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
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EudraCT number |
2014-002845-23 |
Trial protocol |
DE GB BE NL FR PL ES IT |
Global end of trial date |
11 Mar 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
07 May 2023
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First version publication date |
07 May 2023
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CCD-GPLSCD01-03
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Additional study identifiers
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ISRCTN number |
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US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Holostem Terapie Avanzate s.r.l.
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Sponsor organisation address |
Via G. Gottardi, 100, Modena, Italy,
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Public contact |
Clinical Trial Department, Holostem Terapie Avanzate s.r.l., +39 059 2058064 , regulatory@holostem.com
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Scientific contact |
Graziella Pellegrini, Holostem Terapie Avanzate s.r.l., +39 059 2058064 , grzllpellegrini@gmail.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001082-PIP02-11 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
20 Mar 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
11 Mar 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Mar 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Oct 2015
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
1 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 4
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Country: Number of subjects enrolled |
Poland: 20
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Country: Number of subjects enrolled |
Spain: 2
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Country: Number of subjects enrolled |
United Kingdom: 8
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Country: Number of subjects enrolled |
Belgium: 4
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Country: Number of subjects enrolled |
France: 13
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Country: Number of subjects enrolled |
Germany: 12
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Country: Number of subjects enrolled |
Italy: 17
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Worldwide total number of subjects |
80
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EEA total number of subjects |
72
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
2
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Adolescents (12-17 years) |
2
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Adults (18-64 years) |
70
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From 65 to 84 years |
6
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85 years and over |
0
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Recruitment
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Recruitment details |
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Pre-assignment
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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
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||
Arms
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Living tissue equivalent
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Routes of administration |
Implantation
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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.
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Baseline characteristics reporting groups
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Reporting group title |
Overall
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Holoclar
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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)
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
All adult patients who underwent the ACLSCT procedure.
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Subject analysis set title |
Modified Intention-to-Treat population B (mITTb)
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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).
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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
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End point type |
Primary
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End point timeframe |
At 12 months after first Holoclar treatment
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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. |
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No statistical analyses for this end point |
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End point title |
Superficial corneal neo-vascularisation | ||||||||||||||||||||
End point description |
The statistical analysis is descriptive.
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End point type |
Other pre-specified
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End point timeframe |
From baseline to Day 360 post-transplant
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No statistical analyses for this end point |
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End point title |
Shift in central corneal class | ||||||||||||||||||||||||
End point description |
The statistical analysis is descriptive.
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End point type |
Other pre-specified
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End point timeframe |
At 12 months after first Holoclar treatment
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No statistical analyses for this end point |
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End point title |
Ocular symptoms post-transplantation | ||||||||||||||||||||||||
End point description |
The statistical analysis is descriptive.
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End point type |
Other pre-specified
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End point timeframe |
From baseline to Day 360 post-transplant
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No statistical analyses for this end point |
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End point title |
Conjunctival inflammation post-transplantation | ||||||||||||||||||||||||
End point description |
The statistical analysis is descriptive.
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End point type |
Other pre-specified
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End point timeframe |
From baseline to Day 360 post-transplant
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No statistical analyses for this end point |
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End point title |
BCVA post-transplantation | ||||||||||||||||||||||||||
End point description |
BCVA: Best Corrected Visual Acuity
The statistical analysis is descriptive.
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End point type |
Other pre-specified
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End point timeframe |
From the baseline to Day 360
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No statistical analyses for this end point |
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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.
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End point type |
Other pre-specified
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End point timeframe |
At 12 months after first Holoclar treatment
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No statistical analyses for this end point |
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End point title |
Corneal/conjunctival sensitivity and corneal opacity post-transplantation | ||||||||||||||||||||||||
End point description |
The statistical analysis is descriptive.
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End point type |
Other pre-specified
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End point timeframe |
From Baseline to Day 360
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No statistical analyses for this end point |
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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.
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End point type |
Other pre-specified
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End point timeframe |
From Baseline to Day 360
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No statistical analyses for this end point |
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End point title |
Success of transplantation as judged by Site Investigator | ||||||||||
End point description |
The statistical analysis is descriptive.
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End point type |
Other pre-specified
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End point timeframe |
At 12 months after first Holoclar treatment
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No statistical analyses for this end point |
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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.
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End point type |
Other pre-specified
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End point timeframe |
At 12 months after first Holoclar treatment
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From pre-treatment phase to the end of the trial.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Adults
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Reporting group description |
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Reporting group title |
Paediatric
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Reporting group description |
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Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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. |
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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.
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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. |
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30 Sep 2020 |
General Substantial #4
Included swab SARS-CoV-2 (PCR) tests due to COVID pandemic |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |