A Randomized Controlled, Double-Masked, Crossover Clinical Trial Designed To Evaluate The Safety And Exploratory Efficacy Of 1.0 Mg Luminate® (Alg-1001) As A Treatment For Non-Exudative Macular Degeneration
Phase: PHASE2
Conditions: Dry Age-related Macular Degeneration
Sponsor: Allegro Ophthalmics, LLC

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 1 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
 ALLEGRO OPHTHALMICS, LLC 
PROTOCOL: DRY AMD STUDY 101 
 
 
 
 
A PHASE IIa RANDOMIZED, CONTROLLED, DOUBLE-
MASKED, CROSSOVER CLINICAL TRIAL DESIGNED TO 
EVALUATE THE SAFETY AND EXPLORATORY EFFICACY 
OF 1.0 mg LUMINATE® (ALG-1001) AS A TREATMENT FOR 
NON-EXUDATIVE MACULAR DEGENERATION 
 
Rev. 1.6 
 
 
 
 
January 29, 2019   
 
 
 
SPONSOR: 
Allegro Ophthalmics, LLC 
31473 Rancho Viejo Rd, Suite 204 
San Juan Capistrano, CA 92675 
Phone: (949) 940 - 8130 
Fax: (949) 940 - 8121  
 
Allegro Chief Executive Officer: 
Hampar Karageozian 
Office Telephone: (949) 940-8130 
 
Office Fax: (949) 940-8121 
 
Allegro Chief Medical Officer:               Vicken Karageozian, MD 
                                                                    Office Telephone: (949) 940-8130 
 
 Cell Phone: (949) 295-2135 
 
Allegro Medical Safety Physician:         Melvin Sarayba, MD 
                                                                   Cell Phone: (949) 466 - 2856 
                                                                   Email: Msarayba@allegroeye.com 
 
 
 
 
 
CONFIDENTIAL 
The information in this document is confidential and will not be disclosed to others without written authorization from Allegro Ophthalmics, 
LLC, except to the extent necessary to obtain informed consent from persons involved in the clinical study or their legal guardians, or for 
discussions with local regulatory authorities, institutional review boards (IRB), Ethics Committees (EC) or persons participating in the conduct of 
the trial. 
 

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 2 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
Protocol Approval 
 
A PHASE IIa RANDOMIZED CONTROLLED, DOUBLE-MASKED, CROSSOVER 
CLINICAL TRIAL DESIGNED TO EVALUATE THE SAFETY AND EXPLORATORY 
EFFICACY OF 1.0 mg LUMINATE® (ALG-1001) AS A TREATMENT FOR NON-
EXUDATIVE MACULAR DEGENERATION 
 
 
The following individuals approve this protocol dated January 29, 2019. Any changes to this 
version of the protocol must have an amendment or administrative letter. 
 
Allegro Approvals: 
 
 
 
Hampar Karageozian 
Chief Executive Officer 
 
 
 
Date 
Vicken Karageozian, MD 
Chief Medical Officer 
 
Date 
 
 
 
 
Melvin Sarayba, MD 
Medical Monitor 
 
Date 
 
 
 
 
 
 

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 3 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
Signature Page for Investigator: 
Product: LUMINATE® (ALG-1001)  
Study No: Dry AMD Study 101 
 
Title:  
A PHASE IIa RANDOMIZED CONTROLLED, DOUBLE-MASKED, CROSSOVER 
CLINICAL TRIAL DESIGNED TO EVALUATE THE SAFETY AND EXPLORATORY 
EFFICACY OF 1.0 mg LUMINATE® (ALG-1001) AS A TREATMENT FOR NON-
EXUDATIVE MACULAR DEGENERATION  
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with all relevant local regulations, the current International Conference 
on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use Guideline for Good Clinical Practice (GCP), and with the principles of the most recent 
version of the Declaration of Helsinki. 
 
 
 
Investigator Name 
 
Signature 
 
Date 
[PRINT IN BLOCK CAPITAL LETTERS] 
 
 
Institution Name and Address 
 
 

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ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 6 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
LIST OF ABBREVIATIONS 
 
ACD  
Anterior Chamber Depth 
AE 
 
Adverse Event 
AMD  
Age-related Macular Degeneration 
BCVA  
Best Corrected Visual Acuity 
CRA  
Clinical Research Associate 
CRF 
 
Case Report Form 
EC 
 
Ethics Committee 
ERG  
Electroretinography 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
IOP 
 
