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    Clinical Trial Results:
    An interventional, multicenter, single arm, phase I/IIa clinical trial to investigate the efficacy and safety of allo-APZ2-EB on epidermolysis bullosa (EB)

    Summary
    EudraCT number
    		 2018-001009-98
    Trial protocol
    		 DE   AT   GB   FR   IT  
    Global end of trial date
    26 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2022
    First version publication date
    07 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    allo-APZ2-EB-II-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03529877
    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
    22 Feb 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2021
    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 overall improvement of EB symptoms measured by epidermolysis bullosa disease activity and scarring index [EBDASI] score and instrument for scoring clinical outcome of research for epidermolysis bullosa [iscorEB], wound healing assessed by photo documentation, change in pain and itch perception and subjects quality of life in EB [QOLEB] assessment) and safety (by monitoring adverse events [AEs]) of the investigational medicinal product (IMP) allo-APZ2-EB administered intravenously to subjects with EB in three applications (Day 0, Day 17 ±3, Day 35 ±3).
    Protection of trial subjects
    For safety reasons to rule out an autoimmune response, subjects tested positive for antibodies against basement membrane proteins on salt-split skin were excluded from clinical trial participation. To ensure the subjects' safety and to investigate possible transient effects, subjects were monitored during the treatment and efficacy period up to Week 12. The long-term safety was assessed at Month 12 in all countries involved and was additionally assessed at Month 24 in France and the UK. Emergency medications for management of anaphylaxis were available and clinical monitoring was to be done for the full duration of the infusion visit with a post-dosing in-clinic observation period of at least 2 hours. The subject was to be clinically stable before being discharged. A Data Monitoring Committee (DMC) was established to assess the safety and tolerability of the IMP before opening the clinical trial for the next cohort and younger subjects. Subjects were enrolled in a staggered design in age cohorts (Cohort 1: adult subjects [≥18 to ≤55 years]; Cohort 2: subjects aged ≥12 to <18 years; Cohort 3: subjects aged ≥5 to <12 years; Cohort 4: subjects aged ≥12 months to <5 years; Cohort 5: subjects aged 0 to <12 months, only in the UK) of at least 3 subjects, starting with the successive enrollment of 3 subjects ≥18 years. The second and third adult subject were only to be enrolled if the safety and tolerability of the first allo-APZ2-EB administration in the previous subject was acceptable. After the last of the 3 initially treated adult subjects was followed up for 2 weeks after his/her third IMP application, the safety of the IMP was to be assessed by a DMC before opening the clinical trial for younger subjects to minimize the burden and risk in minors. Subjects were to be enrolled only in Cohorts 2, 3, 4 and 5 if the precedent cohort was approved by the DMC (2 weeks after first treatment [in France after third treatment] of third subject).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Feb 2019
    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
    Austria: 2
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 4
    Worldwide total number of subjects
    16
    EEA total number of subjects
    8
    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)
    5
    Adolescents (12-17 years)
    4
    Adults (18-64 years)
    7
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects aged 0 to 55 years with RDEB (diagnosed by genotype assessment [mutation analysis] and phenotype assessment [wound assessment]) and without antibodies against basement membrane proteins on salt-split skin were screened in Europe, UK and USA. First subject signed informed consent form on 07-Feb-2019 and last subject on 09-Feb-2020.

    Pre-assignment
    Screening details
    		 18 subjects signed the informed consent form. 2 subjects were screening failures and not treated with IMP. 7 subjects were enrolled in Cohort 1 (adults), each 4 subjects in Cohorts 2 (≥12 to <18 years) and 3 (≥5 to <12 years), and 1 subject in Cohort 4 (≥12 months to <5 years).

    Period 1
    Period 1 title
    Treatment and 12-month follow-up
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1
    Arm description
    		 Subjects aged ≥18 to ≤55 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    allo-APZ2-EB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    allo-APZ2-EB at a dose of 2 x 10E6 allogeneic ABCB5-positive mesenchymal stem cells/kg was to be administered at Day 0, Day 17 ±3, and Day 35 ±3 by intravenous infusion using a syringe pump at a flow rate of 1-2 mL/min at the investigator's discretion and tube flushing was to be done with Ringer's lactate solution (volume/drop rate at discretion of the investigator). All subjects were to follow the same schedule.

    Arm title
    		 Cohort 2
    Arm description
    		 Subjects aged ≥12 to <18 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    allo-APZ2-EB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    allo-APZ2-EB at a dose of 2 x 10E6 allogeneic ABCB5-positive mesenchymal stem cells/kg was to be administered at Day 0, Day 17 ±3, and Day 35 ±3 by intravenous infusion using a syringe pump at a flow rate of 1-2 mL/min at the investigator's discretion and tube flushing was to be done with Ringer's lactate solution (volume/drop rate at discretion of the investigator). All subjects were to follow the same schedule.

