Clinical trial NCT02348918
Conditions: Diabetic Macular Edema
Sponsor: Allegro Ophthalmics, LLC
Start date: 2014-10-13; Completion date: 2017-06-13
Enrollment: 218 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2 Multi center, Randomized, Controlled, Double-Masked Clinical Trial Designed To Evaluate The Safety And Exploratory Efficacy Of Luminate® (Alg-1001) As Compared To Avastin® In The Treatment Of Diabetic Macular Edema

Detailed description:
To evaluate the safety and efficacy of Luminate® (ALG-1001) as compared to Avastin® in patients with diabetic macular edema

\- Stage 1: 120 eligible subjects with DME will be enrolled and randomized to one of 4 treatment groups at an allocation ratio of 1:1:1:1, i.e., one of three doses (1.0 mg, 2.0 mg and 3.0 mg) of Luminate intravitreal injection or Avastin intravitreal injection. Subjects will be followed monthly for 24 weeks (6 months).

Stage 2 (select sites): 75 eligible subjects with DME will be enrolled and randomized to one of 5 treatment groups at an allocation ratio of 1:1:1:1:1; i.e., one of 2 doses of Luminate intravitreal injection or Avastin intravitreal injection (0.5 mg and 1.0 mg). Subjects will be followed monthly for 20 weeks (5 months).

Arms: arm 1: Stage 1- Luminate 1.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. arm 2: Stage 1 -Luminate 2.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. arm 3: Stage 1- Luminate 3.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. arm 4: Stage 1- Avastin 1.25 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Avastin injection at weeks 12, 16, or 20 for a total of at least 3 and up to 6 Avastin injections. Sham injections may be performed at weeks 12, 16, and 20 if prn Avastin is not required. arm 5: Stage 2 - Week 0 (Baseline): Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 1.0 mg IVT + sham injection Weeks 12 and 16: Sham IVT arm 6: Stage 2- Week 0 (Baseline); Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + sham injection Weeks 12 and 16: Sham IVT arm 7: Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Luminate 1.0 mg + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT arm 8: Stage 2 : Week 0: Sham IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT arm 9: Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Avastin 1.25 mg + Sham IVT Weeks 12 and 16: Avastin PRN
Interventions: intervention 1: Luminate 1.0mg intervention 2: Luminate 2.0mg intervention 3: Luminate 3.0mg intervention 4: Avastin intervention 5: Luminate 0.5mg
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_000.pdf: 
ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 1 
PROTOCOL DME-202B 
  
ALLEGRO OPHTHALMICS, LLC 
PROTOCOL DME 202B (Version 2.66) 
 
A PHASE 2 MULTICENTER, RANDOMIZED, CONTROLLED, 
DOUBLE-MASKED CLINICAL TRIAL DESIGNED TO 
EVALUATE THE SAFETY AND EXPLORATORY EFFICACY 
OF LUMINATE® (ALG-1001) AS COMPARED TO AVASTIN®  
IN THE TREATMENT OF DIABETIC MACULAR EDEMA 
 
March 7, 2016 
IND : 119548 
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 Medical Officer:               Vicken Karageozian, MD 
                                                                    Office Telephone: (949) 940-8130 
 
 Cell Phone: (949) 295-2135 
 
Allegro Medical Safety Physician:         Barbara Wirostko, MD 
                                                                   Cell Phone: (347) 453-1521 
                                                                   Email: barbarawirostko@trialrunners.com 
 
Allegro Executive Clinical Director: 
Melvin Sarayba, MD 
Office Telephone: (949) 444-5727 
 
Office Fax: (949) 940-8121 
Cell Phone: (312) 415-0201 
 
 


ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 2 
PROTOCOL DME-202B 
 
Signature Page for Investigator: 
Product: LUMINATE® (ALG-1001)  
Study No: DME-202B (Version 2.66) 
 
Title:  
A PHASE 2 MULTICENTER, RANDOMIZED, CONTROLLED, DOUBLE-
MASKED CLINICAL TRIAL DESIGNED TO EVALUATE THE SAFETY AND 
EXPLORATORY EFFICACY OF LUMINATE® (ALG-1001) AS COMPARED TO 
AVASTIN® IN THE TREATMENT OF DIABETIC MACULAR EDEMA 
 
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 


ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 3 
PROTOCOL DME-202B 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................... 6 
PROTOCOL SYNOPSIS ................................................................................. 7 
1. 
BACKGROUND AND RATIONALE ............................................... 10 
2. 
STUDY OBJECTIVE ......................................................................... 12 
3. 
STUDY DESIGN................................................................................ 12 
4. 
STUDY OUTCOMES ........................................................................ 16 
4.1 
EFFICACY ............................................................................................. 16 
5. 
STUDY POPULATION ..................................................................... 17 
5.1 
INCLUSION CRITERIA ........................................................................... 17 
5.2 
EXCLUSION CRITERIA .......................................................................... 17 
6. 
STUDY METHODS ........................................................................... 20 
6.1 
SUBJECT SCREENING ............................................................................ 20 
6.2 
SUBJECT ENROLLMENT ........................................................................ 20 
6.3 
 INVESTIGATIONAL MATERIALS ........................................................... 21 
6.4 
INSTRUCTIONS FOR USE AND ADMINISTRATION OF 
INVESTIGATIONAL PRODUCT ................................................................ 21 
6.4.1 INTRAVITREAL INJECTION PREPARATION - LUMINATE ............................ 21 
6.4.2 INTRAVITREAL INJECTION PREPARATION – AVASTIN .............................. 21 
6.4.3 INTRAVITREAL INJECTION PROCEDURE ................................................... 21 
6.5 
RETREATMENT CRITERIA ..................................................................... 23 
6.6 
RESCUE CRITERIA ................................................................................ 23 
6.7 
CONCOMITANT MEDICATIONS ............................................................. 24 
7 
STUDY VISITS AND PROCEDURES ............................................. 25 
7.1 
STAGE 1 VISIT SCHEDULE ............................................................ 26 
7.1.1 VISIT 0 - SCREENING VISIT (-20 TO -3 DAYS) ...................................... 26 
7.1.2 VISIT 1 – WEEK 0 AND DAY OF INJECTION/TREATMENT .................... 26 
7.1.3 VISIT 2 - STUDY WEEK 4 (± 3 DAYS) .................................................. 27 
7.1.4 VISIT 3 - STUDY WEEK 8 (± 3 DAYS) .................................................. 27 
7.1.5 VISIT 4 - STUDY WEEK 12 (± 3 DAYS) ................................................ 27 
7.1.6 VISIT 4.1 - STUDY WEEK 12 (0 TO +5 DAYS) ...................................... 28 
7.1.7 VISIT 5 - STUDY WEEK 16 (± 3 DAYS) ................................................ 28 
7.1.8 VISIT 5.1 - STUDY WEEK 16 (0 TO +5 DAYS) ...................................... 28 
7.1.10 VISIT 6.1 - STUDY WEEK 20 (0 TO +5 DAYS) ...................................... 29 


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PROTOCOL DME-202B 
7.1.11 VISIT 7 - STUDY WEEK 24 (± 3 DAYS) ................................................ 29 
7.2 
STAGE 2 VISIT SCHEDULE............................................................ 32 
7.2.1 VISIT 0 - SCREENING VISIT (-20 TO -3 DAYS) ...................................... 32 
7.2.2 VISIT 1 – WEEK 0 AND DAY OF INJECTION/TREATMENT .................... 32 
7.2.3 VISIT 2 - STUDY WEEK 1 (- 1 DAY) ..................................................... 32 
7.2.4 VISIT 3 - STUDY WEEK 4 (+ 3 DAYS) .................................................. 33 
7.2.5 VISIT 4 - STUDY WEEK 8 (± 3 DAYS) .................................................. 33 
7.2.6 VISIT 5 - STUDY WEEK 12 (± 3 DAYS) ................................................ 33 
7.2.7 VISIT 5.1 - STUDY WEEK 12 (0 TO +5 DAYS) ...................................... 34 
7.2.8 VISIT 6 - STUDY WEEK 16 (± 3 DAYS) ................................................ 34 
7.2.9 VISIT 6.1 - STUDY WEEK 16 (0 TO +5 DAYS) ...................................... 34 
7.2.10 VISIT 7 - STUDY WEEK 20 (± 3 DAYS) ................................................ 35 
8 
STUDY COMPLETION .................................................................... 35 
8.1 
SUBJECT COMPLETION ......................................................................... 35 
8.2 
SUBJECT DISCONTINUATION ................................................................ 35 
8.3  
TERMINATION OF STUDY OR PARTICIPATION BY A CLINICAL SITE OR 
SPONSOR .............................................................................................. 36 
8.4 
EARLY EXIT VISIT ............................................................................... 37 
9 
ADVERSE EVENT REPORTING..................................................... 38 
9.1  ADVERSE EVENT DEFINITIONS................................................................ 38 
9.2 CLASSIFICATION OF ADVERSE EVENTS BY RELATIONSHIP, SEVERITY 
AND ACTION TAKEN ............................................................................... 39 
9.3  ADVERSE EVENTS REQUIRING EXPEDITED REPORTING .......................... 41 
9.4  FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS .............................. 41 
10 
STATISTICS ...................................................................................... 41 
10.1  
SAMPLE SIZE CONSIDERATIONS ........................................................... 41 
10.2  
GENERAL CONSIDERATIONS ................................................................ 42 
10.3  
ANALYSIS POPULATIONS ..................................................................... 42 
10.4   INTERIM ANALYSES ................................................................................ 42 
11 
ETHICAL AND REGULATORY CONSIDERATIONS .................. 42 
12 
PUBLICATION POLICY .................................................................. 43 
APPENDICES ................................................................................................ 44 
APPENDIX B:  EXAMINATION PROCEDURES, TESTS, 
EQUIPMENT, AND TECHNIQUES ................................................. 57 
APPENDIX C: SPONSOR’S OBLIGATIONS ............................................. 71 


ALLEGRO OPHTHALMIC, LLC. 
 
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PROTOCOL DME-202B 
APPENDIX D: INVESTIGATORS OBLIGATIONS ................................... 72 
APPENDIX E:  WORLD MEDICAL ASSOCIATION DECLARATION 
OF HELSINKI .................................................................................... 74 
APPENDIX F:  STUDY MONITORING ...................................................... 77 
APPENDIX G:  PROTOCOL CHANGES AND PROCEDURES ................ 78 
APPENDIX H:  INSTRUCTIONS FOR COMPLETION OF SOURCE 
DOCUMENTS AND CASE REPORT FORMS ................................ 79 
 


ALLEGRO OPHTHALMIC, LLC. 
 
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PROTOCOL DME-202B 
LIST OF ABBREVIATIONS 
 
ACD  
Anterior Chamber Depth 
AE 
 
Adverse Event 
Allegro 
Allegro Ophthalmics, LLC 
BCVA  
Best Corrected Visual Acuity 
CRA  
Clinical Research Associate 
CRF 
 
Case Report Form 
EC 
 
Ethics Committee 
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 
SAE 
 
Serious Adverse Event 
SC 
 
Study Coordinator 
SOP 
 
Standard Operating Procedure 
USP 
 
United States Pharmacopeia 
 


ALLEGRO OPHTHALMIC, LLC. 
 
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PROTOCOL DME-202B 
PROTOCOL SYNOPSIS  
Study Title: 
A Phase 2 Randomized, Controlled, Double-Masked, Multicenter Clinical trial 
Designed to Evaluate the Safety and Exploratory Efficacy of Luminate® (ALG-
1001) as Compared to Avastin® in the Treatment of Diabetic Macular Edema 
(DME) 
Study 
Objectives: 
This 2-stage study will evaluate the safety and efficacy of Luminate® (ALG-
1001) as compared to Avastin® in patients with centrally-involved DME 
Study 
Design: 
Stage 1: 120 eligible subjects with DME will be enrolled and randomized to one 
of 4 treatment groups at an allocation ratio of 1:1:1:1, i.e., one of three doses of 
Luminate intravitreal injection or Avastin intravitreal injection.   Subjects will be 
followed monthly for 24 weeks (6 months).  
 
Stage 2 (select sites): 75 eligible subjects with DME will be enrolled and 
randomized to one of 5 treatment groups at an allocation ratio of 1:1:1:1:1. 
Subjects will be followed monthly for 20 weeks (5 months). 
 