Intraocular Pressure/Tonometry 
IRB 
 
Institutional Review Board 
OCT  
Optical Coherence Tomography 
OD 
 
Right Eye 
OS 
 
Left Eye  
PI 
 
Principal Investigator 
PVD  
Posterior Vitreous Detachment 
RPE 
 
Retinal Pigment Epithelium 
SAE 
 
Serious Adverse Event 
SC 
 
Study Coordinator 
SOP 
 
Standard Operating Procedure 
USP 
 
United States Pharmacopeia 
 

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 7 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
PROTOCOL SYNOPSIS  
Study Title: 
A Phase IIa randomized, controlled, double-masked, crossover clinical trial 
designed to evaluate the safety and exploratory efficacy of 1.0 mg Luminate® 
(ALG-1001) as a treatment for Non-Exudative Macular Degeneration  
Study 
Objectives: 
To evaluate the safety and exploratory efficacy of 1.0mg of Luminate® in patients 
with Intermediate Non-Exudative Macular Degeneration  
Study 
Population 
1. Subjects with symptomatic decrease of VA in the last 12 months 
2. Subjects without evidence of wet AMD 
3. Subjects with moderate areas of RPE disturbances and/or drusen in the 
macula 
4. Subjects with BCVA of 20/40 – 20/200 
5. Evidence of reasonably well-preserved areas of RPE and photoreceptors by 
OCT examination in the central macula 
Study Design: 
Approximately 40 eligible subjects who have been diagnosed with intermediate 
Non-Exudative AMD, that require treatment will be enrolled and randomized 
(1.7:1) to one of 2 treatment groups: 
Treatment Group 1: 25 Non-Exudative AMD subjects with BCVA of 20/40 
– 20/200 will be injected intravitreally with 1.0mg of Luminate® 
Treatment Group 2: 15 Non-Exudative AMD subjects with BCVA of 20/40 
– 20/200 will be treated with a sham injection 
 
At the 16-week visit, the study will be unmasked to the sponsor and injecting 
investigator (observing investigators will remain masked). Subjects in the 
treatment group will receive a 2nd dose of Luminate®. Subjects in the control 
group will be offered the opportunity to crossover to treatment with a single dose 
of Luminate®.   
 
 
 
Investigational 
Drug: 
1.0 mg Luminate® solution for intravitreal injection in 0.05cc isotonic saline 
solution 
Control: 
Sham Injection 
Key Inclusion 
Criteria:  
 
 
 
 
 
 
Key General Inclusion Criteria: 
1. 
Male or female patients, 50 to 85 years of age at screening visit 
2. 
Subject has signed the Informed Consent form 
Key Ocular Inclusion Criteria (Study Eye): 
1. Subjects with Non-Exudative AMD having ETDRS BCVA between 33 and 
72 letters read (equivalent to 20/40 – 20/200 on Snellen Chart) with the level 
of vision caused by the non-exudative AMD and no other factor/s 
Screening
Baseline 
Treatment
Week 16 
Treatment
Screening
Treatment 
Group 1
Luminate
Luminate
Exit
Treatment 
Group 2
Sham
Crossover
Luminate
Exit

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 8 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
  
2. Subjects with symptomatic decrease in visual acuity in the last 12 months 
3. Subjects with combination of areas of RPE disturbances (hyper or 
hypopigmentation) and/or > 1 large druse(n) (>125 microns) and/or multiple 
intermediate drusen (62-124 microns) in the macula as confirmed by the 
central reading center 
4. Subjects with evidence of reasonably well-preserved areas of RPE by 
clinical examination and well-defined RPE and outer segment ellipsoid line 
by OCT examination in the central 1 mm of the macula as confirmed by the 
central reading center. More specifically, reasonably well- preserved central 
1 mm of the macula means: 
a. The RPE and outer retinal layers throughout the central 1 mm are intact 
b. No signs of NVAMD such as intraretinal or sub retinal fluid, or sub 
retinal hyper-reflective material 
c. No serous pigment epithelium detachments >100 microns in height 
Key Exclusion 
Criteria:   
Key General Exclusion Criteria: 
1. Females who are pregnant, nursing, planning a pregnancy during the study or 
who are of childbearing potential not using a reliable method of 
contraception and/or not willing to maintain a reliable method of 
contraception during their participation in the study. Women of childbearing 
potential with a positive urine pregnancy test administered at baseline are not 
eligible to receive study drug.   
2. Participation in an investigational drug or device study within 90 days of 
screening 
Key Ocular Exclusion Criteria: 
1. Subjects with active exudative AMD in the fellow eye 
2. Subjects who had anti-VEGF IVT in either eye in the past 90 days 
Key Ocular Exclusion Criteria (Study Eye): 
1. Subjects with pigment epithelium detachments 
2. Subjects with active exudative AMD  
3. Subjects with any prior retina surgery 
4. Subjects with pathology that could prevent observation and follow-up of 
macular structures and measurement of BCVA (i.e. advanced primary open 
angle glaucoma, any stage of normal tension glaucoma and corneal 
opacification) 
5. Subjects that are likely to require cataract surgery in the opinion of the 
investigator within the study protocol period  
 
Study 
Outcomes 
 
 
 
Primary Efficacy Endpoint: 
1. Percentage of population with ≥ 8 letters (1 ½ lines) BCVA gain in the 
Luminate group (Treatment group 1 that received 2 doses of Luminate) 
from baseline to study week 28 vs the Sham control group from baseline 
to study week 12  

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 9 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
 
 
 
 
 