    Arm title
    		 Cohort 3
    Arm description
    		 Subjects aged ≥5 to <12 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    allo-APZ2-EB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    allo-APZ2-EB at a dose of 2 x 10E6 allogeneic ABCB5-positive mesenchymal stem cells/kg was to be administered at Day 0, Day 17 ±3, and Day 35 ±3 by intravenous infusion using a syringe pump at a flow rate of 1-2 mL/min at the investigator's discretion and tube flushing was to be done with Ringer's lactate solution (volume/drop rate at discretion of the investigator). All subjects were to follow the same schedule.

    Arm title
    		 Cohort 4
    Arm description
    		 Subjects aged ≥12 months to <5 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    allo-APZ2-EB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    allo-APZ2-EB at a dose of 2 x 10E6 allogeneic ABCB5-positive mesenchymal stem cells/kg was to be administered at Day 0, Day 17 ±3, and Day 35 ±3 by intravenous infusion using a syringe pump at a flow rate of 1-2 mL/min at the investigator's discretion and tube flushing was to be done with Ringer's lactate solution (volume/drop rate at discretion of the investigator). All subjects were to follow the same schedule.

    Number of subjects in period 1
    		Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Started
    7
    4
    4
    1
    First IMP application received
    7
    4
    4
    1
    Second IMP application received
    7
    4
    4
    1
    Third IMP application received
    7
    3
    4
    0 [1]
    12-week efficacy follow-up
    7
    3
    4
    1
    Completed
    7
    3
    4
    1
    Not completed
    0
    1
    0
    0
         Physician decision
    -
    1
    -
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The patient in Cohort 4 received no third IMP application, but stayed in the trial and completed the 12-month follow-up.
    Period 2
    Period 2 title
    24-month safety follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1
    Arm description
    		 Subjects aged ≥18 to ≤55 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    allo-APZ2-EB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    allo-APZ2-EB at a dose of 2 x 10E6 allogeneic ABCB5-positive mesenchymal stem cells/kg was to be administered at Day 0, Day 17 ±3, and Day 35 ±3 by intravenous infusion using a syringe pump at a flow rate of 1-2 mL/min at the investigator's discretion and tube flushing was to be done with Ringer's lactate solution (volume/drop rate at discretion of the investigator). All subjects were to follow the same schedule.

    Arm title
    		 Cohort 2
    Arm description
    		 Subjects aged ≥12 to <18 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    allo-APZ2-EB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    allo-APZ2-EB at a dose of 2 x 10E6 allogeneic ABCB5-positive mesenchymal stem cells/kg was to be administered at Day 0, Day 17 ±3, and Day 35 ±3 by intravenous infusion using a syringe pump at a flow rate of 1-2 mL/min at the investigator's discretion and tube flushing was to be done with Ringer's lactate solution (volume/drop rate at discretion of the investigator). All subjects were to follow the same schedule.

    Arm title
    		 Cohort 3
    Arm description
    		 Subjects aged ≥5 to <12 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    allo-APZ2-EB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    allo-APZ2-EB at a dose of 2 x 10E6 allogeneic ABCB5-positive mesenchymal stem cells/kg was to be administered at Day 0, Day 17 ±3, and Day 35 ±3 by intravenous infusion using a syringe pump at a flow rate of 1-2 mL/min at the investigator's discretion and tube flushing was to be done with Ringer's lactate solution (volume/drop rate at discretion of the investigator). All subjects were to follow the same schedule.

    Number of subjects in period 2 [2]
    		Cohort 1 Cohort 2 Cohort 3
    Started
    4
    2
    1
    12-month safety follow-up
    4
    2
    1
    Completed
    3
    2
    1
    Not completed
    1
    0
    0
         Subject's decision
    1
    -
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One patient in Cohort 1 discontinued the trial prematurely after the 12-month follow-up by own decision and did not perform the 24-month follow-up visit.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Subjects aged ≥18 to ≤55 years.

    Reporting group title
    Cohort 2
    Reporting group description
    		 Subjects aged ≥12 to <18 years.

    Reporting group title
    Cohort 3
    Reporting group description
    		 Subjects aged ≥5 to <12 years.

    Reporting group title
    Cohort 4
    Reporting group description
    		 Subjects aged ≥12 months to <5 years.

    Reporting group values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Total
    Number of subjects
    		 7 4 4 1 16
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 25 (20 to 36) 13 (12 to 17) 8 (6 to 10) 4 (4 to 4) -
    Gender categorical
    Units: Subjects
        Female
    		 5 3 1 0 9
        Male
    		 2 1 3 1 7
    Race
    Units: Subjects
        Asian
    		 0 1 0 0 1
        Caucasian
    		 7 2 3 1 13
        Other
    		 0 1 1 0 2
    Body weight
    Units: kilogram(s)
        median (full range (min-max))
    		 41.0 (23.3 to 59.8) 29.2 (26.6 to 51.5) 20.3 (18.9 to 45.9) 15.0 (15.0 to 15.0) -
    Body mass index
    Units: kilogram(s)/square metre
        median (full range (min-max))
    		 17.6 (13.0 to 18.9) 15.2 (12.7 to 18.1) 12.7 (11.5 to 21.5) 14.7 (14.7 to 14.7) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Subjects aged ≥18 to ≤55 years.

    Reporting group title
    Cohort 2
    Reporting group description
    		 Subjects aged ≥12 to <18 years.

