Clinical trial NCT01926535: Amniotic Membrane Graft In Syntomathic Bullous Keratopathy
Official title: Comparative Analysis of Human Amniotic Membrane Graft Versus Contact Lenses in Syntomathic Bullous Keratopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bullous Keratopathy
Keywords: amniotic membrane
contact lens
bullous keratopathy
Lead sponsor: Universidad de Valparaiso
Sponsor class: OTHER
Collaborators: name: Instituto para el Desarrollo Biotecnológico y la Innovación S.A.
name: Universidad de Granada
First posted: 2013-08-21
Enrollment: 20
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The amniotic membrane (AM) is an avascular structure derived from fetus, which is a good choice for regenerative medicine and effective treatment in eye surface pathologies such as bullous keratopathy (BK). This disease generates a chronic corneal edema evolving to the production of vesicles and bullae, chronic eye pain and visual acuity decrease.

Definitive treatment for those patients is corneal transplant; however, donation is not always available and thus requires long waiting times. The currently available palliative treatment consists in the use of contact lenses to prevent the corneal epithelium from falling. However, this may be associated with corneal neovascularization, lens displacement or loss, infections, and discomfort for the patient.

The objective of this work was to compare the use of amniotic membrane grafts versus contact lenses in patients suffering from BK awaiting a corneal transplant.

A randomized clinical trial assay was performed with patients with a clinical diagnosis of BK. Twenty patients were randomized into 2 groups: amniotic membrane and therapeutic contact lenses. Eye pain intensity (Analog visual scale), visual acuity (Snellen questioner), bullae and corneal epithelial defects presence, as well as corneal neovascularization and complications (biomicroscopy) were compared during 6 months.

Detailed description: INTRODUCTION Handling of patients with severe eye surface injuries has always been challenging in the field of ophthalmology. One of the most significant pathologies causing severe injuries is Bullous Keratopathy (BK). This disorder is caused by a failure in corneal endothelial pump (Na+/K+/ATPase) characterized by chronic stromal edema, and it tends to evolve to the production of corneal vesicles and bullae due to the drainage of fluid to the anterior corneal layers as a consequence of intraocular pressure(1). Most common causes of BK are intraocular surgical procedures including those related to cataract surgery(2). This entity conforms the first cause for corneal transplant in the USA (from 26 to 50%) and the second in Europe(3,4,5).

Clinically, BK is characterized by chronic ocular pain, which is secondary to recurrent epithelial defects, ocular surface inflammation and visual sharpness decrease(1). Definitive treatment for patients with BK with remaining visual potential is corneal transplant. However, donor grafts are not always available and they often require long waiting times. For those reasons, medical and surgical palliative measures should be temporarily used to relief ocular pain. Among others, the use of therapeutic contact lenses stands out as one of the best alternatives due to its contribution to the prevention of epithelial falling and ulceration, acting as a mechanical bandage(6,7,8). These contact lenses do not improve visual sharpness neither contribute to the resolution of the problem that originated corneal edema. Besides, prolonged use of contact lenses may be associated to potential complications such as ocular disturbance, superficial neovascularization, inflammation and corneal infections, together with the economical expenses that patients have to deal with(6).

In 1940, De Roth described for the first time the use of human amniotic membrane (AM) in ophthalmology, and since that date, multiple studies guaranteed its application as an efficient treatment for ocular surface diseases(9,10, 11), including BK(12,13,14,15,16,17,18). AM is a thin membrane covering the foetal side of the placenta, and it consists of the external chorion (maternal origin) and the internal amnion (foetal origin). Histologically, it is composed of three layers: epithelium, basal membrane and stroma(19).

The therapeutic effect of the AM involves three basic synergistic actions on the ocular surface: 1) induction of growth and proliferation of new epithelia on the tissues (cornea and/or conjunctiva), 2) control of the inflammation of the tissues under the implant and 3) inhibition of fibrosis and neovascularization of the corneal stroma(19). For all these reasons AM might be an effective treatment to ameliorate disturbances generated by BK. In addition, human amniotic epithelial cells do not express HLA surface antigens, which justifies the absence of graft rejection in this type of transplants(20,21) and makes it a highly safe procedure.

In the present work, we describe the results of a randomized clinical trial in which the AM grafting technique was compared with the use of therapeutic contact lenses for the management of symptomatic bullous keratopathy in patients waiting for a corneal transplant at Carlos Van Buren Hospital from Valparaiso, Chile.

PATIENTS AND METHODS Study design Randomized clinical trial. Patients The universe of this clinical trial are all patients with clinical diagnosis of symptomatic bullous keratopathy (corneal bullae, recurrent eye pain, foreign body sensation and photophobia), diagnosed at the Department of Ophthalmology Hospital Carlos Van Buren, Valparaiso, Chile, who were on the waiting list for corneal transplant from January 2008 to October 2011. Excluded patients were those with medical contraindication to undergo surgery with topical anesthesia, patients with severe systemic conditions and patients with corneal infections.

