Clinical Trial Results:
Pilot Clinical Assessment of Ex Vivo Expanded Corneal Limbal Stem Cell Transplantation in Patients with Severe Ocular Surface Disease (OSD) Arising from Limbal Stem Cell Deficiency
Summary
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EudraCT number |
2010-024409-11 |
Trial protocol |
GB |
Global end of trial date |
14 Mar 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Mar 2017
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First version publication date |
30 Mar 2017
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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 |
LSC-001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
SNBTS
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Sponsor organisation address |
21 Ellens Glen road,, Edinburgh, United Kingdom, EH17 7QT
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Public contact |
Regulatory Compliance Officer, Scottish National Blood Transfusion Service, 0044 131 314 5591, emily.hargreaves@nhs.net
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Scientific contact |
Associate Director Research Development and Innovation, Scottish National Blood Transfusion Service, 0044 1313145677, johncampbell3@nhs.net
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Sponsor organisation name |
NHS Lothian
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Sponsor organisation address |
47 Little France Cres, , Edinburgh, United Kingdom, EH16 4TJ
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Public contact |
Douglas Young, NHS Lothian, 0044 1312423337, douglas.young@luht.scot.nhs.uk
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Scientific contact |
Douglas Young, NHS Lothian, 0044 1312423337, douglas.young@luht.scot.nhs.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
02 Mar 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
14 Mar 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Mar 2016
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Pilot study examining the efficacy and safety of transplanting ex vivo expanded corneal epithelial limbal stem cells on Amniotic Membrane (AM) as a procedure to restore sight and relieve pain for patients with severe Ocular Surface Disease (OSD) arising from Limbal Stem Cell Deficiency (LSCD). Aim was to:
•Generate the data required for reliable sample size calculations for subsequent studies
•Evaluate all the practicalities and logistics of the study including the recruitment process, follow-up procedures, data collection and analysis
•Obtain information on actual recruitment rate
•The study also aimed to obtain preliminary answers to the following questions:-
•Is transplantation of ex vivo expanded corneal limbal stem cells feasible, efficient and safe?
•Does this procedure lead to improvements in vision and quality of the ocular surface?
•How does immunosuppression and limbal stem cell transplantation compare with using immunosuppression and amniotic membrane alone?
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Protection of trial subjects |
Bandage contact lens was placed atop the graft for comfort and protection, also Botox injections were applied to the affected eye lid this induced temporary ptosis which aimed to facilitate the survival of the graft and to protect the epithelium, also a short course of topical antibiotic and steroid eye drops were prescribed to be applied to the affected eye, post surgery.
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Background therapy |
Immunosuppressive therapy was tailored according to the patient’s individual clinical response. • Prednisolone: Initial dose of 60 mg daily tapering at 5mg weekly until 10 mg maintenance dosage plus • Cyclosporine: Initial dose of 100 mg twice a day then tapered to 50mg twice a day or • Mycophenolate mofetil. Dose between 750mg to 1g twice a day Further, prior to surgery, each patient made a single autologous donation of blood. This allowed preparation of autologous serum eye drops for the patient’s own use post-surgery. | ||
Evidence for comparator |
The control product amniotic membrane (AM) is a used extensively to treat ocular surface disorders. It is hypothesised that immunosuppressive therapy and AM alone may allow ocular surface reconstruction by eliminating the inflammatory environment that is detrimental to the function of stem cells. Therefore, one group of patients received donor derived ex vivo expanded corneal limbal stem cells on AM and immunosuppressive therapy, and the second group received AM graft and immunosuppressive therapy. | ||
Actual start date of recruitment |
01 Jul 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
United Kingdom: 17
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Worldwide total number of subjects |
17
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EEA total number of subjects |
17
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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) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
15
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment started on 1st July 2011 and ceased early due to slow recruitment at 17 patients, amendment to cease recruitment approved by the MHRA 09/12/2014. A total of 30 patients were screened for the trial of whom 13 were either not suitable (6) or declined (7). 17 were enrolled of whom 16 were treated (one patient withdrew prior to treatment) | |||||||||||||||||||||
Pre-assignment
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Screening details |
Subjects diagnosed with LSCD were screened for inclusion in trial in compliance with inclusion/exculsion criteria defined in study protocol LSC001. Informed consent for participation in trial gained prior to any study related procedures taking place. | |||||||||||||||||||||
Period 1
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Period 1 title |
Overall Period
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | |||||||||||||||||||||
Roles blinded |
Subject | |||||||||||||||||||||
Blinding implementation details |
The randomisation schedule was generated using Random Permuted Blocks (Pocock S. 1993). Neither the patient, nor the study staff performing the post-operative evaluations, knew to which treatment group they had been allocated.
