Clinical trial NCT01901614
Conditions: Corneal Opacity Keratoconus
Keywords: Keratoconus Corneal Opacity Keratoplasty
Sponsor: Oregon Health and Science University
Start date: 2013-08-01; Completion date: 2017-08-31
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine if a new procedure, called laser-assisted lamellar anterior keratoplasty (LALAK), can achieve the same level of vision with a lower risk of potential complications after surgery compared to another corneal transplant procedure. The current procedure is called Intralase-enabled keratoplasty (IEK) and replaces the entire cornea.

The LALAK procedure involves transplanting only the top layers of the cornea instead of the entire cornea. Only one eye will have this experimental procedure performed. If both eyes need to have surgery your doctor will help you decide on the best non-study option for your other eye.

Detailed description:
Corneal transplantation (keratoplasty) is the most common organ transplant, with 42,606 procedures in the U.S. in 2009. Many surgeons are moving away from full thickness corneal transplantation, also called penetrating keratoplasty (PK), because of risks involving rejection, irregular astigmatism and wound dehiscence. They are moving towards partial thickness (lamellar) transplantations of either the anterior or posterior (endothelial) layers, which can reduce these risks.

The femtosecond laser has been used to create excellent tongue-in-groove junctions between the graft and host in full thickness PK.1 This technique, called IEK (Intralase-enabled keratoplasty), has now become a standard surgical procedure. The tongue-in-groove junction achieved at the circumferential edge of the graft and host leads to a continuous smooth anterior surface and strong wound healing.

The new technique is called dovetail LALAK. In this technique, the femtosecond laser is used to create a 31% anterior lamellar graft with dove tailed side cuts. It is also used to create a shallow anterior lamellar dissection and beveled side cuts on the recipient cornea to match with the dovetail graft.

In the new technique, the depth of the graft and donor dissections will be guided by OCT measurements. The proposed trial will test if the new technique can reproducibly achieve good visual outcomes without the risk of rejection. The outcome of the LALAK procedure will be compared to that of IEK.

Arms: arm 1: laser-assisted lamellar anterior keratoplasty. Optical Coherence Tomography, femtosecond laser, topical anesthesia, and Retrobulbar Block or General Anesthesia will be used. arm 2: Intralase-enabled keratoplasty. Femtosecond laser and Retrobulbar Block or General Anesthesia will be used.
Interventions: intervention 1: LALAK intervention 2: IEK intervention 3: Retrobulbar Block or General Anesthesia intervention 4: optical coherence tomography (OCT) intervention 5: Topical Anesthesia intervention 6: femtosecond laser
Intervention descriptions: intervention 1: 1. A "dovetail" shaped cut will be made on the graft using a femtosecond laser at the eye bank. The cut depth will be proportional to the central stromal thickness of the graft. This graft will be separated from stromal bed by eye bank personnel for examination of the cut surface. High-quality graft will be replaced in preservation medium and shipped to the surgeon prior to surgery.
2. The host cornea will receive femtosecond laser cut consisting of a shallow lamellar cut with angled side cut to match the dovetail graft in a tongue-in-groove fashion. The femtosecond laser treatments will be performed under topical anesthesia in the laser suite. The femtosecond laser is an FDA-approved device for use in this indication (corneal transplantation including lamellar keratoplasty). A protective eye shield is placed over the eye. The graft will be sutured into the host bed. intervention 2: 1. A full thickness graft will be prepared at the eye bank with zigzag side cuts prepared with a femtosecond laser. The graft is separated from the rim, replaced in the preservation medium, and shipped to the surgeon prior to the surgery.
2. In the laser suite, the host cornea will be cut with the femtosecond laser with zigzag side cuts leaving a 70-100 micron bridge. A protective eye shield is placed over the eye. The graft will be sutured into the host bed. intervention 3: None intervention 4: OCT will be used to guide the depth of the graft and donor dissections. intervention 5: None intervention 6: The femtosecond laser system to be used in this study for host cornea preparation will be the Intralase FS system (iFS, AMO, Inc., Santa Ana, CA). The iFS is FDA-approved for corneal surgery including full thickness and lamellar keratoplasty. Eye banks use earlier versions of the Intralase system which are also FDA approved for this indication.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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RANDOMIZED CLINICAL TRIAL OF OCT-GUIDED LASER-ASSISTED 
LAMELLAR ANTERIOR KERATOPLASTY IN ADULTS FOR 
KERATOCONUS 
 
1. INTRODUCTION 
The purpose of this protocol is to compare and develop new surgical technique of partial-thickness 
corneal transplantation for treating keratoconus.  The new technique, called LALAK, will be tested and 
compared with standard full-thickness corneal transplantation. The new technique replace only the 
anterior portion of the cornea and does not have the risks associated with conventional full-thickness 
corneal transplant methods. Additionally, optical coherence tomography (OCT) will be used to guide the 
depth of the graft and donor dissections.   
 