The treatment groups are as follows for Stage 2: 
 
Group 1 
Week 0 (Baseline):  Avastin 1.25 mg IVT 
Weeks 1, 4 and 8:  Luminate 1.0 mg IVT + sham injection 
Weeks 12 and 16:  Sham IVT 
 
Group 2 
Week 0 (Baseline);  Avastin 1.25 mg IVT 
Weeks 1, 4 and 8:  Luminate 0.5 mg IVT + sham injection 
Weeks 12 and 16:  Sham IVT 
 
Group 3 
Week 0 (Baseline):  Sham IVT 
Weeks 1, 4 and 8:  Luminate 1.0 mg + Avastin 1.25 mg IVT 
Weeks 12 and 16:  Sham IVT 
 
Group 4 
Week 0:  Sham IVT 
Weeks 1, 4 and 8:  Luminate 0.5 mg IVT + Avastin 1.25 mg IVT 
Weeks 12 and 16:  Sham IVT 
 
Group 5 
Week 0 (Baseline):  Sham IVT 
Weeks 1, 4 and 8:  Avastin 1.25 mg + Sham IVT 
Weeks 12 and 16:  Avastin PRN 
 
Investigatio
nal Drug: 
Stage 1: 1.0, 2.0, and 3.0 mg Luminate® solution for intravitreal injection in 
0.1cc isotonic saline solution 
Stage 2: 0.5 and 1.0 mg Luminate® solution for intravitreal injection in 0.05cc 
isotonic saline solution 
Control: 
1.25 mg Avastin® intravitreal injection 


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PROTOCOL DME-202B 
Key 
Inclusion 
Criteria:   
Key General Inclusion Criteria: 
1. Male or female, 18 years of age or older 
2. Prior diagnosis of diabetes mellitus (Type 1 or 2) 
Key Ocular Inclusion Criteria (Study Eye): 
3. Decreased vision due to DME involving central foveal subfield, which is 
defined as the central 1000 µm from the center of fovea, at screening 
4. Best-corrected visual acuity (BCVA) ≤ 73 and ≥ 24 (20/40 to 20/320 
Snellen equivalent, respectively) at screening and baseline (prior to 
treatment), as assessed by the investigator 
5. Central retinal thickness (CRT) ≥ 350 µm on spectral-domain optical 
coherence tomography (SD-OCT) at screening and baseline (prior to 
treatment), as assessed by the investigator and confirmed by central 
reading center (CRC)  
6. In the investigator’s opinion, the patient still has significant intraretinal 
fluid with room for improvement in both macular edema and BCVA  
7. Intraocular pressure (IOP) is under control (i.e., IOP  
≤ 25 mmHg) 
 
Key 
Exclusion 
Criteria:   
Key General Exclusion Criteria: 
1. Uncontrolled diabetes mellitus as evidenced by a hemoglobin A1c 
(HbA1c) value > 10% within 3 months of screening visit 
2. Uncontrolled blood pressure at screening, as assessed by the investigator  
3. 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 
4. Participation in any investigational drug (within 60 days) or device study 
(within 30 days) prior to baseline 
 
Key Ocular Exclusion Criteria (Study Eye): 
5. Treatment with an ocular anti-VEGF medication (eg, pegaptanib sodium, 
bevacizumab, ranibizumab, aflibercept) within 45 days of baseline 
6. Treatment with ocular steroid injections or implants, whether by 
subconjunctival, periocular, or intravitreal route of administration within 
6 months prior to baseline or fluocinolone acetonide implant (Iluvien®) 
within 36 months prior to baseline  
7. Panretinal or macular laser photocoagulation within 3 months prior to 
baseline 
8. Active proliferative diabetic retinopathy (PDR) such as NVE, NVD, 
vitreous hemorrhage, or neovascular glaucoma 
9. Current evidence of retinal detachment as assessed by the investigator to 
significantly affect central vision prior to baseline 


ALLEGRO OPHTHALMIC, LLC. 
 
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PROTOCOL DME-202B 
10. Vitreomacular adhesion/traction or epiretinal membrane evident by 
ophthalmoscopy and/or by  spectral-domain optical coherence 
tomography (SD-OCT) examinations at screening, as assessed by the 
investigator to significantly affect central vision and confirmed by central 
reading center 
11. History or evidence of the following procedures at any time unless 
specified: 
• vitrectomy 
• macular surgery  
• incisional glaucoma surgery 
• cataract or refractive surgery within 3 months prior to baseline 
12. YAG laser treatment in last 30 days prior to study enrollment 
13. A history of cataract surgery complications/vitreous loss  
14. Congenital eye malformations 
15. A history of penetrating ocular trauma 
16. High myopia, with a spherical equivalent of  >        - 8.00D at screening 
17. Other ocular pathologies that in the investigator’s opinion, would 
interfere with the subject’s central vision 
Ocular Exclusion Criterion (Either Eye): 
18. Active ocular/intraocular infection or inflammation at baseline 
19. History of recurrent or active uveitis 
Study 
Outcomes 
 
 
 
 
 
 
 
 
Efficacy 
The efficacy outcomes are BCVA and CRT as assessed with SD-OCT 
(quantified by the CRC) , as defined in the Study Analysis Plan (SAP). 
 
Safety 
Safety parameters to be evaluated include adverse events, BCVA, slit-lamp 
biomicroscopy, ophthalmoscopy, fundus photography, and post-injection 
evaluations through the course of this study. 
Statistical 
Methods 
Descriptive statistics will be used to tabulate and summarize study outcomes.  
Background and demographic characteristics will be presented.  Continuous 
variables will be summarized by descriptive statistics (sample size, mean and 
standard deviation, median, minimum, and maximum).  Discrete variables will 
be summarized by frequencies and percentages.  Adverse events will be 
summarized by presenting the number and percentage of patients having any 
adverse event.  Any other information collected (such as severity or relationship 
to study device) will be listed as appropriate.  Any statistical tests performed to 
explore the data will be used only to highlight comparisons that may warrant 
further consideration. 
 


ALLEGRO OPHTHALMIC, LLC. 
 
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PROTOCOL DME-202B 
ALLEGRO OPHTHALMICS, LLC 
PROTOCOL DME 202B 
 
A PHASE 2 MULTICENTER, RANDOMIZED, CONTROLLED,  
DOUBLE-MASKED CLINICAL TRIAL DESIGNED TO EVALUATE THE 
SAFETY AND EXPLORATORY EFFICACYOF LUMINATE® (ALG-1001) AS 
COMPARED TO AVASTIN®  
IN THE TREATMENT OF DIABETIC MACULAR EDEMA 
 
1. 
BACKGROUND AND RATIONALE 
Integrins are heterodimeric transmembrane proteins and are important for cell-cell and 
cell-matrix interactions, which act as transmembrane linkers between their extracellular 
ligands and the cytoskeleton. Through the transmembrane links, integrins provide 
modulation of various outside-in and inside-out signaling pathways essential in the 
biological functions of cells such as: cell migration, differentiation, survival during 
embryogenesis, angiogenesis, wound healing, immune and non-immune defense 
mechanism, hemostasis and oncogenic transformation (Hynes RO., 2002).  
The molecular events involved in the development of NV and CNV have not been fully 
elucidated; however, while VEGF has been shown to play a major role in the 
development of NV and CNV (Umeda et. al., 2006; Friedlander et. al., 1996), integrins 
α5β1, αvβ3, and αvβ5 are also implicated in the angiogenic process, and are known to be 
expressed in neovascular ocular tissue from patients with Wet AMD and proliferative DR 
(Umeda et. al., 2006; Friedlander et. al., 1996).  As shown in Figure 1, targeting integrin 
works against proliferation and invasion, as well as maturation and differentiation 
(Brooks et. al., 1996). 
FIGURE 1 
THE ANGIOGENIC CASCADE: TARGETING VEGF VS. INTEGRIN 


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PAGE 11 
PROTOCOL DME-202B 
Allegro has developed an anti-integrin oligopeptide Luminate® as a first in class 
therapeutic for vascular eye diseases, including wet age-related macular degeneration 
(Wet AMD), diabetic macular edema (DME) and focal symptomatic vitreomacular 
traction (VMA). Specifically, Allegro has discovered a peptide sequence, in either linear 
or cyclic form, that effectively binds to α5β1, αvβ3 and αvβ5 integrins. These integrin 
receptors have been found to be intimately involved in the angiogenesis associated with 
Wet AMD, DME and proliferative DR. 
 
DME is the leading cause of blindness in the working age population 
(www.diabetes.org). In the United States, 10.2 million people over age 40 have been 
diagnosed with diabetes (www.diabetes.org), of which 4.1 million have some form of 
diabetic retinopathy (DR). Further, the prevalence of DME in the U.S. approaches 30% in 
adults who have had diabetes for 20 years or more (Klein et. al., 1984). 
 
DME is the result of thickening of the center part of the retina due to damage of retinal 
capillaries from diabetes. Application of laser to damaged capillaries within thickened 
retina has been the mainstay of treatment for over 25 years (EDTRS Study Group, 1985; 
AAO 2009). Recent results from the Diabetic Retinopathy Clinical Research Network 
demonstrated that in eyes with reduced visual acuity from DME involving the center of 
the macula, anti-VEGF therapy with Lucentis in combination with focal/grid laser 
provides superior vision outcomes and an acceptable safety profile compared with the 
previous standard treatment of laser (ETDRS Research Group, 1985). 
 
Luminate® solution for intravitreal injection approaches DME by collectively suppressing 
the production of aberrant blood vessels; reducing the leakage of aberrant blood vessels; 
and inhibiting the growth of aberrant blood vessels. The most common treatment for 
DME is currently ranibizumab (Lucentis®), aflibercept (Eylea®) and bevacizumab 
(Avastin®). All three of these options are anti-VEGF treatments, and are very large 
antibodies from 20KD to 150KD in size that bind to VEGF receptors. These antibodies 
must be administered at four to six week intervals for Avastin® and Lucentis® and every 
eight weeks for Eylea® at substantial inconvenience, cost, and cumulative risk of 
infection.   
The use of Luminate® solution for intravitreal injection has the potential to be both an 
effective stand-alone product as well as complementary to existing anti-VEGF treatments 
based on its unique mechanism of action and potentially longer duration of treatment 
effect as suggested in Phase 1 DME and wet AMD studies.  
 
The purpose of this study is to explore the safety and efficacy of 3 doses of Luminate® in 
a DME population, as compared to treatment with Avastin. 
 


ALLEGRO OPHTHALMIC, LLC. 
 
PAGE 12 
PROTOCOL DME-202B 
2. 
STUDY OBJECTIVE 
The objective of this study is to evaluate the safety and efficacy of 4 doses of Luminate in 
a population of patients with active DME, and to compare the outcomes of Luminate 
treatment with Avastin treatment. 
3. 
STUDY DESIGN 
This is a 2-stage, prospective, randomized, double-masked multicenter, Phase II clinical 
trial:  
 
Stage 1: One-hundred twenty (120) eligible subjects with active DME will be 
randomized to one of four treatment groups in a 1:1:1:1 ratio. This includes 3 Luminate 
treatment groups (1.0 mg, 2.0 mg or 3.0 mg), and an Avastin® group. An active focal 
laser group was also present in previous versions of this protocol which has since been 
removed. At the time that this laser group was actively included in randomization, the 
randomization design had been a 1:1:1:1:1 ratio.    
 
In addition to the study treatment (Luminate or Avastin with the treatments and schedules 
defined below), during the course of follow-up, prn retreatment will be allowed for any 
subject with central subfield thickness ≥ 350 µm on SD-OCT exam based on review of 
the OCT images by the central reading center.  Retreatment will be performed using the 
originally assigned treatment, i.e., Luminate with Luminate and Avastin with Avastin. 
 
Stage 2 (select sites): Seventy five (75) eligible subjects with active DME will be 
randomized to one of five treatment groups in a 1:1:1:1:1 ratio. These treatment groups 
consist of 2 Luminate treatment groups (0.5 mg and 1.0 mg), 2 Luminate and Avastin 
adjunctive treatment groups, and an Avastin® (1.25 mg) group. The Luminate 
monotherapy arms will also include an Avastin intravitreal injection at Week 0 
(Baseline).    
 
In addition to the study treatment, during the course of follow-up for Stage 2, prn Avastin 
retreatment will be allowed, at Week 12 and Week 16, in the Avastin monotherapy arm 
for any subject with central subfield thickness ≥ 350 µm on SD-OCT exam based on 
review of the OCT images by the central reading center. 
 
Rescue treatment can be administered to any study subject who experiences a significant 
decrease in BCVA, as defined below: 
 
• BCVA loss of > 15 letters from baseline regardless of OCT finding. 
OR 
• BCVA loss of > 10 letters from the prior study visit accompanied by an increase 
in OCT central retinal thickness of > 100 µm as compared to the previous study 
visit based on the investigator’s judgment.  


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PAGE 13 
PROTOCOL DME-202B 
If one of the above criteria is met, rescue treatment may be administered at the discretion 
of the unmasked investigator but should not involve unmasking the subject or any 
additional staff.   
 
If a subject meets one of the above criteria and has not received the assigned study 
treatment in several weeks, Allegro recommends that the first option to be considered by 
the unmasked investigator for rescue is the originally assigned study treatment.  Avastin 
rescue is another option. 
 
Any subject who receives rescue treatment will continue to be followed for 4 weeks after 
the rescue therapy for safety evaluations and then will early exit the study after 
completing exist visit procedures per the protocol.    
 
STAGE 1: 
 
The treatment groups are as follows for stage 1: 
 
Group 1 
Luminate 1.0 mg intravitreal injection administered at baseline (Day 0), 
weeks 4 and 8 with prn Luminate injection at week 20 for a total of at least 
3 and no more than 4 Luminate injections.  Sham injections will be 
performed at weeks 12 and 16 and may also be performed at week 20 if prn 
Luminate is not required. 
 
Group 2 
Luminate 2.0 mg intravitreal injection administered at baseline (Day 0), 
weeks 4 and 8 with prn Luminate injection at week 20 for a total of at least 
3 and no more than 4 Luminate injections.  Sham injections will be 
performed at weeks 12 and 16 and may also be performed at week 20 if prn 
Luminate is not required. 
 
Group 3 
Luminate 3.0 mg intravitreal injection administered at baseline (Day 0),  
weeks 4 and 8 with prn Luminate injection at week 20 for a total of at least 
3 and no more than 4 Luminate injections.  Sham injections will be 
performed at weeks 12 and 16 and may also be performed at week 20 if prn 
Luminate is not required. 
 
Group 4 
Avastin 1.25 mg intravitreal injection administered at baseline (Day 0),  
weeks 4 and 8 with prn Avastin injection at weeks 12, 16, or 20 for a total 
of at least 3 and up to 6 Avastin injections. Sham injections may be 
performed at weeks 12, 16, and 20 if prn Avastin is not required. 
 
An active focal laser arm was also present in previous versions of this protocol which has 
since been removed. Any patients enrolled into the active laser group prior to approval of 
protocol amendment 2.64 will remain in that group and follow that applicable treatment 
schedule accordingly. A table showing the four treatment arms and visits is provided 
below, with the treatments to be administered at each visit. 
 
 


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PROTOCOL DME-202B 
 
 
 
STAGE 1 Study Visits and Treatments Administered 
 
Week 0 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Groups 1, 2 & 3 
 
 
 
 
 
 
 
Luminate 
 
 
 
- 
- 
prn or 
sham 
- 
Sham Injection 
- 
- 
- 
 
 
- 
Group 4 
 
 
 
 
 
 
- 
Avastin 
 
 
 
 prn or 
sham  
 prn or 
sham  
 prn or 
sham  
- 
Sham Injection 
- 
- 
- 
- 
 = study treatment  
 prn = treatment as needed or sham if no active treatment needed per central reading center 
 
 
All study subjects will be masked to the treatment assignment. Additionally, at each 
clinical site, masked examiners will perform ocular examinations as well as IOP, BCVA, 
OCT, FA and fundus photography assessments. 
 