The randomisation was only broken by the Pharmacovigilance Manager at the end of the study, or would have been in the event of an unexpected Serious Adverse Reaction (SAR)
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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IMP Test Arm | |||||||||||||||||||||
Arm description |
Subjects had either bilateral or unilateral LSCD resulting from one of the following underlying condition: - Aniridia -Chemical injury -Autoimmune disorder All subjects treated met inclusion/exclusion criteria defined in the study protocol LSC001 . | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Allogeneic Ex-vivo Expanded Corneal Epithelial Stem Cells on Amniotic Membrane
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Implant
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Routes of administration |
Ocular use, Ophthalmic use
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Dosage and administration details |
Each product was considered to be a single ‘dose’ based with ≥200mm2 macroscopic outgrowth and a diameter ≥15mm in all directions. Administration was via the removal of abnormal tissue over the cornea and the conjunctiva resected and recessed. The graft was placed atop the defect and the edge sewn to the peripheral cornea with 10-0 nylon. The posterior peripheral edge of the AM was sewn to the resected and recessed conjunctiva. A second AM was sewn on top of the product and a bandage contact lens placed to help protect the cells. One of the explants was sewn in the 12 o’clock position. The AMs dissolved gradually and the stem cells establish to the grafted surface
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Arm title
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Control Arm | |||||||||||||||||||||
Arm description |
Subjects had bilateral LSCD resulting from one of the following underlying condition: - Aniridia -Chemical injury -Autoimmune disorder All subjects treated met inclusion/exclusion criteria defined in the study protocol LSC001 . | |||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||
Investigational medicinal product name |
Amniotic Membrane
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Implant
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Routes of administration |
Ocular use
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Dosage and administration details |
Control AM for transplantation alone was prepared using an identical technique as for the IMP Allogeneic Ex-vivo Expanded Corneal Epithelial Stem Cells on AM, the AM was administered in the same way as the IMP arm.
Each cultured AM was considered to be a single ‘dose’. Administration was via the removal of abnormal tissue over the cornea and the conjunctiva resected and recessed. The graft was placed atop the defect and the edge sewn to the peripheral cornea with 10-0 nylon. The posterior peripheral edge of the AM was sewn to the resected and recessed conjunctiva. A second amniotic membrane was sewn on top of the product and a bandage contact lens placed to help protect the graft.
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Baseline characteristics reporting groups
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Reporting group title |
IMP Test Arm
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Reporting group description |
Subjects had either bilateral or unilateral LSCD resulting from one of the following underlying condition: - Aniridia -Chemical injury -Autoimmune disorder All subjects treated met inclusion/exclusion criteria defined in the study protocol LSC001 . | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control Arm
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Reporting group description |
Subjects had bilateral LSCD resulting from one of the following underlying condition: - Aniridia -Chemical injury -Autoimmune disorder All subjects treated met inclusion/exclusion criteria defined in the study protocol LSC001 . | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
aniridia
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Aniridia is a congenital, bilateral, panocular disorder which can develop to affect the iris, cornea, anterior chamber angle, lens, retina and optic nerve with frequent association with multiple ocular abnormalities including limbal stem cell deficiency
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Subject analysis set title |
chemical injury
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Burns involving the eye can lead to destruction of part or all of the limbus on a unilateral or bilateral basis causing LSCD.
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Subject analysis set title |
Autoimmune disorder
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
autoimmune including pemphigoid, may lead to LSCD.
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End points reporting groups
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Reporting group title |
IMP Test Arm
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Reporting group description |
Subjects had either bilateral or unilateral LSCD resulting from one of the following underlying condition: - Aniridia -Chemical injury -Autoimmune disorder All subjects treated met inclusion/exclusion criteria defined in the study protocol LSC001 . | ||
Reporting group title |
Control Arm
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Reporting group description |
Subjects had bilateral LSCD resulting from one of the following underlying condition: - Aniridia -Chemical injury -Autoimmune disorder All subjects treated met inclusion/exclusion criteria defined in the study protocol LSC001 . | ||
Subject analysis set title |
aniridia
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Aniridia is a congenital, bilateral, panocular disorder which can develop to affect the iris, cornea, anterior chamber angle, lens, retina and optic nerve with frequent association with multiple ocular abnormalities including limbal stem cell deficiency
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Subject analysis set title |
chemical injury
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Burns involving the eye can lead to destruction of part or all of the limbus on a unilateral or bilateral basis causing LSCD.
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Subject analysis set title |
Autoimmune disorder
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
autoimmune including pemphigoid, may lead to LSCD.
