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    Clinical Trial Results:
    Multinational, multicentre, prospective, open-label, uncontrolled clinical trial to assess the efficacy and safety of Autologous Cultivated Limbal Stem Cells Transplantation (ACLSCT) for restoration of corneal epithelium in patients with limbal stem cell deficiency due to ocular burns (HOLOCORE).

    Summary
    EudraCT number
    		 2014-002845-23
    Trial protocol
    		 DE   GB   BE   NL   FR   PL   ES   IT  
    Global end of trial date
    11 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 May 2023
    First version publication date
    07 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-GPLSCD01-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Holostem Terapie Avanzate s.r.l.
    Sponsor organisation address
    Via G. Gottardi, 100, Modena, Italy,
    Public contact
    Clinical Trial Department, Holostem Terapie Avanzate s.r.l., +39 059 2058064 , regulatory@holostem.com
    Scientific contact
    Graziella Pellegrini, Holostem Terapie Avanzate s.r.l., +39 059 2058064 , grzllpellegrini@gmail.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001082-PIP02-11
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of Holoclar at one year after the first treatment in patients suffering from moderate (vascularisation in two-three corneal quadrants with central corneal involvement) to severe (vascularisation in four corneal quadrants with central corneal involvement) Limbal Stem Cell Deficiency with severe visual impairment and secondary to ocular burns, in terms of percentage of patients with a success of transplantation at approximately 12 months from the first Holoclar treatment.
    Protection of trial subjects
    The study was performed in compliance with the ‘Declaration of Helsinki’ [1964, last update Fortaleza 2013 and following amendments], International Conference of Harmonization Tripartite Guidelines Guideline for Good Clinical Practice (ICH GCP), current international and national regulations, the study protocol and its amendments and current Standard Operating Procedures (SOPs) of the participating sites, the sponsor and the company in charge of monitoring.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Oct 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 17
    Worldwide total number of subjects
    80
    EEA total number of subjects
    72
    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)
    2
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    70
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were selected among patients suffering from moderate to severe LSCD secondary to physical or chemical ocular burns referred to the investigational sites.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Holoclar
    Arm description
    		 All patients who consented to participate received the study treatment unless they withdrew the consent or dropped-out before biopsy or treatment implantation. Each patient received the treatment prepared using her/his limbal stem cells collected from the healthy donor eye.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Holoclar
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Living tissue equivalent
    Routes of administration
    Implantation
    Dosage and administration details
    The study treatment consisted of a cell-based medicinal product: “ex vivo” expanded autologous human corneal epithelium containing stem cells. The treatment was administered according to the treatment protocol detailed in the product SmPC . Each product contained an individual treatment dose with sufficient number of cells seeded on a 2.2 cm diameter fibrin support to cover the entire corneal surface. The dose of Holoclar was 79,000 - 316,000 cells/cm², corresponding to 1 cm² of product/cm² of defect. Each preparation of Holoclar was intended as a single treatment. The treatment was repeated according to the physician’s prescription. In case of failure, upon Independent Assessors’ judgment, a second transplantation with Holoclar was offered within 2- 6 months from declaration of failure after first Holoclar implantation.

    Number of subjects in period 1
    		Holoclar
    Started
    80
    Completed
    49
    Not completed
    31
         Consent withdrawn by subject
    8
         Adverse event, non-fatal
    4
         Other
    10
         Contingency which do not allow grafting
    1
         Biopsy not adequate
    5
         Lost to follow-up
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    Reporting group values
    		 Overall Total
    Number of subjects
    		 80 80
    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)
    		 2 2
        Adolescents (12-17 years)
    		 2 2
        Adults (18-64 years)
    		 70 70
        From 65-84 years
    		 6 6
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.1 ± 16.2 -
    Gender categorical
    Units: Subjects
        Female
    		 13 13
        Male
    		 67 67

    End points

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    End points reporting groups
    Reporting group title
    Holoclar
    Reporting group description
    		 All patients who consented to participate received the study treatment unless they withdrew the consent or dropped-out before biopsy or treatment implantation. Each patient received the treatment prepared using her/his limbal stem cells collected from the healthy donor eye.