Secondary Efficacy Endpoints: 
1. Percentage of population with ≥ 8 letters (1 ½ lines) BCVA gain from 
baseline to study week 12 (Luminate vs Sham control group) 
2. Percentage of population in the Sham  Luminate crossover population 
with ≥ 8 letters (1 ½ lines) BCVA gain from baseline to study week 12 
vs from study visit week 16 to study visit week 28  
3. Percentage of population with ≥ 10 letters (2 lines) BCVA gain in the 
Luminate group (Treatment group 1 that received 2 doses of Luminate) 
from baseline to study week 28 vs the Sham control group from baseline 
to study week 12 
4. Percentage of population with ≥ 10 letters (2 lines) BCVA gain from 
baseline to study week 12 (1.0mg Luminate vs Sham control) 
5. Percentage of population in the Sham  Luminate crossover population 
with ≥ 10 letters (2 lines) BCVA gain from baseline to study week 12 vs 
from study visit week 16 to study visit week 28  
6. Mean observed changes in ETDRS BCVA between groups at week 12 
7. Mean observed changes in ETDRS BCVA between 1.0mg Luminate at 
week 28 vs Sham at week 12 
8. Mean observed changes in ETDRS BCVA between groups at week 12 in 
the subset of study subjects with a ≥ 8 letters (1 ½ lines) BCVA gain 
from baseline 
9. Mean observed changes in ETDRS BCVA between 1.0mg Luminate at 
week 28 vs Sham at week 12 in the subset of study subjects with a ≥ 8 
letters (1 ½ lines) BCVA gain from baseline 
10. Maximum observed changes in ETDRS BCVA between 1.0 mg 
Luminate and Sham 
11. Percent of population that convert from non-exudative to exudative 
AMD  
 
Exploratory Endpoints: 
1. Percentage of population with ≥ 7 and ≥ 9 letters BCVA gain in the 
Luminate group (Treatment group 1 that received 2 doses of Luminate) 
from baseline to study week 28 vs the Sham control group from baseline 
to study week 12  
2. Improvement in anatomy (by OCT) 
3. Improvement in multi-focal ERG  
4. Improvement in color vision test  
5. Improvement in perimetry  
6. Improvement in microperimetry 
7. Improvement in fundus autofluorescence  
8. Improvement in low luminance visual acuity  
 
Safety Endpoints: 
1. Adverse events 
2. Complete ocular examination including: an external examination of the 
eye and adnexa, slit lamp biomicroscopy, dilated direct and indirect 
ophthalmoscopy, and IOP, OCT, Fundus photo and autofluorescence. 

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 10 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
Statistical 
Methodology 
No formal hypothesis testing is planned; descriptive statistics will be used to 
summarize the study outcomes. 
 
 

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ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 13 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
The safety and efficacy of Luminate® 1.0mg/50µL and sham injection will be evaluated over the 
course of this 32-week study.  Since this is Phase IIa clinical trial, no formal hypothesis testing is 
planned; descriptive statistics will be used to summarize the study outcomes.   
 
 
 
 
Approximately 40 subjects from up to 15 sites will be enrolled in this study. 
 
Study Treatment Group:   
o Treatment Group 1: Non-Exudative AMD subjects with a BCVA of 20/40 – 20/200 
will be administered an intravitreal injection of 1.0 mg Luminate® at Day 0 and 
Week 16 
Control:   
o Treatment Group 2: Non-Exudative AMD subjects with a BCVA of 20/40 – 20/200 
will be administered a sham injection at Day 0  
Sham Crossover:  
o Open-label administration of an intravitreal injection of 1.0 mg Luminate® at 
Week 16 to sham control patients 
Blood Sample for Genetic Analysis:: 
A blood sample will be retained for exploratory genetic analysis that may provide insight into 
Dry AMD and an individual subject’s response to Luminate®. 
 
 
Screening
Baseline 
Treatment
Week 16 
Treatment
Screening
Treatment 
Group 1
Luminate
Luminate
Exit
Treatment 
Group 2
Sham
Crossover
Luminate
Exit

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 14 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
Table 1 Dry AMD STUDY 101 TREATMENT SCHEDULE 
 
 
Visit -1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
 
Day -28 
to Day -2 
Week 0 
(Injection) 
Week 4 
 (post 
injection) 
Week 8 
 (post 
injection) 
Week 12 
 (post 
injection) 
Week 16 
 (post 
injection 
Week 20 
 (post 
injection) 
Week 24 
 (post 
injection) 
Week 28 
 (post 
injection) 
Week 32 
 (post 
injection) 
Group 1 
 
 
 
 
 
 
 
 
 
 
Luminate® 
1.0mg 
BCVA 
20/40 – 20/200 
--- 
 
--- 
--- 
--- 
 
--- 
--- 
--- 
--- 
Group 2 
 
 
 
 
 
 
--- 
--- 
--- 
--- 
Sham Injection 
BCVA 
20/40 – 20/200 
--- 
 
--- 
--- 
--- 
--- 
--- 
--- 
--- 
--- 
Luminate® 
1.0mg(crossover 
injection) 
BCVA 
20/40 – 20/200 
--- 
--- 
--- 
--- 
--- 
 
--- 
--- 
--- 
--- 
 = study treatments 
 
 
 
 

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ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 28 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
• Not Related:  The event is clearly related to other factors such as subject’s clinical condition, 
therapeutic interventions, concomitant disease, therapy administered or accidental trauma of 
the subject and does not follow a known response pattern to the product. 
• Possibly Related:  The event follows a reasonable, temporal sequence from the time of study 
medication administration and/or follows a known response pattern to the study medication, 
but could have been produced by other factors such as the subject’s clinical state, therapeutic 
interventions or concomitant therapy administered to the subject. 
• Related:  The event follows a reasonable, temporal sequence from the time of study 
medication administration or placement and/or follows a known response pattern to the study 
medication and cannot be reasonably explained by other factors such as subject’s clinical 
state, therapeutic interventions or concomitant therapy administered to the subject, and either 
occurs immediately following study medication administration, or improves on stopping the 
study medication, or reappears on repeat exposure, or there is a positive reaction at the 
application site. 
 
