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    Clinical Trial Results:
    Multinational, multicenter, prospective, long-term safety and efficacy follow-up study after Autologous Cultivated Limbal Stem Cells Transplantation (ACLSCT) for restoration of corneal epithelium in patients with limbal stem cell deficiency due to ocular burns (HOLOCORE-FU)

    Summary
    EudraCT number
    		 2015-001344-11
    Trial protocol
    		 BE   PL   FR   DE   GB   ES   NL   IT  
    Global end of trial date
    31 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Apr 2024
    First version publication date
    16 Apr 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-GPLSCD01-03-FU
    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, 41125
    Public contact
    Clinical Trial Department, Holostem Terapie Avanzate s.r.l., 39 0592058064, regulatory@holostem.com
    Scientific contact
    Graziella Pellegrini, Holostem Terapie Avanzate s.r.l., 39 0592058064, grzllpellegrini@gmail.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 Oct 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the long-term safety of one or two autologous cultivated limbal stem cells transplantation (ACLSCTs) with Holoclar in patients suffering from moderate to severe limbal stem cell deficiency (LSCD) secondary to ocular burns.
    Protection of trial subjects
    The study was conducted in compliance with the Declaration of Helsinki (1964, last update Fortaleza 2013 and following amendments), ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice and all other applicable local laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Dec 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    47
    EEA total number of subjects
    46
    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)
    1
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    40
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were selected among patients (adults and paediatrics) who completed the HOLOCORE core study and who consented to roll over to the present extension study at the end of the HOLOCORE follow-up.

    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 (Safety population)
    Arm description
    		 All patients treated in the HOLOCORE clinical trial who consented to roll over to the present extension study at the end of the HOLOCORE were observed for a follow-up period which varied from a minimum of 12 months for the last patient to a maximum of 57 months for the first patient entered.
    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
    No by-protocol treatment was planned for this long-term follow-up study. During the HOLOCORE follow-up study, patients underwent study visits every 6 months and at the time of study closure. The study treatment was administered during the HOLOCORE study and consisted of a cell-based medicinal product: “ex vivo” expanded autologous human corneal epithelium containing stem cells. 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.

    Number of subjects in period 1
    		Holoclar (Safety population)
    Started
    47
    Completed
    44
    Not completed
    3
         Death
    1
         Other
    1
         Lost to follow-up
    1

    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
    		 47 47
    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)
    		 1 1
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 40 40
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.4 ( 16.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 39 39

    End points

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    End points reporting groups
    Reporting group title
    Holoclar (Safety population)
    Reporting group description
    		 All patients treated in the HOLOCORE clinical trial who consented to roll over to the present extension study at the end of the HOLOCORE were observed for a follow-up period which varied from a minimum of 12 months for the last patient to a maximum of 57 months for the first patient entered.

    Subject analysis set title
    Keratoplasty Adult Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Keratoplasty Adult Safety Population comprises adult patients as described above who participated in the Holocore Follow-up study and underwent keratoplasty surgery at least 12 months after Holoclar implantation.

    Subject analysis set title
    Adult Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Adult Safety Population comprises all patients who were ≥18 years of age at the time of enrolment in the Holocore Main study and subsequently participated in the Follow-Up study.

    Primary: Summary of Treatment-Emergent Adverse Events

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    End point title
    		 Summary of Treatment-Emergent Adverse Events [1]
    End point description
    According to the primary aim of this follow-up extension study, which is the evaluation of patients’ long-term safety. Please note that in this section we are presenting just the overview of the adverse events experienced by the trial participants. Please refer to the detailed tables included on the Adverse Event Module for specifics.
    End point type
    Primary
    End point timeframe
    From Baseline to the End of the study
    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
    		 Holoclar (Safety population) Keratoplasty Adult Safety Population
    Number of subjects analysed
    47
    18
    Units: Participants
        Number of TEAEs
    20
    13
        Number of Serious TEAEs
    2
    1
        Number of TRAEs
    1
    0
        Number of Serious TRAEs
    0
    0
        Number of TEAEs Leading to Study withdrawal
    1
    0
        Number of TEAEs with Fatal Outcome
    1
    0
        Number of Treatment Emergent AESIs
    3
    2
    No statistical analyses for this end point

