Comparison of techniques of stem cell transplantation in patients with bilateral ocular surface disease
| ISRCTN | ISRCTN17247726 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17247726 |
| Secondary identifying numbers | BT-1829/CSP-01, BT/01/COE/07/03 |
- Submission date
- 13/07/2024
- Registration date
- 17/07/2024
- Last edited
- 21/10/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Eye Diseases
Plain English summary of protocol
Background and study aims
Bilateral ocular surface disease resulting from Stevens-Johnson Syndrome and chemical injuries are visually debilitating and difficult to treat. Ocular surface reconstruction by various means has been reported with variable results. This study addresses an unmet need for a prospective clinical trial comparing the outcomes of transplanting autologous oral and conjunctival epithelial cell constructs on human amniotic membranes by ex vivo tissue engineering.
Who can participate?
Patients aged between 5-90 years old with ocular surface diseases
What does the study involve?
The study included a total of 50 patients of bilateral limbal stem cell deficiency (LSCD) with limbal affected area at least 6-9clock hours with Schirmer test value less than 5mm and with no systematic disorder contraindication surgical intervention. Autologous regenerative transplantation procedure, randomized into two treatment groups, i.e. COMET and CCET. There were 25 patients in the COMET group and 25 patients in the CCET group. The sample size was calculated in the study by using a clinical superiority design. Statistical Package for Social Sciences (SPSS) version 15.0 is used to generate the random number sequences and participants were randomized to two study groups. All patients underwent comprehensive ophthalmic examination at baseline and every follow-up visit. All patients underwent surgery in one eye only. The study is an open-label design.
What are the possible benefits and risks of participating?
The possible benefit of the autologous treatment is to help reconstruct the ocular surface. No serious or other adverse events are expected during the follow-up of studies.
Where is the study run from?
Dr Rajendra Prasad Centre for Ophthalmic Sciences, Eye Bank Clinic, New Delhi, India
When is the study starting and how long is it expected to run for?
December 2013 to March 2023
Who is funding the study?
Supported by a research grant-in-aid from the Department of Biotechnology, Ministry of Science and Technology, Government of India
Who is the main contact?
1. Prof Radhika Tandon, radhikatandon@aiims.edu
2. Prof Sujata Mohanty, rmohantysujata@gmail.com
3. Prof Seema Sen, ssenop@rediffmail.com
4. Prof Seema Kashyap, dr_skashyap@hotmail.com
Contact information
Public, Scientific, Principal Investigator
Cornea, Cataract & Refractive Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences
New Delhi
110029
India
 ORCID ID |
0000-0001-9554-9933 |
|---|---|
| Phone | +91 011 2965 93145 |
| radhikatandon@aiims.edu |
Principal Investigator
All India Institute of Medical Sciences, Stem cell Facility, 1stFloor ORBO, AIIMS, Ansari Nagar
New Delhi
110029
India
| Phone | +91 011-26593085 |
|---|---|
| drmohantysujata@gmail.com |
Principal Investigator
All India Institute of Medical Sciences, Dr. R.P. Centre for Ophthalmic Sciences, AIIMS, Ansari Nagar
New Delhi
110029
India
| Phone | +91 011-26593172 |
|---|---|
| ssenop@rediffmail.com |
Principal Investigator
All India Institute of Medical Sciences, Dr. R.P. Centre for Ophthalmic Sciences, AIIMS, Ansari Nagar
New Delhi
110029
India
| Phone | +91 011-26593172 |
|---|---|
| dr_skashyap@hotmail.com |
Study information
| Study design | Randomized parallel-group multiple-arm trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Efficacy |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet. |
| Scientific title | Comparative evaluation of the efficacy of conjunctival stem cell transplantation with cultivated oral mucosal epithelial transplantation in patients with bilateral cicatrizing ocular surface diseases |
| Study acronym | RCTCOMETCCET-2017 |
| Study objectives | The corneal epithelial stem cell resides in the basal layer of the limbus, the transitional zone between the cornea and the bulbar conjunctiva. These cells govern the renewal of the corneal epithelium by generating progeny (transient amplifying cells, which are cells committed to epithelial differentiation) with limited renewal capabilities that migrate from the limbus into the basal layer of the cornea. If corneal epithelial stem cells are completely absent owing to limbal disorders such as severe thermal or chemical burns, the source of corneal epithelial cells has been exhausted, the peripheral conjunctival epithelium invades inwardly, and the corneal surface becomes enveloped by vascularized conjunctival scar tissues, resulting in corneal opacification