Implantable Miniature Telescope

(IMT™by Dr. Isaac Lipshitz) for

End-Stage Age-Related Macular Degeneration

P050034

Presentation to the Ophthalmic Devices Advisory Panel

July 14, 2006

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Implantable Miniature TelescopeTM(IMT by Dr. Isaac Lipshitz)

for End-Stage AMD

Introduction
Judy F Gordon, DVM –Clinical and Regulatory Consultant
Background and Device Description
Jeffrey S Heier, MD –Medical Monitor Retina, Clinical Investigator
Surgical Procedure and Study Design
Stephen S Lane, MD –Medical Monitor Anterior Segment, Clinical Investigator
Effectiveness Outcomes
Jeffrey S Heier, MD -Clinical Investigator
Safety Outcomes
Doyle Stulting, MD, PhD -Clinical Investigator
Discussion and Questions from Panel
Drs. Gordon, Lane, Heier, Stulting
Mark Bullimore, MCOptom, PhD –Low Vision, Vision Science Consultant
Yi-Jing Duh, PhD -Statistician
Henry Edelhauser, PhD –Specular Microscopy Reading Center
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P050034

Implantable Miniature Telescope(by Dr. Isaac Lipshitz)

The IMT is indicated for use in adult patients with bilateral, stable moderate to profound central vision impairment (20/80 to 20/800)due to macular degeneration

Patients selected for implantation should meet the following criteria:

55 years of age or older with bilateral, stable central vision deficit resulting from AMD as determined by fluorescein angiography, and evidence of cataract
Distance BCVA between 20/80 and 20/800, and adequate peripheral vision in one eye (the non-implanted eye) to allow for orientation and mobility
Achieve at least a five-letter improvement on the ETDRS chart in the eye scheduled for surgery using an external telescope
Show interest in participating in a postoperative visual rehabilitation program
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Background and Device Description

Jeffrey Heier, MD

Medical Monitor, Retina

Clinical Investigator

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End-Stage Age Related

Macular Degeneration

Approximately 60,000 to 80,0000 cases per year in the U.S.1,2
Majority of patients are legally blind as a result of central vision loss in botheyes due to:
Dry AMD (geographic atrophy)
No treatment available
Stable wet AMD (disciform scar)
Completed all laser and drug treatments for exudation in and around the macula

1!AREDs Report No. 11. Arch Ophthalmol 2003;121:1621-1624

2Wang JJ et al. Bilateral involvementbyage-relatedmaculopathylesions in a population. Br J Ophthalmol 1998;82:743-747

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Vision with and without Scotoma

Normal Central Vision

End-Stage AMD

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Effect on Functional Status

End-stage AMD has a profound effect on Activities of Daily Living (ADL)
Patients have extreme difficulty with:

Household Activities/Self-Care

Preparing tea, shaving, make-up

Social Interaction

Recognizing friends, facial expressions

Reading or TV/Computer

News, leisure reading

Consumer Interaction

Identifying products and paying

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Current Options for Patient Management in End-Stage AMD

Visual rehabilitation and training in the use of low vision aids, including external telescopes, loupes, hand-held magnifiers for reading, illumination
Limitations of current treatment
Only 30% of visually impaired adults use optical devices per Lighthouse National Survey on Vision Loss (1995)
Low utilization of rehabilitation services
Limited psychosocial benefits
Difficulty using low vision aids in both static and dynamic activities
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Optical prosthesis
Two models -WA2.2X, WA3.0X
Improves central vision
Distance/near vision refined with
with spectacles
Quartz tube housing with
two wide angle microlenses
Diameter 3.6 mm
Length 4.4 mm
Carrier haptic 13.5 mm diameter

The Implantable Miniature Telescope(IMT™by Dr. Isaac Lipshitz)

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Designed to improve vision by magnifying the retinal image
Key differences from external telescopes
Wide visual field
Natural eye movements
Normal cosmetic appearance

