AMD Ryan Initiative Study (ARIS)

Objective:

Late age-related macular degeneration (AMD) is the leading cause of blindness among elderly
in the United States. At present, the current classification systems do not take into
consideration advances in imaging technology, visual function biomarkers, as well as
genotyping and phenotyping.

Clinical sites in the United States and around the world will conduct a longitudinal study
that will bring together resources and commitment for the development of a classification
scheme for AMD using imaging and visual function biomarkers, with the plan to correlate
genetic information obtained in the future. These data could eventually help develop an
understanding of the mechanisms involved in the development and progression of AMD. The
project will recruit participants with early AMD or reticular pseudodrusen (RPD) and
controls. All data and images from this longitudinal study will be available to researchers
worldwide to help in the development of visual function biomarker identification and
classification development. The initiative should provide an unparalleled state-of-the-art
standardized phenotype and genotype including AMD status with information on imaging, visual
function and biomarkers, with a particular focus to developing surrogate outcome variables
for proof of principle phase 2 clinical trials.

Study Population:

This cohort study will recruit a minimum of 500 total participants with early AMD or RPD,
including age-matched controls.

Design:

This study is designed as a multi-center, international, prospective, observational cohort
study of participants with early AMD or RPD. Study participants will undergo clinical
assessments, multi-modal imaging and receive the standard of care as determined by the
participant s ophthalmologist.

Outcome Measures:

Further research is necessary to characterize RPD and to understand the progression of AMD
from early to late stage disease. The primary objectives of the longitudinal observational
study are to enroll participants with early AMD (medium size drusen) to assess rate of change
in drusen volume and progression rates to large drusen, and associate these morphologic
changes with psychophysical changes, including visual acuity and dark adaptation. Separately,
participants with RPD (verified by Reading Center review) will be enrolled and followed to
better understand the natural history of RPD as well as to document structural and functional
changes over time and associate them with the psychophysical changes listed above and changes
in quality of life. In addition, control participants with no drusen or little drusen (normal
aging changes) will be enrolled as comparison groups for the early AMD and reticular drusen
groups. Data from this study will be analyzed to identify potential risk factors for disease
progression and possible outcome variables for future studies. The collection of multi-model
imaging at baseline and longitudinally will allow for an assessment of the disease
classification and morphologic changes that might serve as biomarkers for disease progression
for eyes with early AMD or RPD. Psychophysical testing will help assess functional changes
and associations. Information will be disseminated to help the ophthalmic community better
understand the natural course of early AMD and RPD.

To meet these objectives, the study will encourage up to approximately 20 sites participating
in the AMD Ryan Initiative Study (ARIS) to recruit and characterize patients with early AMD
or RPD for the longitudinal study.

The longitudinal phase of ARIS will collect information on consenting participants with early
AMD or RPD seen at participating sites. Routine data collection will focus on the following:

- Enhancing the understanding of the natural history of early AMD and RPD

- Evaluating the functional characteristics of early AMD and RPD

- Compiling information on the potential ocular associations and natural progression of
RPD

- Evaluating risk factors for disease progression in participants with early AMD and RPD

- Evaluating multi-model imaging to understand the mechanisms involved in the pathogenesis
of early AMD and RPD

- Determining the 5-year progression rate to large drusen or late AMD in eyes with early
AMD or RPD

- Determining the rate of change in drusen volume in eyes with early AMD and possibly the
rate of change in the volume of sub-retinal deposits in eyes with RPD

- Developing possible surrogate outcome variables associated with progression to late AMD
or visual acuity loss including change in drusen volume

- Improving classification criteria for RPD

- INCLUSION CRITERIA:

To participate in the longitudinal study, the potential participant must meet all of the
following criteria. These criteria are bilateral for all participants except those with
unilateral RPD.