Potential study participants will be asked to sign an informed consent document prior to 
screening.  Screening will be conducted from -20 days to -3 days prior to randomization 
and treatment during Week 0.  This timing is intended to allow OCT images to be 
reviewed by the central reading center for a determination of eligibility based on CRT ≥ 
350 µm. Subjects will be randomized to one of the four treatment groups once the OCT 
images have been reviewed and the required CRT cut-off being verified by the central 
reading center.  
 
All study subjects will return for examination every 4 weeks through week-24 
(6 months).  The visits and parameters to be evaluated at each study visit are displayed in 
Table 2.1.   
 
The safety and efficacy of 3 doses of Luminate will be evaluated over the course of the 
24-week stage.  Since this is Phase 2 clinical trial, no formal hypothesis testing is 
planned; descriptive statistics will be used to summarize the study outcomes.   
 
 


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PROTOCOL DME-202B 
STAGE 2: 
 
The treatment groups are as follows for stage 2: 
 
Group 1 
Week 0 (Baseline):  Avastin 1.25 mg IVT 
Weeks 1, 4, and 8:  Luminate 1.0 mg IVT + sham injection (~30-60 minutes 
apart) 
Weeks 12 and 16:  Sham IVT 
 
Group 2 
Week 0 (Baseline);  Avastin 1.25 mg IVT 
Weeks 1, 4, and 8:  Luminate 0.5 mg IVT + sham injection (~30-60 minutes 
apart) 
Weeks 12 and 16:  Sham IVT 
 
Group 3 
Week 0 (Baseline):  Sham IVT 
Weeks 1, 4 and 8:  Luminate 1.0 mg + Avastin 1.25 mg IVT (~30-60 
minutes apart) 
Weeks 12 and 16:  Sham IVT 
 
Group 4 
Week 0:  Sham IVT 
Weeks 1, 4, and 8:  Luminate 0.5 mg IVT + Avastin 1.25 mg IVT (~30-60 
minutes apart) 
Weeks 12 and 16:  Sham IVT 
 
Group 5 
Week 0 (Baseline):  Sham IVT 
Weeks 1, 4, and 8:  Avastin 1.25 mg + Sham IVT (~30-60 minutes apart) 
Weeks 12 and 16:  Avastin PRN 
 
 
 
 
STAGE 2 Study Visits and Treatments Administered 
 
Week 0 
(Baseline) 
Week 1 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Groups 1 
 
 
 
 
 
 
 
Luminate 1.0 mg IVT 
- 
 
 
 
- 
- 
- 
Avastin 1.25 mg IVT 
 
- 
- 
- 
- 
- 
- 
Sham IVT 
- 
 
 
 
 
 
- 
Group 2 
 
 
 
 
 
 
 
Luminate 0.5 mg IVT 
- 
 
 
 
- 
- 
- 
Avastin 1.25 mg IVT 
 
- 
- 
- 
- 
- 
- 
Sham IVT 
- 
 
 
 
 
 
- 


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Groups 3 
 
 
 
 
 
 
 
Luminate 1.0 mg IVT 
- 
 
 
 
- 
- 
- 
Avastin 1.25 IVT 
- 
 
 
 
- 
- 
- 
Sham IVT 
 
- 
- 
- 
 
 
- 
Group 4 
 
 
 
 
 
 
 
Luminate 0.5 mg IVT 
- 
 
 
 
- 
- 
- 
Avastin 1.25 mg IVT 
- 
 
 
 
- 
- 
- 
Sham IVT 
 
- 
- 
- 
 
 
- 
Group 5 
 
 
 
 
 
 
 
Avastin 1.25 mg or prn 
IVT 
- 
 
 
 
 prn or 
sham  
 prn or 
sham  
- 
Sham IVT 
 
 
 
 
- 
 = study treatment  
 prn = treatment as needed or sham if no active treatment needed per central reading center 
All study subjects will be masked to the treatment assignment. Additionally, at each 
clinical site, masked examiners will perform ocular examinations as well as IOP, BCVA, 
OCT, FA and fundus photography assessments. 
Potential study participants will be asked to sign an informed consent document prior to 
screening.  Screening will be conducted from -20 days to -3 days prior to randomization 
and treatment during Week 0.  This timing is intended to allow OCT images to be 
reviewed by the central reading center for a determination of eligibility based on CRT ≥ 
350 µm. Subjects will be randomized to one of the five treatment groups once the OCT 
images have been reviewed and the required CRT cut-off being verified by the central 
reading center.  
All study subjects will return for examination 1 week after baseline then every 4 weeks 
through week 20 (5 months).  The visits and parameters to be evaluated at each study 
visit are displayed in Table 2.2.   
The safety and efficacy of study treatments will be evaluated over the course of the 20-
week study.  Since this is a Phase 2 clinical trial, no formal hypothesis testing is planned; 
descriptive statistics will be used to summarize the study outcomes. 
 
4. 
STUDY OUTCOMES 
4.1 
EFFICACY  
The efficacy outcomes are change in BCVA and CRT as assessed with SD-OCT 
(quantified by the CRC), as defined in the Study Analysis Plan (SAP).  
 


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4.2 
Safety  
Safety parameters to be evaluated include BCVA, slit-lamp biomicroscopy, 
ophthalmoscopy, fundus photography, post-injection evaluations, and adverse events 
through the study. 
 
5. 
STUDY POPULATION 
Up to 195 eligible subjects (includes stage 1 and 2) with centrally-involved DME who 
meet the protocol inclusion and exclusion criteria will be enrolled into the study.  
5.1 
INCLUSION CRITERIA   
General Inclusion Criteria: 
1. Male or female, 18 years of age or older 
2. Prior diagnosis of diabetes mellitus (Type 1 or 2) 
3. Patient has completed/signed an informed consent prior to any study-related 
procedures and examinations and is able to follow study instructions and likely to 
complete all required visits 
4. Patient has provided, at screening, written documentation in accordance with the 
relevant local privacy requirements (eg, Written Authorization for Use and 
Release of Health and Research Study Information and written Data Protection 
consent, as required by regional health authorities) 
5. Willing and able to return for all study visits 
Ocular Inclusion Criteria (Study Eye): 
6. Decreased vision due to DME involving central foveal subfield, which is defined 
as the central 1000 µm from the center of fovea, at screening 
7. Best-corrected visual acuity (BCVA) ≤ 73 and ≥ 24 (20/40 to 20/320 Snellen 
equivalent, respectively) at screening and baseline (prior to treatment), as assessed 
by the investigator 
8. Central retinal thickness (CRT) ≥ 350 µm on spectral-domain optical coherence 
tomography (SD-OCT) at screening and baseline (prior to treatment), as assessed 
by the investigator and confirmed by central reading center (CRC)  
9. In the investigator’s opinion, the study eye still has significant intraretinal fluid 
with room for improvement in both macular edema and BCVA 
10. Intraocular pressure (IOP) is under control (i.e., IOP ≤ 25 mmHg in the study eye) 
5.2 
EXCLUSION CRITERIA 
General Exclusion Criteria: 
11. Uncontrolled diabetes mellitus as evidenced by a hemoglobin A1c (HbA1c) value 
> 10% within 3 months of screening visit 
12. Uncontrolled blood pressure at screening, as assessed by the investigator  


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PROTOCOL DME-202B 
13. 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 
14. Participation in any investigational drug (within 60 days) or device study (within 
30 days) prior to baseline 
15. History or current evidence of a medical condition (systemic or ophthalmic 
disease, metabolic dysfunction, physical examination finding or clinical 
laboratory finding) that may in the opinion of the investigator preclude the safe 
administration of study drug, adherence to the scheduled study visits, safe 
participation in the study or affect the results of the study (eg, autoimmune 
disease, advanced coronary artery disease, or cerebral vascular disease, other 
unstable or progressive worsening of a cardiovascular or pulmonary condition, 
Parkinson's disease, liver failure, cancer, or dementia) 
16. History or current evidence of hypersensitivity to any components of the study 
drug or clinically relevant sensitivity to fluorescein dye or iodine, as assessed by 
the investigator 
Ocular Exclusion Criteria (Study Eye): 
17. Treatment with an ocular anti-VEGF medication (eg, pegaptanib sodium, 
bevacizumab, ranibizumab, aflibercept) within 45 days of baseline 
18. Treatment with ocular steroid injections or implants, whether by subconjunctival, 
periocular, or intravitreal route of administration within 6 months prior to baseline 
or fluocinolone acetonide implant (Iluvien®) within 36 months prior to baseline  
19. Panretinal or macular laser photocoagulation within 3 months prior to baseline 
20. Active proliferative diabetic retinopathy (PDR) such as NVE, NVD, vitreous 
hemorrhage, or neovascular glaucoma 
21. Current evidence of retinal detachment as assessed by the investigator to 
significantly affect central vision prior to baseline 
22. Vitreomacular adhesion/traction or epiretinal membrane evident by 
ophthalmoscopy and/or by  spectral-domain optical coherence tomography 
(SD-OCT) examinations at screening, as assessed by the investigator to 
significantly affect central vision and confirmed by central reading center 
23. History or evidence of the following procedures at any time unless specified: 
• vitrectomy 
• macular surgery  
• incisional glaucoma surgery 
• cataract or refractive surgery within 3 months prior to baseline 
24. YAG laser treatment in last 30 days prior to study enrollment 


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PROTOCOL DME-202B 
25. A history of cataract surgery complications/vitreous loss 
26. Congenital eye malformations 
27. A history of penetrating ocular trauma 
28. High myopia, with a spherical equivalent of  >- 8.00D at screening 
29. Other ocular pathologies that in the investigator’s opinion, would interfere with 
the subject’s central vision. 
Ocular Exclusion Criterion (Either Eye): 
30. Active ocular/intraocular infection or inflammation at baseline 
31. History of recurrent or active uveitis 


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6. 
STUDY METHODS 
6.1 
SUBJECT SCREENING  
Subjects will be screened by the investigator based upon the following criteria that are 
detailed in the case report forms to be utilized for the screening visit: 
 
1. Informed consent 
2. Inclusion/Exclusion 
3. For women ages 18 to 60, negative urine pregnancy test at screening 
4. Demographic information 
5. Medical/Ophthalmic History 
6. A screening HbA1c blood test or results within the last 3 months of screening visit 
7. List of concomitant medications 
8. Refraction with ETDRS BCVA at 4/1 meters in the study eye 
9. Afferent Pupillary Defect Assessment 
10. Slit-lamp biomicroscopy 
11. IOP 
12. Indirect ophthalmoloscopy/ dilated fundus exam 
13. Fundus photography 
14. Spectral-domain OCT with appropriate cuts for respective machine 
15. Fluorescein angiography 
16. B-scan ultrasound (for participating sites in Stage 1) 
17. Prophylactic antibiotic drops (when applicable) 
 
Subjects will be cleared for enrollment by the OCT reading center, which will verify that 
the OCT meets the inclusion/exclusion criteria of ≥ 350 µm.  
 
Once all of the study requirements for enrollment are satisfied, all screening documents 
must be forwarded to the Sponsor via the CRO for review and determination that the 
eligibility criteria have been met.  
 
Upon receipt of the screening documents for a given screened subject, the Sponsor or 
designee will notify the investigator in writing or via email whether the subject has been 
cleared for enrollment in the study.  The screening window is from -20 to -3 days prior to 
enrollment/injection to allow 3 days of pre-injection antibiotics. 
6.2 
SUBJECT ENROLLMENT  
Upon enrollment in the study, the study subject will be randomly assigned to one of the 
treatment groups, i.e., one of 3 doses of Luminate or Avastin for stage 1 or one of 2 doses 
of Luminate in conjunction with Avastin for stage 2.  
 


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PROTOCOL DME-202B 
All study subjects will be masked to the treatment assignment.  Additionally, at each 
clinical site, masked examiners will perform ocular examinations as well as IOP, BCVA, 
OCT, FA, and fundus photography assessments.   
 
6.3 
 INVESTIGATIONAL MATERIALS 
The investigational materials will be labeled by Allegro Ophthalmics, LLC, in a manner 
consistent with the study design.  The medications will be identified as an investigational 
compound and will carry the following statement: “CAUTION: NEW DRUG – LIMITED 
BY FEDERAL LAW TO INVESTIGATIONAL USE ONLY”.  The study code and subject 
number will be identified on the label of the medication bottles, along with the batch 
number, expiration date and storage requirements for the study drug.  
 
The investigator or a qualified designee will be responsible for keeping current and 
accurate records of the amount of drug received, dispensed, and returned to the study site.  
During the course of the study, the investigator must maintain an inventory of all study 
supplies in stock, as well as those dispensed and administered to study subjects.  The 
study drug must be stored in a secure area in order to prevent unauthorized distribution.  
The investigational drug is to be administered only to subjects entered into the study, in 
accordance with the conditions specified in the protocol.  
 
At the end of the study, and following a full accounting and recording of all study 
medications, unused supplies of the investigational products will either be returned to the 
Sponsor (or its designee) or disposed of under the direction of the Sponsor or designee.  
The sponsor may authorize disposal of unused supplies of the investigational drug 
provided this alternative disposition does not expose humans to risks from the drug. 
6.4 
INSTRUCTIONS FOR USE AND ADMINISTRATION OF INVESTIGATIONAL PRODUCT 
6.4.1 Intravitreal Injection Preparation - Luminate 
The study drug is supplied in a 0.30 mL conical-shaped glass vial as a sterile liquid 
product ready for injection. Prior to the injection, the unmasked investigator should 
confirm that the vial to be used matches the vials that have been specifically assigned to 
the particular study subject. Luminate® should be stored at refrigerated temperature. 
 
6.4.2 Intravitreal Injection Preparation – Avastin 
Avastin® for intravitreal injection is supplied in a 1.0mL tuberculin syringe as a sterile 
liquid product ready for injection. Prior to the injection, the unmasked investigator should 
confirm the syringe volume and that the syringe to be used matches the randomization 
number specifically assigned to the particular study subject.  
 