Projection on Retina

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Enlarges retinal image 2.2x or 2.7x
Reduces relative size of scotoma
Enlarges and positions relevant information on seeing retina

Enlargement of Retinal Image

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Field of View

External vs Implantable Telescopes

Magnification

External Telescope on Spectacles

Wide Angle Implantable Telescope

2.2x

13°

24°

3.0x, 2.7x

5-6°

20°

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Preoperative Measurement of Scotomaand Simulation of Effect in Study Subject

Simulation

Measurement of Scotomaat Baseline

Eli Peli, OD

SchepensEye Institute

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Measurement of Magnified Field of View and Scotomathrough a 2.2X External Telescope

10°Field of View, Restricted Superiorly by Scotoma

Simulation

Eli Peli, OD

SchepensEye Institute

CText Box: Preoperative of the Field of View and Scotoma through an External Telescope in Study SubjectC

25°Field of View and Relative Reduction in Scotoma

Eli Peli, OD

SchepensEye Institute

Measurement of Magnified Field of View and Scotomathrough IMT

CText Box: Postoperative View Through the Implanted Telescope in Study SubjectC

Surgical Procedure

Stephen Lane, MD

Medical Monitor, Anterior Segment

Clinical Investigator

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Unique Geometrical and Surgical Considerations for the Implantable Telescope

Standard IOL

Implantable Telescope

Loading ImageCCC
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Corneal Clearance

Source: not in PMA

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CText Box: Appearance of Implantable Telescope in the Eye6 Weeks PostoperativeC

Visualization of Retina through the Implantable Telescope

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Clinical Study Investigators

Carl Baker,MD Paducah, KY

Dennis Han, MDMedical College of Wisconsin

SrinivasReddy Sadda, MDDohenyRetina Institute

Daniel Berinstein, MDChevy Chase, MD

Jeffrey Heier, MDBoston, MA

Oliver D. Schein, MDWilmer Eye Institute

David Chang, MDLos Altos, CA

Henry Hudson, MDTucson, AZ

Lawrence J. Singerman, MDBeachwood, OH

Brian Connolly, MDWills Eye Institute

Manus Kraff, MDChicago, IL

Jason S. Slakter, MDManhattan Eye & Ear

Doug Dehning, MDIndependence, MO

Baruch Kuppermann, MDUniversity of California, Irvine

Paul Sternberg, MDVanderbilt University

Sharon Fekrat, MDDuke University Eye Center

Stephen S. Lane, MDStillwater, MN

Donald Stewart, MDCharlotte, NC

Howard Fine, MDEugene, OR

Robert Leonard, MDDean A. McGee Eye Institute

Michael T. Trese, MDRoyal Oak, MI

Stephen Fisher, MDSan Antonio, TX

Paul R. Lichter, MDKellogg Eye Center

KeyeWong, MDSarasota, FL

M. Bowes Hamill, MDBaylor College of Medicine

Dan Martin, MDEmory University Eye Center

Seth Yoser, MDMemphis, TN

Joan Miller, MD/Kathryn Colby,MDMassachusetts Eye & Ear Infirmary

Protocol IMT-002 -Study Design

Patients screened using external telescope in
office and home environment
Gain >5 letters BCDVA with telescope was required to
qualify for enrollment
Monocular implantation
In worse seeing eye if one or both eyes better than 20/200
Doctor/patient select if both eyes less than 20/200
Visit schedule
Day 1, Week 1, Months 1, 3, 6, 9, 12, 18, 24
Vision training
Weeks 1, 2, 4, 6, 10 and 12
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Key Eligibility Criteria

Bilateral, stable, untreatable AMD on fluorescein angiography
Distance BCVA of 20/80 to 20/800
Adequate peripheral vision in fellow eye to allow for navigation
Improvement in BCDVA of >5 letters on ETDRS chart with the external telescope in the eye scheduled for surgery
Anterior chamber depth of ≥2.5mm on A-scan
Endothelial cell density>1600 cells/mm2
Manifest sphere between +4.0 to -6.0 D
Axial length >21 mm
Schaffer grade >2
Controlled glaucoma
No corneal stromal or endothelial dystrophies or disorders, inflammatory ocular disease, zonularweakness, pseudoexfoliation, retinal pathology other than stable end-stage AMD
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Study Methods

