weeks 2, 3, 4, 6, 8, 10 and 12 (without last observation carried forward).
    End point values
    		 Full analysis set
    Number of subjects analysed
    6
    Units: Target wound size reduction [%]
    median (full range (min-max))
        Week 2
    23.14 (6.16 to 29.19)
        Week 3
    23.01 (9.10 to 64.30)
        Week 4
    27.78 (24.16 to 72.54)
        Week 6
    65.86 (47.61 to 83.90)
        Week 8
    57.14 (37.19 to 93.97)
        Week 10
    56.81 (38.37 to 93.17)
        Week 12
    63.38 (32.11 to 100.00)
    No statistical analyses for this end point

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

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    End point title
    		 Absolute wound size reduction at Weeks 2, 3, 4, 6, 8, 10, and 12
    End point description
    The wound size reduction in comparison to the size at the day of APZ2 application was assessed by standardized photography.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 3, 4, 6, 8, 10, and 12.
    End point values
    		 Full analysis set
    Number of subjects analysed
    6
    Units: Target wound size reduction [cm2]
    median (full range (min-max))
        Week 2
    1.94 (0.83 to 4.44)
        Week 3
    2.60 (0.90 to 7.45)
        Week 4
    2.46 (1.54 to 9.63)
        Week 6
    4.89 (2.49 to 10.01)
        Week 8
    5.96 (2.49 to 15.95)
        Week 10
    5.98 (2.24 to 16.78)
        Week 12
    6.24 (2.40 to 13.92)
    No statistical analyses for this end point

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

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    End point title
    		 Proportion of patients achieving complete wound closure at Weeks 2, 3, 4, 6, 8, 10, 12, and at any time point
    End point description
    Wound closure was defined as 95% to 100% epithelialization of the wound and was assessed by the investigator. The number of patients instead of the proportion is repoprted due to the low number of patients.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 3, 4, 6, 8, 10, 12, and at any time point.
    End point values
    		 Full analysis set
    Number of subjects analysed
    6 [2]
    Units: number of patients
        Week 2
    0
        Week 3
    0
        Week 4
    0
        Week 6
    0
        Week 8
    1
        Week 10
    1
        Week 12
    1
    Notes
    [2] - Full analysis set
    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
    Wound closure was defined as 95% to 100% epithelialization of the wound and was assessed by the investigator.
    End point type
    Secondary
    End point timeframe
    Day 0 to Week 12
    End point values
    		 Full analysis set
    Number of subjects analysed
    6 [3]
    Units: days
    53
    Notes
    [3] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to first 30% wound closure

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    End point title
    		 Time to first 30% wound closure
    End point description
    The probabilty of achieving 30% wound closure and the median time to 30% reduction along with the 95% confidence interval were calculated with a Kaplan-Meier analysis.
    End point type
    Secondary
    End point timeframe
    Day 0 to Week 12
    End point values
    		 Full analysis set
    Number of subjects analysed
    6
    Units: Days
        median (confidence interval 95%)
    42 (21.0 to 57.0)
    No statistical analyses for this end point

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

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    End point title
    		 Proportion 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
    Day 0 to Week 12
    End point values
    		 Full analysis set
    Number of subjects analysed
    6
    Units: number of patients
    0
    No statistical analyses for this end point

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

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    End point title
    		 Epithelialization assessed at Weeks 2, 3, 4, 6, 8, 10, and 12
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0 to Week 12
    End point values
    		 Full analysis set
    Number of subjects analysed
    6 [4]
    Units: % of wound area
    median (full range (min-max))
        Week 2
    15.0 (0 to 35)
        Week 3
    27.5 (0 to 60)
        Week 4
    35.0 (2 to 70)
        Week 6
    65.0 (45 to 85)
        Week 8
    55.5 (40 to 95)
        Week 10
    56.5 (40 to 95)
        Week 12
    62.5 (35 to 100)
    Notes
    [4] - At Weeks 4 and 6 only 5 patients were evaluated.
    No statistical analyses for this end point

    Secondary: Formation of granulation tissue before IMP application (Day 0, Weeks 2, 3, 4, 6, 8, 10, and 12)