Twenty patients, corresponding to universe of patients during this period, accepted to participate in this study and were included in this clinical trial. All patients provided written consent to participate in this study, and the trial was approved by the Ethics Committee of the Faculty of Medicine, Universidad de Valparaiso (Nº 10/2011). Patients were randomized on a simple random basis from a prefabricated list and divided into two groups: study group (N=10), with the implant of the AM, and control group (N=10), in which contact lenses were used.

Clinical data and variables considered for the study were: demography, etiology of BK, ocular pain (evaluated by using a visual analogue scale ranging from 0 to 10) and visual acuity (Snellen scale). By using a bio-microscope we evaluated the presence of bullae and epithelial defects per quadrant (with fluorescein test) and neovascularization. After treatment, the same equipment was used to check for presence of traces of AM and complications (infection, wound dehiscence, etc) through serial controls performed over a period of 6 months.

Interventions Human AM was prepared and preserved in the Biomedical Research Centre using a method previously described by Lee and Tseng (1995). In the study group, amniotic membrane (AM) grafts were implanted in the affected eyes using topical anesthesia. Each graft was sutured to the bulbar conjunctive tissue using 10-0 nylon sutures and a reinforcement stitch was applied at the cornea (Figure 1).

Therapeutic contact lenses were applied in all patients included in the control group and the lenses were replaced every two months according to the pre-established gold standard for this procedure.

Clinical follow-up examination was performed on days 1, 7, 30, and then monthly until 6 months for both groups. Both groups were managed with topical gentamicin each 4 hours during the first week after surgery.

Statistical analysis. Data were analysed with Stata SE 12.0 software. Results corresponding to continuous variables were described by medians and interquartile range (IQR) and categorical medians were described by percentages and frequencies. Mann-Whitney statistical test was used to detect statistical differences between two continuous variables, and Fisher exact test was used for categorical variables. Association between quantitative variables was established by Kendal's tau correlation test. For all analysis, a value of p\<0.05 was considered statistically significant and all analyses were carried out double tailed.

Eligibility criteria: Inclusion Criteria:

All patients with clinical diagnosis of symptomatic bullous keratopathy (corneal bullae, recurrent eye pain, foreign body sensation and photophobia), diagnosed at the Department of Ophthalmology Hospital Carlos Van Buren, Valparaiso, Chile, who were on the waiting list for corneal transplant from January 2008 to October 2011

Exclusion Criteria:

Excluded patients were those with medical contraindication to undergo surgery with topical anesthesia, patients with severe systemic conditions and patients with corneal infections.

Primary outcomes:
measure: Ocular pain
timeFrame: 6 months
Secondary outcomes:
measure: Visual acuity
timeFrame: 6 months
measure: Corneal Neovascularization
timeFrame: 6 months
measure: Corneal epithelial defects
timeFrame: 6 months
measure: Complications
timeFrame: 6 months
Other outcomes:
measure: Age
timeFrame: At the enrolling moment
measure: Sex
timeFrame: At the enrolling moment
measure: Affected eye
timeFrame: At the enrolling moment
Locations:
city: Valparaíso
country: Chile
facility: Universidad de Valparaíso
Study officials:
affiliation: Ophthalmology Unit, Van Buren Hospital, Valparaiso, Chile.
name: L. Venegas
role: PRINCIPAL_INVESTIGATOR
affiliation: Ophthalmology Unit, Van Buren Hospital, Valparaiso, Chile.
name: M. Hettich
role: PRINCIPAL_INVESTIGATOR
affiliation: Biomedical Research Centre, School of Medicine, Universidad de Valparaiso, Chile.
name: J. Villena
role: PRINCIPAL_INVESTIGATOR
affiliation: Biomedical Research Centre, School of Medicine, Universidad de Valparaiso, Chile.
name: R. Aris
role: PRINCIPAL_INVESTIGATOR
affiliation: Biomedical Research Centre, School of Medicine, Universidad de Valparaiso, Chile.
name: M. Párraga
role: PRINCIPAL_INVESTIGATOR
affiliation: Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italy.
name: O. Parolini
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Histology, University of Granada, Spain
name: M. Alaminos
role: PRINCIPAL_INVESTIGATOR
affiliation: Biomedical Research Centre, School of Medicine, Universidad de Valparaiso, Chile.
name: A. Campos
role: PRINCIPAL_INVESTIGATOR
affiliation: Biomedical Research Centre, School of Medicine, Universidad de Valparaiso, Chile.
name: S, San Martin
role: STUDY_DIRECTOR
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