This protocol seeks to answer the following question: 
 
Can the OCT-guided partial thickness corneal transplant techniques result in 
equivalent surgical outcome as the conventional full-thickness corneal transplant 
for keratoconus?   
 
This study is part of the NIH/NEI funded grant R01EY018184 entitled “Guiding the treatment of anterior 
eye disease with optical coherence tomography in which” one section of this grant is aimed at 
developing OCT-guided laser-assisted lamellar anterior keratoplasty (LALAK).  
 
2. BACKGROUND 
 
Corneal transplantation (keratoplasty) is the most common organ transplant, with 42,606 procedures in 
the U.S. in 2009. Many surgeons are moving away from full thickness corneal transplantation, also 
called penetrating keratoplasty (PK), because of risks involving rejection, irregular astigmatism and 
wound dehiscence.  They are moving towards partial thickness (lamellar) transplantations of either the 
anterior or posterior (endothelial) layers, which can reduce these risks.   
 
The femtosecond laser has been used to create excellent tongue-in-groove junctions between the graft 
and host in full thickness PK.1 This technique, called IEK (Intralase-enabled keratoplasty), has now 
become a standard surgical procedure.  The tongue-in-groove junction achieved at the circumferential 
edge of the graft and host leads to a continuous smooth anterior surface and strong wound healing. 
 
The new technique is called LALAK.  In this technique, the anterior lamellar graft is prepared by one of 
the following two approaches: 1). the femtosecond laser is used to create an  anterior lamellar graft with 
dove tailed side cuts, The cut depth will be proportional to the central stromal thickness of the donor 
cornea. 2). microkeratome is used to create an anterior lamellar graft of about 300 microns  The 
femtosecond laser is also used to create a shallow anterior lamellar dissection and beveled side cuts 
on the recipient cornea to match the graft.  The excimer laser is then used to create a smooth lamellar 
bed. 
 
In the new technique, the depth of the graft and donor dissections will be guided by OCT 
measurements.  The proposed trial will test if the new technique can reproducibly achieve good visual 
outcomes without the risk of rejection. The outcome of the LALAK procedure will be compared to that of 
IEK.  
 


 
 
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3. INCLUSION CRITERIA  
 
Eyes with keratoconus that cannot be adequately or safely corrected with spectacles, contact lens or 
excimer laser surface ablation. The cornea must have healthy endothelium (endothelial cell density > 
1,500/mm2).    
 
4. EXCLUSION CRITERIA  
1. Preoperative corneal thickness less than 300 microns. 
2. Corneal edema 
3. Central guttata 
4. Inability to give informed consent.  
5. Inability to maintain stable fixation for OCT imaging. 
6. Inability to commit to required visits to complete the study. 
7. Eyes with concurrent cataract, retinal diseases, glaucoma, or other eye conditions that may limit the visual 
outcome after surgery.  
8. Patients with severe collagen vascular diseases or ocular surface disorders 
 
5. SUBJECT CHARACTERISTICS  
 
The study will include adults 18 years of age or older. 
 
6. STUDY DESIGN 
 
A prospective, randomized interventional trial will be conducted in 64 adult subjects with keratoconus. 
The study subjects will be selected from the study subjects enrolled in the observational study of 
keratoconus, corneal opacity and post-keratoplasty eyes in adults (IRB 6612). One eye of each subject 
will receive a LALAK procedure or IEK.  The procedure will be randomly assigned: 
 
 
1/2 of the subjects will receive LALAK 
 
11/2 of the subjects will receive IEK   
 
If both eyes are eligible, the eye to be treated will be randomized in addition to the treatment 
randomization.  The eye that is not randomly chosen for treatment will not be included in the study and 
handled independently of the study eye and as determined by the attending physician. 
 
The OCT systems to be used in this study will be the RTVue-XR (Optovue, Inc., Fremont, CA) or the 
Visante (Carl Zeiss Meditec, Inc., Dublin, CA).  Both are FDA-approved for the mapping of corneal 
thickness. 
 