leading to severe visual impairment. Such pathological characteristics are considered to represent limbal stem cell deficiencies. Limbal Allograft transplantation can be performed in patients with unilateral or bilateral deficiencies, but it requires long-term immunosuppression that involves a high risk of serious eye and systematic complications. In patients with Stevens-Johnson syndrome or ocular pemphigoid, graft failure is common, even with immunosuppression, owing to serious preoperative conditions such as persistent inflammation of the ocular surface, abnormal epithelial differentiation of the ocular surface, severe dry eye and lid-related abnormalities. To avoid allograft rejection and improve surgical outcomes, some patients with unilateral stem cell deficiencies have had limbal autografts taken from the healthy eye as well as corneal epithelial grafts constructed ex-vivo by the expansion of autologous limbal stem cells harvested from healthy contralateral eyes and cultivated on cell carries such as amniotic membranes and fibrin gel with encouraging results. This process, however, cannot be used for bilateral ocular surface diseases or bilateral total limbal stem cell deficiencies. Such patients can be helped by ex-vivo cultivated oral mucosal stem cell transplantation & conjunctival stem cell transplantation. The oral epithelium has attracted attention as a cell source, and favourable results have been obtained in animal and human studies. This study is a comparative study of conjunctival epithelial stem cell transplantation with cultivated oral mucosal epithelial transplantation in patients with bilateral ocular surface diseases i.e. Steven’s Johnson syndrome & Chemical burns. A study by Leonard P. K. Ang and his co-workers showed that ex vivo cultivation of conjunctiva to form transplantable epithelial sheets for corneal replacement is a promising new treatment modality in patients with limbal stem cell deficiency (LSCD). The role of cultivation of oral mucosal stem cells and transplantation onto the ocular surface for bilateral stem cell deficiencies has been well established. However, studies evaluating the role of conjunctival epithelial stem cell transplantation in bilateral cicatrizing ocular surface diseases are needed. The present study intends to evaluate the same and compare the results with cultivated oral mucosal epithelial transplantation as initial surgical therapy in bilateral ocular surface diseases and also to compare direct limbal lenticular, simple limbal epithelial and cultivated limbal epithelial transplantation in patients with unilateral LSCD. |
| Ethics approval(s) |
1. Approved 17/01/2017, Institutional Commitee for Stem Cell Research (All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India; +911126594579; stemcellcommittee@gmail.com), ref: IC-SCR/07/14/(R1) 2. Approved 28/04/2014, Institue Ethics Committee, All India Institute of Medical Sciences (Room No. 102, 1st Floor Old OT Block, Ansari Nagar, New Delhi, 110029, India; +91 011-26594579; ethicscommitteeaiims@gmail.com), ref: IEC/NP-99/11.04.2014 |
| Health condition(s) or problem(s) studied | Reconstruction of ocular surface by using stem cell therapy in patients with ocular surface disease |
| Intervention | Cultivated Oral Mucosal Epithelial Transplantation (COMET) and Conjunctival Cultivated Epithelial Transplantation (CCET) for ocular surface reconstruction in patients with bilateral ocular surface disease due to Stevens-Johnson Syndrome. A. Cultivated Oral Mucosal Epithelial Transplantation (COMET): 1. Preparation: Sterilize the oral cavity with a povidone-iodine 5% solution Harvest a 4 mm x 4 mm tissue strip from the buccal mucosa under local anaesthesia Collect the tissue in a transport medium (DMEM with antibiotics) 2. Cultivation: Wash the harvested tissue with sterile phosphate-buffered saline Culture the tissue over a denuded amniotic membrane with DMEM/F12, 10% autologous serum, and antibiotics Incubate at 37°C in a 5% CO2 incubator, changing the media daily Observe cell growth at 24 hours, day 3, day 5, day 7, and day 11 3. Transplantation: After two weeks, when a confluent cell sheet forms, transplant it in the recipient's eye Dissect the fibrovascular pannus and spread the cell sheet over the cornea and limbus Secure the membrane with fibrin glue and place a bandage contact lens B. Conjunctival Cultivated Epithelial Transplantation (CCET): 1. Preparation: 4 mm x 2 mm tissue strip harvested from the conjunctival fornix Transport media and cultivation procedures were the same as for COMET 2. Cultivation: Culture the tissue over a denuded amniotic membrane using the same method as COMET 3. Transplantation: After two weeks, transplant the confluent cell sheet in the recipient's eye Followed the same transplantation steps as in COMET C. Post-Operative Management and Follow-Up 1. COMET and CCET Recipient Eyes: Moxifloxacin 0.5% eye drops thrice daily for four weeks Carboxymethylcellulose 0.5% eye drops six times daily for two months, then four times daily Prednisolone phosphate 1% eye drops four times daily for two weeks, tapering once daily over three months. Fluorometholone 0.1% eye drops four times daily for two weeks, tapering once daily over three months. 