Intensity (severity) of an adverse event is defined as a qualitative assessment of the level of 
discomfort of an adverse event as is determined by the Investigator or reported to him/her by the 
subject.  The assessment of intensity is made irrespective of study medication relationship or 
seriousness of the event and should be evaluated according to the following scale: 
1 = Mild:  present, but not distressing, and no disruption of normal daily activity 
2 = Moderate:  discomfort sufficient to reduce or affect normal daily activity 
3 = Severe: incapacitating, with inability to work or perform normal daily activity 
 
A change in severity for a reported AE will require a stop date for the previous severity and a 
new start and stop date for the new severity.  For example, a change in severity may go from 
mild to severe or from severe to moderate.  In either case, the start and stop dates should be 
recorded.  
 
Action taken in response to an adverse event is coded as: 
1=None 
2=Test Article interrupted 
3=Test Article discontinued 
4=Non-drug therapy 
5=New OTC or Rx drug added 
6=Hospitalized (>24 hours) 
 
Outcome of an adverse event is coded as: 
1=Recovered without sequelae 
2=Recovered with sequelae 
3=Stable and ongoing 
4=Ongoing 
5=Death 
6=Unknown/ Lost to follow-up 

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ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 32 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
APPENDIX A: EXAMINATION PROCEDURES, TESTS, EQUIPMENT, AND 
TECHNIQUES 
 
1.    VISUAL ACUITY 
 
Visual acuity will be measured using a standard ETDRS chart at 4 meters with a standard test 
luminance of 85 cd/m2.   
 
BCVA at screening should be determined with a new refraction done with a phoropter or using 
trial frames utilizing the ETDRS chart starting at 4 meters. 
Measurement Technique 
The chart should be at a comfortable viewing angle.  The subject should attempt to read each 
letter, line-by-line, left to right, beginning with line 1 at the top of the chart.  The subject should 
be told that the chart has letters only, no numbers.  If the subject reads a number, he or she 
should be reminded that the chart contains no numbers, and the examiner should then request a 
letter in lieu of the number.  The subject should be asked to read slowly, about 1 letter per 
second, so as to achieve the best identification of each letter.  The subject is not to proceed to the 
next letter until a definite response is given. 
If the subject changes a response (e.g., that was a “C” not an “O”) before the next letter has been 
read aloud, then the change must be accepted.  If the subject changes a response having read the 
next letter, then the change is not accepted.  The examiner should never point to the chart or to 
specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. This may include 
encouraging the subject to guess.  If the subject identified a letter as 1 of 2 letters, he or she 
should be asked to choose one letter and, if necessary, to guess.  When it becomes evident that 
no further meaningful readings can be made, despite encouragement to read or guess, the 
examiner should stop the test for that eye.  However, all letters on the last line should be 
attempted, as letter difficulties vary and the last may be the only 1 read correctly. The study 
subject should always try to read the next line down to ensure that they have stopped at the small 
line possible for them to read. The number of letters missed or read incorrectly should be noted. 
These values will be used to compute overall number of letters read.   
Low luminance visual acuity will be tested with the same methodology as described above except 
with the addition of a 2.0-log unit neutral density filter placed in front of the correction of the 
study eye. A 10-minute dark adaptation will be done prior to testing. 

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 33 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
2.  EXTERNAL EYE EXAMINATION AND SLIT LAMP BIOMICROSCOPY 
 
      The physician will examine the eyelid, conjunctiva, cornea, anterior chamber, lens and 
posterior chamber, both through direct observation and with the aid of a slit lamp 
biomicroscope.  Fluorescein dye will be instilled into the eye studied, to facilitate 
visualization of the corneal surface.  The subject will be seated while being examined and 
the adjustable chin rest and forehead strap will stabilize the head.  Observations will be 
graded as follows: 
 
None (Normal) .................. 0 
   Mild ............................. +1 
Moderate………………..+2 
   Severe .......................... +3 
       
     The following examples illustrate the application of the general grading system to the  
     evaluation of various ophthalmic structures.   
 
LID 
Erythema   
 
None (0) ..................... Normal, without any redness 
Mild (+1) .................... A low grade flushed reddish color 
Moderate (+2) ............ Diffused redness encompassing the entire lid margin 
Severe (+3) ................. Deep, diffused reddish color of lid margins and superior or inferior 
eyelid 
Edema 
None (0) ..................... Normal, no swelling of the eyelid tissue 
Mild (+1) .................... Slight swelling, above normal 
Moderate (+2) ............ General swelling 
Severe (+3) ................. Extensive swelling of the eyelid(s), with or without eversion of 
upper and/or lower lids 
 
  
CONJUNCTIVA (Bulbar and Palpebral) 
Congestion 
None (0) ..................... Normal.  May appear blanched to reddish-pink without perilimbal 
injection.  Conjunctival vessels easily observed. 
Mild (+1) .................... A flush, reddish color predominantly confined to the palpebral or 
bulbar conjunctiva 
Moderate (+2) ............ More pronounced red color of the palpebral or bulbar conjunctiva 
Severe (+3) ................. Definite (bright) redness of the palpebral or bulbar conjunctiva 
Edema 
None (0) ..................... Normal, no swelling of the conjunctiva 
Mild (+1) .................... Slight diffuse or regional swelling of the conjunctiva 
Moderate (+2) ............ General swelling of the conjunctiva 
Severe (+3) ................. Extensive swelling of the conjunctiva  
 