    Other pre-specified: Success of transplantation at Day 360

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    End point title
    		 Success of transplantation at Day 360
    End point description
    Invest. = investigator
    End point type
    Other pre-specified
    End point timeframe
    at Day 360
    End point values
    		 Keratoplasty Adult Safety Population Adult Safety Population
    Number of subjects analysed
    18
    45
    Units: Participants
        Success
    12
    17
        Success according to overall Invest. judgement
    14
    25
    No statistical analyses for this end point

    Other pre-specified: Success of Transplantation by Post-Keratoplasty Visit

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    End point title
    		 Success of Transplantation by Post-Keratoplasty Visit
    End point description
    Invest. = investigator
    End point type
    Other pre-specified
    End point timeframe
    at Day 360
    End point values
    		 Keratoplasty Adult Safety Population
    Number of subjects analysed
    18
    Units: Participants
        Success
    12
        Success according to overall Invest. judgement
    13
    No statistical analyses for this end point

    Other pre-specified: Degree of Neo-vascularisation and Central Cornea Involvement

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    End point title
    		 Degree of Neo-vascularisation and Central Cornea Involvement
    End point description
    End point type
    Other pre-specified
    End point timeframe
    at Day 360
    End point values
    		 Keratoplasty Adult Safety Population Adult Safety Population
    Number of subjects analysed
    18
    45
    Units: Participants
        Number of corneal quadrants - 0
    11
    14
        Number of corneal quadrants - 1
    1
    3
        Number of corneal quadrants - 2
    0
    4
        Number of corneal quadrants - 3
    0
    3
        Number of corneal quadrants - 4
    2
    4
        Number of corneal quadrants - Missing
    1
    6
        Central Cornea (6 mm) involvement - Yes
    1
    5
        Central Cornea (6 mm) involvement - No
    13
    23
        Central Cornea (6 mm) involvement - Missing
    1
    6
    No statistical analyses for this end point

    Other pre-specified: Degree of neo-vascularisation and central corneal involvement by Post-Keratoplasty visit

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    End point title
    		 Degree of neo-vascularisation and central corneal involvement by Post-Keratoplasty visit
    End point description
    End point type
    Other pre-specified
    End point timeframe
    at Day 360
    End point values
    		 Keratoplasty Adult Safety Population
    Number of subjects analysed
    18
    Units: Participants
        Number of corneal quadrants - 0
    11
        Number of corneal quadrants - 1
    2
        Number of corneal quadrants - 2
    0
        Number of corneal quadrants - 3
    0
        Number of corneal quadrants - 4
    0
        Number of corneal quadrants - Missing
    1
        Central Cornea (6 mm) involvement - Yes
    0
        Central Cornea (6 mm) involvement - No
    13
        Central Cornea (6 mm) involvement - Missing
    1
    No statistical analyses for this end point

    Other pre-specified: Degree of re-epithelialisation

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    End point title
    		 Degree of re-epithelialisation
    End point description
    End point type
    Other pre-specified
    End point timeframe
    at Day 360
    End point values
    		 Keratoplasty Adult Safety Population Adult Safety Population
    Number of subjects analysed
    18
    45
    Units: Participants
        None
    14
    25
        Trace
    0
    1
        Mild
    0
    1
        Severe
    0
    1
        Missing
    1
    6
    No statistical analyses for this end point

    Other pre-specified: degree of re-epithelialisation by Post-Keratoplasty Visit

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    End point title
    		 degree of re-epithelialisation by Post-Keratoplasty Visit
    End point description
    End point type
    Other pre-specified
    End point timeframe
    At day 360
    End point values
    		 Keratoplasty Adult Safety Population
    Number of subjects analysed
    18
    Units: participants
        None
    13
        Trace
    0
        Mild
    0
        Severe
    1
        Missing
    0
    No statistical analyses for this end point

    Other pre-specified: Clinical Symptoms

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    End point title
    		 Clinical Symptoms
    End point description
    End point type
    Other pre-specified
    End point timeframe
    At Day 360
    End point values
    		 Adult Safety Population
    Number of subjects analysed
    34
    Units: participants
        Presence of Photophobia: Yes
    10
        Presence of Photophobia: No
    18
        Presence of Photophobia: Missing
    6
        Photophobia Severity: None
    18
        Photophobia Severity: Mild
    6
        Photophobia Severity: Moderate
    3
        Photophobia Severity: Severe
    1
        Photophobia Severity: Missing
    6
        Presence of Burning: No
    24
        Presence of Burning: Yes
    4
        Presence of Burning: Missing
    6
        Burning Severity: None
    24
        Burning Severity: Mild
    3
        Burning Severity: Moderate
    1
        Burning Severity: Severe
    0
        Burning Severity: Missing
    6
        Presence of Pain: No
    27
        Presence of Pain: Yes
    1
        Presence of Pain: Missing
    6
        Presence of at least one Ocular Symptoms: No
    16
        Presence of at least one Ocular Symptoms: Yes
    12
        Presence of at least one Ocular Symptoms: Missing
    6
    No statistical analyses for this end point