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End point title |
visual acuity | ||||||||||||
End point description |
Best corrected visual acuity
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End point type |
Primary
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End point timeframe |
The end point of the trial was 18 months post treatment, subjects were reviewed at pre treatment, then post treatment at day 1, 2/3, 7, 14 and month 1, 3, 6, 9,12, 15 and 18 months
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Statistical analysis title |
visual acuity | ||||||||||||
Statistical analysis description |
analysis of reduction in Logmar score by unpaired t-test
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Comparison groups |
IMP Test Arm v Control Arm
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Number of subjects included in analysis |
13
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Analysis specification |
Post-hoc
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Analysis type |
other | ||||||||||||
P-value |
= 0.228 [1] | ||||||||||||
Method |
t-test, 1-sided | ||||||||||||
Confidence interval |
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Notes [1] - no significant difference shown between IMP and control arm for visual acuity |
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End point title |
Ocular Surface Score | ||||||||||||
End point description |
A composite score for the ocular surface disease status of the patients was obtained throughout the study according to the following 5 criteria:
corneal epithelium
conjunctivalisation
corneal neovascularisation
corneal opacification
conjunctival hyperaemia
Each criteria was scored from 0-3 (normal-severe damage) by the trial physicians, and an aggregate score out of 15 obtained.
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End point type |
Secondary
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End point timeframe |
18 months , measurements at pre treatment, post treatment at day 1, 2/3, 7, 14 and month 1, 3, 6, 9,12, 15 and 18 months
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Attachments |
results summary charts |
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Statistical analysis title |
ocular surface score | ||||||||||||
Statistical analysis description |
8 patients in the IMP test arm and 5 patients in the control arm had ocular surface scores which were evaluated throughout, and at conclusion of the trial. All patients showed lower (improved) ocular surface scores at the conclusion of the trial. However, only patients in the test arm who received the IMP Allogeneic Ex-vivo Expanded Corneal Epithelial Stem Cells on Amniotic Membrane product showed a statistically significant higher mean improvement in combined ocular surface score.
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Comparison groups |
IMP Test Arm v Control Arm
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Number of subjects included in analysis |
13
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Analysis specification |
Post-hoc
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.004 [2] | ||||||||||||
Method |
t-test, 1-sided | ||||||||||||
Confidence interval |
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Notes [2] - Statistically significant improvement in combined ocular surface scores when treated with IMP (p=0.0040, unpaired t-test) compared with Control arm, based on the mean change from pre treatment to 18 months post treatment ocular surface score +/- SD. |
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End point title |
Quality of Life | ||||||||||||
End point description |
Quality of life (QoL) assessments using the SF-36 scoring system were analysed as a whole data set, and as delta in each patient relative to each individual’s starting score in each category. There were no statistically significant changes in QoL scoring throughout the trial. The one exception was a significant decrease at 6 months (p= 0.0024) in the Social Function component of the SF36 score which returned to non-significance over baseline thereafter. This likely contributed to a trend towards initial reduction in overall SF-36 score at 6 months which recovered subsequently. Although there was fluctuation over time, SF-36 scores closely tracked to the pre-trial baseline levels by the end of the study
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End point type |
Secondary
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End point timeframe |
18 months
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Attachments |
Quality of Life analysis |
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Notes [3] - Outcome of anaysis is given in the appended document [4] - Outcome of anaysis is given in the appended document |
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No statistical analyses for this end point |
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End point title |
WBC and Cytokine levels | ||||||||||||
End point description |
12/13 patients showed normal WBC levels throughout the study. 1 patient with chemical injury had an elevated WBC – this patient had ongoing ocular inflammation and had to be withdrawn from the study for corneal transplant.
Patients could be stratified into normal or high serum cytokines at the start of the study – the normal group consisted of chemical burns patients and the one patient with autoimmune disease, while the high group consisted of all aniridia patients, 2 chemical burns, and the other patient with an autoimmune disease (pemphigus).
In the high cytokine group, IL-8 was highly elevated in all patients, but IFN-gamma and TNF-alpha levels were not increased. The high group also showed variably increased levels of IL-2, 4, 10 and 12, but there was no consistent pattern. There was no correlation between IL-8 levels and WBC.
the results of this post hoc analysis are appended.
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End point type |
Post-hoc
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End point timeframe |
up to 18 months
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Attachments |
wbc cytokine analysis |
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Notes [5] - Outcome of anaysis is given in the appended document [6] - Outcome of anaysis is given in the appended document |
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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 |
18 months post treatment
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Adverse event reporting additional description |
Patients were monitored for any adverse events during the study period.
Any serious adverse event which arose following use of the limbal stem cell graft or the AM was immediately notified to the SNBTS .
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18
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Reporting groups
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Reporting group title |
IMP Corneal epithelial stem cells on amniotic membrane
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Reporting group description |
AEs from patients receiving the IMP | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
control arm amniotic membrane
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Reporting group description |
Control group receiving amniotic membrane | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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11 Sep 2012 |
Following a Serious Adverse Event, that was unrelated to the study product but
resulted in the death of the patient, Information for Patients was updated to include additional information on the possible
risks of concomitant trial medication, including immunosuppressive therapy. in addition, new investigator site at St Pauls Eye unit Liverpool added as an additional investigator site. |
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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. | |||
The study was terminted early due to slow recruitment, therefore only 17 patients were recruited instead of the planned 20 (10 in each arm), 13 patients completed the study. |