6.4.3 Intravitreal Injection Procedure 
With the exception of the IOP lowering drops pre-injection and cotton swab 
tamponade post-injection, which are required, the rest of the below injection and post-
injection procedures are guidance and sites may use the standard of care procedure at 
their institution.  
 


ALLEGRO OPHTHALMIC, LLC. 
 
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PROTOCOL DME-202B 
The subject is placed in a SITTING position and the procedure explained again to the 
subject in lay terms prior to beginning. 
 
• Apply one drop of brimonidine or similar IOP lowering agent ophthalmic drops to 
the eye to be injected.  
• Apply two (2) drops of proparacaine on the surface to be injected, followed by 
two (2) drops of antibiotic.   
• To disinfect the periocular skin, eyelids, and lashes use 5% povidone iodine 
swabs in a systemic fashion.   
• The investigator wears gloves and a sterile drape is placed on the eye, then the lid 
speculum is placed over the drape. 
• The injection location is at the investigator’s discretion, however the inferior 
temporal or superior temporal location is preferred.  
• Expel two (2) drops of 5% povidone iodine on the ocular surface.  Wait 90 
seconds.  Saturate a sterile cotton tip with proparacaine drops and place over the 
injection site.  Expel excess drug to 0.1 mL.   
• Insert the needle (30 or 31 gauge needle) 3.5 to 4.0 mm posterior to the limbus 
avoiding the horizontal axis. Inject slowly INTO THE CENTRAL VITREOUS 
(neither anterior nor posterior) and remove the needle from the eye slowly to 
avoid loss of drug.  Use the cotton swab as a tamponade to avoid loss of drug at 
injection site. 
• After injection, the investigator will observe the subject for several minutes to 
ensure that untoward complications have not occurred.   
• Check vision with finger counting and if vision is worse for more than 1 minute, 
an anterior chamber paracentesis with a 30 or 31-gauge needle should be 
performed.  
• The IOP can be taken at regular intervals, at the investigator’s discretion, until the 
IOP has stabilized and the investigator has determined that the subject is safe to 
leave the clinic.  
 
 
 
 
 


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6.5 RETREATMENT CRITERIA 
During the course of follow-up, retreatment will be allowed for any subject with central 
subfield thickness ≥ 350 µm on OCT based on review of the OCT images by the central 
reading center.  Study subjects will be retreated at the study visits outlined in Section 3 
Study Design with their respective assigned group (i.e., Luminate with Luminate or 
Avastin with Avastin). 
6.6 RESCUE CRITERIA 
At study Weeks 4, 8, 12, 16, and 20 (for Stage 1 ONLY) rescue treatment is available for 
all groups should there be a significant decrease in BCVA.  
 
 Rescue is to be implemented at the discretion of the principal investigator when: 
• BCVA loss of > 15 letters from baseline regardless of OCT finding. 
OR 
• BCVA loss of > 10 letters from the prior study visit accompanied by an increase 
in OCT central retinal thickness of > 100 µm as compared to the previous study 
visit based on the investigator’s judgment  
 
If one of the above criteria is met, rescue treatment may be given at the discretion of the 
unmasked Investigator but should not involve unmasking the subject or any additional 
staff.   
 
If a subject meets one of the above rescue criteria and has not received the assigned study 
treatment in several weeks, Allegro recommends that the first option to be considered by 
the unmasked investigator for rescue is the originally assigned study treatment,   
 
Avastin rescue is another option, however since Avastin is a final option, any other 
necessary intervention to stabilize the subject should be considered. 
 
Any subject who receives rescue treatment will continue to be followed for 4 weeks after 
the rescue therapy for safety evaluations and then will early exit the study after 
completing exist visit procedures per the protocol.   
 
 
 
 


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PROTOCOL DME-202B 
6.7 CONCOMITANT MEDICATIONS 
Subjects will receive pre-injection and post-injection antibiotic eye drops at the discretion 
of the principal investigator at each site.  It is recommended that study subjects receive 
antibiotic eye drops three days pre-injection and up to one week post-injection.  
 
Clinical sites using antibiotic eye drops will call study subjects three days prior to 
possible retreatment by intravitreal injection on week 4 and week 8 and instruct them to 
restart their antibiotic drops in anticipation of an injection.  
 
Any systemic medications that are considered necessary for the subject’s welfare may be 
used.  Additionally, topical anti-inflammatories, antibiotics, steroids, intraocular pressure 
agents, and/or cycloplegics to treat or assess the ocular condition may be used at the 
discretion of the investigator. All medications administered shall be reported in the 
appropriate section of the source document and electronic case report form (eCRF). Any 
intravitreal injections in the study eye must be cleared by the Sponsor prior to 
administration.  
 
Any intravitreal injections of anti-VEGF agents or intravitreal steroids IN THE 
NON-STUDY EYE must be administered at least 1 week and preferably 2 weeks 
after the STUDY EYE treatment or prior to the next scheduled study visit for the 
STUDY EYE.   
 


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PROTOCOL DME-202B 
7 
STUDY VISITS AND PROCEDURES 
Demographic, medical and medication history of all subjects will be recorded, and the 
following ophthalmic examinations will be conducted and recorded during the course of 
the study as further detailed in Tables 2.1 and 2.2 and shown below:  
• Inclusion/Exclusion criteria  
• Demographics 
• Medical and ophthalmic history 
• List of current medications 
• Baseline negative urine pregnancy test during the screening window if 
female between 18 to 60 years of age. 
• Slit-lamp biomicroscopy 
• Refraction 
• Best-corrected visual acuity determination 
• Intraocular pressure (IOP) 
• Indirect ophthalmoscopy/Dilated fundus exam 
• Spectral-Domain OCT 
• APD 
• Fluorescein Angiography 
• B-scan ultrasound for PVD (sub-study only done for a portion of the study 
sites/ subjects in stage 1) 
• HbA1c 
 
Both eyes will be examined at the screening/baseline visit.  Beginning the day of the first 
injection, only the study eye will be assessed. In subjects where both eyes qualify for 
enrollment, the eye with the worse BCVA should be enrolled. Subjects will return for 
study visits and be examined as detailed in this section of the protocol. 
 
The treatment window from the Screening visit to the Baseline Visit / Drug injection is 
20 days.  During this 20-day window screening OCTs must be submitted and the subject 
deemed eligible by the OCT reading center prior to enrollment. Once the subject is 
deemed eligible by the OCT reading center the subject’s screening documents must be 
submitted to the sponsor and approved by the sponsor/CRO prior to drug administration.   
 
 


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PROTOCOL DME-202B 
7.1 
STAGE 1 VISIT SCHEDULE 
7.1.1 VISIT 0 - SCREENING VISIT (-20 TO -3 DAYS) 
All screening/baseline procedures will be reviewed by the Sponsor or designee to ensure 
the subject is appropriate for enrollment and injection.  After review of the inclusion and 
exclusion criteria for appropriateness of the subject, the following information/procedures 
will be performed:  
1. Inclusion/Exclusion Criteria 
2. Demographics 
3. Medical and Ophthalmic History 
4. List of Current Medications 
5. Refraction and Best-Corrected Visual Acuity  
6. Afferent Pupillary Defect 
7. Slit-Lamp Biomicroscopy 
8. Tonometry (IOP) (applanation or tonopen) 
9. Indirect Ophthalmoscopy/Dilated Fundus Examination 
10. Fundus Photography 
11. Spectral-Domain OCT 
12. Fluorescein Angiography 
13. B-scan ultrasound for PVD (for applicable sites) 
14. HbA1c 
15. If patient is a female between 18 to 60 years old, needs a negative 
pregnancy test during the screening window 
16. Dispense prophylactic antibiotic medication at investigator discretion 
7.1.2 VISIT 1 – WEEK 0 AND DAY OF INJECTION/TREATMENT 
When the subject arrives for the baseline visit on the day of first injection, the following 
procedures will be performed: 
1. List of Current Medications 
2. Refraction and Best-Corrected Visual Acuity  
3. Afferent Pupillary Defect 
4. Slit Lamp Biomicroscopy 
5. Tonometry (IOP) (applanation or tonopen) 
6. Indirect Ophthalmoscopy/Dilated Fundus Examination 
7. Spectral-Domain OCT 
8. Assess adverse events 
9. Intravitreal injection  
10. Dispense/continue prophylactic antibiotic medication at investigator 
discretion 
 
 
 


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PROTOCOL DME-202B 
7.1.3 VISIT 2 - STUDY WEEK 4 (± 3 DAYS) 
When the subject returns for the 4-week post injection visit, the following procedures will 
be performed within the visit window: 
1. List of Current Medications 
2. Refraction and Best-Corrected Visual Acuity  
3. Slit-Lamp Biomicroscopy 
4. Tonometry (IOP) (applanation or tonopen) 
5. Indirect Ophthalmoscopy/Dilated Fundus Examination 
6. Spectral-Domain OCT 
7. B-scan ultrasound for PVD (for applicable sites) 
8. Assess adverse events 
9. Dispense/continue prophylactic antibiotic medication at investigator 
discretion 
10. Intravitreal injection 
7.1.4 VISIT 3 - STUDY WEEK 8 (± 3 DAYS) 
When the subject returns for the 8-week post injection visit, the following procedures will 
be performed within the visit window: 
1. List of Current Medications 
2. Refraction and Best-Corrected Visual Acuity  
3. Slit-Lamp Biomicroscopy 
4. Tonometry (IOP) (applanation or tonopen) 
5. Indirect Ophthalmoscopy/Dilated Fundus Examination 
6. Spectral-Domain OCT 
7. B-scan ultrasound for PVD (for applicable sites) 
8. Assess adverse events 
9. Dispense/continue prophylactic antibiotic medication at investigator 
discretion 
10. Intravitreal injection 
7.1.5 VISIT 4 - STUDY WEEK 12 (± 3 DAYS) 
When the subject returns for the 12-week post injection visit, the following procedures 
will be performed: 
1. List of Current Medications 
2. Refraction and Best-Corrected Visual Acuity  
3. Afferent Pupillary Defect 
4. Slit-Lamp Biomicroscopy 
5. Tonometry (IOP) (applanation or tonopen) 
6. Indirect Ophthalmoscopy/Dilated Fundus Examination 
7. Fundus Photography 
8. Spectral-Domain OCT 
9. Fluorescein Angiography 
10. B-scan ultrasound for PVD (for applicable sites) 
11. Assess adverse events 
12. Dispense/continue prophylactic antibiotic medication at discretion 


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The procedural assessments (other than OCT) required at Visit 4 may be performed at the 
Retreatment Visit 4.1 as long as the visit window is followed appropriately per the protocol 
(-3 to +5 days) and OCT results have been received from Duke Reading Center prior to 
patient retreatment.  
7.1.6 VISIT 4.1 - STUDY WEEK 12 (0 TO +5 DAYS)  
All study subjects will return for this retreatment visit.  Prior to visit 4.1, the OCT 
CRT result from Visit 4 is determined by the central reading center, who will notify 
the sites regarding whether or not the result is ≥ 350 µm. This will allow the site to 
determine which treatment, per the treatment table on page 14 of the protocol, is to 
be administered at Visit 4.1.  All study subjects will receive some form of treatment 
at this visit (either active or sham treatment). 
7.1.7 VISIT 5 - STUDY WEEK 16 (± 3 DAYS) 
When the subject returns for the 16-week post injection visit, the following procedures 
will be performed: 
1. List of Current Medications 
2. Refraction and Best-Corrected Visual Acuity  
3. Slit-Lamp Biomicroscopy 
4. Tonometry (IOP) (applanation or tonopen) 
5. Indirect Ophthalmoscopy/Dilated Fundus Examination 
6. Spectral-Domain OCT 
7. Assess adverse events 
8. Dispense/continue prophylactic antibiotic medication at discretion 
 
The procedural assessments (other than OCT) required in Visit 5 may be performed at the 
Retreatment Visit 5.1 as long as the visit window is followed appropriately per the protocol 
(-3 to +5 days) and OCT results have been received from Duke Reading Center prior to 
patient retreatment. 
7.1.8 VISIT 5.1 - STUDY WEEK 16 (0 TO +5 DAYS)  
All study subjects will return for this retreatment visit.  Prior to visit 5.1, the OCT 
CRT result from Visit 5 is determined by the OCT reading center, who will notify 
the sites whether or not the result is ≥ 350 µm. This will allow the site to determine 
which treatment, per the treatment table on page 14 of the protocol, is to be 
administered at Visit 5.1.  All study subjects will receive some form of treatment at 
this visit (either active or sham treatment). 
 
7.1.9 VISIT 6 - Study Week 20 (± 3 days) 
 
1. List of Current Medications 
2. Refraction and Best-Corrected Visual Acuity  
3. Slit-Lamp Biomicroscopy 
4. Tonometry (IOP) (applanation or tonopen) 


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PROTOCOL DME-202B 
5. Indirect Ophthalmoscopy/Dilated Fundus Examination 
6. Spectral-Domain OCT 
7. Assess adverse events 
8. Dispense/continue prophylactic antibiotic medication at discretion 
 
The procedural assessments (other than OCT) required in Visit 6 may be performed at the 
Retreatment Visit 6.1 as long as the visit window is followed appropriately per the protocol 
(-3 to +5 days) and OCT results have been received from Central Reading Center prior to 
patient retreatment. 
7.1.10 VISIT 6.1 - STUDY WEEK 20 (0 TO +5 DAYS) 
All study subjects will return for this retreatment visit.  Prior to visit 6.1, the OCT 
CRT result from Visit 6 is determined by the OCT reading center, who will notify 
the sites whether or not the result is ≥ 350 µm. This will allow the site to determine 
which treatment, per the treatment table on page 14 of the protocol, is to be 
administered at Visit 6.1.  All study subjects will receive some form of treatment at 
this visit (either active or sham treatment). 
 