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 34 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
Discharge 
None (0) ..................... Normal, no discharge noted 
Mild (+1) .................... Slight discharge 
Moderate (+2) ............ Obvious mucoid discharge 
Severe (+3) ................. Obvious mucoid or mucopurulent discharge with crusting and 
matting of the lid margins. 
CORNEA 
Staining/Erosion  
None (0) ..................... No Fluorescein staining of epithelium, no epithelial defect 
Mild (+1) .................... Slight staining confined to a small area 
Moderate (+2) ............ Regionally dense staining (1mm or greater in diameter) with 
underlying structure moderately visible 
Severe (+3) ................. Marked staining or epithelial loss 
 
Edema 
None (0) ..................... Transparent and clear 
Mild (+1) .................... Slightly dull glass appearance, may include fine isolated droplets 
Moderate (+2) ............ Dull glass appearance with large number of vacuoles 
Severe (+3) ................. Epithelial bullae and/or stromal edema, localized or diffuse, with 
or without stromal striae 
 
Endothelial Changes (i.e. pigment, guttata, etc.) 
None (0) ..................... Normal 
Mild (+1) .................... Slight polymorphism / pleomegathism, slight pigment, 
keratoprecipitates 
Moderate (+2) ............ Moderate polymorphism / pleomegathism, few non-central 
guttata-like bodies, moderate pigment, keratoprecipitates 
Severe (+3) ................. Dense pigment, keratoprecipitates, several / many guttata-like 
bodies involving central cornea, severe polymorphism / 
pleomegathism 
 
ANTERIOR CHAMBER 
Cells 
None (0) ..................... No cells seen 
Mild (+1) .................... Few cells seen (1-5 cells) 
Moderate (+2) ............ Several cells seen (6-25 cells) 
Severe (+3) ................. Numerous cells seen (26-50 cells) 
Hypopyon (+4) ........... Obvious 
purulent 
formation 
in 
the 
anterior 
chamber  
(>50 cells, indicate size of hypopyon) 
Flare 
None (0) ..................... No Tyndall effect 
Mild (+1) .................... Tyndall beam in the anterior chamber has a mild intensity 
Moderate (+2) ............ Tyndall beam in the anterior chamber is of strong intensity 
Severe (+3) ................. Tyndall beam is very intense.  The aqueous has a white, milky 
appearance. 
        Anterior Synechiae 

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 35 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
None (0) ..................... No adhesion of iris to cornea 
Mild (+1) .................... 0-25% of iris adhering to cornea 
Moderate (+2) ............ 26-50% of iris adhering to cornea 
Severe (+3) ................. > 50% of iris adhering to cornea 
 
Posterior Synechiae 
None (0) ..................... No adhesion of iris to lens 
Mild (+1) .................... 0-25% of iris adhering to lens 
Moderate (+2) ............ 26-50% of iris adhering to lens 
Severe (+3) ................. > 50% of iris adhering to lens 
 
      IRIS 
             The iris should be observed for atrophy, nodules, and neovascularization.  These 
            observations should be qualitatively graded as present or absent. 
 
LENS PATHOLOGY 
See AREDS 2008 Clinical Lens Opacity Standard Photographs Below 
Nuclear Landmarks - In the normal or non-sclerotic lens, the “nucleus” consists  
of a central dark interval (sulcus), adjacent bean-shaped brighter areas (lentils - 1 anterior 
and 1 posterior to the sulcus), and brighter curved bands (lamellae or nuclear surface 
bands).  Although nuclear sclerosis Standard 1 shows signs of moderate opalescence, 
many of these features are visible.  
Grading Rules - For grading the severity of nuclear sclerosis, two factors are considered: 
1) the optical density (sometimes described as “opalescence”) of the nuclear landmarks, 
especially the sulcus, and 2) the definitions of these structures (contrast between light and 
dark bands).  Optical density is given greater weight.  In the early stages of nuclear 
sclerosis, increased optical density is noticeable only in the normally dark bands, 
particular the sulcus, but in advanced stages the density of all bands becomes greater.  
With increasing nuclear sclerosis, the definition of nuclear landmarks decreases, and 
finally disappears.  For grading status, the primary consideration is the degree of 
reflectance (sometimes termed “opalescence”) of the sulcus, with secondary 
consideration given to the definition of the nuclear features, i.e. contrast of the dark and 
bright bands. 
Slit Lamp Settings - Grading of nuclear opalescence is done with the illuminating beam 
of the slit lamp angled at 45° to the viewing axis, the slitbeam width set at  
0.3 mm or a comparable slit lamp width and the slitbeam height set at 9 mm. 
If you believe the severity of the opacity is between 2 standard photos, estimate the 
percent of the way between the two standards; e.g., halfway between 1 and 2 would be 
1.5.  If the severity of the opacity is greater than the last standard, estimate the percent of 
the way between the last standard and a completely opacified lens, e.g., 3.8 or 3.3. 
 