Distance visual acuity (BCDVA) –all study visits
Measured with standard ETDRS charts (C110 and C105) with retro-illuminated box; LogMAR computed
Near visual acuity (BCNVA) –all study visits
Measured with ETDRS chart (Precision Vision Chart 2000);
LogMAR computed
VFQ-25 and Activities of Daily Living (ADL) Questionnaires –baseline through 12 months
Administered by trained study personnel
Specular microscopy –baseline through 24 months
Images analyzed by central reading center
(H. Edelhauser, B. McCarey, Emory University)
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Vision Training/Rehabilitation Protocol

Goal to provide patients with the skills to adjust to the IMT and achieve optimal functionality
Conducted by low vision professionals at each clinical site
Five fundamental skills
Localizing-locating an object of interest in the IMT field of view. If difficult, the patient first looked at the object with both eyes, then obscuredthe fellow eye and tried again with implanted eye
Fixating–performed by the implanted eye to enable object identification
Scanning–natural eye movement performed by the implanted eye
Tracing–following a path between objects of interest
Tracking-ability to follow a moving object
Training for distance activities, intermediate distance, readingand writing, static and dynamic environments
IMT bi-ocular function: initial training performed with the fellow eye patched to promote use of the IMT
Fellow eye patched for training in static vision
Implanted eye patched for motility training
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Protocol IMT-002

Safety and Effectiveness Endpoints

Effectiveness Parameters

Change in lines of best corrected visual acuity
Quality of life -VFQ-25 and ADL questionnaires

Safety Parameters

Preservation of best corrected visual acuity
Endothelial cell loss
Adverse events and complications
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Protocol IMT-002

Baseline Information and Effectiveness Data

Jeffrey Heier, MD

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Patient Accountability

1 patient withdrawal

11 eyes not implanted

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Demographic and Baseline Information

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Effectiveness Outcomes

Visual Acuity

NEI VFQ-25, ADL

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Improvement in Distance or Near Vision

at 12 Months (N = 193)

Source: PMA Table A11

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Improvement in Distance or Near Vision

at 24 Months (N = 147)

Source: PMA Table A13

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Improvement in Distance Vision

Source: PMA Table A7

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Improvement in Near Vision at 8”(20 cm)

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Improvement in Near Vision at 16”(40 cm)

Source: PMA Table A9

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Improvement in Distance andNear Vision

Source: PMA Table A11, A12, A13

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Gain ≥2 Lines in Distance Vision at 12 Months Stratified by Age, Gender, Baseline Visual Impairment, Model

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Mean Gain in Distance Vision at

12 Months vs Expected Benefit from Magnification

Source: not in PMA

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Mean Gain in Distance Vision at

Baseline vs Expected Benefit from Magnification

with External Telescope

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National Eye Institute VFQ-25

Validated quality of life questionnaire developed by Mangione etal1,2sponsored by NEI
Assesses vision-targeted functioning3by measuring impact of vision problems on health-related QOL in many eye diseases
Patient reported outcomes, reflects effect of improvement in vision on functionality, quality of life
Validated instrument, employed in numerous clinical trials
DHHS, Agency for Healthcare Research and Quality, Technology Assessment Program, Vision Rehabilitation for Elderly Individuals with Low Vision or Blindness, Oct. 2004, pg 58, QOL

“This outcome measure may be the most meaningful of all measures. This is because an individual’s ability to perform activities of daily living, mood, psychological status, and any adverse events associated with theintervention should –if these changes are meaningful –be reflected by changes in the individual’s quality of life.”

