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    Clinical Trial Results:
    A RANDOMISED, PLACEBO-CONTROLLED, DOUBLE-BLIND, INTERVENTIONAL, MULTICENTER, PHASE I/IIA CLINICAL TRIAL TO INVESTIGATE THE EFFICACY AND SAFETY OF ALLO-APZ2-PAOD FOR THE TREATMENT OF PERIPHERAL ARTERIAL OCCLUSIVE DISEASE (PAOD)

    Summary
    EudraCT number
    2017-000235-14
    Trial protocol
    DE   GB   CZ   AT   PL  
    Global end of trial date
    15 May 2020

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

    Trial information

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    Trial identification
    Sponsor protocol code
    allo-APZ2-PAOD-II-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03339973
    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
    31 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The aim of this clinical trial is to investigate the efficacy (by monitoring the wound size reduction of PAOD-related clinically relevant ulcers) and safety (by monitoring adverse events) of one dose of allo-APZ2-PAOD administered intramuscularly into an affected lower leg of subjects with PAOD.
    Protection of trial subjects
    Optional wound debridement and clearance of necrotic tissue at relevant ulcers was performed and the subject was treated with local anesthetic cream (e.g., Lidocain/Prilocain) if necessary, before the investigational product (IMP) was injected. Local anesthetics intravenously or strong analgesics, e.g., Piritramide (Dipidolor®) were to be given at subject's request or in case of severe pain. After application of the IMP (last injection), the subject was requested to stay in the hospital for 2 hours. If strong analgesics were used, safety monitoring may be extended at the discretion of the investigator. The first 3 subjects were treated at least 2 weeks apart. The Medical Monitor continuously reviewed the safety data and requested assistance from the Independent Data Monitoring Committee (IDMC) as needed. In addition, safety data were reviewed monthly by the IDMC, and a recommendation was made to the sponsor and investigator as to whether administration to patients could be continued or the trial should be discontinued. After 10 subjects completed Week 2, the treatment was temporarily interrupted for a safety analysis by the IDMC. Because of premature termination of the trial due to insufficient patient recruitment, the planned second safety analysis by the IDMC was not performed after 30 subjects completed Week 2.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Mar 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    Germany: 19
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    5
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Male and female subjects aged 45 to 85 years (to 75 years only in Czech Republic) with PAOD (Rutherford category 5) in at least one lower extremity were recruited in 9 centers in Germany and 1 center each in the Czech Republic and Austria. The first subject signed the informed consent form on 05-Mar-2018 and the last subject on 10-Mar-2020.

    Pre-assignment
    Screening details
    24 subjects signed the informed consent. 10 subjects were screening failures and not treated with IMP. 7 subjects each were randomized to allo-APZ2-PAOD treatment (7.5 x 10E6 cells per injection site) or to placebo treatment. 2 subjects randomized to allo-APZ2-PAOD were not treated because of an AE or an other reason of premature discontinuation.

    Period 1
    Period 1 title
    12-week follow-up
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    allo-APZ2-PAOD
    Arm description
    Subjects received 1 dose of allo-APZ2-PAOD per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    allo-APZ2-PAOD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 1 dose of allo-APZ2-PAOD per injection site intramuscularly into the lower leg. allo-APZ2-PAOD contains 7.5 x 10E6 allogeneic skin-derived ABCB5-positive mesenchymal stem cells isolated from skin tissue of healthy donors in 750 µL Human Serum Albumin/Ringer-Lactate/Glucose solution. The used cell amount depended on the number of injection sites (N=20-30), which depended on length of the lower leg. Injection sites were to be started about 6-9 cm below the popliteal space. 3 injections were placed in 1 row horizontally along the vessel axes of the posterior tibial artery, anterior tibial artery and fibular artery. Next horizontal row was 3 cm distal to the last one. In the distal last third of the lower leg only 2 injections were placed in 1 row, 1 on the inner and 1 on the outer leg side, with a row distances of 3 cm. Optional wound debridement and clearance of necrotic tissue at relevant ulcers was performed and the subject was treated with local anesthetic before.