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    End point title
    		 Formation of granulation tissue before IMP application (Day 0, Weeks 2, 3, 4, 6, 8, 10, and 12)
    End point description
    5 patients were analyzed at Weeks 4 and 6.
    End point type
    Secondary
    End point timeframe
    Day 0, Weeks 2, 3, 4, 6, 8, 10, and 12.
    End point values
    		 Full analysis set
    Number of subjects analysed
    6
    Units: % of wound area
    median (full range (min-max))
        Day 0
    75.0 (50 to 100)
        Week 2
    75.0 (55 to 95)
        Week 3
    62.5 (40 to 100)
        Week 4
    65.0 (30 to 98)
        Week 6
    35.0 (15 to 55)
        Week 8
    42.0 (5 to 60)
        Week 10
    42.5 (5 to 60)
        Week 12
    35.0 (0 to 65)
    No statistical analyses for this end point

    Secondary: Wound exudation before IMP application (Day 0, Weeks 2, 3, 4, 6, 8, 10, and 12)

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    End point title
    		 Wound exudation before IMP application (Day 0, Weeks 2, 3, 4, 6, 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
    Day 0 to Week 12
    End point values
    		 Full analysis set
    Number of subjects analysed
    6
    Units: Patients
        low at Day 0
    4
        moderate at Day 0
    2
        high at Day 0
    0
        low at Week 12
    3
        moderate at Week 12
    2
        high at Week 12
    1
    No statistical analyses for this end point

    Secondary: Pain assessment as per numerical rating scale (NRS)

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    End point title
    		 Pain assessment as per numerical rating scale (NRS)
    End point description
    The pain perceived was rated on an NRS ranging from 0 (no pain) to 10 (strongest pain perceivable). The median (full range) pain at Baseline was 4.0 (0 - 5).
    End point type
    Secondary
    End point timeframe
    Day 0 to Week 12
    End point values
    		 Full analysis set
    Number of subjects analysed
    6
    Units: scale values (change from Baseline)
    median (full range (min-max))
        Day 1 - 3
    -1.0 (-4 to 0)
        Day 8
    -1.0 (-2 to 0)
        Week 2
    -1.0 (-2 to 5)
        Week 3
    -1.0 (-2 to 0)
        Week 4
    -2.0 (-2 to 0)
        Week 6
    -1.0 (-3 to 0)
        Week 8
    -0.5 (-3 to 1)
        Week 10
    -1.5 (-3 to 0)
        Week 12
    -0.5 (-5 to 0)
    No statistical analyses for this end point

    Secondary: Assessment of quality of life (QoL) using the Short Form Health Survey 36 (SF-36) questionnaire

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    End point title
    		 Assessment of quality of life (QoL) using the Short Form Health Survey 36 (SF-36) questionnaire
    End point description
    Quality of life was assessed using the SF-36 questionnaire. Changes from Baseline at Week 12 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: 37.50 (0.0 - 85.0) Limitations in role activities due to problems in physical health: 12.50 (0.0 - 100.0) Bodily pain: 41.00 (21.0 - 100.0) General health: 48.50 (30.0 - 82.0) Vitality (fatigue and energy): 45.00 (25.0 - 100.0) Limitations in social functioning due to physical or emotional problems: 75.00 (50.0 - 100.0) Limitations in usual role due to emotional problems: 66.65 (0.0 - 100.0) Mental health (depressed or happy): 72.00 (44.0 - 92.0) Health transition: 2.50 (1.0 - 4.0)
    End point type
    Secondary
    End point timeframe
    Day 0 to Week 12
    End point values
    		 Full analysis set
    Number of subjects analysed
    6 [5]
    Units: Subscale - change from Baseline
    median (full range (min-max))
        Limitations in physical functioning
    -5.00 (-31.4 to 90.0)
        Limit. in role act. due to probl. in phys. health
    0.00 (-25.0 to 0.0)
        Bodily pain
    5.50 (-20.0 to 39.0)
        General health
    0.00 (-17.0 to 25.0)
        Vitality (fatigue and energy)
    -4.15 (-11.7 to 0.0)
        Limit. in soc. funct. due to phys. or emot. probl.
    -12.50 (-50.0 to 12.5)
        Limit. in usual role due to emotional problems
    -33.35 (-100.0 to 0.0)
        Mental health (depressed or happy)
    -14.00 (-37.0 to 4.0)
        Health transition
    -0.50 (-1.0 to 1.0)
    Notes
    [5] - The change from Baseline of "Limitations in physical functioning" was reported for 5 patients.
    No statistical analyses for this end point