1 Mangione et al. Arch Ophthalmol 2001:119:1050-8

2 Mangione et al. Arch Ophthalmol 1998;116:1496-1504

3 Clemons et al. Arch Ophthalmol 2003;21:211-7

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NEI VFQ-25

A total of 25 items representing 12 subscales
General vision -1 item
Near activities -3 items (newsprint, up close, objects on shelf)
Distance activities -3 items (movies, stairs, street signs)
100 point scale, 0 = worst, 100 = best
Clinical relevance established -5-10 point change corresponds to a 2 to 3 line change in vision1
Defined scoring algorithm

1 Globe et al. Ophthalmol 2004;111:1141-9

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Change from Baseline on VFQ-25 Subscales

at 12 Months

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Source: not in PMA

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Change from Baseline on VFQ-25 Subscales

IMT vs Low Vision Services

Source: not in PMA

Text Box:        *Scott IU, et al. Quality of life of low-vision patients and the impact of low-vision services. AJO 1999;128:5C

Distribution of Outcomes on VFQ-25 at 12 Months for

Subjects Reporting Extreme Difficulty at Baseline

Questions 5 through 9

Source: not in PMA

BASELINE

VFQ5

Reading Newspaper

VFQ6

Hobbies

VFQ7Finding on Crowded Shelf

VFQ8

Street Signs and Stores

VFQ9

Stairs, or Curbs in Dim Light

Patients who stopped activity or had extreme difficulty

N = 185

N = 112

N = 101

N = 144

N = 71

12 MONTHS

Stopped activity

59%

17%

2%

23%

12%

Had extreme difficulty

26%

27%

37%

29%

28%

Moderate difficulty

9%

41%

43%

29%

41%

No or little difficulty

5%

15%

18%

19%

18%

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Activities of Daily Living

Change in Subscales from Baseline

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Summary of Effectiveness

Protocol target for effectiveness significantly exceeded
85% gain >2 lines distance or near
60% gain >3 lines distance or near
50% gain >3 lines distance andnear
IMT performed as intended, with study subjects on average achieving the predicted gain in vision based on magnification
Significant relationship between gain in
BCVA and improvement in VFQ-25
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Safety Outcomes

Doyle Stulting, MD, PhD

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Safety Parameters

Loss of lines of acuity
Intraocular pressure
Complications
Adverse events
Endothelial cell density (ECD)
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Change in Distance Vision

Baseline to Last Available Visit

Source: not in PMA

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Mean Gain in BSCVA

Expected Change from Magnification

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Mean Gain in BSCVA

Expected Change from Magnification

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Intraocular Pressure

Mean, Change from Baseline

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Operative and PerioperativeComplications

Cumulative Incidence ≥1%

All Eyes –Implanted (N = 206) and Non-Implanted (N = 11)

Source: A004 Table 46, 48; A003 Table 46 rev., 14.2-14.6

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Ocular Adverse Events

Cumulative Incidence <5% (N = 206)

Source: A004 Table 46, 48; A003 Table 46 rev., 14.2-14.6

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Ocular Adverse Events with Incidence ≥5%

(N = 206)

Source: A004 Table 46, 48; A003 Table 46 rev., 14.2-14.6; persistent AE not in PMA

Cumulative

Persistent (≥ 1 Year)

Iris transillumination defects

11 eyes (5.3%)

10 eyes (5.1%)

Iritis

12 eyes (5.8%)

0 eyes (0%)

Posterior synechiae

15 eyes (7.3%)

9 eyes (5%)

Guttae

16 eyes (7.8%)

15 eyes (7.6%)

Pigment deposits on IMT

23 eyes (11.2%)

15 eyes (7.6%)

Inflammatory deposits on IMT

51 eyes (24.8%)

32 eyes (16.2%)

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Inflammatory Deposits on IMT

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Inflammatory Deposits on IMT

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IMT Removals

(N = 8)

Device failures (N=2)
Dissatisfaction with outcome (N=4)
Corneal decompensation (N=2)
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IMT Removal Due to Device Failure

(N = 2)

??????????,?????????,?????????????8????????,??Text Box: Condensation in the telescopeCracks in lateral wall of the telescopeNo recurrences afterPhysician training on hand