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 36 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
 
 
 
VITREOUS PATHOLOGY 
Vitreous pathology will include an examination of the anterior vitreous that can be 
visualized with the slit lamp technique.  Special notation should be made for hemorrhage, 
cells, or flare.  Each condition is to be noted and graded according to the following scale: 
 
               None (Normal) ...    0 
            Mild .................... +1 
      Moderate……........+2 
               Severe .................. +3 
 
 
 
3.       INTRAOCULAR PRESSURE MEASUREMENTS  
Intraocular pressure will be measured with the aid of a TonoPen™ instrument or 
Goldmann Tonometer. In either case the intraocular pressure will be recorded in the Case 
Report forms and the method by which the pressure was obtained will also be recorded. 

 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 37 
PROTOCOL Dry AMD Study 101 Rev. 1.6 
4.        INDIRECT OPHTHALMOSCOPY 
Ophthalmoscopy is an examination of the back part of the eyeball (fundus), which 
includes the retina, optic disc, choroid, and blood vessels. 
Indirect ophthalmoscopy and slit-lamp ophthalmoscopy are performed after eye drops are 
placed to dilate the pupils. Direct ophthalmoscopy can be performed with or without 
dilation of the pupil. 
The examiner performs this examination by holding the eye open. The examiner wears an 
indirect ophthalmoscope on the head. While holding the eye open each quadrant of the 
eye will be examined and noted for any pathology utilizing a hand-held lens (preferably 
20D). If any pathology is found or suspected in the periphery of the retina a scleral 
depressed examination will also be performed.  
5.    
DILATED FUNDUS EXAM  
All readings will be conducted by the Ophthalmologist at the facility where the study is 
being conducted.  
Pupillary Dilation 
It is recommended that all subjects whenever possible be dilated to a minimum of  
6 to 8mm.  This will allow for better quality imaging and will assist in obtaining high 
quality stereo images. A proven method is the instillation of 1 drop of 1% Tropicamide 
(or equivalent) followed by 1 drop of 2.5% Phenylephrine (or equivalent). Subjects with 
heavily pigmented irises will take longer to achieve full dilation.  
 
6. 
OPTICAL COHERENCE TOMOGRAPHY (OCT)  
Please refer to the device operator’s manual and study training manual for complete 
details on this procedure. 
 
7.  
MULTI-FOCAL ERG: 
Please refer to the device operator’s manual and study training manual for complete 
details on this procedure. 
 
8.  
FUNDUS PHOTOGRAPHY AND AUTOFLUORESCENCE: 
Please refer to the device operator’s manual and study training manual for complete 
details on this procedure. 
 
9.  
COLOR VISION TEST: 
Please refer to the Lanthony D-15 operator’s manual and study training manual for 
complete details on this procedure. 
 

 
ALLEGRO OPHTHALMIC, LLC. 
 
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PROTOCOL Dry AMD Study 101 Rev. 1.6 
 
 
APPENDIX B: SPONSOR’S OBLIGATIONS 
 
Allegro Ophthalmics, LLC is committed to: 
 
1. Complying with the local health authority regulations for the conduct of clinical research 
studies. 
2. Informing the investigator of any new information about the study drug, which may affect the 
subject’s welfare or which may influence the subject’s decision to continue participation in the 
study. 
3. Providing to the investigator the most up-to-date editions of the Clinical Investigator’s 
Brochure (for the study medication/products), the protocol, and a full set of Case Report Forms 
for each subject entered into the study, to document the study evaluation parameters. 
4. Providing study medications/products suitably masked/blinded (as applicable), coded and 
packaged for use with subjects entered into the study. 
5. Providing statistical and report writing resources to complete appropriate reporting of study 
results. 
6. Ensuring equity considerations among all investigators in multi center studies, including all 
matters of publications and meeting presentations, etc. 

 
ALLEGRO OPHTHALMIC, LLC. 
 
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PROTOCOL Dry AMD Study 101 Rev. 1.6 
APPENDIX C: INVESTIGATORS OBLIGATIONS 
 
The Investigator is obligated to: 
 
1. 
Obtain and submit to the Sponsor a copy of his/her Institutional (Ethical) Review Board’s 
(IRB) approval of the protocol prior to initiating the study. 
 
2. 
Obtain signed informed consent from each subject or his/her legal guardian, prior to 
acceptance of the subject into the study, and provide a copy of the signed informed consent 
to the Sponsor. 
 
3.  
In the event of a serious, severe or unexpected incident or adverse experience, whether 
related to the use of the investigational drug or device or not, or the death of a subject, the 
investigator is responsible for notifying the Sponsor immediately (see Appendix E, 
Procedures for Handling and Reporting Adverse Reactions).   
 
4. 
Read, and agree to adhere to the study protocol prior to the initiation of the study.  Deviations 
from the study protocol are not to be implemented without the prior written approval of the 
Sponsor, unless protection of the safety and welfare of the study subjects requires prompt 
action.  During the study, if the investigator feels that in his/her clinical judgment, it is 
necessary to promptly terminate one or more subjects from the study, or to promptly 
implement reasonable alternatives to, or deviations from the protocol in consideration of the 
safety of study subjects, the Sponsor is to be notified of these terminations, and deviations, 
and reasons for such changes are to be documented in the study records.  The investigator is 
to also notify any Institutional Review Board to which he/she is responsible of any such 
changes. 
 
5. 
Accurately record, at the clinical site, all required data on each subject’s Case Report Form.  
The original Case Report Form will be forwarded to the Sponsor in a manner mutually agreed 
upon by the investigator and the Sponsor.  Copies of the completed Case Report Forms will 
remain in the investigator’s possession.  Any change in data made on a Case Report Form 
by the investigator should be done by marking out the incorrect data with a single line, and 
dating and initialing the change made, explaining if necessary, without obscuring the original 
entry.  Only Black ink should be used on Case Report Forms and “white-out” is not to be 
used. 
 