    Arm title
    Placebo
    Arm description
    Subjects received 1 dose of placebo per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 1 dose of placebo (750 µL Human Serum Albumin/Ringer-Lactate/Glucose solution) per injection site intramuscularly into the lower leg. The number of injection sites (N=20-30) depended on the length of the lower leg. Injection sites were to be started about 6-9 cm below the popliteal space. 3 injections were placed in 1 row horizontally along the vessel axes of the posterior tibial artery, anterior tibial artery and fibular artery. Next horizontal row was 3 cm distal to the last one. In the distal last third of the lower leg only 2 injections were placed in 1 row, 1 on the inner and 1 on the outer leg side, with a row distances of 3 cm. Optional wound debridement and clearance of necrotic tissue at relevant ulcers was performed and the subject was treated with local anesthetic before.

    Number of subjects in period 1 [1]
    allo-APZ2-PAOD Placebo
    Started
    5
    7
    Completed
    5
    7
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Twenty-four patients signed the informed consent. Ten patients were defined as screening failures and not treated with IMP. Two patients were randomized to allo-APZ2-PAOD but not treated: 1 patient had an AE and 1 patient discontinued the trial before treatment by other reason. Twelve patients were included in the full- and the safety-anlysis set for final analysis after early clinical trial termination.
    Period 2
    Period 2 title
    12-month safety follow-up
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    allo-APZ2-PAOD
    Arm description
    Subjects received 1 dose of allo-APZ2-PAOD per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for safety for 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    allo-APZ2-PAOD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 1 dose of allo-APZ2-PAOD per injection site intramuscularly into the lower leg. allo-APZ2-PAOD contains 7.5 x 10E6 allogeneic skin-derived ABCB5-positive mesenchymal stem cells isolated from skin tissue of healthy donors in 750 µL Human Serum Albumin/Ringer-Lactate/Glucose solution. The used cell amount depended on the number of injection sites (N=20-30), which depended on length of the lower leg. Injection sites were to be started about 6-9 cm below the popliteal space. 3 injections were placed in 1 row horizontally along the vessel axes of the posterior tibial artery, anterior tibial artery and fibular artery. Next horizontal row was 3 cm distal to the last one. In the distal last third of the lower leg only 2 injections were placed in 1 row, 1 on the inner and 1 on the outer leg side, with a row distances of 3 cm. Optional wound debridement and clearance of necrotic tissue at relevant ulcers was performed and the subject was treated with local anesthetic before.

    Arm title
    Placebo
    Arm description
    Subjects received 1 dose of placebo per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for safety for 12 months.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 1 dose of placebo (750 µL Human Serum Albumin/Ringer-Lactate/Glucose solution) per injection site intramuscularly into the lower leg. The number of injection sites (N=20-30) depended on the length of the lower leg. Injection sites were to be started about 6-9 cm below the popliteal space. 3 injections were placed in 1 row horizontally along the vessel axes of the posterior tibial artery, anterior tibial artery and fibular artery. Next horizontal row was 3 cm distal to the last one. In the distal last third of the lower leg only 2 injections were placed in 1 row, 1 on the inner and 1 on the outer leg side, with a row distances of 3 cm. Optional wound debridement and clearance of necrotic tissue at relevant ulcers was performed and the subject was treated with local anesthetic before.

    Number of subjects in period 2
    allo-APZ2-PAOD Placebo
    Started
    5
    7
    Completed
    2
    4
    Not completed
    3
    3
         Adverse event, serious fatal
    1
    1
         Early trial termination by sponsor
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    allo-APZ2-PAOD
    Reporting group description
    Subjects received 1 dose of allo-APZ2-PAOD per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received 1 dose of placebo per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks.