IMT Removal Due to Dissatisfaction

(N = 4)

Four subjects dissatisfied with outcome
Three subjects requested removal of the IMT based on complaints of glare in bright light
One subject complained of haze, loss of peripheral vision in implanted eye, loss of depth perception
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IMT Removal Due to Corneal Decompensation

(N = 2)

Operative complications
In both eyes, positive vitreous pressure during implantation resulted in iris prolapse andshallowing of the anterior chamber, and significant early endothelial cell loss
In one of the two cases, one haptic was placed in the capsular bag and the other, in the sulcus
Corneal transplantation and IOL exchange was performed
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Major Non-Ocular Adverse Events

(N = 206)

Source: PMA Table A49

Arrhythmia

7 subjects

3.4%

Cancer

12 subjects

5.8%

CVA/TIA

5 subjects

2.4%

Death

10 subjects

4.9%

Falls

3 subjects

1.5%

Fractures

5 subjects

2.4%

Infection

19 subjects

9.2%

Myocardial Infarction

5 subjects

2.4%

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Major Non-Ocular Adverse Events

(N = 206)

Source: PMA Table A49

Arrhythmia

7 subjects

3.4%

Cancer

12 subjects

5.8%

CVA/TIA

5 subjects

2.4%

Death

10 subjects

4.9%

Falls

3 subjects

1.5%

Fractures

5 subjects

2.4%

Infection

19 subjects

9.2%

Myocardial Infarction

5 subjects

2.4%

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Fractures/Falls (N = 8)

Patient ID

Description of Event

Relationship to IMT(Per Investigator)

008-21363-year-old male

Patient slid off ladder and fractured heel bone

Not Related

010-20961-year-old female

Patient fell 4 weeks after knee replacement, required right knee repair

Not Related

014-20275-year-old male

Fracture of the femur from a fall from a chair while attempting to pick up an object

Not Related

014-20483-year-old female

Patient hurriedly stood up to see across the street, tripped, fell, fractured wrist

Not Related

019-20473-year-old female

Patient fell out of bed

Not Related

023-20488-year-old female

Patient lost balance and fell

Not Related

023-21278-year-old female

Patient was sexually assaulted and, in addition to other trauma, fractured toe

Not Related

026-20785-year-old female

Patient stumbled backwards over her slipper, fell and fractured her hip

Not Related

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Falls in the Elderly

Source: Beaver Dam Eye Study

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Endothelial Cell Density

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Specular Microscopy Methods

Images analyzed at Emory University Specular Microscopy Reading Center (H Edelhauser, B McCarey)
Endothelial images were scanned and then analyzed with Konan KSS-300 software
3 images per eye (implanted eye and fellow) for each visit were analyzed and the mean was calculated
Specular images were difficult to obtain in the study population
At baseline, some difficulty fixating due to scotoma
Glare and reflection from the anterior surface of the IMT
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Specular Microscopy

Estimates of Precision

Best case -2% SD (47 cells) for a single clinical site, single photographer imaging his own eye, and a single reader1
For multicenter study, precision varies from 8% to 10% with a single reader

1Jones SS et al. Effect of laser in situkeratomileusison the corneal endothelium. AJO 1998;125:465-71

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Specular Images from Subject 23-201

Male, 79 Years of Age, Pseudophakic Fellow Eye

OS -IMT-Implanted Eye at 3 Months

1805 cells/mm2

OD -Fellow Eye at 3 Months

1798 cells/mm2(pseudophakic)

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Results of Specular Microscopy

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Endothelial Cell Density

IMT-Implanted Eyes (mean, SD)

ECD (cells/mm2)

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Percentage Change in ECD from Baseline

IMT-Implanted Eyes (mean, SD)

Source: PMA Table A29

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ECD In Subjects With

Pseudophakic Fellow Eyes

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ECD (mean, SD) for IMT-Implanted Eyes,

Pseudophakic and Phakic Fellow Eyes

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Percentage Change (mean, SD) in ECD Between Consecutive Visits

IMT-Implanted Eyes vs Pseudophakic & Phakic Fellow Eyes

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How does the loss in ECD following

IMT implantation compare to published data on

conventional cataract surgery?