    Other pre-specified: Clinical Symptoms by Post-Keratoplasty Visit

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    End point title
    		 Clinical Symptoms by Post-Keratoplasty Visit
    End point description
    End point type
    Other pre-specified
    End point timeframe
    At Day 360
    End point values
    		 Keratoplasty Adult Safety Population
    Number of subjects analysed
    14
    Units: participants
        Presence of Photophobia: No
    10
        Presence of Photophobia: Yes
    4
        Presence of Photophobia: Missing
    0
        Photophobia Severity: None
    10
        Photophobia Severity: Mild
    1
        Photophobia Severity: Moderate
    3
        Photophobia Severity: Severe
    0
        Photophobia Severity: Missing
    0
        Presence of Burning: No
    11
        Presence of Burning: Yes
    3
        Presence of Burning: Missing
    0
        Burning Severity: None
    11
        Burning Severity: Mild
    2
        Burning Severity: Moderate
    1
        Burning Severity: Severe
    0
        Burning Severity: Missing
    0
        Presence of Pain: No
    12
        Presence of Pain: Yes
    1
        Presence of Pain: Missing
    1
        Presence of at least one Ocular Symptoms: No
    9
        Presence of at least one Ocular Symptoms: Yes
    5
        Presence of at least one Ocular Symptoms: Missing
    0
    No statistical analyses for this end point

    Other pre-specified: BCVA improvement

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    End point title
    		 BCVA improvement
    End point description
    BCVA: best corrected visual acuity
    End point type
    Other pre-specified
    End point timeframe
    At Day 360
    End point values
    		 Adult Safety Population
    Number of subjects analysed
    45
    Units: Participants
    21
    No statistical analyses for this end point

    Other pre-specified: BCVA improvement by Post-Keratoplasty Visit

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    End point title
    		 BCVA improvement by Post-Keratoplasty Visit
    End point description
    BCVA: best corrected visual acuity
    End point type
    Other pre-specified
    End point timeframe
    At Day 360
    End point values
    		 Keratoplasty Adult Safety Population
    Number of subjects analysed
    18
    Units: Participants
    14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from Baseline to the End of the Study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Holoclar (Safety population)
    Reporting group description
    		 All patients treated in the HOLOCORE clinical trial who consented to roll over to the present extension study at the end of the HOLOCORE were observed for a follow-up period which varied from a minimum of 12 months for the last patient to a maximum of 57 months for the first patient entered.

    Serious adverse events
    		 Holoclar (Safety population)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 47 (4.26%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Mediastinum neoplasm
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Suture rupture
         subjects affected / exposed
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Holoclar (Safety population)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 47 (31.91%)
    Injury, poisoning and procedural complications
    Suture related complication
         subjects affected / exposed
    3 / 47 (6.38%)
         occurrences all number
    3
    Eye disorders
    Blepharitis
         subjects affected / exposed
    3 / 47 (6.38%)
         occurrences all number
    3
    Corneal epithelium defect
         subjects affected / exposed
    3 / 47 (6.38%)
         occurrences all number
    3
    Ocular hypertension
         subjects affected / exposed
    3 / 47 (6.38%)
         occurrences all number
    5
    Infections and infestations
    Coronavirus infection
         subjects affected / exposed
    3 / 47 (6.38%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jan 2017
    General Substantial Amendment including alignment with main HOLOCORE (CCD-GPLSCD01-03) study procedures and administrative changes.
    05 Jun 2020
    Substantial Amendment for clinical trial Sponsorship and Holoclar Marketing Authorisation Holder transfer from Chiesi Farmaceutici S.p.A. to Holostem Terapie Avanzate S.r.l. Pharmacovigilance Contacts have been updated. The time window allowed for Keratoplasty (K) visits have been also included.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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