    Subject analysis set title
    Modified Intention-to-Treat population A (mITTa)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All adult patients who underwent the ACLSCT procedure.

    Subject analysis set title
    Modified Intention-to-Treat population B (mITTb)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All adult patients who underwent the ACLSCT procedure excluding patients treated with out of specification grafts (sub-potent batches).

    Primary: Successful transplantation at 12 months after first Holoclar treatment

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    End point title
    		 Successful transplantation at 12 months after first Holoclar treatment [1]
    End point description
    Incidence of success is calculated as the proportion of patients with less than 2 superficial neo-vascularization corneal quadrants, with no central corneal involvement by CNV and absence of epithelial defects (none or trace) at Day 360 ±14 days after first Holoclar treatment. CNV: Corneal Neo-Vascularisation
    End point type
    Primary
    End point timeframe
    At 12 months after first Holoclar treatment
    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: The statistical analysis is descriptive.
    End point values
    		 Modified Intention-to-Treat population A (mITTa) Modified Intention-to-Treat population B (mITTb)
    Number of subjects analysed
    69
    65
    Units: Successful transplantation Percentage
    number (confidence interval 95%)
        All patients
    36.2 (25 to 49)
    33.8 (23 to 47)
        Patients with Evaluable Results
    37.9 (26 to 51)
    35.5 (24 to 49)
        Patients (12M Visit + Evaluable results)
    41 (29 to 54)
    38.6 (26 to 52)
    No statistical analyses for this end point

    Other pre-specified: Superficial corneal neo-vascularisation

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    End point title
    		 Superficial corneal neo-vascularisation
    End point description
    The statistical analysis is descriptive.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Day 360 post-transplant
    End point values
    		 Modified Intention-to-Treat population A (mITTa)
    Number of subjects analysed
    69
    Units: Percentage of patients
    number (not applicable)
        4 corneal quadrants - Baseline
    78.3
        4 corneal quadrants - Day 360
    21.3
        3 corneal quadrants - Baseline
    20.3
        3 corneal quadrants - Day 360
    9.8
        Central corneal involvement - Baseline
    98.6
        Central corneal involvement - Day 360
    31.1
    No statistical analyses for this end point

    Other pre-specified: Shift in central corneal class

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    End point title
    		 Shift in central corneal class
    End point description
    The statistical analysis is descriptive.
    End point type
    Other pre-specified
    End point timeframe
    At 12 months after first Holoclar treatment
    End point values
    		 Modified Intention-to-Treat population A (mITTa)
    Number of subjects analysed
    69
    Units: Percentage of patients
    number (not applicable)
        Severe at Baseline
    78.1
        Severe at Day 360
    21.9
        Moderate at Baseline
    21.9
        Moderate at Day 360
    34.3
        Mild at Baseline
    0
        Mild at Day 360
    25
        None at Baseline
    0
        None at Day 360
    18.8
    No statistical analyses for this end point

    Other pre-specified: Ocular symptoms post-transplantation

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    End point title
    		 Ocular symptoms post-transplantation
    End point description
    The statistical analysis is descriptive.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Day 360 post-transplant
    End point values
    		 Modified Intention-to-Treat population A (mITTa)
    Number of subjects analysed
    69
    Units: Percentage of patients
    number (not applicable)
        One ocular symptom - Baseline
    87.0
        One ocular symptom - Day 360
    55.7
        Burning - Baseline
    47.8
        Burning - Day 360
    24.6
        Phtotophobia - Baseline
    73.9
        Phtotophobia - Day 360
    44.3
        Pain - Baseline
    40.6
        Pain - Day 360
    21.3
    No statistical analyses for this end point