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What factors contributed to the acute and the overall reduction in ECD?

Candidate Predictive Factors

Day 1 corneal edema
ACD
Surgical Order
Incision Type
Incision Size
Age at implantation
Preoperative ECD
Surgeon
Axial Length
Use of HealonV
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Factors Affecting Change in ECD

Final Models

Source: PMA Table A39; A002 Table Q3.5.9

3 Month Change in ECD

Day 1 Corneal Edema

<.0001

Surgeon's Specialty

0.0336

Total Change in ECD

Day 1 Corneal Edema

<.0001

Surgeon's Specialty

0.0336

Surgical Order

0.0023

Day 1 Corneal Edema and Surgical Order Interaction

0.0679

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Percentage Change in ECD Stratified by Surgeon’s Specialty

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Percentage Change in ECD Stratified by Surgeon’s Specialty and Surgical Order

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Effect of Anterior Chamber Depth on Change in ECD

Linear effect on % change in ECD for surgical order ≤3 cases
p=0.01 for baseline to 3 months
p=0.03 for baseline to 24 months
Noeffect for surgical order ≥4 cases
p=0.20 for baseline to 3 months
p=0.13 for baseline to 24 months
Predictive power (coefficient of determination or R2)is low
0.05 for baseline to 3 months
0.07 for baseline to 24 months

Source: A003 Table 3.1A, 3.3A

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How can we mitigate these contributors to endothelial cell loss?

Surgeon training
Extensive training program described in PMA
Meticulous attention to surgical detail to avoid iris prolapse, flat anterior chamber and Day 1 corneal edema
Suggest high ECD and deep ACD for first 5 cases for each surgeon
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Following the initial surgical loss, does the rate of ECD loss decrease over time?

Percentage Change (mean, SD) in ECD Between Consecutive Visits

IMT-Implanted Eyes vs Pseudophakic & Phakic Fellow Eyes

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Annual Percentage Change in ECD

Source: PMA Table A37; A002 Table Q6.6

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Relationship Between Early Loss of ECD and Later Loss of ECD

ECD at 3 months is notpredictive of the rate of ECD loss at later time points
No difference in corneas with 3-month loss of
ECD <20% vs loss of ECD > 20%
No difference in corneas with 3-month loss of ECD <1000 cells/mm2 vsECD > 1000 cells/mm2

Source: PMA Table A37; A002 Table Q6.6

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What is the rate of ECD loss more than two years after implantation?

Three-Piece Regression Model

Change in rate of endothelial cell loss at
3 and 9 months
Consistent with pathophysiologyof endothelial cell loss after intraocular surgery
Acute loss at time of surgery
Endothelial cell migration
Continuing, long-term loss
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Chronic Change in ECD

Baseline ECD 1600, 2000 and 2500 cells/mm2and ACD 3.0 mm

Piecewise Regression Model (3-Piece)

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How can the corneal endothelium be protected?

Recommendations

Establish a minimum endothelial cell density based on age and life expectancy
High ECD and deep ACD for the first 5 cases
Comprehensive surgeon training program
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How can the loss in ECD be balanced against the

significant improvement in vision and quality of life?

Source: not in PMA

??????????,?????????,?????????????8????????,??Text Box: Change in ICD-9-CM Categories for Visual Impairment in IMT-Implanted Eyes

Source: not in PMA

??????????,?????????,?????????????8????????,??Text Box: Change in ICD-9-CM Categories for Visual Impairment in IMT-Implanted Eyes
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Implantable Miniature Telescope

Defined risk, not substantially
different from that of routine,
modern, cataract surgery
Risk is manageable by
Training
Appropriate selection of subjects
Informed consent
Multidisciplinary approach, including postoperative visual rehabilitation
Substantial improvement in functional vision for an under-served population with limited treatment options
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