7.1.11 VISIT 7 - STUDY WEEK 24 (± 3 DAYS) 
1. Medical and Ophthalmic History  
2. List of Current Medications 
3. Refraction and Best-Corrected Visual Acuity  
4. Afferent Pupillary Defect 
5. Slit-Lamp Biomicroscopy 
6. Tonometry (IOP) (applanation or tonopen) 
7. Indirect Ophthalmoscopy/Dilated Fundus Examination 
8. Fundus Photography 
9. Spectral-Domain OCT 
10. Fluorescein Angiography 
11. B-scan ultrasound for PVD (for applicable sites) 
12. HbA1c 
13. Assess adverse events 


 
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PROTOCOL DME-202B 
 
 
TABLE 2.1 - SCHEDULE OF VISITS FOR DME-202B STUDY [STAGE 1] 
 
 
1 The window for the retreatment visits (4.1, 5.1, 6.1) of 0-5 days is in relation to the expected visits 4, 5 and 6, respectively, based on the randomization date.    
 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 4.1 
Retreatment 
Visit 5 
Visit 5.1 
Retreatment 
Visit 6 
Visit 6.1 
Retreatment 
Visit 7 
 
Screening 
(-20 to -3 
days) 
Week 0 & 
Day of 
Injection 
Week 4 
Week 8 
Week 12 
Week 121 
 (0 to +5 days) 
Week 16 
Week 161 
 (0 to +5 days) 
Week 
20 
Week 201 
 (0 to +5 days) 
Week 24 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
Inclusion & exclusion 
criteria  
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
women < 60 years of age 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
 
 
 
 
 
 
 
 
 
 
 
Medical and ophthalmic 
history 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
Refraction and ETDRS 
BCVA  
 
 
 
 
 
 
 
 
 
 
 
Afferent pupillary defect 
 
 
 
 
 
 
 
 
 
 
 
Slit-Lamp biomicroscopy 
 
 
 
 
 
 
 
 
 
 
 
IOP 
 
 
 
 
 
 
 
 
 
 
 
Indirect ophthalmoscopy/  
dilated fundus exam 
 
 
 
 
 
 
 
 
 
 
 
Fundus photography 
 
 
 
 
 
 
 
 
 
 
 
OCT- Spectral Domain 
 
 
 
 
 
 
 
 
 
 
 
Fluorescein Angiography 
 
 
 
 
 
 
 
 
 
 
 
B-scan (where applicable) 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
 
 
 
 
Prophylactic antibiotic 
medication (if applicable) 
 
 
 
 
 
 
 
 
 
 
 


 
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PROTOCOL DME-202B 
 
TABLE 2.2 - SCHEDULE OF VISITS FOR DME-202B STUDY [STAGE 2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 The window for the retreatment visits (4.1, 5.1) of 0-5 days is in relation to the expected visits 4 and 5, respectively, based on the randomization date.
 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 5.1 
Retreatment 
Visit 6 
Visit 6.1 
Retreatment 
Visit 7 
 
Screening 
(-20 to -3 
days) 
Week 0 
Baseline 
Week 1 
(-1 day) 
Week 4 
(+3 days) 
Week 8 
(± 3days) 
Week 12 
(± 3days) 
Week 121 
 (0 to +5 days) 
Week 16 
(± 3days) 
Week 161 
 (0 to +5 days) 
Week 20 
(± 3days) 
Informed consent 
 
 
 
 
 
 
 
 
 
 
Inclusion & exclusion 
criteria  
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
women < 60 years of age 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
 
 
 
 
 
 
 
 
 
 
Medical and ophthalmic 
history 
 
 
 
 
 
 
 
 
 
 
HbA1c 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
Refraction and ETDRS 
BCVA  
 
 
 
 
 
 
 
 
 
 
Afferent pupillary defect 
 
 
 
 
 
 
 
 
 
 
Slit-Lamp biomicroscopy 
 
 
 
 
 
 
 
 
 
 
IOP 
 
 
 
 
 
 
 
 
 
 
Indirect ophthalmoscopy/  
dilated fundus exam 
 
 
 
 
 
 
 
 
 
 
Fundus photography 
 
 
 
 
 
 
 
 
 
 
OCT- Spectral Domain 
 
 
 
 
 
 
 
 
 
 
Fluorescein Angiography 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
 
 
 
Prophylactic antibiotic 
medication (if applicable) 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL DME-202B 
7.2 
STAGE 2 VISIT SCHEDULE 
7.2.1 VISIT 0 - SCREENING VISIT (-20 TO -3 DAYS) 
 
All screening/baseline procedures will be reviewed by the Sponsor or designee to 
ensure the subject is appropriate for enrollment and injection.  After review of the 
inclusion and exclusion criteria for appropriateness of the subject, the following 
information/procedures will be performed:  
1. Inclusion/Exclusion Criteria 
2. Demographics 
3. Medical and Ophthalmic History 
4. List of Current Medications 
5. Refraction and Best-Corrected Visual Acuity  
6. Afferent Pupillary Defect 
7. Slit-Lamp Biomicroscopy 
8. Tonometry (IOP) (applanation or tonopen) 
9. Indirect Ophthalmoscopy/Dilated Fundus Examination 
10. Fundus Photography 
11. Spectral-Domain OCT 
12. Fluorescein Angiography 
13. HbA1c 
14. If patient is a female between 18 to 60 years old, needs a negative 
pregnancy test during the screening window 
15. Dispense prophylactic antibiotic medication at investigator discretion 
 
7.2.2 VISIT 1 – WEEK 0 AND DAY OF INJECTION/TREATMENT 
When the subject arrives for the baseline visit on the day of first injection, the following 
procedures will be performed: 
1. List of Current Medications 
2. Refraction and Best-Corrected Visual Acuity  
3. Afferent Pupillary Defect 
4. Slit Lamp Biomicroscopy 
5. Tonometry (IOP) (applanation or tonopen) 
6. Indirect Ophthalmoscopy/Dilated Fundus Examination 
7. Spectral-Domain OCT 
8. Assess adverse events 
9. Intravitreal injection  
10. Dispense/continue prophylactic antibiotic medication at investigator 
discretion 
 
7.2.3 VISIT 2 - STUDY WEEK 1 (- 1 DAY) 
When the subject returns for the 1-week post baseline visit, the following procedures 
will be performed within the visit window: 
1. List of Current Medications 


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PROTOCOL DME-202B 
2. Refraction and Best-Corrected Visual Acuity  
3. Tonometry (IOP) (applanation or tonopen) 
4. Spectral-Domain OCT 
5. Assess adverse events 
6. Dispense/continue prophylactic antibiotic medication at investigator 
discretion 
7. Intravitreal injections  
7.2.4 VISIT 3 - STUDY WEEK 4 (+ 3 DAYS) 
When the subject returns for the 4-week post baseline visit, the following procedures 
will be performed within the visit window: 
1. List of Current Medications 
2. Refraction and Best-Corrected Visual Acuity  
3. Slit-Lamp Biomicroscopy 
4. Tonometry (IOP) (applanation or tonopen) 
5. Indirect Ophthalmoscopy/Dilated Fundus Examination 
6. Spectral-Domain OCT 
7. Assess adverse events 
8. Dispense/continue prophylactic antibiotic medication at investigator 
discretion 
9. Intravitreal injections (Week 4 should never occur less than 3 weeks 
after Week 1, to ensure proper spacing between treatment visits for 
safety purposes) 
7.2.5 VISIT 4 - STUDY WEEK 8 (± 3 DAYS) 
When the subject returns for the 8-week post baseline visit, the following procedures 
will be performed within the visit window: 
1. List of Current Medications 
2. Refraction and Best-Corrected Visual Acuity  
3. Slit-Lamp Biomicroscopy 
4. Tonometry (IOP) (applanation or tonopen) 
5. Indirect Ophthalmoscopy/Dilated Fundus Examination 
6. Spectral-Domain OCT 
7. Assess adverse events 
8. Dispense/continue prophylactic antibiotic medication at investigator 
discretion 
9. Intravitreal injections 
7.2.6 VISIT 5 - STUDY WEEK 12 (± 3 DAYS) 
When the subject returns for the 12-week post baseline visit, the following procedures 
will be performed: 
1. List of Current Medications 
2. Refraction and Best-Corrected Visual Acuity  
3. Slit-Lamp Biomicroscopy 
4. Tonometry (IOP) (applanation or tonopen) 


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PROTOCOL DME-202B 
5. Indirect Ophthalmoscopy/Dilated Fundus Examination 
6. Fundus Photography 
7. Spectral-Domain OCT 
8. Assess adverse events 
9. Dispense/continue prophylactic antibiotic medication at discretion 
 
The procedural assessments (other than OCT) required at Visit 5 may be performed at 
the Retreatment Visit 5.1 as long as the visit window is followed appropriately per the 
protocol (-3 to +5 days) and OCT results have been received from Duke Reading Center 
prior to patient retreatment. 
 
7.2.7 VISIT 5.1 - STUDY WEEK 12 (0 TO +5 DAYS) 
All study subjects will return for this retreatment visit.  Prior to visit 5.1, the 
OCT CRT result from Visit 5 is determined by the OCT reading center, who will 
notify the sites whether or not the result is ≥ 350 µm. This will allow the site to 
determine which treatment, per the treatment table on page 15 of the protocol, is 
to be administered at Visit 5.1.  All study subjects will receive some form of 
treatment at this visit (either active or sham treatment). 
 
7.2.8 VISIT 6 - STUDY WEEK 16 (± 3 DAYS) 
When the subject returns for the 16-week post baseline visit, the following procedures 
will be performed: 
1. List of Current Medications 
2. Refraction and Best-Corrected Visual Acuity  
3. Slit-Lamp Biomicroscopy 
4. Tonometry (IOP) (applanation or tonopen) 
5. Indirect Ophthalmoscopy/Dilated Fundus Examination 
6. Spectral-Domain OCT 
7. Assess adverse events 
8. Dispense/continue prophylactic antibiotic medication at discretion 
 
The procedural assessments (other than OCT) required in Visit 6 may be performed at 
the Retreatment Visit 6.1 as long as the visit window is followed appropriately per the 
protocol (-3 to +5 days) and OCT results have been received from Duke Reading 
Center prior to patient retreatment. 
 
7.2.9 VISIT 6.1 - STUDY WEEK 16 (0 TO +5 DAYS) 
All study subjects will return for this retreatment visit.  Prior to visit 6.1, the 
OCT CRT result from Visit 6 is determined by the OCT reading center, who will 
notify the sites whether or not the result is ≥ 350 µm. This will allow the site to 
determine which treatment, per the treatment table on page 15 of the protocol, is 
to be administered at Visit 6.1.  All study subjects will receive some form of 
treatment at this visit (either active or sham treatment). 


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PROTOCOL DME-202B 
7.2.10 VISIT 7 - STUDY WEEK 20 (± 3 DAYS) 
1. Medical and Ophthalmic History  
2. List of Current Medications 
3. Refraction and Best-Corrected Visual Acuity  
4. Afferent Pupillary Defect 
5. Slit-Lamp Biomicroscopy 
6. Tonometry (IOP) (applanation or tonopen) 
7. Indirect Ophthalmoscopy/Dilated Fundus Examination 
8. Fundus Photography 
9. Spectral-Domain OCT 
10. Fluorescein Angiography 
11. HbA1c 
12. Assess adverse events 
 
8 
STUDY COMPLETION 
8.1 
SUBJECT COMPLETION 
Subjects are considered to have completed the study if they have completed all 
required examinations through Week 24 for Stage 1 and through Week 20 for Stage 
2. The study is considered to be completed when all randomized subjects have either 
completed or been terminated from the trial. 
8.2 
SUBJECT DISCONTINUATION  
Subjects who experience an unacceptable lack of effectiveness and who have not 
responded to retreatment (as defined above), or intolerable side effects or adverse 
reactions should be discontinued at the investigators discretion from the study and 
should receive appropriate treatment at the discretion of the investigator. Subjects 
who discontinue from the study within the first month (4 weeks) of participation can 
be replaced.  
 
Other reasons for discontinuing a subject from a study include non-compliance with 
the required visits or with the treatment regimen. Subjects have the right to withdraw 
from participation in the study at any time, for any reason without prejudice to further 
treatment.  The investigator may elect to discontinue any subject for reasons unrelated 
to the study product.  The following may be justifiable reasons for the Investigator to 
withdraw a subject from the study: 
• A subject is uncooperative, or misses two or more consecutive follow-up 
visits. 
• A subject was erroneously included in the study. 
• A subject develops an exclusion criterion or concurrent disease. 
• The Sponsor terminates the study. 


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PROTOCOL DME-202B 
Details of a subject’s exit from the study should be recorded in the subject’s clinical 
records. 
The study subject may be discontinued by an investigator or by the sponsor.  Should 
an investigator decide to discontinue the study subject, based on clinical observations, 
this should be reported to the sponsor with reasons for the discontinuation.  
Appropriate notification will be provided to the sponsor within approximately five 
working days.   
8.3  
TERMINATION OF STUDY OR PARTICIPATION BY A CLINICAL SITE OR 
SPONSOR 
The Sponsor or Clinical Site reserves the right to discontinue the study at a single site 
for safety or administrative reasons at any time.  If the Sponsor or Investigator 
discovers conditions during the study indicating that the study or participation by a 
clinical site should be terminated, this action may be taken after appropriate 
consultation between the Sponsor and Investigator.   


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PROTOCOL DME-202B 
Conditions that may warrant termination of the study include, but are not limited to: 
• 
The discovery of an unexpected, serious, or unacceptable risk to the subjects 
enrolled in the study. 
• 
The decision on the part of the Sponsor to suspend or discontinue testing, 
evaluation, or development of the study at any time.  
 
Conditions that warrant discontinuation of the study at a specific study site include: 
• 
Failure of the Investigator to enroll subjects into the study at an acceptable 
rate. 
• 
Failure of the Investigator to comply with the Protocol or pertinent 
regulations. 
• 
Submission by the Investigator of false information from the research facility 
to the Sponsor. 
 
Any subject who completes all study visits will be considered to have completed the 
study. 
8.4 
EARLY EXIT VISIT 
A study subject may exit from the study prior to completion in the following 
situations: 
• The principal investigator determines that it is not in the best interest 
of the subject to continue participation  
• The study subject wishes to withdraw from the study for any reason. 
The following assessments must be completed by the investigator prior to exiting the 
study subject from the study. Furthermore the Sponsor must be contacted prior to 
exiting the study subject.  
1. List of current medications 
2. Refraction and BCVA  
3. Afferent pupillary defect 
4. Slit-lamp biomicroscopy 
5. Tonometry (IOP) (applanation or tonopen) 
6. Indirect ophthalmoscopy/dilated fundus examination 
7. Fundus photography 
8. Spectral-domain OCT  
9. Fluorescein angiography 
10. Assess adverse events 
These assessments can be found in the Early Termination Visit schedule in the  
Case Report Forms. 