    Other pre-specified: Conjunctival inflammation post-transplantation

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    End point title
    		 Conjunctival inflammation post-transplantation
    End point description
    The statistical analysis is descriptive.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Day 360 post-transplant
    End point values
    		 Modified Intention-to-Treat population A (mITTa)
    Number of subjects analysed
    69
    Units: Percentage of patients
    number (not applicable)
        Normal limbal hyperaemia - Baseline
    30.4
        Normal limbal hyperaemia - Day 360
    49.2
        Trace limbal hyperaemia - Baseline
    30.4
        Trace limbal hyperaemia - Day 360
    26.2
        Mild limbal hyperaemia - Baseline
    23.2
        Mild limbal hyperaemia - Day 360
    18.0
        Moderate limbal hyperaemia - Baseline
    15.9
        Moderate limbal hyperaemia - Day 360
    4.9
    No statistical analyses for this end point

    Other pre-specified: BCVA post-transplantation

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    End point title
    		 BCVA post-transplantation
    End point description
    BCVA: Best Corrected Visual Acuity The statistical analysis is descriptive.
    End point type
    Other pre-specified
    End point timeframe
    From the baseline to Day 360
    End point values
    		 Modified Intention-to-Treat population A (mITTa)
    Number of subjects analysed
    69
    Units: BCVA
    arithmetic mean (standard deviation)
        BCVA - Baseline
    1.94 ± 0.49
        BCVA - Day 90
    1.53 ± 0.76
        BCVA - Day 90 Change from baseline
    -0.39 ± 0.55
        BCVA - Day 180
    1.47 ± 0.83
        BCVA - Day 180 Change from baseline
    -0.45 ± 0.57
        BCVA - Day 270
    1.32 ± 0.91
        BCVA - Day 270 Change from baseline
    -0.62 ± 0.69
        BCVA - Day 360
    1.30 ± 0.91
        BCVA - Day 360 Change from baseline
    -0.63 ± 0.70
    No statistical analyses for this end point

    Other pre-specified: BCVA improvement post-transplantation vs stromal scarring

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    End point title
    		 BCVA improvement post-transplantation vs stromal scarring
    End point description
    BCVA: Best Corrected Visual Acuity The statistical analysis is descriptive.
    End point type
    Other pre-specified
    End point timeframe
    At 12 months after first Holoclar treatment
    End point values
    		 Modified Intention-to-Treat population A (mITTa)
    Number of subjects analysed
    69
    Units: Percentage patients
    number (not applicable)
        Patients with stromal scarring - Day 29
    32.7
        Patients with stromal scarring - Day 360
    57.8
        Patients without stromal scarring - Day 29
    50.0
        Patients without stromal scarring - Day 360
    100.0
    No statistical analyses for this end point

    Other pre-specified: Corneal/conjunctival sensitivity and corneal opacity post-transplantation

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    End point title
    		 Corneal/conjunctival sensitivity and corneal opacity post-transplantation
    End point description
    The statistical analysis is descriptive.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to Day 360
    End point values
    		 Modified Intention-to-Treat population A (mITTa)
    Number of subjects analysed
    69
    Units: Percentage of patients
    number (not applicable)
        Normal corneal sensitivity - Baseline
    37.7
        Normal corneal sensitivity - Day 360
    44.3
        Corneal hypoesthesia - Baseline
    62.3
        Corneal hypoesthesia - Day 360
    45.9
        Corneal opacity - Baseline
    100
        Corneal opacity - Day 360
    95.1
        Corneal anesthesia - Baseline
    4.3
        Corneal anesthesia - Day 360
    9.8
    No statistical analyses for this end point