    Reporting group title
    Cohort 3
    Reporting group description
    		 Subjects aged ≥5 to <12 years.

    Reporting group title
    Cohort 4
    Reporting group description
    		 Subjects aged ≥12 months to <5 years.
    Reporting group title
    Cohort 1
    Reporting group description
    		 Subjects aged ≥18 to ≤55 years.

    Reporting group title
    Cohort 2
    Reporting group description
    		 Subjects aged ≥12 to <18 years.

    Reporting group title
    Cohort 3
    Reporting group description
    		 Subjects aged ≥5 to <12 years.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All enrolled subjects who received allo-APZ2-EB at least once.

    Subject analysis set title
    Per-protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All enrolled subjects who received allo-APZ2-EB at least once and had no major protocol deviation as defined at the data review meeting.

    Primary: Percentage change of EBDASI score at Week 12 (with LOCF)

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    End point title
    		 Percentage change of EBDASI score at Week 12 (with LOCF) [1]
    End point description
    The primary efficacy endpoint was the overall improvement of EB symptoms 12 weeks after first IMP application or at last available post-baseline measurement if the Week 12 measurement was missing (last observation carried forward [LOCF]), and was measured by percentage change of a subject's EBDASI score (overall score, activity score, and damage score) from Baseline (Day 0, pre-dose).
    End point type
    Primary
    End point timeframe
    From Baseline (Day 0, pre-dose) until the end of the 12-week efficacy follow-up (Week 12).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: In a post-hoc analysis, statistical hypothesis testing was performed in the FAS for the primary endpoint and the null hypothesis H0: median change = 0 using a Wilcoxon signed rank test. The following p-values, median values and 95% confidence intervals (lower; upper) were reported: - EBDASI overall score: p=0.0580; -3.4 (-9.4; 0.0)% - EBDASI activity score: p=0.0494; -13.0 (-30.0; -2.9)% - EBDASI damage score: p=0.2661; -0.7 (-6.9; 3.2)%
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Full analysis set Per-protocol set
    Number of subjects analysed
    7
    3 [2]
    4
    1 [3]
    15 [4]
    14
    Units: Percentage
    median (full range (min-max))
        Overall score
    -3.4 (-27.1 to 9.0)
    -9.4 (-12.2 to -6.2)
    -1.3 (-7.2 to 13.1)
    -3.1 (-3.1 to -3.1)
    -3.4 (-27.1 to 13.1)
    -4.8 (-27.1 to 13.1)
        Activity score
    -10.0 (-67.9 to 24.0)
    -31.4 (-34.8 to -9.1)
    -6.5 (-25.9 to 53.3)
    -21.4 (-21.4 to -21.4)
    -13.0 (-67.9 to 53.3)
    -11.5 (-67.9 to 53.3)
        Damage score
    -0.9 (-12.7 to 5.5)
    -5.5 (-7.3 to -0.7)
    1.6 (-3.2 to 3.8)
    2.0 (2.0 to 2.0)
    -0.7 (-12.7 to 5.5)
    -0.8 (-12.7 to 5.5)
    Notes
    [2] - 1 subject terminated the trial prematurely due to physician's decision, no post-baseline measurement
    [3] - Week 12 measurement was missing, LOCF method was applied and Day 17 data were used
    [4] - 1 subject terminated the trial prematurely due to physician's decision, no post-baseline measurement
    No statistical analyses for this end point

    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) in Austria, Germany and USA and until the end of 24-month follow-up (Month 24) in France and the UK.
    Adverse event reporting additional description
    Adverse event reporting ended in 1 subject before Week 12 because of premature trial termination due to physician's decision and in 1 subject in France at Month 12 because of premature trial termination due to subject's decision.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Subjects aged ≥18 to ≤55 years.

    Reporting group title
    Cohort 2
    Reporting group description
    		 Subjects aged ≥12 to <18 years.

    Reporting group title
    Cohort 3
    Reporting group description
    		 Subjects aged ≥5 to <12 years.

    Reporting group title
    Cohort 4
    Reporting group description
    		 Subjects aged ≥12 months to <5 years.

    Serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Precancerous skin lesion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin bacterial infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    4 / 4 (100.00%)
    3 / 4 (75.00%)
    0 / 1 (0.00%)
    Investigations
    Blood cholinesterase decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lip injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Neuralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Eye disorders
    Conjunctival bleb
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Corneal erosion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Dysphagia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lip blister
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    12
    0
    Oral mucosa erosion
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Oral mucosal blistering
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Dermal cyst
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Henoch-Schonlein purpura
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin erosion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pseudosyndactyly
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Beta haemolytic streptococcal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blister infected
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Conjunctivitis viral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear infection fungal
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin bacterial infection
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    1
    0
    0
    Skin candida
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Tooth abscess
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Wound infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Wound infection bacterial
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Mar 2020
    Subject recruitment was stopped due to the COVID-19 pandemic and related restritions. In addition, IMP production was halted due to impairments and failures in the logistics chain as a result of the COVID 19 pandemic.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34665781
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