- Men and women aged 55 and older;

- Clinical and Reading Center verification:

- Cohort 1 - Early AMD, N=200 (Medium drusen >63mu and less than or equal to 125mu)
OU

- Cohort 2 - RPD, N=200, At least one eye with RPD with no more than 1 large drusen
(>125mu) in either eye

- Cohort 3 - Controls, N=100, No drusen >63mu, no RPD or pigmentary changes OU

- Best Corrected Visual Acuity of 20/25 or better;

- Previous ocular surgeries allowed include cataract surgery more than three months
prior to enrollment in ARIS and peripheral laser, cryotherapy for peripheral tears;

- Participant must be able to review and understand the informed consent form, agree to
the contents and be able to sign the informed consent.

EXCLUSION CRITERIA:

A participant is not eligible if any of the following exclusion criteria are present.

- Any evidence of CNV or GA in either eye.

- Ocular disease other than AMD in either eye, in the Investigator's opinion, which may
confound assessment of the retina including:

- Amblyopia (in study eye only for Cohort 2)

- Angioid streaks

- Choroidal nevus within 2 DD of the center of the macula associated with
depigmentation or overlying atypical drusen

- Epiretinal membrane of significant size located in the macular area that
potentially can cause vision loss

- Myopic crescent of the optic disc the width of which is greater than or
equal to 50% of the longest diameter of the disc, or pigmentary
abnormalities in the posterior pole considered by the clinic ophthalmologist
more likely to be due to myopia than to AMD

- Central Serous Choroidopathy

- Optic Atrophy

- Diabetic retinopathy unless retinopathy is limited to fewer than 10
microaneurysms and/or small retinal hemorrhages

- Macular hole or pseudohole

- Pigmentary abnormalities considered by the Clinical Site ophthalmologist to
be less typical of AMD than of some other condition, such as pattern
dystrophy or chronic central serous retinopathy

- Retinal vein occlusion, active uveitis, presumed ocular histoplasmosis syndrome,
other sight-threatening retinopathies, and other retinal degenerations,
significant explained or unexplained visual field loss, or any other type of
retinopathy or retinal degeneration

- Previous retinal or other ocular surgical procedures, the effects of which may now or
in the future complicate assessment of the progression of AMD in the Investigator s
opinion;

- These surgeries can be divided into those for 1) glaucoma: argon laser
trabeculoplasty, trabeculectomy, and other penetrating glaucoma surgery involving
valves, etc., 2) retinal diseases: laser photocoagulation (except to repair a
peripheral retinal hole), cryosurgery (except any procedure to repair a
peripheral retinal hole), intravitreal injections, vitrectomy 3) Refractive
surgery:

Lasik, peripheral radial keratotomy (PRK), KAMRATM (corneal inlay for correction of
presbyopia), 4) corneal diseases: lamellar keratoplasty, penetrating keratoplasty (PKP),
Descement Membrane Endothelial Keratoplasty (DMEK), Descemet Stripping Endothelial
Keratoplasty (DSEK), DSEK-A (DSEK-automated), Ultra-thin DESK, Deep Anterior lamellar
Keratoplasty (DALK),

5) pterygium surgery that affects or threatens the visual axis, Others) radiation for
ocular tumor, repair of corneal or sclera laceration.

- Retinal laser treatments and cryosurgery for retinal tears is not an exclusion.

- Any other ocular condition requiring long-term therapy or surgery during the
study or any other retinal pathology that in the Investigator s opinion will
interfere with the interpretation of the macular AMD findings (e.g., CRVO);

- Participants with confirmed glaucoma (visual field and/or disc/nerve fiber layer
defects);

- Participants with a current IOP > 26, a history of the diagnosis of increased
intraocular pressure, glaucoma, past or present use of medications to control
intraocular pressure, or disc/nerve fiber layer defects suggestive of glaucoma can be
eligible if the absence of a glaucomatous visual field defect can be documented by a
normal Goldmann, Humphrey or Octopus perimetry test within six months prior to
qualification.

- Participant has photographically significant corneal or media opacities;

- Participant has, in the opinion of the Investigator, any physical or mental
condition that would increase the risk of participation in the study or may
interfere with the study procedures, evaluations and outcome assessments;

- Participant is medically unable to comply with study procedures or follow-up
visits.

- Participation in research study involving treatment for AMD.