    Reporting group values
    allo-APZ2-PAOD Placebo Total
    Number of subjects
    5 7 12
    Age categorical
    Units: Subjects
        Adults (45-85 years)
    5 7 12
    Age continuous
    Units: years
        median (full range (min-max))
    63 (55 to 76) 74 (66 to 80) -
    Gender categorical
    Units: Subjects
        Female
    0 2 2
        Male
    5 5 10

    End points

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    End points reporting groups
    Reporting group title
    allo-APZ2-PAOD
    Reporting group description
    Subjects received 1 dose of allo-APZ2-PAOD per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received 1 dose of placebo per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for efficacy for 12 weeks.
    Reporting group title
    allo-APZ2-PAOD
    Reporting group description
    Subjects received 1 dose of allo-APZ2-PAOD per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for safety for 12 months.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received 1 dose of placebo per injection site (N=20-30) intramuscularly into the lower leg along the vessel axes at Day 0 and were followed up for safety for 12 months.

    Primary: Percent change in total wound size from Baseline at Week 12

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    End point title
    Percent change in total wound size from Baseline at Week 12
    End point description
    The primary efficacy endpoint was the percent change from Baseline to Week 12 in total wound size of the target leg. The total wound size of the target leg was calculated as sum of the wound sizes of all relevant ulcers of the target leg. The last observation carried forward (LOCF) approach was applied for 1 patient in the allo-APZ2-PAOD group. The measurement at Week 12 was missing, therefore the last available post-baseline measurement (in this case the value at Week 2) was used for the primary endpoint analysis.
    End point type
    Primary
    End point timeframe
    From Baseline (Day 0, pre-dose) until the end of 12-week follow-up (Week 12).
    End point values
    allo-APZ2-PAOD Placebo
    Number of subjects analysed
    5 [1]
    7 [2]
    Units: Percentage
    median (full range (min-max))
        All
    -38.40 (-82.5 to 141.6)
    -49.80 (-100.0 to 59.9)
        Diabetics
    -3.65 (-49.7 to 141.6)
    -46.55 (-88.5 to 59.9)
        Non-diabetics
    -82.5 (-82.5 to -82.5)
    -49.80 (-100.0 to 13.4)
    Notes
    [1] - Diabetics are N=4 and non-diabetics are N=1.
    [2] - Diabetis are N=4 and non-diabetics are N=3.
    Statistical analysis title
    Change in total wound size from Baseline (t-test)
    Statistical analysis description
    The 95% confidence interval for the mean change of total wound size from Baseline (pre-dose) at Week 12 was calculated. LOCF for missing data was applied. The primary efficacy endpoint was analyzed with a t-test with treatment as independent variable. The significance level was 0.05 (2-sided). Stratification by diabetes was not possible because the diabetic stratum sizes were too small (e.g., less than 3 subjects within the stratum). The data were previously tested for normal distribution.
    Comparison groups
    allo-APZ2-PAOD v Placebo
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.4036
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    37.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -57.99
         upper limit
    132.57
    Variability estimate
    Standard deviation
    Dispersion value
    73.03
    Notes
    [3] - The primary efficacy variable was subjected to confirmatory statistical analysis in a two-stage group sequential study design. The primary null hypothesis to be tested was H0: µallo-APZ2-PAOD = µPlacebo vs H1: µallo-APZ2-PAOD ≠ µPlacebo where µ is the mean percent change from Baseline to Week 12 in total wound size of the target leg.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From administration of the IMP until the end of 12-month follow-up (Month 12).
    Adverse event reporting additional description
    In 4 subjects (2 per treatment group), adverse event reporting ended before Month 12 due to early trial termination by the Sponsor. Two subjects died (1 per treatment group) before Month 12.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.01
    Reporting groups
    Reporting group title
    allo-APZ2-PAOD
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    allo-APZ2-PAOD Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 5 (80.00%)
    5 / 7 (71.43%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract stoma complication
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Dry gangrene
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Tremor
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint destruction
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gangrene
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 7 (42.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    allo-APZ2-PAOD Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 5 (60.00%)
    6 / 7 (85.71%)
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Ureteric injury
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Vascular injury
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    3