6. 
Replace subjects who fail to complete the study because they choose to drop out of the 
investigation, fail to keep their specified appointments, or are discontinued by the 
investigator for administrative reasons unrelated to the investigational drugs or devices. 

 
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PROTOCOL Dry AMD Study 101 Rev. 1.6 
7. 
Keep accurate records of the number of investigational drug or device units received from 
the Sponsor and dispensed or administered to each subject during the study, and return any 
unused study drugs or devices to the Sponsor at the completion of the study.  Before returning 
the investigational drugs or devices to the Sponsor, a detailed inventory should be recorded 
and placed in the investigator’s file. 
 
8. 
Assure that investigational drugs or devices will be dispensed or administered only to 
subjects under his/her personal supervision, or under the supervision of authorized co-
investigators responsible to him/her. 
 
9. 
Allow a representative of the Sponsor’s clinical research team and/or representatives of 
health regulatory agencies to inspect all Case Report Forms and corresponding portions of 
each study subject’s original office, hospital, and laboratory records at mutually convenient 
times, at regular intervals during the study, and upon request after the study has been-
completed.  The purpose of these on-site monitoring visits is to provide the Sponsor the 
opportunity to evaluate the progress of the study, document compliance with the protocol 
and with regulatory requirements, verify the accuracy and completeness of subjects’ Case 
Report Forms, resolve any apparent discrepancies or inconsistencies in the study records, 
and account for all investigational supplies. 
 
10. Provide the Sponsor with a brief (i.e. one to three pages) Investigator’s Summary within 90 
working days of the study completion. 
 
11. Complete the study within the time limits agreed upon with the Sponsor prior to the initiation 
of the study.  Ensure the accuracy, completeness, legibility and timeliness of the data reported 
to the sponsor in the case report forms and all required reports. 
 
12. Retain essential documents until at least 2 years after the last approval of a marketing 
application in the USA and, as applicable, other countries in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region, or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the investigational 
product and the appropriate regulatory agencies have been notified. These documents should 
be retained for a longer period, however, if required by the applicable regulatory bodies, or 
upon special arrangements with the sponsor. The sponsor will inform the 
investigator/institution as to when these documents no longer need to be retained. 
 
If for any reason the investigator withdraws from the responsibility for maintaining the study 
records, document custody may be transferred to other suitable person or institution, which 
has the capacity and accept responsibility for safeguarding the records for the remainder of 
the required time period.  The Sponsor is to be notified in writing of any intention to transfer 
study documentation, at least 30 days before the transfer takes place. 
 
 

 
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PROTOCOL Dry AMD Study 101 Rev. 1.6 
APPENDIX D:  WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects 
 
I. 
BASIC PRINCIPLES 
 
1. 
Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and animal 
experimentation and on a thorough knowledge of the scientific literature. 
 
2. 
The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol which should be transmitted for 
consideration, comment and guidance to a specially appointed committee independent of 
the investigator and the sponsor, provided that this independent committee is in conformity 
with the laws and regulations of the country in which the research experiment is performed. 
 
3. 
Biomedical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  The 
responsibility for the human subject must always rest with a medically qualified person 
and never rest on the subject of the research, even though the subject has given his or her 
consent. 
 
4. 
Biomedical research involving human subjects cannot legitimately be carried out unless 
the importance of the objective is in proportion to the inherent risk to the subject. 
 
5. 
Every biomedical research project involving human subjects should be preceded by careful 
assessment of predictable risks in comparison with foreseeable benefits to the subject or to 
others.  Concern for the interests of the subject must always prevail over the interests of 
science and society. 
 
6. 
The right of the research subject to safeguard his or her integrity must always be respected.  
Every precaution should be taken to respect the privacy of the subject and to minimize the 
impact of the study on the subject’s physical and mental integrity and on the personality of 
the subject. 
 
7. 
Physicians should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable.  Physicians 
should cease any investigation if the hazards are found to outweigh the potential benefits. 
 
 
 

 
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PROTOCOL Dry AMD Study 101 Rev. 1.6 
8. 
In publication of the results of his or her research, the physician is obliged to preserve the 
accuracy of the results.  Reports of experimentation not in accordance with the principles 
laid down in this Declaration should not be accepted for publication. 
 
9. 
In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail.  He or she should be informed that he or she is at liberty to abstain 
from participation in the study and that he or she is free to withdraw his or her consent to 
participation at any time.  The physician should then obtain the subject’s freely-given 
informed consent, preferably in writing. 
 
10. 
When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress.  In that case the informed consent should be obtained by a physician 
who is not engaged in the investigation and who is completely independent of this official 
relationship. 
 
11. 
In case of legal incompetence, informed consent should be obtained from the legal guardian 
in accordance with national legislation.  Where physical or mental incapacity makes it 
impossible to obtain informed consent, or when the subject is a minor, permission from the 
responsible relative replaces that of the subject in accordance with national legislation. 
 
 
Whenever the minor child is in fact able to give consent, the minor’s consent must be 
obtained in addition to the consent of the minor’s legal guardian. 
 