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PROTOCOL DME-202B 
9 
ADVERSE EVENT REPORTING 
An adverse event is any untoward and unintended sign, symptom or disease temporally 
associated with the use of an investigational drug or other protocol-imposed intervention 
whether or not considered drug-related.   
 
All treatment-emergent adverse events/adverse reactions occurring during the study should 
be recorded, regardless of the assumption of causal relationship.  If a subject has an 
ongoing adverse events/adverse reactions at the time of study completion, the ongoing 
adverse events/adverse reactions must be followed-up and provided appropriate medical 
care until the signs and symptoms have remitted or stabilized. 
 
Conditions or diseases that are chronic but stable should not be recorded on AE pages of 
the CRF.  Changes in a chronic condition of disease that are consistent with natural disease 
progression are NOT adverse events and also should not be recorded on the AE pages of 
the CRF.   
9.1  
ADVERSE EVENT DEFINITIONS 
The following definitions of terms apply to this section: 
 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
 
Life-threatening adverse event or life-threatening suspected adverse reaction. An adverse 
event or suspected adverse reaction is considered “life-threatening” if, in the view of either 
the Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.  
 
Serious adverse event or suspected adverse reaction. An adverse event or suspected 
adverse reaction is considered ‘‘serious’’ if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes:  
 
• Results in death. 
• Is life-threatening. 
• Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
• Requires inpatient hospitalization. 
• Prolongs inpatient hospitalization. 
• Is a congenital anomaly/birth defect. 
• Is a significant medical event (i.e., one that may jeopardize the subject or may 
require intervention to prevent one or more of the other outcomes listed above). 
 


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PROTOCOL DME-202B 
Sight-threatening adverse events include the following: 
• It caused a decrease in visual acuity of 30 ETDRS letters (compared with the 
last assessment of visual acuity prior to the most recent treatment) lasting >1 
hour. 
• It caused a decrease in visual acuity to the level of Light Perception or worse 
lasting >1 hour. 
• It required surgical intervention (e.g., conventional surgery, vitreous tap or 
biopsy with intravitreal injection of anti-infectives, or laser or retinal cryopexy 
with gas) to prevent permanent loss of sight. 
• It is associated with severe intraocular inflammation (i.e., 4+ anterior chamber 
cell/flare or 4+ vitritis). 
• In the opinion of the investigator, it may require medical intervention to prevent 
permanent loss of sight. 
Sight-threatening events (as defined above) should be reported as SAEs. 
 
A non-serious adverse event is any AE that does not meet the definitions for SAEs as 
described above.  
 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
‘‘reasonable possibility’’ means there is evidence to suggest a causal relationship between 
the drug and the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a 
drug.  
 
Unexpected adverse event or unexpected suspected adverse reaction. An adverse event or 
suspected adverse reaction is considered ‘‘unexpected’’ if it is not listed in the Investigator 
brochure or is not listed at the specificity or severity that has been observed.   
9.2 
CLASSIFICATION OF ADVERSE EVENTS BY RELATIONSHIP, SEVERITY AND ACTION 
TAKEN 
The study medication relationship for each adverse event/adverse reaction should be 
determined by the Investigator using these explanations: 
• 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. 
 
 


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PROTOCOL DME-202B 
• 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) 
7=Hospitalized (>= 24 hours) 
 
Outcome of an adverse event is coded as: 
1=Recovered without sequelae 
2=Stable and ongoing 
3=Ongoing 
4=Death 
5=Unknown/ Lost to follow-up 
 
 
 


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PROTOCOL DME-202B 
Please note: the term “severe” is used to describe the intensity (severity, see above) of an 
event/reaction; the event/reaction itself may be of relatively minor medical significance 
(such as severe headache).  This is not the same as a “Serious” Adverse Event, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to the subject’s life or vital functions.  “Serious” (NOT severity) serves as a guide for 
defining regulatory reporting obligations. 
9.3  
ADVERSE EVENTS REQUIRING EXPEDITED REPORTING  
Serious adverse events (SAEs) and suspected unexpected serious adverse reactions 
(SUSARs) require expedited reporting to the Sponsor or designee regardless of relationship 
to study Insert or study procedure.  
 
All SAEs and SUSARs must be reported to the study Sponsor or designee by telephone and  
e-mail or fax within 48 hours of knowledge of the event and to the IRB within the required 
reporting window of each IRB.  Information on whether or not the event is considered drug 
related, or whether there is a reasonable possibility that the drug caused the event should be 
included with this report. 
 
All reported AEs should be followed until resolution or until the adverse event has 
stabilized with no further change anticipated. Subjects who have an ongoing SAE or 
SUSAR at study completion or at discontinuation from the study will be followed by the 
Investigator or his or her designee until the event is resolved or determined to be 
irreversible, chronic, or stable by the Investigator. 
9.4  
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS 
If an adverse events/adverse reactions occur, the Investigator will institute support and/or 
treatment as deemed appropriate.  If a non-SAE/adverse reaction is unresolved at the time 
of the last visit, an effort will be made to follow up until the adverse event/adverse reaction 
is resolved or stabilized, the subject is lost to follow-up, or there is other resolution to the 
event.   
 
10 
STATISTICS 
10.1  
SAMPLE SIZE CONSIDERATIONS 
Since this is a Phase 2 exploratory clinical study, no formal hypothesis testing will be 
performed.  The sample size was determined based on establishing a reasonable number of 
subjects to provide adequate safety and efficacy information to proceed to the next phase of 
clinical development.     
 
 


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PROTOCOL DME-202B 
10.2  
GENERAL CONSIDERATIONS 
Descriptive statistics will be used to tabulate and summarize study outcomes.   
Background and demographic characteristics will be presented.  Continuous variables will 
be summarized by descriptive statistics (sample size, mean and standard deviation, median, 
minimum and maximum).  Discrete variables will be summarized by frequencies and 
percentages.  Adverse events will be summarized by presenting the number and percentage 
of patients having any adverse event.  Any other information collected (such as severity or 
relationship to study device) will be listed as appropriate.  Any statistical tests performed to 
explore the data will be used only to highlight any interesting comparisons that may 
warrant further consideration. 
10.3  
ANALYSIS POPULATIONS 
The modified Intent to Treat (mITT) data set will include all randomized subjects who 
receive at least one dose of study drug and have at least one follow-up visit.  Last 
observation carry forward (LOCF) will be used to impute missing data from subjects.  If a 
subject receives rescue therapy, that subject’s worst reported value will be imputed for all 
subsequent visits. Data will be analyzed as randomized.  
 
The Per Protocol (PP) data set will include all subjects who meet all inclusion and none of 
the exclusion criteria at the eligibility visit, who are compliant with all study requirements 
and who complete the study through Weeks 20 and 24 (Stage 2 and Stage 1 respectively).  
Missing data will not be imputed. Data recorded after rescue therapy will be excluded.  
Data will be analyzed as treated. 
 
The safety dataset will include all subjects who receive study drug.  Missing data will not 
be imputed.  Data will be analyzed as treated.  
10.4   INTERIM ANALYSES 
An interim analysis might be performed to support planning of further clinical 
development.  To maintain the integrity of the ongoing study, individuals who are directly 
involved in study conduct and data management (eg, personnel at investigational sites, 
Allegro Medical Safety Physician, Clinical Operations, and Data Management) would 
remain masked to treatment assignment of individual patients until study completion. 
 
11 
ETHICAL AND REGULATORY CONSIDERATIONS 
The proposed study is subject to all applicable governmental rules and regulations concerning 
the conduct of clinical trials on human subjects.  This includes, but is not necessarily limited 
to, the approval of local Institutional Review Board (IRB) or Ethics Review Committee (EC) 
(where applicable); obtaining prospective informed consent; monitoring of the conduct of the 
study and the completeness of the CRF by the Sponsor or its designee(s); and appropriate 
record retention by the Investigator.  Applicable institutional review, Investigator/Sponsor 
obligations, study monitoring and protocol change procedures are detailed in appendices. 
 


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PROTOCOL DME-202B 
12 
PUBLICATION POLICY 
All manuscripts, abstracts or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by Allegro in advance of submission. The 
review is aimed at protecting Allegro’s proprietary information existing either at the date of 
the commencement of the study or generated during the study. 
 
The detailed obligations regarding the publication of any data, material results or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each Investigator and Allegro as appropriate. 
 
 
 


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PROTOCOL DME-202B 
APPENDICES 
A SAMPLE SUBJECT INFORMED CONSENT 
B EXAMINATION PROCEDURES, TESTS, EQUIPMENT AND TECHNIQUES 
C SPONSOR OBLIGATIONS 
D  INVESTIGATOR OBLIGATIONS 
E  WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
F  STUDY MONITORING 
G  PROTOCOL CHANGES AND PROCEDURES 
H  INSTRUCTIONS FOR COMPLETION OF CASE REPORT FORMS 
 
 


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APPENDIX A: SAMPLE INFORMED CONSENT  
An Informed Consent Form will be provided and is to be read by and discussed with each 
subject prior to initiating the trial.  When signed and dated by the subject, it becomes the 
investigator’s record of Informed Consent.  The signed informed consent document will be 
kept on file at the investigational site and a copy should be given to the subject for his or 
her records. 
 


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SUBJECT INFORMATION AND CONSENT FORM (EXAMPLE) 
 
A SAFETY AND EFFICACY STUDY COMPARING LUMINATE®, 
AVASTIN®, AND FOCAL LASER IN PATIENTS WITH DIABETIC 
MACULAR EDEMA 
 
PROTOCOL #: 
DME – 202B 
 
SPONSOR: 
Allegro Ophthalmics, LLC 
31473 Rancho Viejo Rd, Suite 204 
San Juan Capistrano, CA 92675 
 
PRINCIPAL INVESTIGATOR: 
 
 
_____________________________ 
 
 
 
ALLEGRO MEDICAL OFFICER  
 
VICKEN KARAGEOZIAN, MD 
 
ADDRESS(ES): 
 
 
 
31473 RANCHO VIEJO ROAD #204 
 
 
 
 
SAN JUAN CAPISTRANO 
 
 
 
 
CALIFORNIA, 92675 
 
 
Purpose of the Subject Information and Consent Form 
This consent form may contain words that you do not understand.  Please ask 
the study doctor or the study staff to explain any words or information that 
you do not clearly understand. 
 
The purpose of this form is to give you information about the research study 
and, if signed, will give your permission to take part in the study.  The form 
describes the purpose, procedures, benefits, risks, discomforts and precautions of 
the research study.  You should take part in the study only if you want to do so.  
You may refuse to take part or withdraw from this study at any time without 
penalty or loss of benefits to which you are otherwise entitled.  Please read this 
Subject Information and Consent Form and ask as many questions as needed. 
You should not sign this form if you have any questions that have not been 
answered to your satisfaction. 
 
You will receive a copy of this signed consent form for your records. 
 


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Purpose of Study 
You have been asked to participate in this research study, sponsored by 
Allegro Ophthalmics, LLC, to determine whether an new class of drugs to 
treat bleeding disorders of the eye would be effective as compared to the 
current standard of care drugs or laser treatments used in treating diabetic 
macular edema (swelling in the back of the eye from your diabetes). In this 
study 1.0, 2.0, or 3.0 mg of Luminate® will be compared to the current 
standards-of-care of 1.25mg Avastin.®   
 
Luminate® is an experimental product which has been tested in both animals 
and human patients in the past for safety and initial efficacy. In addition, 
improvements in vision and resolution of macular swelling have been 
observed in human subjects when the drug has been used alone.  
 
You are being chosen for this study because your treating physician feels that 
your Diabetic Macular Edema (swelling in the back of the eye from your 
diabetes) is not resolved with the current standard of care medication (i.e., 
Avastin®) or without further medical intervention. As the study drug, 
Luminate®, has a different mechanism of action, meaning it works in a 
different way than the current standard of care drugs on the market, it has 
been found in animal and other human studies to provide an additional level 
of benefit in treating bleeding disorders of the eye above and beyond those 
benefits in vision or retinal anatomy seen with Avastin® (the current standard 
of care). Your participation in this study may directly benefit you by further 
improving the anatomy of the eye and improving your ability to see. 
  
Luminate® is experimental when used in the eye, such as for this use, and has 
not been approved by the Food and Drug Administration.  The safety and 
efficacy of Luminate® will be evaluated in this study. 
 
Approximately 120 subjects are expected to participate. 
 
Duration of Participation 
You will be in this study for approximately six months. 
 
 
 
 
 


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PROTOCOL DME-202B 
Study Procedures 
If you agree to take part in this study, you will first sign this Subject 
Information and Consent Form before any study-related procedures are 
performed.  Before enrolling into this study, your study doctor or his staff will 
take your medical history to make sure you have no other medical problems 
that would interfere with your participation in this study, and are not using any 
medications which might make your participation unsafe.  You will also receive 
an eye examination.  This exam includes: 
 
Slit Lamp Exam is an examination of your eye by the Study Doctor using a 
special microscope that allows your physician to see both the outside and the 
inside of your eye under magnification. The doctor will look at your pupil and 
eye movements. The lens and back of your eye will also be examined after 
drops have been placed in your eyes to dilate your pupil. This exam will be 
performed on both eyes at the Screening Visit, but only on the study eye 
during all remaining visits.  
 
Fundus Exam is an examination with an ophthalmoscope (an instrument with 
a strong light and a magnifying lens) of the interior lining of the eyeball, 
including the retina, optic disc (the head of the nerve to the eye), and the 
macula. This exam will be conducted by your Study Doctor. This exam will 
be performed on both eyes at the Screening Visit, but only on the study eye 
during all remaining visits. . 
 
Intraocular Pressure is a measure of the pressure of the fluid inside your eye. 
This exam will be performed on both eyes at the Screening Visit, but only on 
the study eye during all remaining visits.  
  