The femtosecond laser system to be used in this study for host cornea preparation will be the Intralase 
FS system (iFS, AMO, Inc., Santa Ana, CA).  The iFS is FDA-approved for corneal surgery including 
full thickness and lamellar keratoplasty.  Eye banks use earlier versions of the Intralase system which 
are also FDA approved for this indication.  The iFS has been used by several investigators to 
successfully perform PK using zigzag,2 mushroom,3 and tophat 4, 5 configurations.  It has also been 
used to facilitate big-bubble DALK using the zigzag configuration.6-8 
 


 
 
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The LALAK for keratoconus:  
a. Both fresh corneal tissue and VisionGraft sterile cornea allograft will be considered for use as the 
graft tissue. VisionGraft is currently approved for use in lamellar keratoplasty. One of the two 
methods will be use to prepare the graft tissue: 1). a “dovetail” shaped cut will be made on the graft 
using a femtosecond laser at the eye bank. The cut depth will be proportional to the central stromal 
thickness of the graft. 2). microkeratome is used to create an anterior lamellar graft of about 300 
microns at the eye bank. This graft will be separated from stromal bed by eye bank personnel for 
examination of the cut surface.  High-quality graft will be replaced in preservation medium and 
shipped to the surgeon prior to surgery. 
b. The host cornea will receive femtosecond laser cut consisting of a shallow lamellar cut with angled 
side cut to match the graft in a tongue-in-groove fashion.    The central cornea will then be ablated 
with the excimer laser to the desired depth using predetermined settings.  Both laser treatments will 
be performed under topical anesthesia. The femtosecond laser is an FDA-approved device for use 
in this indication (corneal transplantation including lamellar keratoplasty). The excimer laser is FDA-
approved for refractive surgery but will be used off-label for the preparation of the host stromal bed. 
10, 11 The excimer laser ablations will consist of a combination of hyperopic astigmatism and myopic 
ablations as is commonly used in phototherapeutic keratectomy off-label treatments. A protective 
eye shield is placed over the eye. 
c. The patient is transported to an operating room in the Casey Eye Institute Outpatient Surgery 
Center.  Retrobulbar block or general anesthesia is given as is customary for corneal 
transplantation surgery. 
d. The graft will be sutured into the host bed.   
 
The IEK technique:  
a. A full thickness graft will be prepared at the eye bank with zigzag side cuts prepared with a 
femtosecond laser. The graft is separated from the rim, replaced in the preservation medium, and 
shipped to the surgeon prior to the surgery. 
b. In the laser suite, the host cornea will be cut with the femtosecond laser with zigzag side cuts 
leaving a 70-100 micron bridge. A protective eye shield is placed over the eye. 
c. The patient is transported to an operating room in the Casey Eye Institute Outpatient Surgery 
Center.  Retrobulbar block or general anesthesia is given as is customary for corneal 
transplantation surgery. 
d. The graft will be sutured into the host bed.   
 
Postoperative medications in the operative eye will include a 4th generation flouroquinolone eye drop to 
prevent infection (such as gatifloxacin 0.3%) 4 times daily for 1 week or longer, until the surface is re-
epithelialized. Prednisolone acetate 1% eye drops will be used 4 times daily for 1 week, 3 times daily 
for 3 weeks, twice daily for 1 month, and once daily for 1 month to prevent inflammation This drop 
regimen is standard post-operative treatment for patients receiving PK via the physicians in the Cornea 
department at Casey Eye Institute.  
 
Clinic staff will confirm with subjects’ insurance companies prior to surgery that the cost of surgery will 
be covered. The OCT will be charged to the study as well as the use of the femtosecond laser. The 
surgeons will waive their fee for the laser treatment in order to reduce the amount charged to the study. 
 
7. DATA COLLECTION, MANAGEMENT AND ANALYSIS  
 
a. Informed Consent:  


 
 
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Patients attending Casey Eye Institute clinics will be invited to participate in the study.  Informed 
consent for participation in the study will be discussed and obtained by the time of their initial visit.  
 
.   
b. Assignment of Study Identification Number 
 
All patients that sign a consent form will be assigned a study identification number (Study ID).  This 
number will be assigned by the study coordinator in chronological order, using the next available 
number on the AED OCT Coordinating Center subject tracker spreadsheet.   
 
 
c. Subject Data Collection 
 
OCT and ancillary testing will be performed by trained ophthalmic technicians and photographers. Clinical 
history will be obtained by the clinical investigators and ophthalmic technicians. Eye examinations will be 
performed by clinical investigators who are board-certified ophthalmologists.  Surgeries will be performed 
by clinical investigators who are board-certified ophthalmologists and fellowship-trained specialists in 
corneal and refractive surgery. OCT will be performed specifically for the study.  
 
The following information will be collected: 
1. OCT images and derived measurements 
2. Corneal topography. 
3. Clinical history  
4. Record of eye examination  
5. Demographic information  
6. Results of ancillary testing  
7. Details of surgical procedures performed, postoperative management, clinical and visual outcomes. 
 
d. Clinical Procedures 
Patients will be examined 1 day, 1 week, 1 month, 3-5, 6-8, 12-14 and 22-24 months.  
 