    Secondary: Assessment of dermatology-specific quality of life based on the Dermatology Life Quality Index (DLQI) questionnaire

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    End point title
    		 Assessment of dermatology-specific quality of life based on the Dermatology Life Quality Index (DLQI) questionnaire
    End point description
    The dermatology-specific QoL was assessed based on the DLQI questionnaire. 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 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 (full range) dermatology-specific quality of life summary score was 3.5 (1 - 7).
    End point type
    Secondary
    End point timeframe
    Day 0 to Week 12
    End point values
    		 Full analysis set
    Number of subjects analysed
    6 [6]
    Units: Summary score (change from Baseline)
    median (full range (min-max))
        Week 4
    0.0 (-6 to 9)
        Week 8
    2.5 (-1 to 9)
        Week 12
    0.5 (-4 to 11)
    Notes
    [6] - Analysis at Week 4 and Week 12 included 4 patients.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs that occurred after the patient provided informed consent until the safety follow-up (Month 12) were reported. AEs were followed up until they were resolved, stabilized, or assessed to be chronic. The final status was obtained at safety follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    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
    3 / 9 (33.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastric haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 9 (11.11%)
         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
    		 Safety analysis set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 9 (88.89%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Skin injury
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    4
    Influenza like illness
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Gastrointestinal disorders
    Gastric haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Hiatus hernia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Pancreatitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Decubitus ulcer
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Ingrowing nail
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Skin irritation
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Skin ulcer
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Back pain
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    3
    Soft tissue infection
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 9 (11.11%)
         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
    08 Jun 2016
    The first patients were enrolled under trial protocol version 3.0. The main changes in the trial protocol Version 3.0 compared to Version 2.0 were: - Inclusion criterion 5 was changed from "Patients suffering from 2 ulcers at the same extremity, as long as these ulcers are separated by a minimum bridge of 1 cm of epithelialized skin" to "Patients suffering from 2 or more ulcers at the same extremity, as long as these ulcers are separated by a minimum bridge of 1 cm of epithelialized skin". - Exclusion criterion 3 was changed from "Diabetes mellitus that has to be evaluated by blood test (Hemoglobin A1c [HbA1c] 6.5 – 7.5%)" to "Diabetes mellitus that has to be evaluated by blood test (Hemoglobin A1c [HbA1c] >7.5%);". - Formation of granulation tissue was to be assessed after debridement instead of before debridement. - Sample size calculation (section 15.1): "To be able to still determine that the product has sufficient activity to warrant more extensive study and development, sample size calculation was performed based on responders using the optimal two stage design" was changed to "To be able to still determine that the product has sufficient activity to warrant more extensive study and development, sample size calculation was performed based on responders using the Minimax two stage design according to R. Simon".
    11 Nov 2016
    The main changes in the trial protocol Version 4.0 compared to Version 3.0 were: - Two subchapters “General exclusion criteria” and “Exclusion criteria for efficacy assessments” were included. - The former exclusion criterion 9, i.e. “A wound size enlargement of more than 25% between the wound assessment at the screening visit and the wound assessment at Visit 5” and the exclusion criterion 8, i.e. “A wound size reduction of more than 50% between the wound assessment at the screening visit and wound assessment at Visit 5” were listed as “Exclusion criteria for efficacy assessments”. - Procedures to ensure sufficient IMP supply for patients with wound size enlargement of more than 25% were specified. - The biopsy period was extended from “6 to 12 weeks” to “6 to 20 weeks”. - The general exclusion criterion 8 was included specifying that the wound size must be at least 1.5 cm² at Visit 5. - The time window for Visit 7 was extended from “Day 3” to “Day 1 to 3”. - It was clarified that in case of multiple CVU wounds the target wound for IMP administration was to be selected only at Visit 5. - The clinical trial duration was extended. - “Screening” was replaced by “screening period” in the flow chart and the schedule of assessments. - The last protocol version with the change history is provided in Appendix 16.1.1.

    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.
    No control arm was implemented in this clinical trial, but the trial demonstrated that one dose of topically administered APZ2 on CVUs was overall safe and well tolerated. The trial was prematurely discontinued due to the COVID-19 pandemic.
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    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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