Visual Acuity uses letters projected on a screen to measure how well your eye 
can see at a specific distance. This exam will be performed on both eyes at the 
Screening Visit, but only on the study eye during all remaining visits.   
  
Optical Coherence Tomography (OCT) uses light to measure the thickness of 
the retina. You may be familiar with ultrasound used to obtain pictures of 
pregnancies. OCT uses light instead of sound to obtain pictures of the inside 
of your eye. Like ultrasound, it is painless. You will be asked to look into the 
front of the OCT machine. While the instrument acquires an image, you will 
see lights of various colors. This exam will be performed on both eyes at the 
Screening Visit, but only on the study eye during all remaining visits. 
  


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Fundus Photography, i.e., photographs of your retina, will be taken. Eye 
drops will dilate your pupils, allowing for the inside of your eye to be 
examined. A special camera will then be used to take photographs. The bright 
flashes used to take the photographs may be annoying, but are not painful and 
cause no damage to the eye. Photography will be performed on both eyes at 
the Screening Visit, and on the study eye on follow up visits.  
 
Fluorescein Angiography is a test in which pictures of your retina are taken 
using a yellow dye. The dye, called fluorescein, will be injected into a vein 
(blood vessel) in your arm or hand. This dye will travel through your blood 
vessels to your eyes. The camera will then flash a special light into your eye 
and will take pictures of your retina; the pictures will show the amount of dye 
leaking out of the blood vessels into your retina. This test will be performed 
on both eyes at the Screening Visit, and on the study eye on follow up visits.  
 
Intravitreal Injections will be given in one of your eyes (the “study eye”) 
within 20 days following your screening visit, and at intervals during the 
course of the study. The pupil of your eye will be dilated, and your eye will be 
anesthetized (numbed). You will then receive an injection into your eye. 
 
If you are a woman of childbearing potential (under age 60), you must have a 
negative pregnancy test to participate in this study. 
 
If you are eligible for the study, you will receive injections into your eye of 
1.0, 2.0, or 3.0 mg of Luminate®, or 1.25mg of Avastin®.  
 
The study drug will be drawn up into a small syringe and with your eye 
anesthetized (numbed), the drug will be injected into the white of the eye 
usually under the upper or lower lid.  There will be only a single injection at 
Baseline.  
 
Following the injections, you will need to return for additional examinations 
at study weeks 4, 8, 12, 16, 20, and 24.   At these visits, you will have an eye 
examination.  
 
If you decide to participate in the study, it is important that you return to the 
study site at the scheduled times for observation of your overall well-being. 
 


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PROTOCOL DME-202B 
Risks or Discomforts 
Your eye condition may or may not improve or may worsen while 
participating in this study. 
 
If you experience any side effects during the study, you should tell the study 
staff. 
 
While there are no known side effects specifically related to the study drug, 
the potential side effects from an intravitreal injection may include: 
 
• burning/stinging 
• headache 
• foreign body sensation 
• brow-ache 
• photophobia (intolerance to light) 
• excessive tearing 
• eye inflammation 
• pain 
• lowering of eye pressure 
• transient macular edema 
 
What are the possible risks or discomforts? 
 
Risk of Eye Examination and Dilation 
As part of the eye exam, drops will be put in your eyes to dilate the pupils. 
The drops may blur your vision and make you sensitive to light. The drops 
will wear off over several hours. There is a small risk of an allergic reaction to 
the drops. There is also a small risk that the drops could cause the eye 
pressure to rise. If this happens, it will be treated, but there is a very small risk 
of losing vision from the pressure rise. Due to the blurring effect on your 
vision and possible light sensitivity, you will be advised not to drive until the 
drops have worn off and, if necessary, have someone come with you who can 
drive after the exam.  
 
Risk of Optical Coherence Tomography  
The vast majority of people feel no discomfort on exposure to the light source 
used to obtain the images of the retina.  However, as with any bright light 
source some people may experience photophobia (sensitivity to light).  
 
 


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Risks of Intravitreal Injection with Luminate® 
Luminate® has been tested in two previous human clinical trials and has been 
found to be safe and well tolerated. In this study, you will be examined for the 
need to receive Luminate® at monthly to quarterly intervals depending on the 
study arm you are enrolled into.  
 
Prior to injection, your eye is numbed with an eye drop and it may be cleaned 
with betadine. You may experience redness or swelling of the eye or eyelid, or 
bleeding, tearing or watering of your eye. You may experience corneal 
abrasion (scratch on the clear front surface of the eye) if you rub your eye 
while numb. These events are likely to clear up quickly. You may experience 
an allergy to the numbing drops or betadine. This is usually treated by 
antihistamines that are given by mouth or by injection if your symptoms are 
severe. 
 
In clinical studies conducted with Luminate® to date, the most common eye-
related side effects were: 
 
1. Conjunctival hemorrhage (bleeding under the clear covering of the eye) 
• Mild eye pain 
• Vitreous floaters (small specks floating in your field of vision) 
2. Transient increased eye pressure 
• Vitreous detachment  (a common condition that occurs naturally with the 
aging of the eye in which the clear gel that fills the space between the lens 
and the back of the eye separates away from the back of the eye) 
• Intraocular inflammation (swelling and redness inside the eye) 
• Foreign body sensation in eye  
• Eye irritation (redness) 
 
Other Risks 
You should be aware that there might be additional risks that are currently 
unknown and unforeseeable. Your condition may not improve, or may worsen 
while participating in the study. You may still require the current standard of 
care treatment Avastin® or focal laser whether you participate in this study or 
not. 
 
 
 


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PROTOCOL DME-202B 
Additionally, there is the risk of the injection procedure that is inherent in any 
type of injection into the eye.  These risks include infection, retinal 
detachment, bleeding in the vitreous cavity, temporary rise in eye pressure, 
and cataract formation, any of which could affect your vision in that eye. 
 
If you do not understand what the symptoms of the side effects are, ask your 
study doctor to explain them to you. 
 
Other possible side effects can occur which may have no symptoms.  There 
may be risks associated with the use of this study drug that are currently 
unknown. 
 
Reproductive Risks 
You must not participate in this study if you are a woman who is breast-
feeding, pregnant, considering a pregnancy, or not using effective birth 
control methods during the study period. 
 
Medically acceptable forms of birth control include: 
 
• IUD (intrauterine device) 
• Condom + spermicide 
• Diaphragm + spermicide 
• Birth control pills, implants (like Norplant), or injections (like Depo-
Provera) used with a condom or diaphragm 
 
If you think you are pregnant during the study, you must tell the study doctor 
immediately.  If you become pregnant, you will be removed from the study 
and your pregnancy will be followed to its outcome. 
 
If you are a female between 18 to 60 years old, you will need a negative urine 
pregnancy test during the screening window to be eligible for enrollment. 
 
Alternative Treatment 
The only currently available definitive treatment option for your condition is 
focal laser or anti-VEGF treatment such as Avastin®. If you continue to 
deteriorate despite treatment with to your study designated treatment regime 
during the study the investigator has the option to perform a “rescue treatment” 
with one of these alternative treatment options. As you consider your 
participation in this study, your other alternative is not to participate in this 
study. 


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PROTOCOL DME-202B 
Benefits 
Your participation in this study may directly benefit you.  Your participation 
will also help provide information about the safety and effectiveness of 
Luminate® for treating focal vitreomacular adhesion. 
 
Costs 
You will receive the study drug, other medications and the eye examinations 
free of charge. If travelling to the clinic for treatment and follow up 
examinations is a burden, travel cost reimbursement is available on an as 
needed basis. 
 
Compensation for Injury 
If you are injured as a result of the study drug or study procedures performed 
during your participation in this research study, you should seek medical 
attention at the medical provider of your choice.  The Sponsor will cover the 
medical expenses necessary to treat the injury only to the extent that such 
costs are not covered by your health insurance policy, by a government 
program, or by any other third party. 
 
You must follow the directions of the study doctor to be eligible for this 
coverage. 
 
Neither the Sponsor nor the study doctor has a program in place to provide 
other compensation in the event of an injury. 
 
Legal Rights 
The above section does not restrict your right to seek legal assistance.  You do 
not waive any legal rights by signing this Subject Information and Consent 
Form. 
 
Voluntary Participation/Withdrawal 
YOUR PARTICIPATION IN THIS STUDY IS ENTIRELY VOLUNTARY.  
YOU MAY REFUSE TO PARTICIPATE OR MAY WITHDRAW FROM 
THIS STUDY AT ANY TIME AND STILL RECEIVE MEDICAL CARE 
OR ANY BENEFITS TO WHICH YOU MAY BE ENTITLED AT THIS 
SITE. 
 
 
 


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PROTOCOL DME-202B 
Before withdrawing from this study, notify your study doctor that you wish 
to withdraw.  This notice will allow your study doctor to inform you if there 
are any potential medical risks of withdrawal.  You may be asked to return 
to the clinic for tests. 
 
Your study doctor, according to his judgment, may stop the study at any time. 
Allegro Ophthalmics, LLC may also stop the study or your participation at 
any time with or without your consent. 
 
New Findings 
Your study doctor will inform you of any new information about this drug, 
which might develop during the course of this research and which might 
influence your willingness to participate in this study. 
 
Confidentiality 
Information from this study will be submitted to the sponsor and to the U.S. 
Food and Drug Administration.  It may be submitted to governmental 
agencies in other countries where the study drug may be considered for 
approval.  Medical records and the consent form signed by you will be 
inspected by the sponsor or an agent for the sponsor, and may be inspected by 
the U.S. Food and Drug Administration or Ministry of Health and your 
physician’s Ethics Review Committee. 
 
Because of the need to release information to these parties, absolute 
confidentiality cannot be guaranteed. 
 
The results of this research project may be presented at meetings or in 
publications; however, your identity will not be disclosed in those 
presentations. 
 
Videography/Photography 
Your procedure may be photographed, videotaped or observed for medical, 
scientific or educational purposes.  Only your affected eye and the area nearby 
will be used.  Your identity will not be revealed by the pictures or by any 
descriptive text accompanying them. 
 
Questions 
If you have any questions concerning your participation in this study or if at 
any time you feel you have experienced a research-related injury or reaction 
to the study drug, contact: 


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PROTOCOL DME-202B 
Principal Investigator:  
 
Daytime telephone number(s): _________________________ 
24-hour contact number(s): 
_________________________ 
 
If you have questions about your rights as a research subject, you may contact 
“______________________”.  An Independent Review Board is a group of 
scientific and non-scientific individuals who perform the initial and ongoing 
ethical review of the research study with the study subject’s safety and 
welfare in mind.  If you have study-related comments, complaints or 
concerns, you should first contact the study investigator.  Please call the 
“________________ IRB” if you want to talk to someone other than the study 
investigator or have difficulty reaching the study investigator.  For further 
information regarding the clinical trials process and your role as a research 
subject, you may contact “__________________ IRB” 
 
Subject’s Statement of Consent 
DME-202b - A SAFETY AND EFFICACY STUDY COMPARING LUMINATE®, 
AVASTIN®, AND FOCAL LASER IN HUMAN SUBJECTS WITH DIABETIC MACULAR 
EDEMA 
 
I have read or have had read to me this consent form.  I have been encouraged 
to ask questions about anything regarding this study or this consent form that I 
do not understand and I have received satisfactory answers to my questions so 
far.  I voluntarily consent to participate in this study. 
 
I consent to the release of my medical records to the sponsor or its designees, 
the U.S. FDA or other regulatory agencies, and my physician’s Ethics Review 
Committee. 
 
By signing this consent form, I have not waived any of the legal rights that I 
otherwise would have as a participant in a research study. 
 
_____________________________________________________________ 
Subject’s Signature 
 
 
 
 
 
Date 
 
___________________________________________________________ 
Printed Name of Subject 
 
__________________________________________________________ 
Signature of Person Obtaining Consent 
 
 
Date 
 
__________________________________________________________ 
Printed Name of Person Obtaining Consent 


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PROTOCOL DME-202B 
Witness Statement: 
I verify that the information in this consent form has been read by the subject 
or read to the subject, if necessary: 
 
 
______________________________________________________________ 
Witness Signature  
 
 
 
 
 
Date 
 
_____________________________________________________________ 
Investigator’s Signature  
 
 
 
 
Date 


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PROTOCOL DME-202B 
APPENDIX B:  EXAMINATION PROCEDURES, TESTS, EQUIPMENT, AND 
TECHNIQUES 
 
1.    VISUAL ACUITY 
 
Visual acuity will be measured using a standard ETDRS chart at 4 meters.   
 
Visual Acuity Charts 
 
ETDRS BCVA  
 
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.   
Please refer to the Study procedure manual for further details. 


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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  
 


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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 / 
pleomegathis 
 
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. 


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Anterior Synechiae 
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 nonsclerotic 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. 
 


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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. 


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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 study training manual for complete details on this procedure. 
 
7.  
FLUORESCEIN ANGIOGRAPHY 
Please refer to the study training manual for complete details on this procedure. 
 
8.  
B-SCAN ULTRASOUND FOR PVD 
The following b-scan instructions are simply additional guidance. The formal b-scan 
protocol for site use throughout this study will be provided directly from Duke 
Reading Center. 
 
Posterior vitreous detachment is a common condition associated with aging.  It occurs 
when the posterior hyaloid detaches or separates from the retina as the vitreous liquefies.  
B-scan is a useful tool for detecting the presence of a PVD in both opaque and clear ocular 
media.  A summary of this protocol can be found in Exhibit A (page 10). 
 
 
 


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Instrumentation 
The Ellex Innovative Imaging v3 B-scan instrument or similar kinetic B-scan is to be used 
for B-scan examinations on study subjects.  The Ellex machine provides a 10 MHz 
transducer and allows the storage of both static images (echograms) and video footage 
(movies) in 10 second increments.  The suggested steps to be followed in the use of the v3 
machine are listed in Exhibit B (page 13). 
 
