Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04843839 |
| Other study ID # |
LEC-BHR-P-10-20-526 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
December 15, 2020 |
| Est. completion date |
December 15, 2022 |
Study information
| Verified date |
April 2021 |
| Source |
L.V. Prasad Eye Institute |
| Contact |
Neet Y Mehta, MBBS |
| Phone |
9712002747 |
| Email |
mehta.neet28[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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, Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK),
and Descemet's 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 (NSAID's) 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 and/or
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 0.1%w/v. Given at the dosage of 4 drops to be instilled in
the test eye 1 drop 4 times a day (every 4 hourly).That 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 0.5%w/v 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 patient's 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.