12. 
The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration are 
complied with. 
 
II. 
MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE (CLINICAL 
RESEARCH) 
 
1. 
In the treatment of the sick person, the physician must be free to use a new diagnostic and 
therapeutic measure, if in his or her judgment it offers hope of saving life, reestablishing 
health or alleviating suffering. 
 
2. 
The potential benefits, hazards and discomfort of a new method should be weighed against 
the advantages of the best current diagnostic and therapeutic methods. 
 
3. 
In any medical study, every patient - including those of a control group, if any - should be 
assured of the best proven diagnostic and therapeutic methods.  This does not exclude the 
use of inert placebo in studies where no proven diagnostic or therapeutic method exists. 
 
4. 
The refusal of the patient to participate in a study must never interfere with the physician-
patient relationship. 
 

 
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PROTOCOL Dry AMD Study 101 Rev. 1.6 
5. 
If the physician considers it essential not to obtain informed consent, the specific reasons 
for this proposal should be stated in the experimental protocol for transmission to the 
independent committee (I, 2). 
 
6. 
The physician can combine medical research with professional care, the objective being 
the acquisition of new medical knowledge, only to the extent that medical research is 
justified by its potential diagnostic or therapeutic value for the patient. 
 
III. 
NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN 
SUBJECTS (NON-CLINICAL BIOMEDICAL RESEARCH) 
 
1. 
In the purely scientific application of medical research carried out on a human being, it is 
the duty of the physician to remain the protector of the life and health of that person on 
whom biomedical research is being carried out. 
 
2. 
The subjects should be volunteers - either healthy persons or subjects for whom the 
experimental design is not related to the patient’s illness. 
 
3. 
The investigator or the investigating team should discontinue the research if in his/her or 
their judgment it may, if continued, be harmful to the individual. 
 
4. 
In research on man, the interest of science and society should never take precedence over 
considerations related to the well-being of the subject. 

 
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PROTOCOL Dry AMD Study 101 Rev. 1.6 
APPENDIX E:  STUDY MONITORING 
 
1. 
Member(s) of the Sponsor’s clinical research team or designee will meet with the 
investigator prior to the initiation of the study, to assess the adequacy of the investigator’s 
patient population, facilities, and equipment, and to familiarize the investigator with the 
protocol. 
 
2. 
A member of the Sponsor’s clinical research team or designee will meet with the 
investigator after several of the subjects have initiated the study, to ensure that the subjects 
are being properly selected, that adequate supplies for the study have been provided and 
that the assignment of medication is properly recorded.  In addition, the monitor will verify 
that the investigator follows the approved protocol and all approved amendments, if any, 
by reviewing the investigator’s regulatory documents, source documents, informed consent 
forms, and case report forms of study subjects. 
 
3. 
A member of the Sponsor’s clinical research team or designee will meet with the 
investigator when all subjects have completed the Final Visit of the study, to collect the 
Case Report Forms, unused drugs, and unused supplies and materials. 
 
4. 
Interim monitoring visits and telephone consultations will occur as necessary, to ensure the 
proper progression and documentation of the study. 
 

 
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PROTOCOL Dry AMD Study 101 Rev. 1.6 
APPENDIX F:  PROTOCOL CHANGES AND PROCEDURES 
If the investigator desires to modify the procedure and/or design of the study, he or she  
must contact and obtain the consent of the Sponsor and, where applicable, local Institutional 
Review Board, regarding the proposed changes. Any changes to the Study Protocol will only be 
made in the form of protocol amendments, signed by the Investigator and the authorized Sponsor 
representative(s), and approved by the Institutional Review Board, prior to their implementation. 
 

 
ALLEGRO OPHTHALMIC, LLC. 
 
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PROTOCOL Dry AMD Study 101 Rev. 1.6 
APPENDIX G:  INSTRUCTIONS FOR COMPLETION OF SOURCE DOCUMENTS 
AND CASE REPORT FORMS 
 
1. 
Complete source documents will be supplied to the study sites. The source documents 
should be filled out using a black ink ball-point pen.   
 
2. 
At each subject visit, the appropriate source document must be completed.  The data will 
be entered into the CRF.  Be sure to provide all information requested including subject 
identification number and initials, name of investigator, date(s), etc.  All applicable 
questions should be answered and all data requested should be supplied.  Those areas, 
which require a response but are not filled in correctly are considered incomplete or 
erroneous entries, and will have to be corrected.  Supplying all the necessary data the first 
time saves office time for the investigator during subsequent audits and monitoring visits. 
 
3. 
If the investigator needs to correct an erroneous entry on the source documents, the only 
acceptable procedure is to draw a single horizontal line through the incorrect entry, enter 
the correct data next to it, then initial and date the new entry, explain if necessary, without 
obscuring the original entry.  Even if the correction is made on the same date as at the top 
of the form, the date must still be supplied next to the correction, since there is no other 
way of identifying when the correction was made.  Correction fluid (“Whiteout”), eraser, 
or any other correction methods that would obscure the original entry are NOT allowed. 
 
4. 
All medications used should be recorded on the Concomitant Medication form, with the 
appropriate start and stop date as applicable. 
 
5. 
All Adverse Events should be recorded on the Adverse Event form with appropriate event 
name, start and stop dates, relation to study drug, intensity, and outcome. 
 
6. 
The completed source documents are to be reviewed and signed by the Principal 
Investigator or designee.