B-scan Basics  
The B-scan probe contains a transducer surrounded by fluid.  The transducer oscillates 
rapidly back and forth, producing a focused sound beam.  The sound beam moves to and 
from a marker located on the probe housing.  Once emitted into the eye, the sound beam is 
reflected from any acoustic interfaces in its path (e.g., vitreous pathology and the retina) 
and corresponding echoes are displayed on the display screen of the instrument. The 
acoustic section obtained is very thin, much like the slice of the knife.  Therefore, for a 
thorough examination of the posterior segment, the sound beam must be moved throughout 
the vitreous cavity. 
     
Proper interpretation of a B-scan echogram requires knowing where the probe is positioned 
and where the probe marker is directed.  The B-scan echogram is demarcated on the left by 
the initial line that represents the location of the probe face on the eye.  The right side of 
the echogram corresponds to the portion of the eye located opposite the center of the probe 
face.  The upper aspect of the echogram represents the region of eye where the probe 
marker is directed.  The lower aspect of the echogram corresponds to the region of the eye 
located opposite the probe marker (Fig 1).   
 
Subject Confidentiality and Naming Convention 
Per established HIPAA guidelines, the identity of study subjects must be masked.  
Therefore, no identifiable subject data should be visible on any study materials. 
 
A naming convention is used to identify the site, subject, and visit on each A- or B-scan 
image.  The four components of the convention, separated by an underscore ( _), include 
the site number, subject number, subject initials, and visit label.  These identifiers are 
recorded as follows: three-digit site number_, three-digit subject number_, three letter 
subject initials_, and a one-digit visit number (e.g., 001_001_ABC_1).  B-scan images 
must also be labeled according to the area of eye examined (see “Labeling B-scan 
Images”).     
 
 
 


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The Visit Schedule for this trial is as follows: 
 
Visit Schedule 
Study Visit  
 
Visit Label 
0 
 
 
Screening 
2 
 
 
Week 4 
3 
 
 
Week 8  
4 
 
 
Week 12  
7 
 
 
Week 24  
 
*B-scan examination will be performed per the schedule described above.  Should the 
subject have an unscheduled visit with a B-scan examination, that visit # is 99.   
 
NOTE:  Whenever the investigator determines (by clinical exam and B-scan) that a subject 
has a total PVD, then B-scan examinations will not be performed on the subject at 
subsequent visits to the site.   
 
B-scan Screening Examination of the Posterior Segment 
Before starting the examination, ensure that patient identifiers have been placed on the 
instrument screen (see “Subject Confidentiality and Naming Convention”).  The gain is set 
at maximum and the screen brightness is adjusted appropriately for the detection of low 
reflective echoes within the vitreous cavity.  An ophthalmic coupling gel is applied to the 
probe.  A preservative free gel (e.g., Gen Teal Gel) is recommended to minimize irritation 
to the eye.   
 
The patient is positioned comfortably, preferably in a reclined position, with the eye to be 
examined situated close to the screen display to facilitate hand-eye coordination.  Local 
anesthetic drops are instilled and the room lighting is dimmed. The subject is asked to 
fixate away from the probe, toward the portion of eye being examined.  The examination is 
conducted with the probe placed directly on the conjunctiva.  Placement of the probe on the 
conjunctiva promotes sound beam penetration and helps determine which area of the eye is 
being examined.   
 
The posterior segment of the eye is examined systematically using basic screening 
techniques (i.e., specific transverse and longitudinal scans).  The findings of each patient 
examination are documented with certain echograms and movies. 
 
Longitudinal Scans 
In a longitudinal probe position, the sound beam produces a radial section.  The beam 
sweeps perpendicular to the limbus and parallel to a single meridian of the opposite fundus 
(i.e., one clock hour).  For the screening examination, longitudinal scans are performed 
along the 12:00, 3:00, 6:00, and 9:00 meridians.  The sound beam passes through the optic 
nerve posteriorly and sweeps anteriorly toward the ciliary body (Fig 2).  Peripheral aspects 
of a meridian are best displayed with the probe resting near the fornix. 
 
 
 


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The probe marker is always directed toward the center of the cornea and the meridian being 
examined.  As the probe is slowly shifted from limbus to fornix, it is simultaneously rocked 
slightly from side to side to help ensure lesion detection.  Longitudinal scans are performed 
as follows: 
• 12:00 meridian; probe is placed at 6:00 
• Nasal meridian; probe is placed at 9:00 OD or 3:00 OS 
• 6:00 meridian; probe is placed at 12:00 
• Temporal meridian; probe is placed at 3:00 OD or 9:00 OS  
 
B-scan Characteristics of a PVD 
A total PVD is a complete separation of the posterior hyaloid from the retina.  As defined 
in this protocol, a total PVD can either remain adherent to or can be detached from the 
optic disc.  On B-scan, a total PVD produces an extensive, thin, membranous acoustic 
interface of low reflectivity that typically exhibits undulating mobility.  In many cases, a 
total PVD can be shown to insert into the vitreous base.  Also, a Weiss ring usually can be 
identified when a total PVD is detached from the optic disc.  The Weiss ring produces one 
or two distinct, bright, point-like echoes within the plane of the PVD, typically located in 
the vicinity of the optic disc (Fig 3).  However, in a highly elevated and/or folded PVD, the  
 
Weiss ring will usually be situated more anteriorly (and not necessarily overlying the optic 
disc).  Therefore, detection of the Weiss ring may be more challenging in this form of total 
PVD. 
 
A partial PVD is attached to the retina in one or more areas and may still be attached to the 
macula and optic disc.  Insertion of the PVD into the vitreous base is sometimes 
demonstrated.  When limited in extent, a partial PVD typically appears as a smooth, 
shallow membranous acoustic interface that exhibits little or no mobility.  A Weiss ring 
usually cannot be identified in a partial PVD. 
 
No PVD is detected when the posterior hyaloid is completely attached to both the retina 
and the optic disc. 
 
Assessment of Mobility 
An important aspect of diagnosing an extensive PVD with B-scan is the evaluation of 
mobility.  An extensive or total PVD typically exhibits an undulating motion.  The mobility 
of membranous acoustic interfaces is captured in a movie. 
 
To evaluate mobility, the area of interest is displayed, the probe is held stationary, and the 
patient is asked to move their eye back and forth two or three times.  Sufficient gel is 
applied to the probe face and a scan is performed with the patient fixating away from the 
probe, toward the area being examined.  IMPORTANT: The area of interest should 
remain on the screen throughout the procedure.  This is accomplished by asking the 
patient to move their eye in the same direction as the sound beam is oscillating.   
 
 
 


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For longitudinal scans (e.g., LM and RM), the patient is asked to move their eye in a radial 
manner, toward (but not into) the probe face.  During this procedure, the optic nerve void is 
displayed before, during, and following the eye movement.  Maintaining display of the 
optic nerve void provides for the assessment of lesion mobility in relation to the optic disc 
(and the macula for the LM and RM views).   
 
Documentation of Findings 
The presence or absence of a PVD should be clearly documented in both movies and 
echograms.  The purpose of documentation is to record all pertinent findings of the B-scan 
examination.  When any membranous acoustic interfaces are detected, the appearance, 
location (including any insertions into the fundus), presence of a Weiss ring, and mobility 
should be well demonstrated.  Movies and echograms are initially stored on the internal 
hard drive of the instrument (see Exhibit B).  
 
To make a movie for the purpose of demonstrating mobility, the first step is to localize the 
area of interest.  Once the pathology is clearly displayed, the probe is held steady, the 
patient is asked to maintain their fixation, and the image is frozen.  The probe is then 
restarted and the patient is asked to move their eye back and forth two or three times (to fill 
the 10 second time-frame).  By following this procedure, lesion mobility can be captured 
adequately in the 10 second movie.   
 
Once all findings have been documented, the images should be reviewed for quality and 
completeness.  If the required images fail to demonstrate the examination findings or are of 
inferior technical quality, they should be replaced.  Additional movies are encouraged if 
necessary to thoroughly document all pertinent findings.      
 
The images stored on the internal hard drive are then archived to a flash drive (see  
Exhibit C).  The final step is to upload the images on the flash drive to a website for 
grading by the Ultrasound Reading Center (see Uploading B-scan Images to Secure 
Website).  
 
Baseline Visit 
Vitreous status and mobility is captured in the movies. The required images are: 
 
a. Longitudinal macula (LMAC) 
i. Probe is placed at the horizontal (nasal) limbus (right eye 3:00, left eye 9:00) with marker 
pointing temporally towards the center of cornea. 
ii. This captures on the monitor as scan (as seem from top of monitor to bottom) the 
temporal horizontal retina, macula, optic nerve, and nasal periphery on the bottom of the 
screen. 
 
b. Reverse macula (RMAC) 
i. Probe is placed at the horizontal (temporal) limbus (right eye 9:00, left eye 3:00) with 
marker pointing nasally towards the center of the cornea 
ii. This captures on the monitor a scan (as seen from top of monitor to bottom) the nasal 
horizontal retina, optic nerve shadow, macula and temporal periphery on the bottom of the 
screen. 


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c. Longitudinal to 12:00 (L12) 
i. Probe is placed at the inferior (6:00) limbus (same location in right and left eye) with 
marker pointing superiorly to 12:00 towards the center of the cornea. 
ii. The eyelids typically need to be held open and the patient should be encouraged to keep 
their fellow eye open during the exam to help align the study eye 
iii. In this protocol, the probe direction needs to be slightly nasally displaced to include the 
optic nerve in the image 
iv. This captures on the monitor (as seen from the top of the monitor to the bottom) the 
superior retina, optic nerve, and inferior periphery 
 
d. Longitudinal to 6:00 (L6) 
i. Probe is placed at the superior (12:00) position (same location in the right and left eye) 
with marker pointing inferiorly to 6:00 towards the center of the cornea 
ii. In this protocol, the probe direction needs to be slightly nasally displaced to include the 
optic nerve in the image 
iii. This captures on the monitor (as seen from the top of the monitor to the bottom) the 
inferior retina, optic nerve, and superior periphery 
 
NOTE: Additional movies and echograms should be obtained, as needed, to adequately 
demonstrate pertinent findings.  
 
 
 
 
 


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Post Injection Follow-Up Visits 
Vitreous status and mobility is captured in the movies. The required images are as stated at 
Baseline Visit 
 
 
NOTE: Additional movies and echograms should be obtained, as needed, to adequately 
demonstrate pertinent findings.  
 
 
Labeling B-scan Images 
For the Baseline visit, movies of the transverse screening procedure are only labeled 
according to the clock hour examined (i.e., 12, 3, 6 or 9).  
 
Echograms and other movies are labeled according to the area of eye examined. The 
labeling scheme for these images is described below (see also Fig 4). 
 
Further Details could be found in the procedure manual for B-scan ultrasonography. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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EXHIBIT A 
 
I 3 SYSTEMv3  
Posterior B-scan Procedure 
 
(1) 
POWER:  Press the switch on the front panel or the switch on the power strip on the 
cart; an indicator will light.   
(2) 
BEGIN: Click on the user name & enter password (if necessary). The I3 power-up 
screen will appear.   
(3) 
SELECT MODE from Mode screen:  New Patient screen will appear. 
(4) 
SUBJECT ID: Enter data in New Patient screen; press ENTER; press Save.   
(5) 
B-SCAN IMAGE: Appears after Subject ID data has been saved; depress Left 
Footswitch to activate scan. 
(6) 
FREEZE SCAN: depress LEFT FOOTSWITCH. 
(7) 
MOVIE: Last 10 seconds of the examination is automatically stored as a movie. 
(8) 
ADVANCE OR REWIND MOVIE: Turn Threshold knob as desired. 
(9) 
SAVE MOVIE TO INTERNAL HARD DRIVE: Press Shift F11 or click Save 
Movie.  
(10) 
SAVE ECHOGRAM TO INTERNAL HARD DRIVE: Press F12 or Right 
Footswitch or click Save Frame. 
(11) 
LABEL IMAGE: Probe orientation Field will open; enter label; click OK or press 
ENTER. 
 
WARNING: Proper Windows shut down procedure must be followed to turn off the instrument.  Click 
on the X at the top right of the screen.  A box will pop up saying you are logging off; click YES.  Once shut down of the application 
is complete, you will see a Windows screen; click TURN OFF COMPUTER, then click TURN OFF in the next box…when 
you see static on the screen it is safe to turn off the power strip. 
Failure to follow this procedure will potentially result in loss of ALL patient data. 
Gus Kohn, CRA, COT, ROUB, RDMS 
Clinical Applications Specialist 
Ellex Innovative Imaging Inc.  
Cell: 916-798-7617 
Efax: 512-233-2560 
mailto: guskohn@earthlink.net 
 
 


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EXHIBIT B 
 
I 3 SYSTEMv3  
ARCHIVING IMAGES FROM THE INTERNAL HARD DRIVE 
TO THE EXTERNAL HARD DRIVE  
 
1) 
Click on the Archive tab at the top of the screen. 
2) 
Click on Create Archive at the bottom of the screen. 
a. A search window will open.  
b. Find your removable drive letter and click it once. 
c. Click Create new folder to make a folder. 
i. Rename the new folder by dragging your mouse across the folder name 
and highlighting it. 
ii. Rename the folder using the appropriate naming convention. 
iii. Press Enter. 
3) 
Click OK. 
4) 
The subjects will be listed in the upper half of the Archive screen. 
5) 
Select individual subjects or click Select All on the middle bar.  
a. Click the Down Arrow on the middle bar.  
i. The scans selected will move to the bottom half of the screen. 
6) 
Click Archive at the bottom. 
7) 
When Archive is complete a pop-up will ask, “Delete archived records? Yes/no 
a. To keep patient data on the internal hard drive press NO 
b. To delete patient data from the internal hard drive press YES 
 


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APPENDIX C: 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. 


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APPENDIX D: 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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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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APPENDIX E:  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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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. 
 


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4. 
The refusal of the patient to participate in a study must never interfere with the 
physician-patient relationship. 
 
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. 


ALLEGRO OPHTHALMIC, LLC. 
 
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PROTOCOL DME-202B 
APPENDIX F:  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, in order 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, in order 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, in order 
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. 
 


ALLEGRO OPHTHALMIC, LLC. 
 
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PROTOCOL DME-202B 
APPENDIX G:  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. 
 
PAGE 79 
PROTOCOL DME-202B 
APPENDIX H:  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. 

SAP_001.pdf: