Ignite Creation Date:
2024-05-06 @ 4:01 PM
Last Modification Date:
2024-10-26 @ 2:02 PM
Study NCT ID:
NCT04843839
Status:
UNKNOWN
Last Update Posted:
2021-04-14
First Post:
2021-04-02
Brief Title:
CHED - Congenital Hereditary Endothelial Dystrophy New Paradigm Shift in Therapy Using Topical Eye Drops
Sponsor:
LV Prasad Eye Institute
Organization:
LV Prasad Eye Institute
Study Overview
Official Title:
Corneal Dystrophies Caused by SLC4A11 Mutation A Promising New Paradigm Shift in Therapy Using an Ophthalmic Nonsteroidal Anti-Inflammatory Eye Drops
Status:
UNKNOWN
Status Verified Date:
2021-04
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
CHED- Congenital Endothelial Endothelial Dystrophy is a condition that causes corneal cloudiness
Since currently only surgery is being done to cure this condition we are taking up the research of using topical eye drops for this condition which is a very simple and easy method
Also there are no significant side effects to this treatment
Since currently only surgery is being done to cure this condition we are taking up the research of using topical eye drops for this condition which is a very simple and easy method
Also there are no significant side effects to this treatment
Detailed Description:
Introduction
Corneal endothelial cell loss is often associated with blinding endothelial corneal dystrophies relatively seen more frequently dominantly inherited 5 FECD Fuchs Endothelial Corneal Dystrophy and rare recessive CHED1 Mutations of SLC4A11 an abundant corneal solute transporter cause CHED and some cases of FECD SLC4A11 is a unique member of the SLC4 family of bicarbonate transport proteins localized at the basolateral surface of corneal endothelial cells that contributes to osmotically-driven water flux from the stroma to aqueous humour to maintain corneal fluid-balance2
While mutations and loss of functional SLC4A11 are reported to be associated with degeneration and death of endothelial cells the detailed physiological roles of SLC4A11 still remain unknown Seventy-eight different mutations including 42- missense 9- nonsense 4- splice sites and 23 insertion-deletion mutations have been scattered across the gene reported in families with CHED from Indian populations3 Current therapeutic interventions Penetrating keratoplasty Descemets Stripping Automated Endothelial Keratoplasty DSAEK and Descemets Membrane Endothelial Keratoplasty DMEK face problems such as shortage of donor corneas complex surgical procedure and incidence of graft failure in acute and chronic phases4 5
When studied in model cells the most common molecular phenotype of mutant membrane proteins is mild misfolding This biosynthetic defect renders the protein incapable of transit from the endoplasmic reticulum ER site of synthesis to its normal cellular location Note that SLC4A11 localization in corneas of endothelial dystrophy patients has not been examined the conclusion of ER retention presently rests on data from cell culture models Correcting such biosynthetic defects is an attractive therapeutic approach for some genetic diseases affecting membrane proteins best exemplified by the efficacy of the drug Lumacaftor in rescuing the cell-surface misfolded cystic fibrosis transmembrane conductance regulator CFTR the protein product of the cystic fibrosis CF gene
Thus there is an urgent need to find alternative therapy which is reliable simple and affordable A lot of interest has being taken now a day in opting for a non-invasive way of modality over invasive ones In SLC4A11 mutation corneal dystrophies one such topic of interest is the hypothesized role of Non-Steroidal Anti-Inflammatory Drugs NSAIDs as a medical management of corneal endothelial dystrophies
Most SLC4A11 mutations lead to biosynthetic defects marked by accumulation of the protein in the Endoplasmic Reticulum and their degradation before reaching the plasma membrane This generated increased reactive oxygen species thus making the cell more vulnerable to oxidative and mitochondrial damage and more prone to apoptotic death
A small-scale drug screen showed that Glafenine a disused NSAID was able to move some SLC4A11 mutants to the cell surface suggesting that other NSAIDs might also have therapeutic potential
Further the retained protein in the Endoplasmic reticulum and the effects of various drugs on its expression to the surface was taken up by studies conducted by Alka et al on HEK293 cells expressing CHED and FECD mutation They showed the efficacy of Diclofenac Voltaren Ophthalmic and Nepafenac over other NSAIDs in moving the endoplasmic reticulum-retained missense mutant SLC4A11 in 20 out of 30 test cells Which showed a potential role of NSAIDs in these conditions
This project is thus to screen NSAIDs available as eye drops for their ability to correct the cell-surfacing trafficking of SLC4A11 proteins
Since their first introduction in ophthalmology the use of NSAIDs have been exponentially expanded from therapeutic applications including treatment of pain and inflammation associated with ophthalmic surgeries to prevention and treat cystoid macular edema CME associated with cataract surgery enhance mydriasis intraoperatively and in multiple inflammatory ophthalmic diseases such as seasonal allergic conjunctivitis viral conjunctivitis uveitis episcleritis and scleritis as well as in retinal and choroidal diseases
The main reason for this being that they are- i Easy to handle ii Non-invasive iii Well-tolerated iv Sufficient ocular drug concentrations while avoiding the systemic side effects associated with oral administration
Nevertheless the ocular drug bioavailability in the conventional topical formulations is notoriously poor as only 1-5 of drug applied to the surface penetrates the cornea
Besides these ocular anatomical and physiological constraints another limiting factor encountered with anti-inflammatory drugs or immunosuppressive agents is their poor water solubility
The prodrug approach is a chemical way to enhance drug permeability The synthesized inactive prodrug exhibits a better corneal penetration and once in situ is either chemically andor enzymatically metabolized to become active It was studied that nepafenac an amide prodrug of amfenac belonging to the pharmacological NSAID class of aryl-acetic in vitro demonstrated a nearly six-fold greater permeation coefficient than diclofenac
In vivo nepafenac easily crosses corneal and retinal tissues following topical ocular administration
In this context the study is intended in exploring the specific application of NSAID eye drops Nepafenac as a promising novel therapeutic approach for treating children with CHED
There are no published reports of human trials for the application of NSAID eye drops in cases of Congenital Hereditary Endothelial Dystrophy
Objectives
To ascertain the clinical utility of topical ophthalmic NSAIDs in reversing or delaying the corneal cloudiness in children with CHED
Study Area Setting Cornea and Anterior Segment Services Kallam Anji Reddy campus L V Prasad Eye Institute Hyderabad
Study Duration 2 Years 15th December 2020- 15th December 2022
Sample Size Since it is a novel study with no other prior works population size will be minimum 30 eyes
Study Population Diagnosed cases of Congenital Hereditary Endothelial Dystrophy fulfilling the inclusion criteria
Study Design Double-blinded Placebo-controlled Simple randomized control trial A Paired eye study
Statistical Method The data of this study will be compared by using the t-test or χ2 test depending if the data is parametric or non-parametric in nature
Methodology
Targeting SLC4A11 mutation using ophthalmic NSAIDs preparation
Test drug is Nepafenac eye drops 01wv Given at the dosage of 4 drops to be instilled in the test eye 1 drop 4 times a day every 4 hourlyThat is at morning afternoon evening and at night This is to be continued for a 6 months duration
Control drug is Carboxy-methylcellulose sodium lubricant eye drops 05wv at the same dosage as the test eye drop but in the control eye
The test eye will be chosen by Simple Randomization For all the cases with an even serial number the Right eye will be the test eye and for the odd numbered cases the Left eye will be the test eye
In order to ensure blinding of the patient and the investigators both the drops will be dispensed in identical bottles and will be relabeled with the letter R and L signifying which eye the patient will be using them This will be done in prior with only one member of the study having the list of the identity of drugs The same person will also be providing the appropriately labeled drug for the patients and will not be a part of clinical evaluation and analysis of the patients data
To check for the patients compliance the patients will be required to get the used bottles at every visit and new ones will be provided Since each bottle contains 5 ml of solution they would last for 25-30 days each as will be our follow-up schedule for the patients
Corneal endothelial cell loss is often associated with blinding endothelial corneal dystrophies relatively seen more frequently dominantly inherited 5 FECD Fuchs Endothelial Corneal Dystrophy and rare recessive CHED1 Mutations of SLC4A11 an abundant corneal solute transporter cause CHED and some cases of FECD SLC4A11 is a unique member of the SLC4 family of bicarbonate transport proteins localized at the basolateral surface of corneal endothelial cells that contributes to osmotically-driven water flux from the stroma to aqueous humour to maintain corneal fluid-balance2
While mutations and loss of functional SLC4A11 are reported to be associated with degeneration and death of endothelial cells the detailed physiological roles of SLC4A11 still remain unknown Seventy-eight different mutations including 42- missense 9- nonsense 4- splice sites and 23 insertion-deletion mutations have been scattered across the gene reported in families with CHED from Indian populations3 Current therapeutic interventions Penetrating keratoplasty Descemets Stripping Automated Endothelial Keratoplasty DSAEK and Descemets Membrane Endothelial Keratoplasty DMEK face problems such as shortage of donor corneas complex surgical procedure and incidence of graft failure in acute and chronic phases4 5
When studied in model cells the most common molecular phenotype of mutant membrane proteins is mild misfolding This biosynthetic defect renders the protein incapable of transit from the endoplasmic reticulum ER site of synthesis to its normal cellular location Note that SLC4A11 localization in corneas of endothelial dystrophy patients has not been examined the conclusion of ER retention presently rests on data from cell culture models Correcting such biosynthetic defects is an attractive therapeutic approach for some genetic diseases affecting membrane proteins best exemplified by the efficacy of the drug Lumacaftor in rescuing the cell-surface misfolded cystic fibrosis transmembrane conductance regulator CFTR the protein product of the cystic fibrosis CF gene
Thus there is an urgent need to find alternative therapy which is reliable simple and affordable A lot of interest has being taken now a day in opting for a non-invasive way of modality over invasive ones In SLC4A11 mutation corneal dystrophies one such topic of interest is the hypothesized role of Non-Steroidal Anti-Inflammatory Drugs NSAIDs as a medical management of corneal endothelial dystrophies
Most SLC4A11 mutations lead to biosynthetic defects marked by accumulation of the protein in the Endoplasmic Reticulum and their degradation before reaching the plasma membrane This generated increased reactive oxygen species thus making the cell more vulnerable to oxidative and mitochondrial damage and more prone to apoptotic death
A small-scale drug screen showed that Glafenine a disused NSAID was able to move some SLC4A11 mutants to the cell surface suggesting that other NSAIDs might also have therapeutic potential
Further the retained protein in the Endoplasmic reticulum and the effects of various drugs on its expression to the surface was taken up by studies conducted by Alka et al on HEK293 cells expressing CHED and FECD mutation They showed the efficacy of Diclofenac Voltaren Ophthalmic and Nepafenac over other NSAIDs in moving the endoplasmic reticulum-retained missense mutant SLC4A11 in 20 out of 30 test cells Which showed a potential role of NSAIDs in these conditions
This project is thus to screen NSAIDs available as eye drops for their ability to correct the cell-surfacing trafficking of SLC4A11 proteins
Since their first introduction in ophthalmology the use of NSAIDs have been exponentially expanded from therapeutic applications including treatment of pain and inflammation associated with ophthalmic surgeries to prevention and treat cystoid macular edema CME associated with cataract surgery enhance mydriasis intraoperatively and in multiple inflammatory ophthalmic diseases such as seasonal allergic conjunctivitis viral conjunctivitis uveitis episcleritis and scleritis as well as in retinal and choroidal diseases
The main reason for this being that they are- i Easy to handle ii Non-invasive iii Well-tolerated iv Sufficient ocular drug concentrations while avoiding the systemic side effects associated with oral administration
Nevertheless the ocular drug bioavailability in the conventional topical formulations is notoriously poor as only 1-5 of drug applied to the surface penetrates the cornea
Besides these ocular anatomical and physiological constraints another limiting factor encountered with anti-inflammatory drugs or immunosuppressive agents is their poor water solubility
The prodrug approach is a chemical way to enhance drug permeability The synthesized inactive prodrug exhibits a better corneal penetration and once in situ is either chemically andor enzymatically metabolized to become active It was studied that nepafenac an amide prodrug of amfenac belonging to the pharmacological NSAID class of aryl-acetic in vitro demonstrated a nearly six-fold greater permeation coefficient than diclofenac
In vivo nepafenac easily crosses corneal and retinal tissues following topical ocular administration
In this context the study is intended in exploring the specific application of NSAID eye drops Nepafenac as a promising novel therapeutic approach for treating children with CHED
There are no published reports of human trials for the application of NSAID eye drops in cases of Congenital Hereditary Endothelial Dystrophy
Objectives
To ascertain the clinical utility of topical ophthalmic NSAIDs in reversing or delaying the corneal cloudiness in children with CHED
Study Area Setting Cornea and Anterior Segment Services Kallam Anji Reddy campus L V Prasad Eye Institute Hyderabad
Study Duration 2 Years 15th December 2020- 15th December 2022
Sample Size Since it is a novel study with no other prior works population size will be minimum 30 eyes
Study Population Diagnosed cases of Congenital Hereditary Endothelial Dystrophy fulfilling the inclusion criteria
Study Design Double-blinded Placebo-controlled Simple randomized control trial A Paired eye study
Statistical Method The data of this study will be compared by using the t-test or χ2 test depending if the data is parametric or non-parametric in nature
Methodology
Targeting SLC4A11 mutation using ophthalmic NSAIDs preparation
Test drug is Nepafenac eye drops 01wv Given at the dosage of 4 drops to be instilled in the test eye 1 drop 4 times a day every 4 hourlyThat is at morning afternoon evening and at night This is to be continued for a 6 months duration
Control drug is Carboxy-methylcellulose sodium lubricant eye drops 05wv at the same dosage as the test eye drop but in the control eye
The test eye will be chosen by Simple Randomization For all the cases with an even serial number the Right eye will be the test eye and for the odd numbered cases the Left eye will be the test eye
In order to ensure blinding of the patient and the investigators both the drops will be dispensed in identical bottles and will be relabeled with the letter R and L signifying which eye the patient will be using them This will be done in prior with only one member of the study having the list of the identity of drugs The same person will also be providing the appropriately labeled drug for the patients and will not be a part of clinical evaluation and analysis of the patients data
To check for the patients compliance the patients will be required to get the used bottles at every visit and new ones will be provided Since each bottle contains 5 ml of solution they would last for 25-30 days each as will be our follow-up schedule for the patients
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None