2. Donor Eyes in CCET Group: Moxifloxacin 0.5% eye drops thrice daily and gatifloxacin 0.3% ointment at bedtime for one week. Carboxymethylcellulose 0.5% eye drops four times daily for three months 3. Oral Mucosa in COMET Group: Povidone-iodine 5% rinse and gargle for four days Mild painkiller twice daily for three days Patients will be reviewed at baseline and on the first postoperative day, at one week, two weeks, four weeks, two months, three months, and six months. Comprehensive ophthalmic examinations were conducted at each visit. Randomization process: Randomization was done using SPSS version 15.0. |
| Intervention type | Biological/Vaccine |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Cultivated oral mucosal epithelial transplantation (COMET), Conjunctival cultivated epithelial transplantation (CCET) |
| Primary outcome measure | The following primary outcome measures were assessed at baseline, post-op weeks 1, 2 and 4, and months 2, 3 and 6: 1. Surgical success, defined as complete epithelization and a clinically stable corneal surface, evaluated through slit lamp biomicroscopy and clinical photographs measured using ImageJ software 2. Vascularization, defined as a complete success if the cornea is avascular and partial success if there is mild vascularization not reaching up to the centre of the cornea which is completely epithelized, assessed by using slit lamp biomicroscopy and clinical photographs measured using ImageJ software 3. Conjunctivalization, defined as a complete success if there is an absence of conjunctivalization and a partial success if there is mild conjunctivalization, examined by using slit-lamp biomicroscopy and clinical photographs measured using ImageJ software |
| Secondary outcome measures | The following secondary outcome measures were assessed at baseline, post-op weeks 1, 2 and 4, and months 2, 3 and 6: 1. Improvement in best corrected visual acuity (BCVA) measured using a Snellen Visual acuity Chart 2. Improvement in corneal transparency evaluated by using slit-lamp biomicroscopy and measured using a clinical photograph and corneal grading system |
| Overall study start date | 02/12/2013 |
| Completion date | 31/03/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 5 Years |
| Upper age limit | 90 Years |
| Sex | Both |
| Target number of participants | 50 |
| Total final enrolment | 50 |
| Key inclusion criteria | 1. Pediatric patients from the age group 5-18 years old 2. Adult patients from the age group above 18 years old 3. Unilateral and bilateral ocular burns i.e. Steven Johnson syndrome and chemical burns 4. In unilateral affected patients limbal area affected should be 6 - 9 clock hours 5. Schirmer test value of at least 5 mm 6. Willing to follow-up for at least 6 months 7. No systematic disorder contradicting surgical intervention 8. Patients in whom primary insult occurred at least >4 months ago |
| Key exclusion criteria | Untreated concurrent problems, such as adnexal problems, glaucoma and infection |
| Date of first enrolment | 10/01/2018 |
| Date of final enrolment | 05/11/2022 |
Locations
Countries of recruitment
- India
Study participating centre
New Delhi
110029
India
Sponsor information
Government
Department of Biotechnology 6th-8th Floor, Block 2 and 4th-5th Floor, Block 3 CGO Complex, Lodhi Road
New Delhi
110003
India
| Phone | +91 011 2436 9613 |
|---|---|
| webupload@dbt.nic.in | |
| Website | https://dbtindia.gov.in/ |
"ROR" |
https://ror.org/03tjsyq23 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- Dept. of Biotechnology, Govt of India, बायोटेक्नोलॉजी विभाग विज्ञान और प्रौद्योगिकी मंत्रालय, भारत सरकार, Department of Biotechnology, Department of Biotechnology, Ministry of Science & Technology, India, Department of Biotechnology, GOI, Dept. of Biotechnology, Govt. of India, Department of Biotechnology, Ministry of Sc & Tech, Govt of India, DBT
- Location
- India
Results and Publications
| Intention to publish date | 30/08/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | The dataset generated during and analysed during the current study will be available upon request from Prof Radhika Tandon, radhikatandon@aiims.edu |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | 17/07/2024 | No | No | ||
| Results article | 18/10/2024 | 21/10/2024 | Yes | No |
Additional files
Editorial Notes
21/10/2024: Publication reference added.
15/07/2024: Study's existence confirmed by the Institue Ethics Committee, All India Institute of Medical Sciences.
