Amniotic Membrane Graft In Syntomathic Bullous Keratopathy (AMBUK)

August 22, 2013 updated by: RICARDO ARIS, Universidad de Valparaiso

Comparative Analysis of Human Amniotic Membrane Graft Versus Contact Lenses in Syntomathic Bullous Keratopathy

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Chile
      • Valparaíso, Chile
        • Universidad de Valparaiso

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Implant of amniotic membrane grafts
Amniotic membrane 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
Procedure: Implant of amniotic membrane grafts
Amniotic membrane 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
Active Comparator: Therapeutic contact lenses
Therapeutic contact lenses were applied in all patients and the lenses were replaced every two months according to the pre-established gold standard for this procedure.
Device: Therapeutic contact lenses
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ocular pain
Time Frame: 6 months
Evaluated by using a visual analogue scale ranging from 0 to 10
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Visual acuity
Time Frame: 6 months
Snellen scale
6 months
Corneal Neovascularization
Time Frame: 6 months
Evaluation using a bio-microscope
6 months
Corneal epithelial defects
Time Frame: 6 months
Evaluation using a bio-microscope per quadrant with fluorescein test
6 months
Complications
Time Frame: 6 months
Evaluation using a bio-microscope
6 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Age
Time Frame: At the enrolling moment
In years
At the enrolling moment
Sex
Time Frame: At the enrolling moment
Male or Female
At the enrolling moment
Affected eye
Time Frame: At the enrolling moment
left eye or right eye
At the enrolling moment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Universidad de Valparaiso

Collaborators

Universidad de Granada
Instituto para el Desarrollo Biotecnológico y la Innovación S.A.

Investigators

  • Principal Investigator: L. Venegas, Ophthalmology Unit, Van Buren Hospital, Valparaiso, Chile.
  • Principal Investigator: M. Hettich, Ophthalmology Unit, Van Buren Hospital, Valparaiso, Chile.
  • Principal Investigator: J. Villena, Biomedical Research Centre, School of Medicine, Universidad de Valparaiso, Chile.
  • Principal Investigator: R. Aris, Biomedical Research Centre, School of Medicine, Universidad de Valparaiso, Chile.
  • Principal Investigator: M. Párraga, Biomedical Research Centre, School of Medicine, Universidad de Valparaiso, Chile.
  • Principal Investigator: O. Parolini, Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italy.
  • Principal Investigator: M. Alaminos, Department of Histology, University of Granada, Spain
  • Principal Investigator: A. Campos, Biomedical Research Centre, School of Medicine, Universidad de Valparaiso, Chile.
  • Study Director: S, San Martin, Biomedical Research Centre, School of Medicine, Universidad de Valparaiso, Chile.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2011

Primary Completion (Actual)

May 1, 2012

Study Completion (Actual)

June 1, 2012

Study Registration Dates

First Submitted

August 15, 2013

First Submitted That Met QC Criteria

August 17, 2013

First Posted (Estimate)

August 21, 2013

Study Record Updates

Last Update Posted (Estimate)

August 26, 2013

Last Update Submitted That Met QC Criteria

August 22, 2013

Last Verified

August 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RARIS-001

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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