Slit-lamp photography, OCT scans, confocal microscopy, topography, refraction, and visual acuity will 
be acquired preoperatively and 3-5, 6-8, 12-14 and 22-24 months after the surgery. The primary 
outcome measures will be best spectacle-corrected visual acuity (BSCVA) using the Snellen chart and 
intraoperative perforation rate. Secondary outcome measures will be postoperative refractive error, 
topographic astigmatism, interface clarity (masked OCT and confocal microscopy grading), endothelial 
cell count (specular microscopy), and complications (rejection, interface opacification, others).  
 
Table 1  Visit Schedule 
 
Initial Visit 
 
Visit 1 
1 D 
(± 1d) 
Visit 2 
1 Wk 
(± 1d) 
Visit 3 
1 Mo 
(±1wk) 
Visit 4  
4 mo 
(±1mo) 
Visit 5 
7 mo 
(±1mo) 
Visit 6 
13 mo 
(±1mo) 
Visit 7 
23 mo 
(±1mo) 
Informed consent  
X 
 
 
 
 
 
 
 
Initial history 
X 
 
 
 
 
 
 
 
Interval history 
 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Photography 
X 
 
 
 
X 
X 
X 
X 


 
 
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Specular Microscopy 
X 
 
 
 
 
X 
 
X 
Topography 
X 
 
 
 
X 
X 
X 
X 
Refraction 
X 
 
 
 
X 
X 
X 
X 
BSCVA 
X 
 
 
 
X 
X 
X 
X 
OCT 
X 
 
 
 
X 
X 
X 
X 
Surgery 
 
X 
 
 
 
 
 
 
e.  
e. Data Analysis and Outcomes– 
Postoperative refractive error, topographic astigmatism, interface clarity (masked OCT and 
confocal microscopy grading), endothelial cell count, and complications.   
 
f. Data and Safety Monitoring Plan 
A Data and Safety Monitoring Plan (DSMP) has been developed in order to oversee the safety 
activities of this protocol.  This DSMP is included as part of the NIH/NEI grant application 
2R01EY018184 which is included with this IRB application.  
 


 
 
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REFERENCES  
 
1. Nuzzo V, Aptel F, Savoldelli M, et al. Histologic and ultrastructural characterization of corneal femtosecond 
laser trephination. Cornea 2009;28(8):908-13. 
2. Farid M, Kim M, Steinert RF. Results of penetrating keratoplasty performed with a femtosecond laser 
zigzag incision initial report. Ophthalmology 2007;114(12):2208-12. 
3. Buratto L, Bohm E. The use of the femtosecond laser in penetrating keratoplasty. Am J Ophthalmol 
2007;143(5):737-42. 
4. Steinert RF, Ignacio TS, Sarayba MA. "Top hat"-shaped penetrating keratoplasty using the femtosecond 
laser. Am J Ophthalmol 2007;143(4):689-91. 
5. Kaiserman I, Bahar I, Rootman DS. Half-top-hat--a new wound configuration for penetrating keratoplasty. 
Br J Ophthalmol 2008;92(1):143-6. 
6. Price FW, Jr., Price MO, Grandin JC, Kwon R. Deep anterior lamellar keratoplasty with femtosecond-laser 
zigzag incisions. J Cataract Refract Surg 2009;35(5):804-8. 
7. Buzzonetti L, Laborante A, Petrocelli G. Standardized big-bubble technique in deep anterior lamellar 
keratoplasty assisted by the femtosecond laser. J Cataract Refract Surg 2010;36(10):1631-6. 
8. Farid M, Steinert RF. Deep anterior lamellar keratoplasty performed with the femtosecond laser zigzag 
incision for the treatment of stromal corneal pathology and ectatic disease. J Cataract Refract Surg 
2009;35(5):809-13. 
9. Krumeich JH, Schoner P, Lubatschowski H, et al. [Excimer laser treatment in deep lamellar keratoplasty 
100 micrometer over Descemet's membrane]. Ophthalmologe 2002;99(12):946-8. 
10. Spadea L, Giammaria D, Fiasca A, Verrecchia V. Excimer laser-assisted lamellar keratoplasty for the 
surgical treatment of keratoconus. J Cataract Refract Surg 2009;35(1):105-12. 
11. Kornmehl EW, Steinert RF, Puliafito CA. A comparative study of masking fluids for excimer laser 
phototherapeutic keratectomy. Arch Ophthalmol 1991;109(6):860-3.