    Other pre-specified: Change in NEI VFQ-25 score

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    End point title
    		 Change in NEI VFQ-25 score
    End point description
    The National Eye Institute 25-Item Visual Function Questionnaire questionnaire (NEI VFQ) measured the dimensions of self-reported vision-targeted health status that were most important for people who had chronic eye diseases. It consisted of a base set of 25 vision targeted questions representing 11 vision-related constructs as follows: global vision rating, difficulty with near vision activities, difficulty with distance vision activities, limitations in social functioning due to vision, role limitations due to vision, dependency on others due to vision, mental health symptoms due to vision, driving difficulties, limitations with peripheral and colour vision, and ocular pain. Additionally, the VFQ-25 contained the single general health rating question which had been shown to be a robust predictor of future health and mortality in population-based studies The statistical analysis is descriptive.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline to Day 360
    End point values
    		 Modified Intention-to-Treat population A (mITTa)
    Number of subjects analysed
    69
    Units: Composite score
    arithmetic mean (standard deviation)
        Composite score - Baseline
    70.1 ± 17.9
        Composite score - Day 360
    78.3 ± 15.3
    No statistical analyses for this end point

    Other pre-specified: Success of transplantation as judged by Site Investigator

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    End point title
    		 Success of transplantation as judged by Site Investigator
    End point description
    The statistical analysis is descriptive.
    End point type
    Other pre-specified
    End point timeframe
    At 12 months after first Holoclar treatment
    End point values
    		 Modified Intention-to-Treat population A (mITTa)
    Number of subjects analysed
    69
    Units: Percentage of patients
    number (not applicable)
        Successful overall outcome
    77.0
    No statistical analyses for this end point

    Other pre-specified: Success of transplantation and LSCD as per Global Consensus guidelines

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    End point title
    		 Success of transplantation and LSCD as per Global Consensus guidelines
    End point description
    LSCD: Limbal Stem Cells Deficiency SoT: Success of transplantation The statistical analysis is descriptive.
    End point type
    Other pre-specified
    End point timeframe
    At 12 months after first Holoclar treatment
    End point values
    		 Modified Intention-to-Treat population A (mITTa)
    Number of subjects analysed
    69
    Units: Percentage of patients
    number (not applicable)
        SoT - All patients
    42.0
        SoT - Patients (12M Visit + Evaluable results)
    50.9
        Improvement in LSCD staging
    60.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From pre-treatment phase to the end of the trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Adults
    Reporting group description
    		 -

    Reporting group title
    Paediatric
    Reporting group description
    		 -

    Serious adverse events
    		 Adults Paediatric
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 76 (15.79%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Eye operation complication
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Corneal epithelium defect
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal perforation
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal thinning
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye pain
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Adults Paediatric
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 76 (57.89%)
    2 / 4 (50.00%)
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Injury, poisoning and procedural complications
    Eye operation complication
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Suture related complication
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    11 / 76 (14.47%)
    0 / 4 (0.00%)
         occurrences all number
    14
    0
    Corneal epithelium defect
         subjects affected / exposed
    8 / 76 (10.53%)
    0 / 4 (0.00%)
         occurrences all number
    14
    0
    Dry eye
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    Ulcerative keratitis
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Blepharitis
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Cataract
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Corneal erosion
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Corneal thinning
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Eye irritation
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Photophobia
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Chalazion
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Corneal disorder
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Eye discharge
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Lacrimation increased
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Conjunctivitis
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Pharyngitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2016
    General Substantial #1 Included exhaustive descriptions of few study procedures not detailed in previous version, specifications of side effects and deepening of treatment risk/benefit assessment.
    31 Jan 2017
    General Substantial #2 Included deletion of an invasive assessment (impression cytology), change of IC#4 for minors (the stability of Limbal Stem Cell Deficiency (LSCD) was reduced to 12 months) and re-arrangement along the study of few assessments for efficacy evaluation (QoL questionnaires removed at V11 and opacity assessment was introduced at Visit 6 after removal of the pannus) and specification of sup-potent batches release for the so called “Last chance patient”. Moreover, the involvement of the Third Independent Assessor was included as was the exclusion of some concomitant treatment during the study.
    05 Jun 2020
    General Substantial #3 Clinical trial sponsorship and Holoclar MAH transfer from Chiesi Farmaceutici S.p.A. to Holostem Terapie Avanzate S.r.l.
    30 Sep 2020
    General Substantial #4 Included swab SARS-CoV-2 (PCR) tests due to COVID pandemic

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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