    Vascular disorders
    Dry gangrene
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Extremity necrosis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Dysaesthesia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Muscle contractions involuntary
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    2
    Impaired healing
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Injection site haematoma
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    Pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Skin ulcer
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Infected skin ulcer
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    4
    Influenza
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Localised infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Apr 2018
    Protocol v5.0 with the following changes to v4.0: - Inclusion criterion 3 was specified in more detail; inclusion criterion 4 was changed (maximum wound size of 20 cm² instead of 10 cm²), wording of inclusion criterion 9 was changed (from “Patients with hypertension, if they are treated…” to “If patients are hypertensive, they have to be treated…”) - Exclusion criterion 6 was changed (from “…with bone exposure” to “…with exposure of destructive bone lesion”), exclusion criterion 7 was split into 2 criteria and specifying details were added; the numbering of subsequent exclusion criteria was changed accordingly - The option to use intravenous injections of strong analgesics upon subject request and longer safety observation time in case of strong analgesics use at the discretion of the investigator was added - The use of vitamin K and direct oral anticoagulants as concomitant medications was specified in more detail - The visit window for screening was changed (from “14 days to 7 days before treatment” to “21 days to 7 days before treatment”).
    19 Apr 2018
    Protocol v6.0 with the following changes to v5.0: - Exclusion criterion 6 was rephrased (from “… with ulcers with exposure of destructive bone lesions” to “…with osteomyelitis at ulceration”).
    27 Aug 2018
    Protocol v7.0 with the following changes to v6.0: - The trial was changed from a national (Germany) to an international trial with additional sites in the United Kingdom, Austria, Czech Republic, and Poland - Inclusion criterion 3 was changed to allow angiography results not older than 6 months (formerly 3 months) - The safety observation time after IMP injection was specified to be at least 2 hours; accordingly, vital signs were to be assessed the earliest 2 hours after the IMP administration - Unblinding via randomization envelopes was changed to unblinding via the electronic case report form system.
    07 Feb 2019
    Protocol v8.0 with the following changes to v7.0: - The specification that no minimal number of subjects with diabetes or without diabetes was added - Inclusion criterion 7 was changed (from “No evidence of change of wound size of more than 25% for at least 6 weeks before screening” to “No evidence of wound healing after standard of care treatment for at least 1 week before screening”) - Exclusion criterion 1, the origin of skin lesions was rephrased (from “mixed anterior-venous” to “leading venous”) - Exclusion criterion 9 was changed to include subjects with surgical/interventional reconstruction more than 1 week before screening or with not successful revascularization - Exclusion criterion 10 was changed to include subjects with major amputations of lower extremities within 12 months before screening - Exclusion criterion 22 was changed to allow previous use of glucocorticoid-medication above the cushing threshold dose. Medications that might influence wound healing, hyperbaric oxygen therapy, spinal cord stimulation and sympathectomy, as well as vasoactive substances other than the test drug, haemodilution or rheological therapy were not allowed from screening until Week 12 - Octenisept for wound care was only to be used in subjects without a history of allergic reactions to the product - The visit window for screening was changed (from “21 days to 7 days before treatment” to “21 days to 2 days before treatment”) - The examination of injection sites was added for Visits 2-9 - Relationship assessment of adverse events to the procedure was added - Suspected unexpected serious adverse reaction reporting was expanded from German legislation to include applicable European and other applicable national regulatory requirements.
    05 Apr 2019
    In Czech Republic, subjects were studied on protocol version CZE 3.0, dated 05-Apr-2019, which corresponds to Version 8.0, dated 07-Feb-2019, except that only subjects aged 45 to 75 years were to be included.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Mar 2020
    Subject recruitment was interrupted due to the COVID-19 pandemic. The sponsor of the trial decided to terminate the clinical trial early due to insufficient subject recruitment, which was not only due to the COVID-19 pandemic. The clinical trial termination was submitted to responsible ethics committees and authorities on 15-May-2020.
    -

    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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